In patients with cirrhosis, nitric oxide (NO), asymmetric dimethylarginine (ADMA), and possibly symmetric dimethylarginine (SDMA) have been linked to the severity of the disease. We investigated whether plasma levels of dimethylarginines...
moreIn patients with cirrhosis, nitric oxide (NO), asymmetric dimethylarginine (ADMA), and possibly symmetric dimethylarginine (SDMA) have been linked to the severity of the disease. We investigated whether plasma levels of dimethylarginines and NO are elevated in patients with hepatorenal syndrome (HRS), compared with patients with cirrhosis without renal failure (no-HRS). Plasma levels of NO, ADMA, SDMA, and l-arginine were measured in 11 patients with HRS, seven patients with no-HRS, and six healthy volunteers. SDMA concentration in HRS was higher than in no-HRS and healthy subjects (1.47 +/- 0.25 vs. 0.38 +/- 0.06 and 0.29 +/- 0.04 microM, respectively; P < 0.05). ADMA and NOx concentrations were higher in HRS and no-HRS patients than in healthy subjects (ADMA, 1.20 +/- 0.26, 1.11 +/- 0.1, and 0.53 +/- 0.06 microM, respectively; P < 0.05; NOx, 94 +/- 9.1, 95.5 +/- 9.54, and 37.67 +/- 4.62 microM, respectively; P < 0.05). In patients with HRS there was a positive correlation...
Vasopressin not only acts directly on blood vessels through V1-receptor stimulation but also may modulate adrenergic-mediated responses in animal experiments in vitro and in vivo. The aim of the present study was to investigate whether...
moreVasopressin not only acts directly on blood vessels through V1-receptor stimulation but also may modulate adrenergic-mediated responses in animal experiments in vitro and in vivo. The aim of the present study was to investigate whether subpressor concentrations of vasopressin could modify the constrictor responses to norepinephrine and electrical stimulation of the perivascular nerves in human mesenteric arteries. Human mesenteric artery rings (3-3.5 mm long, 0.8-1.2 mm OD) were obtained from 38 patients undergoing abdominal operations. The arterial rings were suspended in organ bath chambers for isometric recording of tension. Vasopressin (3 x 10(-11) M) enhanced the contractions elicited by electrical stimulation at 2, 4, and 8 Hz (by 100, 100, and 72%, respectively) and produced a leftward shift of the concentration-response curves to norepinephrine (half-maximal effective concentration decreased from 2.2 x 10(-6) to 5.0 x 10(-7) M; P < 0.05) without any alteration in maximal ...
To examine whether low concentrations of endothelin-1 potentiate the vasoconstrictor response to adrenergic stimulation, we recorded the isometric response of rings of rabbit pulmonary artery to electrical stimulation and noradrenaline....
moreTo examine whether low concentrations of endothelin-1 potentiate the vasoconstrictor response to adrenergic stimulation, we recorded the isometric response of rings of rabbit pulmonary artery to electrical stimulation and noradrenaline. Endothelin-1 (10(-10) M) potentiated the contractions induced by electrical stimulation and noradrenaline. The endothelin ET(B) receptor antagonist (2,6-dimethylpiperidinecarbonyl-gamma-methyl-Leu-N(in)-[Methoxycarbonyl]-D-Trp-D-Nle) (BQ-788, 10(-6) M), but not the endothelin ET(A) receptor antagonist cyclo(D-Asp-Pro-D-Val-Leu-D-TRP) (BQ-123, 10(-6) M), inhibited the potentiating effects of endothelin-1. Pretreatment with the cyclooxygenase inhibitor indomethacin, the thromboxane synthase inhibitor furegrelate and the thromboxane receptor antagonist [1S-[1alpha,2alpha(Z),3alpha,4alpha]]-7-[3-[[[[(1-oxoheptyl)amino]acetyl]amino] methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid (SQ-30741) (all at 10(-5) M) prevented the potentiation induced by endothelin-1 on adrenergic stimulation. The Ca(2+) channel antagonist nifedipine (10(-6) M) did not affect the potentiation induced by endothelin-1. The results indicate that endothelin-1 potentiates the responses to electrical stimulation and noradrenaline by activating endothelin ET(B) receptors. This potentiation depends on the production of cyclooxygenase-generated factors, probably thromboxane A(2).
Vasopressin not only acts directly on blood vessels through V1-receptor stimulation but also may modulate adrenergic-mediated responses in animal experiments in vitro and in vivo. The aim of the present study was to investigate whether...
moreVasopressin not only acts directly on blood vessels through V1-receptor stimulation but also may modulate adrenergic-mediated responses in animal experiments in vitro and in vivo. The aim of the present study was to investigate whether subpressor concentrations of vasopressin could modify the constrictor responses to norepinephrine and electrical stimulation of the perivascular nerves in human mesenteric arteries. Human mesenteric artery rings (3-3.5 mm long, 0.8-1.2 mm OD) were obtained from 38 patients undergoing abdominal operations. The arterial rings were suspended in organ bath chambers for isometric recording of tension. Vasopressin (3 x 10(-11) M) enhanced the contractions elicited by electrical stimulation at 2, 4, and 8 Hz (by 100, 100, and 72%, respectively) and produced a leftward shift of the concentration-response curves to norepinephrine (half-maximal effective concentration decreased from 2.2 x 10(-6) to 5.0 x 10(-7) M; P &lt; 0.05) without any alteration in maximal contractions. Vasopressin also potentiated KCl- and calcium-induced contractions. The V1-receptor antagonist 1-[beta-mercapto-beta,beta-cyclopentamethylenepropionic acid-2-O-methyl-tyrosine, 8-arginine]vasopressin (10(-6) M) prevented the potentiation evoked by vasopressin in all cases. The calcium antagonist nifedipine (10(-6) M) did not affect the potentiation of electrical stimulation and norepinephrine induced by vasopressin but abolished KCl-induced contractions. The results suggest that vasopressin, in addition to its direct vasoconstrictor effect, strongly potentiates the responses to adrenergic stimulation and KCl depolarization. Both the direct and indirect effects of vasopressin appear to be mediated by V1-receptor stimulation. The amplifying effect of vasopressin on constrictor responses may be relevant in those clinical situations characterized by increased plasma vasopressin levels.
Cirrhosis is associated with marked abnormalities in the circulatory function that involve a reduction in systemic vascular resistance. An important cause of this vasodilatation is the increased production or activity of nitric oxide (NO)...
moreCirrhosis is associated with marked abnormalities in the circulatory function that involve a reduction in systemic vascular resistance. An important cause of this vasodilatation is the increased production or activity of nitric oxide (NO) in the splanchnic circulation. During portal hypertension and cirrhosis an increased endothelial NO synthase (eNOS) activity is demonstrated in splanchnic vessels. In contrast, the activity of eNOS in the cirrhotic liver is decreased, which suggests a different regulation of eNOS in the liver and in the splanchnic vessels. Asymmetric dimethylarginine (ADMA) is an endogenous NO inhibitor and higher plasma levels of ADMA are related to increased cardiovascular risk in both the general population and among patients with cirrhosis. It has been demonstrated that the liver is a key player in the metabolism of ADMA. This observation was further supported by investigations in human patients, showing a close correlation between ADMA plasma levels and the degree of hepatic dysfunction. ADMA is degraded to citrulline and dimethylamine by dimethylarginine dimethylaminohydrolases (DDAHs). DDAHs are expressed as type 1 and 2 isoforms and are widely distributed in various organs and tissues, including the liver. In this review, we discuss experimental and clinical data that document the effects of dimethylarginines on vascular function in cirrhosis. Our increasing understanding of the routes of synthesis and metabolism of methylarginines is beginning to provide insights into novel mechanisms of liver disease and allowing us to identify potential therapeutic opportunities.
Cirrhosis is associated with marked abnormalities in the circulatory function that involve a reduction in systemic vascular resistance. An important cause of this vasodilatation is the increased production or activity of nitric oxide (NO)...
moreCirrhosis is associated with marked abnormalities in the circulatory function that involve a reduction in systemic vascular resistance. An important cause of this vasodilatation is the increased production or activity of nitric oxide (NO) in the splanchnic circulation. During portal hypertension and cirrhosis an increased endothelial NO synthase (eNOS) activity is demonstrated in splanchnic vessels. In contrast, the activity of eNOS in the cirrhotic liver is decreased, which suggests a different regulation of eNOS in the liver and in the splanchnic vessels. Asymmetric dimethylarginine (ADMA) is an endogenous NO inhibitor and higher plasma levels of ADMA are related to increased cardiovascular risk in both the general population and among patients with cirrhosis. It has been demonstrated that the liver is a key player in the metabolism of ADMA. This observation was further supported by investigations in human patients, showing a close correlation between ADMA plasma levels and the de...
We investigated the potentiating effect of U-46619, a synthetic analogue of thromboxane A(2) (TXA(2)), on the adrenergic responses in human saphenous vein. Saphenous vein rings were obtained from 35 patients undergoing coronary artery...
moreWe investigated the potentiating effect of U-46619, a synthetic analogue of thromboxane A(2) (TXA(2)), on the adrenergic responses in human saphenous vein. Saphenous vein rings were obtained from 35 patients undergoing coronary artery bypass surgery. The rings were suspended in organ bath chambers for isometric recording of tension. U-46619 (10(-10)-3 x 10(-7) mol/l) produced concentration-dependent and endothelium-independent contractile responses. U-46619 (10(-10) mol/l) potentiated the contractions elicited by electrical stimulation and potassium chloride, and produced leftward shifts of the concentration-response curve for noradrenaline. The TXA(2) receptor antagonist SQ-30741 (10(-8) mol/l) prevented the potentiation evoked by U-46619. The dihydropyridine calcium antagonist nifedipine (10(-6) mol/l) did not affect the potentiation of electrical stimulation and noradrenaline induced by U-46619, but abolished the potentiation of U-46619 on KCl-induced contractions. U-46619 facilitates sympathetic neurotransmission and potentiates constrictor effects of noradrenaline in human saphenous veins through stimulation of TXA(2) receptors. These effects are independent of calcium entry through dihydropyridine calcium channels.
Background and AimIncreased basal release of nitric oxide (NO) in the splanchnic circulation contributes to elevated plasma levels of NO observed in decompensated cirrhosis. We evaluated in rat mesenteric arteries whether the differences...
moreBackground and AimIncreased basal release of nitric oxide (NO) in the splanchnic circulation contributes to elevated plasma levels of NO observed in decompensated cirrhosis. We evaluated in rat mesenteric arteries whether the differences in basal release of NO, revealed by asymmetric dimethylarginine (ADMA)- and NG-nitro-L-arginine methyl ester (L-NAME)-induced contractions, were associated with changes in messenger RNA (mRNA) expression of endothelial NO synthase (eNOS) and dimethylarginine dimethylaminohydrolases (DDAHs).Increased basal release of nitric oxide (NO) in the splanchnic circulation contributes to elevated plasma levels of NO observed in decompensated cirrhosis. We evaluated in rat mesenteric arteries whether the differences in basal release of NO, revealed by asymmetric dimethylarginine (ADMA)- and NG-nitro-L-arginine methyl ester (L-NAME)-induced contractions, were associated with changes in messenger RNA (mRNA) expression of endothelial NO synthase (eNOS) and dimethylarginine dimethylaminohydrolases (DDAHs).MethodsRat small mesenteric arteries from 14 Sham-control, from 14 with partial portal vein ligation (PPVL), and from 14 with bile duct excision (BDE)-induced cirrhosis were precontracted under isometric conditions with norepinephrine, and additional contractions were induced with ADMA and L-NAME. mRNA expression of eNOS, DDAH-1, and DDAH-2 in mesenteric arteries were evaluated by real-time polymerase chain reaction.Rat small mesenteric arteries from 14 Sham-control, from 14 with partial portal vein ligation (PPVL), and from 14 with bile duct excision (BDE)-induced cirrhosis were precontracted under isometric conditions with norepinephrine, and additional contractions were induced with ADMA and L-NAME. mRNA expression of eNOS, DDAH-1, and DDAH-2 in mesenteric arteries were evaluated by real-time polymerase chain reaction.ResultsADMA and L-NAME caused concentration- and endothelium-dependent contractions. pD2 values to L-NAME were similar in all groups. In contrast, pD2 values to ADMA were similar in PPVL and BDE but were significantly lower than those of the L-NAME and the Sham groups. Relaxation to acetylcholine was not modified by ADMA or L-NAME but was abolished by charybdotoxin plus apamin. There was an increased mRNA expression of eNOS, DDAH-1, and DDAH-2 in mesenteric arteries from PPVL and BDE compared with the Sham group.ADMA and L-NAME caused concentration- and endothelium-dependent contractions. pD2 values to L-NAME were similar in all groups. In contrast, pD2 values to ADMA were similar in PPVL and BDE but were significantly lower than those of the L-NAME and the Sham groups. Relaxation to acetylcholine was not modified by ADMA or L-NAME but was abolished by charybdotoxin plus apamin. There was an increased mRNA expression of eNOS, DDAH-1, and DDAH-2 in mesenteric arteries from PPVL and BDE compared with the Sham group.ConclusionBasal release of NO is increased in mesenteric arteries of PPVL and BDE rats. The rise in expression of DDAHs indicates a higher degradation of ADMA. This would result in an increased generation of endothelial NO and mesenteric vasodilation.Basal release of NO is increased in mesenteric arteries of PPVL and BDE rats. The rise in expression of DDAHs indicates a higher degradation of ADMA. This would result in an increased generation of endothelial NO and mesenteric vasodilation.
The time-course for aging-associated effects on vascular reactivity to U46619, a stable analogue of thromboxane A2 (TXA2), was studied in aorta from female senescence-accelerated mice-prone (SAMP8), a murine model of accelerated...
moreThe time-course for aging-associated effects on vascular reactivity to U46619, a stable analogue of thromboxane A2 (TXA2), was studied in aorta from female senescence-accelerated mice-prone (SAMP8), a murine model of accelerated senescence. SAMP8 and senescence-accelerated mice-resistant (SAMR1) were divided into three groups: 3-, 6- and 10-month-old. Contractile curves to U46619 (10−9 to 10−6 M) were performed in aortic rings in the absence or in the presence of nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 10−4 M) and/or cyclooxygenase (COX) inhibitor indomethacin (10−5 M). Protein and gene expression for COX-1 and COX-2 were determined by immunofluorescence and real-time PCR, respectively. Maximal contraction to U46619 was markedly higher in SAMP8 at all ages. In SAMR1, increases were seen at 10 months, while SAMP8 displays augmented contraction at 6 months, which was further increased at 10 months. l-NAME enhanced U46619 contractions in both 6-month-old groups, although the increase was higher on vessels from SAMR1 at this age. Indomethacin equally increased U46619 contractions in both 3-month-old groups, suggesting the production of vasodilator prostaglandin in young animals. In contrast, at 6 and 10 months indomethacin decreased U46619 contractions in both groups, indicating an aging-associated swap to a release of contractile prostanoids in aorta. In conclusion, aging enhances contractile responses to TXA2 in aorta from female mice by a mechanism involving a decrease of NO production and increased action of contractile prostanoids. This process occurs earlier in SAMP8 mice, establishing these mice as good model to study cardiovascular aging in a convenient and standard time-course.
We studied the role of K+ channels and Na+,K+-ATPase in the presynaptic inhibitory effects of prostaglandin E1 (PGE1) and PGE2 on the adrenergic responses of human vas deferens. Furthermore, we determined the effects of increasing...
moreWe studied the role of K+ channels and Na+,K+-ATPase in the presynaptic inhibitory effects of prostaglandin E1 (PGE1) and PGE2 on the adrenergic responses of human vas deferens. Furthermore, we determined the effects of increasing extracellular K+ concentrations ([K+]o) and inhibition of Na+,K+-ATPase on neurogenic and norepinephrine-induced contractile responses. Ring segments of the epididymal part of the vas deferens were taken from 45 elective vasectomies and mounted in organ baths for isometric recording of tension. The neuromodulatory effects of PGEs were tested in the presence of K+ channel blockers. PGE1 and PGE2 (10−8 to 10−6 M) induced inhibition of adrenergic contractions. The presence of tetraethylammonium (10−3 M), charybdotoxin (10−7 M), or iberiotoxin (10−7 M), prevented the inhibitory effects of PGE1 and PGE2 on the adrenergic contraction. Both glibenclamide (10−5 M) and apamin (10−6 M) failed to antagonize PGE1 and PGE2 effects. Raising the [K+]o from 15.8 mM to 25.8 mM caused inhibition of the neurogenic contractions. Ouabain at a concentration insufficient to alter the resting tension (10−6 M) increased contractions induced by electrical stimulation but did not alter the contractions to norepinephrine. The inhibition of neurogenic responses induced PGE1, PGE2 and increased extracellular concentration of K+ was almost completely prevented by ouabain (10−6 M). The results demonstrate that PGE1 and PGE2 inhibit adrenergic responses by a prejunctional mechanism that involves the activation of large-conductance Ca2+-activated K+ channels and Na+,K+-ATPase.
The aim of the present study was to evaluate the intervention of COX-1- and COX-2-derived prostaglandins in the responses of human gastroepiploic artery to sympathetic stimulation and norepinephrine.Rings of human gastroepiploic artery...
moreThe aim of the present study was to evaluate the intervention of COX-1- and COX-2-derived prostaglandins in the responses of human gastroepiploic artery to sympathetic stimulation and norepinephrine.Rings of human gastroepiploic artery were obtained from 45 patients (26 men and 19 women) undergoing gastrectomy. The rings were suspended in organ baths for isometric recording of tension. We studied the responses to electrical field stimulation, norepinephrine, and acetylcholine, in the absence and presence of COX-1 or COX-2 inhibition.The COX-1 and COX-2 inhibitor aspirin at high concentrations (10−6 to 10−5 mol/L) and the COX-2 inhibitor nimesulide (10−6 mol/L) potentiated the contractile responses of the arterial rings to sympathetic neurogenic stimulation and norepinephrine. In contrast, lower concentrations of aspirin (10−8 to 10−7 mol/L) or the COX-1 inhibitor SC-560 (3 ×10−8 mol/L) did not affect these responses. The vascular relaxation induced by acetylcholine was not affected by COX-1 and COX-2 inhibition.The results provide functional evidence that vasodilator prostaglandins are active components of the response of human gastroepiploic artery to neurogenic stimulation and norepinephrine. Aspirin at high concentrations and the COX-2 selective inhibitor nimesulide potentiated the contractile response of gastroepiploic artery to adrenergic stimulation by inhibiting COX-2-derived PGI2. Aspirin at low concentrations and the COX-1 selective inhibitor SC-560 did not modify the contractile responses, possibly due to minor importance of vasoconstrictor prostaglandins (TXA2) as active components of the response of gastroepiploic artery to adrenergic stimulation.
The effect of 4-hydroxynonenal (4-HNE), a circulating lipid peroxidation product, on the vascular tone of human mesenteric arteries is studied. 4-HNE promotes relaxation of human mesenteric arterial rings in a concentration-dependent...
moreThe effect of 4-hydroxynonenal (4-HNE), a circulating lipid peroxidation product, on the vascular tone of human mesenteric arteries is studied. 4-HNE promotes relaxation of human mesenteric arterial rings in a concentration-dependent manner. Removal of the endothelium or treatment with NG-nitro-l-arginine methyl ester hydrochloride (L-NAME; 10−4 M) partially prevented 4-HNE-induced relaxation, thus suggesting the intervention of nitric oxide from endothelial origin in the vascular effects of 4-HNE.
The aim of this work was to characterize a mouse model of experimental menopause and cardiovascular aging that closely reflects menopause in women. Senescence accelerated mouse (SAM)-Resistant type 1 (SAMR1, n = 30) and SAM-Prone type 8...
moreThe aim of this work was to characterize a mouse model of experimental menopause and cardiovascular aging that closely reflects menopause in women. Senescence accelerated mouse (SAM)-Resistant type 1 (SAMR1, n = 30) and SAM-Prone type 8 (SAMP8, n = 30) were separated at 5 months of age into three groups: 1) sham-operated (Sham); 2) ovariectomized (Ovx); and 3) ovariectomized chronically-treated with estrogen (Ovx + E2). Contractile responses to KCl (60 mM) and thromboxane A2 were greater in aorta from SAMP8 mice compared with SAMR1 in all groups. Neither ovariectomy nor estrogen replacement modified the contractile responses from SAMR1 mice. Conversely, in Ovx SAMP8 the increased maximal contractions were reversed by estrogen treatment. Rings with endothelium from all SAMR1 groups showed a greater relaxation to acetylcholine than SAMP8 groups. In SAMR1, endothelium-dependent relaxation was not altered in Ovx or Ovx + E2 groups. Rings from Ovx SAMP8 showed a decreased maximal response to acetylcholine compared to Sham SAMP8. Estrogen replacement restored the response to acetylcholine altered by ovariectomy. Nitric oxide inhibition by L-NAME markedly reduced acetylcholine responses in all groups, but this effect was less pronounced in SAMP8 and Ovx groups (determined by area under the curve reduction). These results indicate that SAMP8 exhibit a significant decreased endothelium-dependent and NO-mediated relaxation and increased vasoconstrictor responses that are potentiated by the lack of estrogen. Because these responses are closely in agreement with vascular dysfunction observed in menopausal women, we propose SAMP8 Ovx as a new model to concomitantly study the effects of aging and menopause in female mice.►SAMP8 ovariectomized mice is a new model to study the effects of aging and menopause. ►SAMP8 exhibit a decrease of endothelium-dependent NO-mediated relaxation ►SAMP8 show an increased contraction to U46619 that is aggravated by ovariectomy. ►In SAMP8 aging effects in the vasculature are potentiated by the lack of estrogen. ►Detrimental effect induced by ovariectomy in SAMP8 is restored by estrogens.
We measured cyclic GMP formation and relaxation response to sildenafil given either alone or in combination with sodium nitroprusside (SNP) in pulmonary arteries obtained from 13 multi-organ donors. Sildenafil (10− 9–10− 4 M) caused...
moreWe measured cyclic GMP formation and relaxation response to sildenafil given either alone or in combination with sodium nitroprusside (SNP) in pulmonary arteries obtained from 13 multi-organ donors. Sildenafil (10− 9–10− 4 M) caused concentration-dependent relaxations and amplified the relaxation induced by SNP. Relaxation was unaffected by endothelium removal or by pre-treatment with the inhibitor of nitric oxide synthase L-NMMA (10− 4 M). SNP (10− 7 M) caused elevation of cyclic GMP levels that was potentiated by sildenafil (10− 6 M). Thus, the enhancement of SNP-induced relaxation by sildenafil is mainly due to an increase in cyclic GMP accumulation.
The present study was designed to evaluate the role of K+ channels in the adrenergic responses of human vas deferens as well as the intervention of dihydropyridine-sensitive Ca2+ channels on modulation of adrenergic responses by K+...
moreThe present study was designed to evaluate the role of K+ channels in the adrenergic responses of human vas deferens as well as the intervention of dihydropyridine-sensitive Ca2+ channels on modulation of adrenergic responses by K+ channel inhibitors.Ring segments of the epididymal part of the vas deferens were taken from 32 elective vasectomies and mounted in organ baths for isometric recording of tension. We then studied the effects of K+ channel blockers on neurogenic and norepinephrine-induced contractile responses.Addition of tetraethylammonium (TEA, 10−3 M), a nonspecific K+ channel blocker, or charybdotoxin (10−7 M), a nonselective inhibitor of large- and intermediate-conductance Ca2+-activated K+ channel, increased the contractile responses to norepinephrine and electrical field stimulation-induced contractions (P < .01), whereas iberiotoxin (10−7 M), a selective blocker of large-conductance Ca2+-activated K+ channels, apamin (10−6 M), a blocker of small-conductance Ca2+-activated K+ channels, or glibenclamide (10−5 M), an inhibitor of ATP-sensitive K+ channels, were without effect. TEA- and charybdotoxin-induced potentiation of contractions elicited by electrical field stimulation and norepinephrine was blocked by L-type Ca2+ channel blocker nifedipine (10−6 M).The results suggest that charybdotoxin-sensitive, but iberiotoxin-insensitive, K+ channels are activated by stimulation with norepinephrine and electrical field stimulation to counteract the adrenergic-induced contractions of human vas deferens. Thus, inhibition of these channels increases significantly the contraction, an effect that appears to be mediated by an increase in Ca2+ entry through L-type voltage-dependent Ca2+ channels.
We studied the relaxant effects of milrinone, an inhibitor of phosphodiesterase 3, and rolipram, an inhibitor of phosphodiesterase 4, on contracted human penile dorsal artery and deep dorsal vein. Vascular rings from 12 multi-organ donors...
moreWe studied the relaxant effects of milrinone, an inhibitor of phosphodiesterase 3, and rolipram, an inhibitor of phosphodiesterase 4, on contracted human penile dorsal artery and deep dorsal vein. Vascular rings from 12 multi-organ donors were suspended in organ baths for isometric recording of tension. Both milrinone and rolipram inhibited (100%) the contraction induced by noradrenaline and shifted the relaxation–response curves to the cAMP forming agents prostaglandin E1 and forskolin to the left. The findings indicate that the cAMP pathway appears to be a main determinant of relaxation in human penile vessels.
The present experiments were designed to evaluate differences in the effects of cyclooxygenase (COX)-1 and COX-2 inhibition on contractile responses of human gastroepiploic artery and saphenous vein elicited by vasopressin. Laboratory...
moreThe present experiments were designed to evaluate differences in the effects of cyclooxygenase (COX)-1 and COX-2 inhibition on contractile responses of human gastroepiploic artery and saphenous vein elicited by vasopressin. Laboratory investigation. University laboratory. Rings of human gastroepiploic artery were obtained from 32 patients undergoing gastrectomy, and rings of saphenous vein were obtained from 30 patients undergoing coronary artery bypass surgery. The rings were suspended in organ baths for isometric recording of tension. We studied the responses to vasopressin in the absence and in the presence of either the vasopressin V1-receptor antagonist d(CH2)5Tyr(Me)AVP or the COX inhibitors aspirin, nimesulide, or SC-560. Vasopressin (10(-11)-10(-6) mol/L) produced concentration-dependent contractions with an EC50 value of 4.3 x 10(-10) mol/L for gastroepiploic artery and 3.4 x 10(-8) mol/L for saphenous vein. The vasopressin V1-receptor antagonist d(CH2)5Tyr(Me)AVP (10(-7) mol/L) induced significant shifts (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001) of the control curves to the right. The COX-1 and COX-2 inhibitor aspirin (10(-6)-10(-5) mol/L) and the COX-2 inhibitor nimesulide (10(-6) mol/L) induced leftward shifts of the concentration-response curve for vasopressin in gastroepiploic artery. Lower concentrations of aspirin or the COX-1 inhibitor SC-560 (10(-8) mol/L) did not affect the responses of gastroepiploic artery. COX-1 or COX-2 inhibition did not modify the contraction of saphenous vein to vasopressin. The results provide functional evidence that aspirin at high concentrations and the COX-2 selective inhibitor nimesulide potentiate the contractile response of gastroepiploic artery to vasopressin, thus suggesting the release of relaxant prostaglandins by the peptide. However, contractions of human saphenous vein were unaffected by COX inhibition, indicating that vasopressin does not stimulate the release of prostanoids. The amplifying effect of aspirin on vasopressin-induced contraction may contribute to early graft failure when the gastroepiploic artery is used as a coronary artery bypass graft.
This study was designed to measure cyclic guanosine 3′5′ monophosphate (cGMP) formation and relaxation response to sildenafil given either alone or in combination with sodium nitroprusside in saphenous veins obtained from normotensive and...
moreThis study was designed to measure cyclic guanosine 3′5′ monophosphate (cGMP) formation and relaxation response to sildenafil given either alone or in combination with sodium nitroprusside in saphenous veins obtained from normotensive and hypertensive patients.Saphenous vein rings were obtained from 13 hypertensive and nine normotensive patients undergoing coronary artery bypass surgery. The vein rings were suspended in organ bath chambers for isometric recording of tension. The effect of sildenafil on sodium nitroprusside-induced cGMP formation was also assessed.Sildenafil (10 nmol/L to 100 μmol/L) and sodium nitroprusside (0.01 to 100 nmol/L) caused concentration-dependent relaxations that were of greater magnitude in veins from normotensive patients. Sildenafil (1 to 10 μmol/L) amplified the relaxation induced by sodium nitroprusside in both groups of veins, but this effect was more pronounced in veins from hypertensive patients. Levels of cGMP in response to sodium nitroprusside were significantly lower in veins from hypertensive subjects. However, in the presence of sildenafil, the increase in cGMP levels in response to sodium nitroprusside was significantly greater in the hypertensive as compared with the normotensive group.Although the relaxant effects of sildenafil are less pronounced in veins from hypertensive patients, the synergistic interaction sildenafil–sodium nitroprusside is more effective in veins from hypertensive patients, mainly due to an increase in cGMP accumulation.
Aims The therapeutic action of tricyclic agents may be accompanied by unwanted effects on the cardiovascular system. The evidence for the effects on vascular and nonvascular smooth muscle comes from animal studies. Whether these studies...
moreAims The therapeutic action of tricyclic agents may be accompanied by unwanted effects on the cardiovascular system. The evidence for the effects on vascular and nonvascular smooth muscle comes from animal studies. Whether these studies can be extrapolated to human vessels remains to be determined. Therefore, the present study was designed to investigate the influence of amitriptyline, nortriptyline and sertraline on the contractile responses of human isolated mesenteric arteries to electrical field stimulation, noradrenaline and potassium chloride. Methods Arterial segments (lumen diameter 0.8–1.2 mm) were obtained from portions of the human omentum during the course of 41 abdominal operations (22 men and 19 women), and rings 3 mm long were mounted in organ baths for isometric recording of tension. In some artery rings the endothelium was removed mechanically. Results In precontracted artery rings amitriptyline, nortriptyline and sertraline (3×10−7–10−4 m ) produced concentration-dependent relaxation that was independent of the presence or absence of vascular endothelium. Incubation with indomethacin (3×10−6 m ) reduced the pD2 values thus indicating the participation of dilating prostanoid substances in this response. Amitriptyline and nortriptyline inhibited both the neurogenic-and noradrenaline-induced contractions. In contrast, only the highest concentration of sertraline reduced the adrenergic responses. Amitriptyline, nortriptyline and sertraline inhibited contractions elicited by KCl and produced rightward shifts of the concentration-response curve to CaCl2 following incubation in calcium-free solution. Conclusions These results indicate that amitriptyline and nortriptyline could act as adrenoceptor antagonists and direct inhibitors of smooth muscle contraction of human mesenteric arteries, whereas sertraline might principally exert its action only as direct inhibitor of smooth muscle contraction. This relaxant mechanism involves an interference with the entry of calcium.
The objective of this study was to characterize the neurogenic contraction and relaxation of the human gastroepiploic artery and to determine whether the responses are mediated by nitric oxide (NO) from neural or endothelial origin.Rings...
moreThe objective of this study was to characterize the neurogenic contraction and relaxation of the human gastroepiploic artery and to determine whether the responses are mediated by nitric oxide (NO) from neural or endothelial origin.Rings of human gastroepiploic artery were obtained from 18 patients (12 men, 6 women) undergoing gastrectomy. The rings were suspended in organ baths for isometric recording of tension. We studied the contractile and relaxant responses to electrical field stimulation.In arteries under resting conditions, electrical field stimulation (2 to 8 Hz) caused frequency-dependent contractions that were of greater magnitude in arteries denuded of endothelium and blocked by tetrodotoxin (10−6 mol/L). The inhibitor of NO synthesis NG-monomethyl-l-arginine (L-NMMA, 10−4 mol/L) increased contractile responses only in arteries with endothelium. In preparations contracted with norepinephrine in the presence of guanethidine (10−6 mol/L) and atropine (10−6 mol/L), electrical stimulation induced frequency-dependent relaxations. This neurogenic relaxation was prevented by L-NMMA (10−4 mol/L) and tetrodotoxin (10−6 mol/L), but was unaffected by removal of the endothelium.The results provide functional evidence that NO is released by autonomic nerves of the human gastroepiploic artery. We hypothesize that the release of NO from both endothelial and neurogenic origin may modulate resistance of the human gastroepiploic artery. Dysfunction in any of these sources of NO should be considered in some form of vasospasm.
We studied the effects of vasopressin on isolated rings of human deferential artery and vas deferens (prostatic portion) obtained from patients undergoing radical cystectomy (n = 11) or prostatectomy (n = 10). Ring segments of artery or...
moreWe studied the effects of vasopressin on isolated rings of human deferential artery and vas deferens (prostatic portion) obtained from patients undergoing radical cystectomy (n = 11) or prostatectomy (n = 10). Ring segments of artery or vas deferens were studied in organ bath experiments at optimal resting tension. In artery rings, vasopressin produced concentration-dependent, endothelium-independent contractions with an EC50 of 4.5 × 10−10 M. The presence of NG-nitro-l-arginine methyl ester hydrochloride (10−4 M), an inhibitor of nitric oxide synthase, did not change significantly (P > 0.05) the vasopressin-induced contraction. In ring preparations of the prostatic part of the vas deferens, vasopressin induced phasic contractions with an EC50 of 7.0 × 10−9 M. The vasopressin V1 receptor antagonist, d(CH2)5Tyr(Me)AVP (10−8 and 10−6), displaced to the right in parallel the control curve to vasopressin in artery and vas deferens rings. These results indicate that vasopressin exerts a powerful constrictor action on human deferential artery and vas deferens by direct stimulation of V1 receptors. It is concluded that the deferential artery may dampen the passage of blood to the vas deferens in circumstances characterized by increased plasma vasopressin levels.
The aim of this work was to investigate the influence of endothelium-derived nitric oxide and prostaglandins on the contractile responses of isolated dog pulmonary arteries to electrical field stimulation and noradrenaline. Electrical...
moreThe aim of this work was to investigate the influence of endothelium-derived nitric oxide and prostaglandins on the contractile responses of isolated dog pulmonary arteries to electrical field stimulation and noradrenaline. Electrical field stimulation (1–8 Hz, 20 v, 0.25 ms duration, for 30 s) produced frequency-dependent contractions that were abolished by tetrodotoxin, guanethidine and, prazosin (all at 10−6 M). Noradrenaline induced concentration-dependent contractions with an EC50 of 1.85 × 10−6 M. The increases in tension induced by electrical stimulation and noradrenaline were of greater magnitude in arteries denuded of endothelium. In segments with endothelium, NG-nitro-l-arginine methyl ester (10−4 M) or indomethacin (10−5 M) had no effects on the basal tone, but significantly enhanced the neurogenic and noradrenaline-induced contractions. The potentiation by NG-nitro-l-arginine methyl ester of electrical stimulation-induced contractile responses was partially reversed by l-arginine (10−4 M). In the presence of NG-nitro-l-arginine methyl ester together with indomethacin the electrical stimulation-induced contractile responses were higher than those obtained when only NG-nitro-l-arginine methyl ester or indomethacin was used. NG-nitro-l-arginine methyl ester and indomethacin did not influence neurogenic-induced contractile responses of endothelium-denuded arteries. The results suggest that endothelial cells of isolated dog pulmonary arteries depress the contractile response to electrical field stimulation of intramural nerves and that endothelium-derived dilator prostaglandins and nitric oxide may interact to inhibit contractile effects of adrenergic stimulation.
Objectives: Plasma levels of endogenous guanidino-substituted analogues of L-arginine are increased in various pathologic conditions. In the present study we determined the effects of some of these compounds on basal and stimulated...
moreObjectives: Plasma levels of endogenous guanidino-substituted analogues of L-arginine are increased in various pathologic conditions. In the present study we determined the effects of some of these compounds on basal and stimulated release of nitric oxide in human internal thoracic and radial arteries. Methods: Rings of human internal thoracic and radial arteries were obtained from 16 multiorgan donors. The rings were suspended in organ baths for isometric recording of tension. Results: NG-monomethyl L-arginine (10–6 to 10–3 mol/L) and NG,NG-dimethyl L-arginine (10–6 to 10–3 mol/L) caused concentration- and endothelium-dependent contractions. Maximal force of contractions for NG-monomethyl L-arginine and NG,NG-dimethyl L-arginine in the internal thoracic artery were 18.0% ± 4.3% and 17.8% ± 3.8%, respectively, of the contraction to 100 mmol/L KCl, and those found in the radial artery were 9.6% ± 2.5% and 9.1% ± 2.4%, respectively. Aminoguanidine (10–5 to 3 × 10–3 mol/L) and methylguanidine (10–5 to 3 × 10–3 mol/L) produced endothelium-independent contractions. L-Arginine (10–3 mol/L) prevented the contractions by NG-monomethyl L-arginine and NG,NG-dimethyl L-arginine but did not change contractions induced by aminoguanidine and methylguanidine. NG-monomethyl L-arginine and NG,NG-dimethyl L-arginine inhibited, in a concentration-dependent manner, the endothelium-dependent relaxation to acetylcholine in the internal thoracic artery and had little attenuating effect in the radial artery; aminoguanidine and methylguanidine were without effect. Conclusions: The results suggest that the contractions induced by NG-monomethyl L-arginine and NG,NG-dimethyl L-arginine are due to inhibition of both basal and stimulated nitric oxide production, whereas aminoguanidine and methylguanidine do not affect the synthesis of nitric oxide. An increase in the plasma concentration of NG-monomethyl L-arginine and NG,NG-dimethyl L-arginine is likely to represent a risk factor for abnormal vasomotor tone in conduit arteries used as coronary grafts. (J Thorac Cardiovasc Surg 2000;120:729-36)
To examine whether low concentrations of endothelin-1 potentiate the vasocontrictor response to adrenergic stimulation, we recorded the isometric response of rings of rabbit pulmonary artery to electrical stimulation and noradrenaline....
moreTo examine whether low concentrations of endothelin-1 potentiate the vasocontrictor response to adrenergic stimulation, we recorded the isometric response of rings of rabbit pulmonary artery to electrical stimulation and noradrenaline. Endothelin-1 (10−10 M) potentiated the contractions induced by electrical stimulation and noradrenaline. The endothelin ETB receptor antagonist (2,6-dimethylpiperidinecarbonyl-γ-methyl-Leu-Nin-[Methoxycarbonyl]-d-Trp-d-Nle) (BQ-788, 10−6 M), but not the endothelin ETA receptor antagonist cyclo(d-Asp-Pro-d-Val-Leu-d-TRP) (BQ-123, 10−6 M), inhibited the potentiating effects of endothelin-1. Pretreatment with the cyclooxygenase inhibitor indomethacin, the thromboxane synthase inhibitor furegrelate and the thromboxane receptor antagonist [1S-[1α,2α(Z),3α,4α]]-7-[3-[[[[(1-oxoheptyl)amino]acetyl]amino] methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid (SQ-30741) (all at 10−5 M) prevented the potentiation induced by endothelin-1 on adrenergic stimulation. The Ca2+ channel antagonist nifedipine (10−6 M) did not affect the potentiation induced by endothelin-1. The results indicate that endothelin-1 potentiates the responses to electrical stimulation and noradrenaline by activating endothelin ETB receptors. This potentiation depends on the production of cyclooxygenase-generated factors, probably thromboxane A2.
The effects of vasopressin were studied in isolated rings from branches (2–3mm in external diameter) of human renal arteries obtained from 18 patients undergoing nephrectomy for non-obstructive neoplasia. In arterial rings under resting...
moreThe effects of vasopressin were studied in isolated rings from branches (2–3mm in external diameter) of human renal arteries obtained from 18 patients undergoing nephrectomy for non-obstructive neoplasia. In arterial rings under resting tension, vasopressin produced concentration-dependent and endothelium-independent contractions with an EC50 of 9.1×10−10molL−1. The vasopressin V1 receptor antagonist d(CH2)5Tyr(Me)AVP (10−6molL−1) displaced the control curve to vasopressin 564-fold to the right in a parallel manner. In precontracted arterial rings and previously treated with the V1 antagonist (10−6molL−1) vasopressin caused endothelium-independent relaxation. The relaxation to vasopressin was reduced significantly by indomethacin (10−6molL−1) and unaffected by the V1/V2 receptor antagonist desGly d(CH2)5-d-Tyr(Et)ValAVP (10−6molL−1) or by NG-nitro-l-arginine methyl ester (10−4molL−1). These observations indicate that vasopressin is primarily a constrictor of human renal arteries by V1-receptor stimulation. Vasopressin causes prostaglandin-mediated dilatation of human renal arteries only if V1-receptor blockade is present. The effects of vasopressin on human renal arteries may be relevant in those clinical situations characterized by increased plasma vasopressin levels.
In arteries, agonists such as acetylcholine release an endothelium-derived hyperpolarizing factor (EDHF) that is neither nitric oxide nor prostacyclin. To examine the responses to acetylcholine in segments of forearm veins from patients...
moreIn arteries, agonists such as acetylcholine release an endothelium-derived hyperpolarizing factor (EDHF) that is neither nitric oxide nor prostacyclin. To examine the responses to acetylcholine in segments of forearm veins from patients with chronic renal failure who either had never received dialysis or had undergone long-term dialysis, and to determine the contribution of nitric oxide and EDHF to endothelium-dependent relaxation in veins from patients with chronic renal failure. Isometric tension was recorded in rings of forearm vein from 34 non-dialysed patients, 27 dialysed patients and 14 multiorgan donors (controls). Relaxation in response to acetylcholine was reduced in veins of non-dialysed and dialysed patients. The inhibitors of nitric oxide synthase NG-monomethyl-l-arginine (l-NMMA) and NG,NG-dimethyl-l-arginine (ADMA) reduced by 50% the maximum relaxation in response to acetylcholine in veins from controls and non-dialysed patients; the remaining relaxation was inhibited by 20 mmol/l KCl or by the K+ channel blockers tetraethylammonium chloride, iberiotoxin, charybdotoxin and the combination of barium plus ouabain, but not by apamin or glibenclamide. Relaxation in veins from dialysed patients was inhibited by K+ channel blockade but not by l-NMMA or ADMA. The results demonstrate that the endothelium-dependent relaxation in forearm veins from controls and non-dialysed patients is mediated by release of nitric oxide and EDHF. In contrast, the relaxation in veins from dialysed patients is mediated mainly by EDHF. EDHF-induced relaxation involves activation of large-conductance Ca2+-activated K+ channels.
Arginine vasopressin (AVP) not only acts directly on blood vessels through vasopressin V1 receptor stimulation but also may modulate adrenergic-mediated responses in animal experiments. The aim of the present study was to assess whether...
moreArginine vasopressin (AVP) not only acts directly on blood vessels through vasopressin V1 receptor stimulation but also may modulate adrenergic-mediated responses in animal experiments. The aim of the present study was to assess whether subpressor concentrations of AVP could contribute to an abnormal adrenergic contractile response of human renal arteries. Renal artery rings were obtained from 27 patients undergoing nephrectomy. The rings were suspended in organ bath chambers for isometric recording of tension. AVP (10(-10) mol/l) and the vasopressin V1 receptor agonist [Phe2, Orn8]-vasotocin (10(-10) mol/l) produced a leftward shift of the concentration-response curve to noradrenaline (half-maximal effective concentration decreased from 1.1 x 10(-6) mol/l to 3.1 x 10(-7) mol/l). The enhancement of noradrenaline-induced contractions was inhibited by the vasopressin V1 receptor antagonist d(CH2)5Tyr(Me)AVP (10-8 mol/l) and unaffected by endothelium removal or pretreatment with the inhibitor of nitric oxide (NO) synthase NG-monomethyl-l-arginine (l-NMMA). The vasopressin V2 receptor agonist 1-desamino-8-D-arginine vasopressin (dDAVP) (10(-10)-10(-8) mol/l) did not modify contractile responses to noradrenaline. In the presence of the dihydropyridine calcium antagonist nifedipine (10(-6) mol/l), vasopressin failed to enhance the contractile response to noradrenaline. The results demonstrate that subpressor concentrations of vasopressin potentiate the contractile effects of noradrenaline without intervention of the NO system. The effects appear to be mediated by vasopressin V1 receptor stimulation, which brings about an increase in calcium entry through dihydropyridine-sensitive calcium channels.