ABSTRACT Hypertension (HTN) increases the risk for cardiac disease and stroke. Endogenous hydrogen sulfide (H2S), which plays a prominent role in a multitude of pathologies like inflammation/sepsis, hypertension, peripheral and...
moreABSTRACT Hypertension (HTN) increases the risk for cardiac disease and stroke. Endogenous hydrogen sulfide (H2S), which plays a prominent role in a multitude of pathologies like inflammation/sepsis, hypertension, peripheral and cerebro-vascular, and coronary artery disease, is now well characterized as a physiologic vasodilator [1]. H2S is produced by cystathionine-γ-lyase (CSE) in vascular endothelium. It caters to relaxation through sulfhydration (posttranslational modification) of IK, SK and KATP channels, resulting in vascular smooth muscle cell hyperpolarization. This effect is independent of the Nitric Oxide (NO)/cGMP/PKG axis [2]. Tang et al. studied H2S in spontaneously hypertensive (SHR) rats and demonstrated a loss of CSE/H2S in HTN and a decrease in BP (blood pressure) on substitution of H2S [3]. Aim To elicit if loss of endogenous H2S contributes to the pathogenesis of hypertension. Results Tail cuff was used to measure BP in SHR and control Wistar Kyoto (WKY) rats starting at age 4 weeks (w) up until SHRs became hypertensive. Infusion of glybenclamide (20 mg/kg) a KATP channel blocker, revealed a significant increase in systolic BP (SBP) in 4-week-old SHR (ΔSBP = 43.16 ± 24.24%, n = 5) and 4 w WKY (ΔSBP = 89.97 ± 41.40%, n = 4), while little change was demonstrated in hypertensive 90 w SHR (ΔSBP = 24.07 ± 21.99%, n = 4), measured invasively via aortic catheterization.In a separate experiments, aortic rings isolated from age matched SHRs (n = 5) and WKYs (n = 5), were mounted on a myograph, prepared in physiologic buffer at 37 °C, and constricted with phenylephrine (1 μM), for assessment of endothelial function. Acetylcholine (ACH) dependent maximum relaxation on treatment with L-Name (eNOS inhibitor) was modestly attenuated in aortas of 4 w WKY (92.79 ± 2.64–83.26 ± 3.35%), 4 w SHR (83.50 ± 4.47–59.48 ± 8.75%) and 90-week-old WKYs (71.39 ± 15.06–15.77 ± 5.16%). Contrary to that, this response was completely blocked in 90 w SHRs (35.32 ± 5.16–0.24 ± 3.17%). Treatment with propargylglycine (CSE blocker) did not affect ACH mediated maximum relaxation in 90 w SHR (35.32 ± 5.16–29.40 ± 5.86%), but it significantly attenuated the responses in 4 w WKYs (92.79 ± 2.64–56.30 ± 4.55), 4 w SHRs (83.50 ± 4.47–71.63 ± 12.25) and 90 w SHRs (71.39 ± 15.06–8.13 ± 4.61%). Strikingly, rings from normotensive 16 w SHR had a complete L-Name sensitive attenuation of endothelial relaxation (63.25 ± 5.15–2.74 ± 1.75%). Conclusion There appears to be a NO independent component of endothelial relaxation in normotensive blood vessels, which is sensitive to CSE inhibitors and blockage of KATPchannels. This NO independent component of relaxation is absent in HTN and pre-HTN vessels; hence implying that loss of the CSE/H2S/KATP axis could be a mechanism preceding HTN. We aims to measure CSE activity and sulfhydration of Kir 6.1-Cysteine 43 and GAPDH in normotensive/pre and post HTN blood vessels in different animal models of HTN to elicit if CSE/H2S/KATP axis is a potential target for the treatment of hypertension.