Hydrogen Sulfide in the Rostral Ventrolateral Medulla Inhibits Sympathetic Vasomotor Tone through ATP-Sensitive K⁺ Channels

Abstract

Hydrogen sulfide (H 2 S) acts as an endogenous gaseous transmitter in the central nervous system and plays important roles in regulating cardiovascular function. The rostral ventrolateral medulla (RVLM) is a putative critical central region in the control of sympathetic vasomotor tone and plays an important role in the baroreflex by integrating the inputs from a variety of visceral and somatic stimuli. In this study, we tested the hypothesis that H 2 S decreases sympathetic vasomotor tone through ATP-sensitive potassium channels (K ATP ) in the RVLM. The arterial blood pressure (ABP), heart rate (HR), and renal sympathetic nerve activity (RSNA) of anesthetized rats were recorded. Bilateral microinjections of sodium hydrosulfide (NaHS; 4, 8, and 16 mM, 50 nl), an H 2 S donor, into the RVLM decreased ABP, HR, and RSNA in a dose-dependent manner. Preinjection of glibenclamide (40 M, 50 nl), a K ATP channel blocker, abolished the sympathoinhibitory effects of NaHS (8 mM, 50 nl). Preinjection of a nitric-oxide synthase inhibitor, N -nitro-L-arginine methyl ester (200 M, 50 nl) partially inhibited the sympathoinhibitory effects of NaHS. Prior microinjection of 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-[trifluoromethyl]phenyl)pyridine-3-carboxylic acid methyl ester (Bay K8644) (1 M, 50 nl), an agonist of Ca 2ϩ channels, did not alter the effects of NaHS. Infusion of hydroxylamine (30 mM, 50 nl), a cystathionine ␤-synthase inhibitor, increased ABP, HR, and RSNA. Taken together, these findings suggest that exogenous H 2 S in the RVLM inhibits sympathetic vasomotor tone by opening K ATP channels. Nitricoxide signaling may partially be involved in the sympathoinhibitory effect of H 2 S in the RVLM.

Gene transfer of cystathionine β-synthase into RVLM increases hydrogen sulfide-mediated suppression of sympathetic outflow via KATP channel in normotensive rats

“…One experiment has suggested that NaHS evokes a concentration-dependent hyperpolarization and decreases the input resistance of CA1 neurons by opening of K ATP channels (24). In addition, microinfusion of NaHS into the RVLM decreases arterial blood pressure by opening K ATP channel in rats (13). These results indicate that K ATP channels are involved in the action of H 2 S in the central nervous system.…”

“…Previous experiments have demonstrated that bilateral microinjection of sodium hydrosulfide (NaHS), an H 2 S donor, into the RVLM decreases arterial blood pressure, and the CBS inhibitor hydroxylamine (HA) produces a pressor response (13). Contrary, another study has shown that the microinjection of NaHS into the RVLM has no effect on mean arterial pressure (MAP) (26).…”

“…The HR was measured by triggering from the pulsatile blood pressure. The RSNA was recorded as previously described (13). The left kidney was exposed through a retroperitoneal incision, and a small branch of the left renal sympathetic nerve around the renal vessels was carefully isolated from the surrounding tissue and clamped distally to ensure that afferent activity was not recorded.…”

“…Recent studies (9,13,34) have also reported its physiological functions in the central nervous system. In mammalian tissues, H 2 S is produced through degradation of L-cysteine mainly by two main enzymes: cystathionine ␤-synthase (CBS) and cystathionine ␥-lyase (15).…”

“…CBS is primarily found in the brain, whereas CSE is mainly expressed in the peripheral tissues (15). CBS has been found in regions of the brain, such as the paraventricular nucleus (11) and rostral ventrolateral medulla (RVLM) (13), which are responsible for the regulation of sympathetic nerve activity and thus arterial blood pressure.…”