Intermittent Hypoxia in Rats Increases Myogenic Tone Through Loss of Hydrogen Sulfide Activation of Large-Conductance Ca -Activated Potassium Channels

Rationale: Myogenic tone, an important regulator of vascular resistance, is dependent on vascular smooth muscle (VSM) depolarization, can be modulated by endothelial factors, and is increased in several models of hypertension. Intermittent hypoxia (IH) elevates blood pressure and causes endothelial dysfunction. Hydrogen sulfide (H 2 S), a recently described endothelium-derived vasodilator, is produced by the enzyme cystathionine ␥-lyase (CSE) and acts by hyperpolarizing VSM. I n epidemiological studies, obstructive sleep apnea (OSA) is an independent risk factor for hypertension and other cardio-vascular diseases. 1 Previously, we reported that exposing rats to eucapnic intermittent hypoxia (IH), a model of sleep apnea, elevates systemic blood pressure and arterial constrictor sensitivity to ET-1 2 with an associated increase in vascular reactive oxygen species (ROS). Furthermore, the antioxidant tempol prevents IH-induced hypertension. 3 These results suggest that IH might also augment nonagonist-induced vasoconstriction. Myogenic, or spontaneously developed tone, can augment agonist-induced increases in blood pressure 4 through increased vascular resistance. Furthermore, myogenic tone is increased in some experimental models of hypertension. 5 Myogenic tone appears to be initiated by activation of mechanosensitive cation channels, leading to membrane depolarization and opening of L-type voltage-gated Ca 2ϩ channels (L-type VGCC). 6 Modulation of this pathway, leading to elevated resting myogenic tone, could therefore contribute to systemic hypertension. H 2 S, a recently described vasodilator, is produced endog-enously from L-cysteine by 3 enzymes: cystathionine ␤-synthase (CBS), cystathionine ␥-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST). 7 CSE has been reported to be the primary source of H 2 S in the vasculature, although 3MST may also contribute in some vascular beds. H 2 S is a reducing compound that can react with superoxide anion (O 2 Ϫ) to form sulfite 8 or with nitric oxide (NO) to form a nitrosothiol, potentially limiting the bioavailability of both gasotransmitters. 9 Most studies attribute H 2 S vasodilation to activation of vascular smooth muscle (VSM) ATP-sensitive potassium channels (K ATP), 10 but other mechanisms have also been reported. 11 Genetic deletion of CSE in mice elevates blood pressure. 12 In this study, CSE expression was primarily in the endothelium of mesenteric arteries, and large mesenteric arteries from CSE Ϫ/Ϫ mice exhibited endothelial dysfunction. We hypothesized that IH decreases endothelium-dependent H 2 S generation to enhance myogenic tone in small mesenteric arteries. We observed that small mesenteric arteries from IH-exposed rats have increased myogenic tone and depolar-ized VSM membrane potential (E m). Increased …