No abstract

Background-Oxidative stress increases in hypertension. The aim of this study was to determine whether reactive oxygen species (ROS) are increased in the rostral ventrolateral medulla (RVLM) in the brainstem, where the vasomotor center is located, in stroke-prone spontaneously hypertensive rats (SHRSP), and, if so, to determine whether the increased ROS contribute to neural mechanisms of hypertension in SHRSP. Methods and Results-We measured ROS levels in the RVLM of SHRSP and compared them with those in Wistar-Kyoto rats (WKY). Thiobarbituric acid-reactive substances were increased in SHRSP compared with WKY. ROS were measured by electron spin resonance (ESR) spectroscopy. The ESR signal decay rate in the RVLM of SHRSP was significantly increased compared with that in WKY, and this increase was abolished by dimethylthiourea (a hydroxyl radical scavenger). The increased ESR signal decay rate was reduced to the same extent in the presence of desferrioxamine, catalase, and Tiron, indicating that hydroxyl radicals are derived from superoxide anions and hydrogen peroxide. In addition, total superoxide dismutase (SOD) activity in the RVLM was decreased in SHRSP compared with WKY. Furthermore, bilateral microinjection of tempol into the RVLM decreased blood pressure in SHRSP but not in WKY, and MnSOD overexpression in the RVLM of SHRSP decreased blood pressure and inhibited sympathetic nerve activity. Conclusions-These results suggest that superoxide anions in the RVLM, which generate hydroxyl radicals, are increased in SHRSP and contribute to the neural mechanisms of hypertension in SHRSP.

Abstract-Rho-kinase plays an important role in modulating Ca 2ϩ sensitivity of vascular smooth muscle and has been suggested to be involved in the increased systemic vascular resistance in hypertensive animals. However, it remains to be examined whether this is also the case in patients with essential hypertension. Recently, it has been shown that fasudil is a specific Rho-kinase inhibitor. The aim of this study was to examine whether Rho-kinase is involved in the pathogenesis of hypertension in humans by using this Rho-kinase inhibitor. Studies were performed in hypertensive patients (HT group, nϭ14) and age-matched normotensive subjects (NT group, nϭ12). Forearm blood flow was measured by a strain-gauge plethysmograph during intra-arterial infusion of graded doses of fasudil (3.2, 6.4, 12.8, and 25.6 g/min) or sodium nitroprusside (0.4, 0.8, 1.6, and 3.2 g/min). Resting forearm vascular resistance was significantly higher in the HT group than in the NT group (22Ϯ4 versus 17Ϯ5 U, respectively; PϽ0.05). The extent of the increase in forearm blood flow evoked by fasudil was significantly greater in the HT group than in the NT group (12.3Ϯ1.4 versus 6.0Ϯ0.6 mL · min Ϫ1 · 100 mL Ϫ1, respectively; PϽ0.01). The percent decrease in forearm vascular resistance was significantly greater in the HT group than in the NT group (63.6Ϯ4.7% versus 29.6Ϯ3.9%, respectively; PϽ0.01). By contrast, forearm vasodilator response evoked by sodium nitroprusside was comparable between the 2 groups. These results provide the first evidence that Rho-kinase may be involved in the pathogenesis of the increased peripheral vascular resistance in hypertension in humans. Key Words: hypertension, essential Ⅲ muscle, smooth, vascular Ⅲ blood flow Ⅲ vascular resistance I ncreased systemic vascular resistance plays an important role in the pathogenesis of hypertension; however, the molecular mechanism remains to be elucidated. Phosphorylation of myosin light chain (MLC) is a crucial step for vascular smooth muscle (VSMC) contraction, the extent of which is regulated in a dual manner by MLC kinase and MLC phosphatase (MLCPh). 1 Inhibition of MLCPh results in an increase in MLC phosphorylation and subsequent VSMC hypercontraction (Ca 2ϩ sensitization). 1 Indeed, this Ca 2ϩ sensitization mechanism of VSMCs has been reported to be enhanced in hypertensive animals. 2 Rho-kinase/ROK␣/ROCKII, 3-5 which is activated by the small GTPase Rho, inhibits MLCPh activity and thus plays a key role in Ca 2ϩ sensitization and hypercontraction of VSMCs. 1,6 It has been previously reported that Y-27632, a Rho-kinase inhibitor, preferentially lowers arterial pressure in rat models of hypertension in vivo, which indirectly suggests an involvement of Rho-kinase in hypertension. 7 We have recently demonstrated that Rho-kinase is upregulated and plays a key role in VSMC contraction in a porcine model of coronary artery spasm 8 and in spontaneously hypertensive rats (SHR). 9 However, it remains to be examined whether this is also the case in humans.Fasudil, 10 a protein ki...

BACKGROUND This study aimed to determine if cholesterol-lowering therapy improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. METHODS AND RESULTS Nine patients with hypercholesterolemia were studied before and after cholesterol-lowering therapy with pravastatin (an inhibitor of HMG-CoA reductase) for 6 +/- 3 months, which lowered serum cholesterol from 272 +/- 8 to 187 +/- 16 mg/dL (P < .01). Control patients with serum cholesterol of 218 +/- 23 mg/dL also were studied twice in a similar interval (8 +/- 2 months) with no cholesterol-lowering drugs. Acetylcholine (the endothelium-dependent vasodilator) and papaverine and nitrate (endothelium-independent vasodilators) were infused into the study coronary artery. Changes in the diameter of the epicardial coronary artery and coronary blood flow were assessed by quantitative coronary arteriography and an intracoronary Doppler catheter. In patients with hypercholesterolemia, acetylcholine-induced vasoconstriction of the epicardial artery was less (P < .05) and the acetylcholine-induced increases in coronary blood flow were greater (P < .001) after than before pravastatin. In control patients, responses of the epicardial coronary artery and coronary blood flow to acetylcholine did not change over the follow-up period. The vasomotor responses to papaverine or nitrate were similar between the two groups, and no interval changes in their responses were noted in either group. CONCLUSIONS These results suggest that cholesterol-lowering therapy with pravastatin may improve endothelium-dependent coronary vasomotion, which may possibly contribute to the improvement of myocardial perfusion as well as the regression of coronary atherosclerosis.

These findings suggest that endothelium-dependent dilatation of the resistance coronary arteries is defective in patients with anginal chest pain and normal coronary arteries, which may contribute to the altered regulation of myocardial perfusion in these patients.