Jin Hoshino

Exaggerated vascular response due to endothelial dysfunction and role of the renin-angiotensin system at early stage of renal hypertension in rats.

We investigated whether endothelial dysfunction might contribute to the exaggerated vasoconstriction that was induced by the administration of norepinephrine at the early stage of one-kidney, one-clip renal hypertension (1K1C) in rats. We also studied the role of the renin-angiotension system in this phenomenon. Male Wistar rats were killed 48 hours after the induction of renal artery stenosis or sham operation, and ring preparations of the thoracic aorta were obtained. The isometric contraction and relaxation of aortic strips produced by norepinephrine and acetylcholine, respectively, were recorded with a force-displacement transducer. The aorta of 1K1C rats showed a significantly (P < .05) exaggerated contractile response to norepinephrine as compared with that of control rats. Rubbing the endothelium and treatment with methylene blue or NG-monomethyl L-arginine acetate augmented the contractile responses to norepinephrine to a greater extent in control rats than in 1K1C rats; therefore, the responses of the groups did not differ significantly. In the second experiment, rats received 0.05% captopril, 0.02% enalapril, or 0.02% nicardipine in the drinking water for 1 day before and for 48 hours after the induction of renal artery stenosis or sham operation. The increased contractile responses of the aorta to norepinephrine in 1K1C rats were normalized to the level of the control rats by treatment with either captopril or enalapril but not with nicardipine. These results suggest that the endothelial dysfunction may contribute to the exaggerated norepinephrine-induced vasoconstriction observed in the 1K1C rats and that angiotensin I-converting enzyme inhibitors can restore the endothelial function.

Antihypertensive agents prevent nephrosclerosis and left ventricular hypertrophy induced in rats by prolonged inhibition of nitric oxide synthesis.

We investigated the ability of the angiotensin converting enzyme (ACE) inhibitor imidapril hydrochloride, and of the calcium channel blocker amlodipine besilate, to prevent nephrosclerosis and left ventricular hypertrophy (LVH) in rats with hypertension induced by chronic inhibition of nitric oxide (NO). Male Wistar rats were given distilled water (control), NG-nitro-L-arginine methyl ester (L-NAME) 500 mg/L, L-NAME plus imidapril 10 mg/L or 100 mg/L, or L-NAME plus amlodipine 50 mg/L or 100 mg/L in the drinking water (n = 10-12). We then collected 24-h urine samples at 2, 4, and 6 weeks, obtained blood samples at 6 weeks, and histologically examined the kidney and heart. L-NAME markedly reduced the levels of NO metabolites in serum and urine while increasing the tail-cuff blood pressure, the urinary albumin level (1.90 +/- 0.65 v 0.05 +/- 0.02 mg/day/100 g in control), and the area of the left ventricular wall (83.3 +/- 3.0 v 69.8 +/- 1.8 mm2 in control). Nephrosclerosis and myocardial interstitial fibrosis were documented histologically. The plasma renin activity was significantly higher in rats treated with L-NAME than in the control rats. The concomitant administration of imidapril (10 mg/L) with L-NAME completely normalized the tail-cuff pressure, the LVH (70.8 +/- 1.8 mm2), the albuminuria (0.05 +/- 0.01 mg/day/100 g), and the histologic changes. Amlodipine (50 mg/L) also ameliorated the L-NAME-induced effects, but to a lesser extent. Thus, the chronic inhibition of NO synthesis in rats produced nephrosclerosis and LVH that were effectively prevented by giving imidapril at a dose lower than that of amlodipine. We conclude that ACE inhibitors can prevent nephrosclerosis and LVH even in the presence of a reduction in NO production, implying that in rats the inhibition of the renin-angiotensin system is more effective than the blockade of calcium channels in preventing hypertensive tissue injury.

Selective angiotensin receptor antagonism with valsartan decreases arterial stiffness independently of blood pressure lowering in hypertensive patients.

Angiotensin II plays a key role in the development of vascular disease. We examined the long-term effects of selective angiotensin II receptor (ATR) blockade with valsartan on arterial wall stiffness. Brachial to ankle pulse wave velocity (baPWV) was measured in 28 women and 25 men with hypertension (mean age: 62±2 years). The measurements were repeated after 24 weeks of treatment with valsartan, 40 to 160 mg/day, with (n=10) or without (n=36) concomitant statin therapy. By multiple regression analysis, baseline baPWV was correlated with age (p<0.001), systolic blood pressure (SBP, p<0.0001), body mass index (p=0.018), and pulse pressure (p=0.005), but not with total cholesterol (p=0.446). Valsartan lowered mean SBP and diastolic blood pressure (DBP) from 155±3 to 140±3 mmHg and from 90±2 to 82±2 mmHg, respectively, and mean baPWV from 1,853±49 to 1,682±52 cm/s. Lowering of baPWV was not influenced by statin therapy. An overlap analysis was performed to separate the effect of angiotensin II receptor blockade from that of blood pressure (BP) lowering. The decrease in the baPWV value of 1,794±46 cm/s before valsartan (n=39) vs. 1,663±45 cm/s during valsartan (p=0.048, n=31) at a similar mean SBP level (149±2 vs. 146±3 mmHg, p=0.304) confirmed that ATR blockade had a beneficial effect independent of BP lowering. SBP strongly influences baPWV. However, the decrease in baPWV with valsartan was independent of BP lowering. Statins had no synergistic effect on baPWV. Lowering of baPWV may account for the therapeutic benefit conferred by valsartan independent of its BP-lowering effect.

Effect of Enalapril on Exhaled Nitric Oxide in Normotensive and Hypertensive Subjects

We investigated whether an angiotensin-converting enzyme (ACE) inhibitor increases the production of nitric oxide (NO) in exhaled air in normotensive and hypertensive subjects. In study 1, 8 normotensive male subjects received a single oral dose of enalapril (5 mg) or nitrendipine (10 mg) in a crossover manner. Exhaled air was collected at baseline, and at 2, 4, and 8 hours after administration of the drug. In study 2, 10 normotensive subjects (6 men and 4 women) and 10 hypertensive subjects (6 men and 4 women) received a single oral dose of enalapril (5 mg). Exhaled air was collected at baseline and at 2 and 4 hours after administration of the drug. In study 1, enalapril significantly increased the NO release rate from the lung in normotensive subjects (36.9±5.1 pmol/s at baseline versus 58.3±7.3 pmol/s at 4 hours, P <0.01). Nitrendipine did not change the NO release rate. In study 2, enalapril significantly increased the release of NO from the lung in normotensive subjects (40.4±6.0 pmol/s at baseline versus 70.3±11.4 pmol/s at 4 hours, P <0.01) but not in hypertensive subjects. ACE inhibition increased NO production from the lung in normotensive subjects but not in hypertensive patients. The reduction of angiotensin II production and/or the accumulation of bradykinin in the pulmonary tissue may be responsible for increased NO production in components of the lung, such as the pulmonary vascular endothelium, bronchial epithelial cells, macrophages, nasopharyngeal cells, and neurons. However, the effects of ACE inhibition on NO production from the lung differ between hypertensive subjects and normotensive subjects.

Renal Artery Stenosis Associated with Epidermal Nevus Syndrome

Epidermal nevus syndrome is an unusual neurocutaneous disorder in which epidermal nevi are associated with abnormalities of the skeleton and central nervous system, including the eyes and somtimes the cardiovascular system. We treated a patient in whom the latter included renal artery stenosis. An 18-year-old man with epidermal nevi was diagnosed as having the syndrome based on the additional presence of scoliosis, an arachnoid cyst in the middle cranial fossa, and microphthalmos. Hypertension was diagnosed when the patient was 15 years old. The plasma renin activity (9.7 ng/ml/h) was elevated. Right renal artery stenosis was demonstrated by angiography, and the abdominal aorta was narrowed distal to the ostium of the superior mesenteric artery. The plasma renin activity in the right renal vein (16 ng/ml/h) was higher than contralaterally (10 ng/ml/h). Several cardiovascular manifestations have been reported as a complication of epidermal nevus syndrome. Hypertension in an individual with epidermal nevi and congenital anomalies should prompt a search for a vascular anomaly.

Lecithinized superoxide dismutase induces vasodilation; evidence of direct contribution of superoxide anions to modulating vascular tone

The purpose of this study was to examine the role of superoxide anions in modulating the vascular tone. The effects of unmodified and lecithinized superoxide dismutase (SOD) on vascular tone were determined in aortic ring preparations of mice. In lecithinized SOD, 4 molecules of a phosphatidylcholine derivative were covalently bound to each dimer of recombinant human copper-zinc SOD to facilitate tissue accumulation. Unmodified SOD did not change vascular tone. However, lecithinized SOD induced dose-dependent vasodilation of aortic ring preparations. The pretreatment with NG-nitro-L-arginine methylester (L-NAME) 10(-4) mol/L abolished the vasodilation induced by lecithinized SOD. The results of this study indicate that superoxide anions play a prominent role in modulating the vascular tone by enhancing the breakdown of nitric oxide.

Effect of vasopressin V1 (OPC-21268) and V2 (OPC-31260) antagonists on renal hemodynamics and excretory function

Our objective was to assess the effect of endogenous AVP on renal hemodynamics and excretory function. We measured mean arterial pressure (MAP), renal blood flow (RBF), glomerular filtration rate (GFR) and urine osmolality before and after the intravenous infusion of a V1 antagonist (OPC-21268), a V2 antagonist (OPC-31260) and their vehicle (saline) in anesthetized male Wistar rats. The infusion of the V2 antagonist increased the urine flow rate and reduced the urine osmolality significantly (p < 0.05). The infusion of saline and the V1 antagonist did not change the urine flow rate or the urine osmolality. The infusion of saline, the V1 antagonist and the V2 antagonist had no effect on MAP, RBF or GFR. These results suggest that endogenous AVP plays a critical role in the regulation of renal water reabsorption mediated through the V2 receptor.

Antagonism of ANG II type 1 receptors protects the endothelium during the early stages of renal hypertension in rats

The degree of involvement of the renin-angiotensin system in endothelial dysfunction was investigated by using a one-kidney, one-clip (1K,1C) model of renal hypertension. Male Wistar rats received 0.02% enalapril, 0.02% losartan, or tap water for 1 day before and for 48 h after the induction of renal artery stenosis or sham operation. The aorta of 1K,1C rats showed increased contraction and decreased relaxation responses produced by norepinephrine and acetylcholine, respectively, vs. control responses. Exposure to 10(-5) mol/l NG-monomethyl-L-arginine acetate augmented the contractile responses to norepinephrine to a greater extent in control rats than in the 1K,1C rats. The increased contraction and decreased relaxation responses to these agonists in the 1K,1C rats were normalized by enalapril or losartan. The addition of HOE-140 to the bath did not alter these normalized responses. Results suggest that angiotensin II causes endothelial dysfunction and reduces nitric oxide levels in 1K,1C rats. Such endothelial dysfunction enhanced the norepinephrine-induced contraction during the early-stage hypertension in 1K,1C rats.The degree of involvement of the renin-angiotensin system in endothelial dysfunction was investigated by using a one-kidney, one-clip (1K,1C) model of renal hypertension. Male Wistar rats received 0.02% enalapril, 0.02% losartan, or tap water for 1 day before and for 48 h after the induction of renal artery stenosis or sham operation. The aorta of 1K,1C rats showed increased contraction and decreased relaxation responses produced by norepinephrine and acetylcholine, respectively, vs. control responses. Exposure to 10-5 mol/l N G-monomethyl-l-arginine acetate augmented the contractile responses to norepinephrine to a greater extent in control rats than in the 1K,1C rats. The increased contraction and decreased relaxation responses to these agonists in the 1K,1C rats were normalized by enalapril or losartan. The addition of HOE-140 to the bath did not alter these normalized responses. Results suggest that angiotensin II causes endothelial dysfunction and reduces nitric oxide levels in 1K,1C rats. Such endothelial dysfunction enhanced the norepinephrine-induced contraction during the early-stage hypertension in 1K,1C rats.