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Although angiotensin converting enzyme inhibitors and a,-blockers have been reported to improve insulin sensitivity, their mechanisms of action have not been elucidated. To investigate the role of kinins in insulin sensitivity, we treated 4-week-old spontaneously hypertensive rats with either an angiotensin converting enzyme inhibitor (enalapril), an a,-blocker (doxazosin), or an angiotensin II antagonist (losartan) for 3 weeks. A control group received no drugs. In addition, 18 rats treated with enalapril or doxazosin received a simultaneous administration of a kinin antagonist (Hoe 140). Glucose clamp testing was performed in each group. Enalapril (128±1 mmHg) and doxazosin (132±2 mm Hg) decreased mean blood pressure compared with control levels (148±1 mm Hg) (P<.01). The glucose requirement for the clamp test during the administration of enalapril (25.8±0.5 mg/kg per A lthough recent antihypertensive medications con-/ \ trol blood pressure (BP) as expected, it has not J. \ -been entirely determined that they prevent cardiovascular events.1 The management of concomitant conditions such as obesity, diabetes mellitus, and hyperlipidemia is advocated as one of the keys to improving the prevention of cardiovascular events. Insulin resistance is common in the above-mentioned conditions, and hypertension itself is believed to be an insulin-resistant state.2 It has been proposed that the management of insulin resistance may contribute to the prevention of cardiovascular events.1 Thus, in the management of hypertension, consideration should be given to the influence of antihypertensive medication on insulin sensitivity. It has been demonstrated that angiotensin converting enzyme (ACE) inhibitors and a,-blockers have a beneficial effect on insulin sensitivity. 3With regard to the effect of ACE inhibitors, the reninangiotensin system, kallikrein-kinin system, or both have been suggested to participate, but the precise mechanisms of action of ACE inhibitors have not been determined. ACE is also known as kininase II and acts to degradate several kinins. Thus, ACE inhibitors de-

SUMMARY The causative mechanisms of hypertension were investigated by studying the renal function (pressure-natriuresis) curve in patients with primary aldosteronism (JI = 6) and renovascular hypertension (n = 6). Before and after radical operation (removal of adenoma in primary aldosteronism and percutaneous transluminal angioplasty in renovascular hypertension), dietary NaCl intake was altered from 10 to 13 g/day in Week 1 to 1 to 3 g/day in Week 2. Mean arterial pressure (MAP) and urinary sodium excretion were measured on the last 3 days of each week. By restricting sodium intake before operation, MAP was reduced from 122 ± 7 to 113 ± 7 mm Hg (p<0.025) in primary aldosteronism but not in renovascular hypertension (130 ± 6 to 128 ± 5 mm Hg). The renal function curve was drawn by plotting urinary sodium excretion on the ordinate and MAP on the abscissa before and after operation. The slope of the curve was analyzed between the plotted points, and each curve was extrapolated to zero sodium excretion as an estimate of the degree of shift of the curve along the MAP axis. Before, as compared with after operation, the extrapolated v-intercept of the curve was shifted rightward in both primary aldosteronism (111 ± 7 vs 87 ± 4 mm Hg; p<0.025) and renovascular hypertension (128 ± 5 vs 95 ± 2 mm Hg; p<0.025) and the slope was depressed in primary aldosteronism (16 ± 1 vs 40 ±17 [mEq/day]7mm Hg; p < 0.025) but not in renovascular hypertension (130 ± 75 vs 40 ± 13 [mEq/day]/mm Hg). After operation, the renal function curves in primary aldosteronism and renovascular hypertension were normalized. The rightward shift of the curve in renovascular hypertension probably was due to an increase in renal vascular resistance caused by the stenotic renal vascular lesion as well as to increased resistance caused by stimulation of the reninangiotensin system. The rightward shift in primary aldosteronism presumably was due to enhancement of renal tubular sodium reabsorption by aldosterone; the depressed slope likely resulted from suppression of the renin-angiotensin feedback mechanism by the excess aldosterone and resultant volume expansion. Thus, an abnormal renal function curve seems to have played a major role in the genesis of each of these forms of secondary hypertension. (Hypertension 10: 11-15, 1987) KEY WORDS • arterial pressure-natriuresis relationship hypertension • primary aldosteronism pathogenesis • renovascular B ASED on the hypothesis of Guyton and colleagues, 1 -2 the renal function curve (pressurenatriuresis relationship) must always be affected in the genesis of hypertension regardless of the factors that initiate the hypertension process (if the From the Department of Medicine, National Cardiovascular Center, Osaka, Japan.Supported by a research grant for cardiovascular diseases (59C-8) from the Ministry of Health and Welfare.Presented in part at the 1 lth Scientific Meeting of the International Society of Hypertension, Heidelberg, West Germany, 1986. Address for reprints: Dr. Genjiro Kimura, Division of Nephrol...

We investigated the role of insulin in salt-sensitive hypertension in Dahl salt-sensitive and salt-resistant rats. The rats were kept in metabolic cages, and sodium intake and urinary sodium excretion were measured. In salt-sensitive rats receiving a 03% NaCI diet, sodium retention was significantly greater at weeks 1 and 2 in rats that received an insulin infusion than in those receiving a saline infusion. Mean arterial blood pressure and plasma norepinephrine levels were significantly higher at week 3 in insulin-treated rats than in saline-treated rats (mean arterial pressure, 137±3 mm Hg versus 119±3 mm Hg, p<0.05; plasma norepinephrine, 0.40±0.02 ng/ml versus 0.27±0.01 ng/ml, p<0.05). Insulin did not influence sodium retention, mean arterial pressure, or plasma norepinephrine in salt-resistant rats. Coadministration of an or-blocker (bunazosin, 10 rag/kg per day for 3 weeks) in salt-sensitive rats abolished the insulin-induced elevations in mean arterial pressure and sodium retention. When salt-sensitive rats were fed a low salt diet (0.03% NaCI), Insulin did not raise mean arterial pressure. Thus, insulin elevated blood pressure only in the salt-sensitive model. The sympathetic nervous system and sodium retention in the early phase of insulin overload may contribute to elevation of mean arterial pressure in this model. (Hypertension 1992^0:596-600) KEY WORDS • insulin • rats, Dahl salt-sensitive • sympathetic nervous system O besity and non-insulin-dependent diabetes mellitus are frequently accompanied by hypertension. 1 -2 In obese hypertensive patients, a loss of body weight is often associated with parallel decreases in blood pressure and insulin levels.3 An inverse relation between whole body glucose uptake and blood pressure in nonobese subjects has been reported. 4 -3 These observations have focused attention on the relation between hyperinsulinemia and hypertension, 6 but since hyperinsulinemia is not always accompanied by hypertension, it is not clear whether hyperinsulinemia increases the blood pressure.It is possible that insulin may increase the blood pressure of some subjects but not others. Data from several studies have suggested that the activation of the sympathetic nervous system and sodium retention may play roles in insulin-induced increases in blood pressure. -8 These two mechanisms have also been reported to be involved in salt-overload hypertension (salt-sensitive hypertension). 9 These observations suggest that hyperinsulinemia may affect salt sensitivity.We investigated the effects of chronic hyperinsulinemia on blood pressure and its mechanisms in Dahl salt-sensitive (DS) and salt-resistant (DR) rats.From the Department of Cardiology, Surugadai Nihon University Hospital, Tokyo, Japan.Address for reprints: Hirofumi Tonuyama, MD, PhD, Department of Cardiology, Surugadai Nihon University Hospital, 1-8-13, Kandasurugadai, Chjyoda-ku, Tokyo, Japan, 101.Received December 6, 1991; accepted in revised form July 17, 1992. MethodsFour-week-old male DS and DR rats were obtained from Brookhav...

Insulin has been shown to attenuate pressor-induced vascular contraction, but the mechanism for this vasodilatory action is unknown. This study examines the effect of insulin on angiotensin II (ANG II)-induced increments in cytosolic calcium in cultured rat vascular smooth muscle cells (VSMC). 20-min incubations with insulin (10 ,U/ml to 100 mU/ml) did not alter basal intracellular calcium concentration (ICa2I,), but inhibited the response to 100 nM ANGII in a dose-dependent manner (ANG II alone, 721±54 vs. ANG II + 100 mU/ml insulin, 315±35 nM, P < 0.01). A similar effect of insulin on ANGII action was observed in calcium poor buffer. Moreover, insulin did not effect calcium influx. ANG II receptor density and affinity were not affected by 24-h incubation with insulin. To further clarify the mechanisms of these observations, we measured ANG II-induced production of inositol 1,4,5-triphosphate (IP3), and IP3-releasable 45Ca. Insulin treatment did not alter ANG Il-stimulated IP3 production. However, IP3-stimulated release of45Ca in digitonin permeabilized cells was significantly reduced after 5-min incubations with 100 mU/ml insulin. Thapsigargin induced release of calcium stores was also blocked by insulin. Thus, insulin attenuates ANG 11-stimulated ICa2"I, primarily by altering IP3-releasable calcium stores. Insulin effects on ANG II-induced ICa2`Ii were mimicked by preincubation of VSMC with either sodium nitroprusside or 8-bromo-cGMP. As elevations in cGMP in vascular tissue lower ICa2I1j, it is possible that insulin affects IP3 release of calcium by a cGMP-dependent mechanism that would contribute to its vasodilatory effects. (J. Clin. Invest. 1993. 92:1161-1167