Kinins contribute to the improvement of insulin sensitivity during treatment with angiotensin converting enzyme inhibitor.

Abstract

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-

Next generation multifunctional angiotensin receptor blockers

“…25,26 Few randomized, double-blind, placebo-controlled trials have been performed that have examined the antidiabetic effects of other ARBs in patients without heart failure. 27 Just as ACE inhibitors are believed to improve glucose metabolism through at least two or more primary mechanisms (for example, inhibition of the renin-angiotensin system and activation of the bradykinin/nitric oxide pathways), [28][29][30][31] it is possible that telmisartan might also be improving glucose metabolism and cardiovascular protection through two or more key pathways (for example, inhibition of the renin-angiotensin system and activation of PPARg). By the use of multifunctional ARBs that have the potential to target multiple points in the hypertension-diabetes cascade (Figure 2), it is conceivable that one might achieve greater metabolic and cardiovascular protection than that attained with the angiotensin receptor blockade Next generation multifunctional angiotensin receptor blockers TW Kurtz and U Klein alone.…”

Effects of Angiotensin II Receptor Antagonists on Insulin Resistance Syndrome and Leptin in Sucrose-Fed Spontaneously Hypertensive Rats.

“…It is suggested that hypertension may be associated with hyperinsulinemia in part via glucose intolerance-induced alterations such as sodium retention, vasculopathy, and nephropathy (4). Therefore, ARA on insulin sensitivity have been conflicting, with some studies showing no influence on insulin sensitivity (10)(11)(12) and others demonstrating an improvement of insulin sensitivity (13)(14)(15). Therefore, it appears important to examine the effect of ARA on insulin sensitivity in genetic hypertensive animals with insulin resistance.…”

Effects of ACE inhibition and AT1-receptor antagonism on endothelial function and insulin sensitivity in essential hypertensive patients

“…21,22 FMD, which is considered to be a measure of endothelial function, correlated positively with calculated insulin sensitivity index in hypertensive patients. Since insulin sensitivity was not improved significantly in the losartan-treated group, insulin resistance couldn't be implicated as the primary factor in impaired endothelial function in essential hypertension.…”

“…21,23 The beneficial effects of ACE-Is on endothelial function may depend on both of these mechanisms. The Figure 3 FMD was positively correlated with serum NOx levels (r=0.39, p=0.01) and negatively correlated with erythrocyte TBARs levels (r=-0.53, p=0.0002).…”