The ACE-inhibitor captopril improves myocardial perfusion in spontaneously diabetic (BB) rats

Abstract

SummaryThe aim of this study was to examine the influence of inhibition on angiotensin converting enzyme (ACE) of myocardial function and perfusion of the rat impaired by diabetes. Spontaneously diabetic rats were treated with the ACE-inhibitor captopril for 4 months. Cardiac performance was analysed in the isolated heart perfused at constant volume. Epicardial perfusion was determined by measuring changes in epicardial fluorescence after injection of a bolus of fluoresceinisothiocyanate-dextrane (3 kDa) as described previously. As compared to untreated diabetic controls, captopril prevented the increase of end diastolic pressure, coronary perfusion pressure and vascular resistance. The intravascular volume was enlarged and the epicardial perfusion rate increased in hearts of diabetic rats treated with captopril as compared to diabetic controls. Treatment of diabetic rats with the ACE-inhibitor captopril (1) increases the number of perfused capillaries, and (2) can partly prevent the development of cardiac dysfunction in diabetes. Together with morphological data demonstrating an inhibition of interstitial and perivascular fibrosis in hearts of diabetic rats treated with captopril, our data suggest that ACE-inhibition is cardioprotective in diabetes. These observations are also compatible with the assumption that an accelerated generation of angiotensin II may be involved in the pathophysiological chain of events leading to diabetic cardiopathy. [Diabetologia (1995) 38: 509-517] Key words Diabetes mellitus, cardiopathy, ACE-inhibition, captopril, BB rats, regional perfusion, myocardial function.The incidence of cardiovascular complications is severely increased in diabetes mellitus by the development of macrovascular complications. However, coronary heart disease can only partly explain the increased rate of cardiovascular complications in diabetes, since cardiac risk remains elevated even in the absence of atherosclerosis [1][2][3]. In patients, impairment of diastolic relaxation and signs of cardiac neu- ropathy have been consistently reported [3,4]. Additionally, cardiac performance is further impaired in diabetic patients by development of small vessel disease [5,6]. In animal models using chemically-induced forms of insulin deficiency or spontaneously diabetic rats and mice, the metabolic disturbances following insulin deficiency cause impairment of diastolic and systolic heart performance, which can be totally prevented by treatment of the animals with insulin [7][8][9][10][11]. The various forms of cardiac dysfunction in diabetes which develop independently from coronary heart disease, are often called "diabetic cardiomyopathy" [12][13][14].The mechanisms underlying these complex disturbances of heart function in diabetes are not fully understood and several hypotheses have been suggested to link the metabolic disturbances observed in the diabetic heart with impairment of heart function [4,

Effects of Insulin Replacements, Inhibitors of Angiotensin, and PKCβ's Actions to Normalize Cardiac Gene Expression and Fuel Metabolism in Diabetic Rats

“…This finding supports our previous report that mice with cardiac-specific overexpression of PKC␤ isoform developed cardiac hypertrophy and fibrosis similar to diabetic cardiomyopathy, which were reversed by ruboxistaurin treatment (10,11). Similarly, inhibition of ACE has been shown to reduce interstitial and perivascular fibrosis in hearts of diabetic rats (46). These new findings suggest that PKC activation could contribute to the increase in stiffness of the myocardium induced by diabetes or angiotensin II, possibly by increasing the expressions of transforming growth factor-␤ or connective tissue growth factor as previously reported (11,22,46).…”

“…Similarly, inhibition of ACE has been shown to reduce interstitial and perivascular fibrosis in hearts of diabetic rats (46). These new findings suggest that PKC activation could contribute to the increase in stiffness of the myocardium induced by diabetes or angiotensin II, possibly by increasing the expressions of transforming growth factor-␤ or connective tissue growth factor as previously reported (11,22,46).…”

Determinants of subclinical diabetic heart disease

“…It may also be due to a number of other beneficial humoral effects caused by ACE inhibitors, including increases in kinin levels (which stimulate production of endothelium-derived nitric oxide, prostacyclin and hyperpolarising factor) and reduction of endothelin-1 levels. These effects may increase the number of perfused capillaries in diabetic subjects [17] and improve endothelial dysfunction and coronary blood flow. Finally, improved insulin sensitivity and glycaemic control with ACE inhibitors may also contribute to improved LV systolic function.…”

Female Children and Adolescents With Type 1 Diabetes Have More Pronounced Early Echocardiographic Signs of Diabetic Cardiomyopathy

“…Most advanced glycation end products can increase the crosslinking of proteins like collagen and elastin, causing reduced tissue elasticity and decreased protein turnover (8,9). ACE inhibition and nonselective ␤-blockers have been proposed to prevent or treat diabetic cardiomyopathy (32,33), but more studies are needed to determine the timing of such an intervention.…”