Increased Tissue Angiotensin-Converting Enzyme Activity Impairs Bradykinin-Induced Dilation of Coronary Arterioles in Obesity

Bradykinin (BK) is continuously produced in the heart by the tissue kinin-kallikrein system,1 and is considered to be a key endogenous regulator of coronary blood flow. In this context, Groves et al demonstrated that intracoronary infusion of the BK B2 receptor antagonist, HOE 140, reduced the diameter of epicardial coronary arteries and decreased coronary blood flow in patients without significant coronary occlusion.2 In patients with no signs of coronary artery disease, intracoronary infusion of BK increased coronary artery diameter and elevated coronary blood flow.3 It is known that the rate of BK production increases in response to ischemic insults,4 aiming to maintain coronary dilation and tissue perfusion.5 However, this mechanism often fails in the diseased heart because of the unresponsiveness of coronary resistance arteries to exogenous or endogenous BK.6 Obesity and metabolic syndrome have been shown to have a detrimental effect on the coronary microcirculation of patients undergoing percutaneous coronary intervention.7 Previously, we have shown that BK-induced coronary arteriolar dilation is reduced in obese-normotensive patients, when compared with lean-normotensive individuals.8 The underlying mechanisms responsible for impaired BK-dependent regulation of coronary vascular resistance in obesity are not fully understood. In the circulation, BK is readily cleaved and inactivated by angiotensin-converting enzyme (ACE). The presence of tissue ACE has been described in cardiac myocytes and coronary vessels.9 In the myocardium, ACE plays a crucial role in various homeostatic pathways, including cell growth, extracellular matrix formation and apoptosis.10 In pathological conditions, such as atherosclerosis, hypertension and obesity, upregulation of tissue ACE is known to contribute to morphological changes in the heart by initiating cardiac and vascular hypertrophy.11 These adverse effects are mainly mediated by an increased ACE-dependent, localized production of angiotensin II (AngII).11 Less is known about the functional changes that may occur in coronary resistance arteries as a consequence of tissue ACE activation. The important ACE end-product, AngII, normally dilates coronary resistance arteries through activation of type 2 AngII receptors (AT2Rs).12,13 However, recent studies revealed that AT2R activation may also lead to constriction of resistance arteries in various disease states.14 In this context, Zhang et al have shown that AngII induces constriction of coronary arteries obtained from dogs fed a high-fat diet (HFD), an experimental model of obesity and metabolic dysfunction.15 These authors concluded that activation of tissue ACE could lead to enhanced production of AngII, thus promoting coronary vasoconstriction in obesity. This mechanism remains unconfirmed in human obesity. In addition, it is possible that the upregulated ACE in coronary microvessels interferes with the dilator effects of endogenously produced BK, a pathological mechanism that may also limit myocardial perfusion. In support of this scenario, Kuga et al demonstrated that the diameter of epicardial coronary arteries is increased after intracoronary infusion of the ACE inhibitor, enalaprilat, in patients without significant coronary stenosis.3 Previous studies have shown that systemic administration of an ACE inhibitor improves vasodilator responses in animal models of obesity.16,17 For instance, Russell et al reported that in ramipril-treated JCR:LA-cp obese rats, coronary blood flow in response to BK was significantly enhanced.17 It is important to note that in those studies only indirect evidence has been provided for the upregulated tissue ACE in coronary microvessels in obesity. Beneficial effects of systemic ACE inhibition could be related to the blood pressure (BP)-lowering effect and/or improved insulin resistance in obesity.16,17 Whether upregulated tissue ACE directly interferes with the dilator function of coronary resistance arteries in obesity remains unknown. Thus, in the current study we set out to elucidate the direct vascular effects of ACE inhibition, with the aims of providing evidence for the upregulation of coronary microvascular ACE in obesity and clinical relevance to obese patients. To this end, BK-induced dilator responses were investigated in isolated coronary arterioles in a rat model of diet-induced obesity.