The renin-angiotensin-aldosterone system and cardiac ischaemia

Abstract

The renin-angiotensin-aldosterone system is a remarkably complex homoeostatic neuroendocrine entity. It is an endocrine system regulating vascular tone and salt and water balance. It is a tissue based system with paracrine and autocrine effects, and also a neuromodulator. These attributes result in an extensive range of actions on the heart, many of which play an important role in cardiac ischaemia and hence are of immense interest to clinicians and basic scientists.There are several theoretical reasons why the renin-angiotensin system should play a pivotal role in cardiac ischaemia. Angiotensin II is a potent coronary and systemic vasoconstrictor and a positive inotropic and chronotropic agent. These attributes of angiotensin II promote ischaemia in vulnerable areas of the myocardium. Initial attempts to block these pro-ischaemic effects by angiotensin converting enzyme (ACE) inhibitors produced equivocal results, due largely to inadequacies of experimental design, are were themselves the victims of inadequate knowledge. More recently, with better understanding of the fundamental biophysiology of the renin-angiotensin system and better drugs, blockade of the system in patients after acute myocardial infarction has yielded promising results, especially in patients with impaired systolic left ventricular function. Research has now focused on ways and means of using these newly discovered anti-ischaemic properties of ACE inhibitors as agents for secondary and perhaps also for primary prevention of acute and chronic coronary events. Research into this aspect of the renin-angiotensin system appears set for spectacular growth as knowl- In this article I shall endeavour to review the basic physiological action of angiotensin II on the coronary vasculature and the myocardium as well as the therapeutic use of angiotensin blocking agents in the management of acute and chronic ischaemic conditions. Actions on myocardial oxygen supply: demand ratio Experimental and clinical data indicate that angiotensin II has a modest action on the heart in normal subjects when the renin-angiotensin system is not activated.1 2 However, if the system is stimulated by sodium deprivation,' diuretic therapy,3 acute cardiac ischaemia,4 8 or renovascular hypertension,9 then the cardiovascular effects are intensified.The earliest view of the effects of angiotensin II effects on the heart was that it had four major actions. First, it had a direct positive inotropic action on the ventricular myocardium.'0 " Second, there was a further inotropic effect resulting from its neuromodulator role of augmenting sympathetic tone.'2 Third, angiotensin II increased heart rate directly and through augmentation of sympathetic activity.'3 14 Fourth, there was tonic modulation of sympathetic coronary vasoconstriction. I5Left ventricular hypertrophy is a common consequence of systemic hypertension and has been shown to be associated with a considerably enhanced risk of cardiovascular morbid events, including myocardial infarction.'618' A consequence of left vent...

Downregulation of ANG II receptor is associated with compensated pressure-overload hypertrophy in the young dog

“…In contrast, our dogs did not have extensive interstitial fibrosis despite a threefold elevation in LV ANG II levels. Taken together, these results suggest it is the chronic myocardial changes such as fibrosis and/or superimposed ischemia (9,19) that are arrhythmogenic, not the isolated acute effects of ANG II itself.…”

“…tissues and that augmented formation of ANG II, acting through the ANG II type 1 (AT 1 ) receptor on cardiomyocytes and fibroblasts, participates in the paracrine regulation of cardiac remodeling and ventricular function (36). Furthermore, prolonged elevation of ANG II has been associated with cardiac fibrosis (15,16), exacerbation of impaired contractility and relaxation in the hypertrophied failing heart (7,9,27,32), and arrhythmogenesis (9,19). These structural and functional consequences of hemodynamic overload have also been associated with changes in AT 1 receptor expression in the heart.…”

Mechanisms of Sudden Cardiac Death

“…251, 252 RAS activation is known to increase myocardial oxidative stress and downregulate ventricular gap junction protein Cx43. 253–255 Transgenic mouse models with enhanced cardiac RAS activity 255, 256 have high incidence of conduction abnormality, ventricular arrhythmias and sudden death owing to reduced cardiac Cx43 and abnormal gap junction function.…”

“…262 Taken together, these data suggest the critical roles of mitochondrial oxidative stress and Cav1 in AngII–induced gap junction remodeling and arrhythmia. As mitochondrial ROS are increased in myocardial ischemia 251, 252 and heart failure, 56, 57 both of which are associated with RAS activation, reduced ventricular Cx43 and increased risk for ventricular arrhythmias and SCD, it would be of great interest to test if the treatment with mitochondria-targeted antioxidant can normalize Cx43 expression and prevent ventricular arrhythmias and SCD in these pathological conditions.…”

The effects of Z13752A, a combined ACE/NEP inhibitor, on responses to coronary artery occlusion; a primary protective role for bradykinin

“…The cardioprotective effects of ACE inhibition in myocardial ischaemia are well documented in both experimental animal models (Parratt, 1994; Linz et al ., 1995; Liu et al ., 1996) and in clinical situations (e.g. Lonn et al ., 1994; Ikram, 1996), and a clear role for bradykinin in mediating these protective effects has been demonstrated based mainly on studies in which its effects on bradykinin (B 2 ) receptors were antagonized (Schölkens et al ., 1989; Linz et al ., 1990; Martorana et al ., 1990; 1991; Ehring et al ., 1994; Liu et al ., 1996; Shimada & Avkiran, 1996).…”