Prostaglandin E₂ and cyclic AMP in the coronary vasodilatation due to cardiac hyperactivity

Abstract

In the isolated perfused rat heart, the dose-related cardiostimulation produced by norepinephrine (NE) or calcium chloride (Ca2+) was followed by a corresponding increase in coronary flow (CF) and in the cardiac level of adenosine 3',5'-cyclic phosphate (cAMP). Prolonged prostaglandin E2 (pge2) infusion did not change the basic force of contraction, CF, or cAMP level but when NE or Ca2+ were administered, only the responses of the CF and the cAMP were diminished. A phosphodiesterase inhibitor, diazoxide (Dx), caused insignificant increase in the basal cAMP, without affecting the force of contraction or CF. With NE or Ca2+, during Dx both the changes in CF and cAMP were augmented compared to the nontreated hearts. The inhibitory effects of NE or Ca2+ remained unchanged. Propranolol abolished the NE but not the Ca2+ effects. It is suggested that PGE2 modulates the cardiac cAMP level and that the latter plays an important role in the adaptive regulation of the CF. It is also postulated that changes in cAMP levels may be brought about by the hyperactivity per se produced by a variety of cardiostimulating agents.

Myocardial Synthesis of Prostaglandin‐like Substances and Coronary Reactions to Cardiostimulation and to Hypoxia

“…During this period, the coronary flow normalized if a vasodilator effect of AA had appeared, and the MCD responses remained unchanged. A similar picture was obtained for PGE2 administration, confirming results of our previous studies (Sunahara & Talesnik, 1974;Sen et al, 1976). The slowness of AA in producing blockade of MCD may be ascribed to the buLild-Lip of a suitable intramyocardial cell concentration that would activate the prostaglandin-synthetase and induce the StLbsequent production of prostaglandins; the intracellular increase of prostaglandins would inhibit the adenylate cyclase activation induced by cardiostimulating agents (Sen et al, 1977).…”

“…In the present experiments, we administered AA in the perfusate and found that it stimulated the production of endogenous PGL. The subsequent coronary reactions to cardiostimulation or to hypoxia quite closely resembled the changes obtained when exogenous PGE2 was administered under similar experimental conditions (Sen et al, 1976).…”

“…We demonstrated in the mammalian isolated perfused heart that the increased coronary flow resulting from cardiac hyperactivity correlates with the activation of adenylate cyclase and we postulated that the increased cyclic AMP level in the heart triggered a vasodilatory mechanism that adapted the coronary flow to the increased oxygen demands (Sen et al, 1976;Sen et al, 1977). The increased myocardial contractility, heart rate and activation of adenylate cyclase due to NA (Robison, Butcher, Oye, Morgan & Sutherland, 1965) Ca2+ (Sen et al, 1976), tachycardia (Sen et al, 1977;Renyi-Vaimos, 1977) or glucagon (Bussuttil, Paddock, Fisher & George, 1976), are abundantly documented. We included glucagon in the present experiments because it has repeatedly been shown that its administration produces an increase in cardiac work, oxygen consumption and activation of the adenylate cyclase enzyme (Nayler, McInnes, Chipperfield, Carson & Daile, 1970) and because the increase in coronary flow after glucagon administration appears as a consequence of the metabolic effects due to the increased myocardial contractility (Von Tarnow, Gethmann, Patschke, Weymar & Eberlein, 1975).…”

“…The data presented in this paper support our contention that there are at least two types of coronary vasodilatation: one, in response to increased cardiac activity, would be modulated by endogenously synthesized prostaglandins while another, reactive hyperaemia, appears to be independent of prostaglandins. The excess cardiac synthesis of prostaglandins or lack of its metabolic degradation, could lead to a diminished adenylate cyclase activation and subsequent reduced levels of cyclic AMP necessary to trigger the mechanism responsible for MCD reactions (Sen et al, 1976;Sen et al, 1977). Thus, abnormally high levels of prostaglandin might be, at least in part, the underlying mechanism of coronary insufficiency reported in humans with normal coronary arteriogram (Neill, Judkins, Dhindsa, Metcalfe, Kassebaum & Kloster, 1972;Bamrah, Bahler and Rakita, 1974;Rocher, Fayard, Manin, Bens, Guermonprez, Vagner, Leclerc, Ourbak & Maurice, 1974;Lawson, Rosch & Rahimtoola, 1976;Rosenblatt & Selzer, 1977;Oliva & Breckinridge, 1977;Selzer, 1977).…”

“…The exogenous administration of prostaglandin E1 (PGE1) or E2 inhibits the MCD response to cardiostimulation and it has also been shown that this inhibition correlates with a diminution in the cardiac levels of adenosine 3',5'-cyclic monophosphate (cyclic AMP) induced by cardiostimulation (Sen et al, 1976). In addition, a distinction between MCD and 'reactive hyperaemia' responses was pharmacologically substantiated (Sen, Sunahara & Talesnik, 1977).…”