Coronary Reactions to Cardiac Hyperactivity and to Hypoxia in Isolated Perfused Heart of Rat

Abstract

I Continuous recording of cardiac force of contraction, heart rate and coronary flow from isolated perfused hearts of rats was used to study coronary reactions: (a) to cardiostimulation with noradrenaline, CaCl2, or electrically induced tachycardia; (b) to short duration stoppage of coronary inflow (hypoxia). 2 The heart rate was controlled by electrical pacing. Coronary vasodilatation resulted from cardiostimulation or hypoxia. This coronary response was greater at higher heart rates. 3 In parallel experiments administration of noradrenaline to hearts paced at different frequencies resulted in a rate-dependent elevation of adenosine-3',5'-cyclic monophosphate (cyclic AMP). 4 Duration of hypoxia leading to different degrees of reactive hyperaemia did not change the cardiac cyclic AMP levels. SCoronary vasodilatation due to increased cardiac metabolism produced by noradrenaline, Ca2+ or tachycardia was enhanced by the phosphodiesterase inhibitors diazoxide and papaverine while it was inhibited during the administration of prostaglandin E2. 6 Reactive hyperaemia was unaffected by diazoxide, papaverine or prostaglandin E2. 7 Catecholamine depletion by reserpine did not influence metabolic coronary dilatation nor the reactive hyperaemic responses. 8 We postulate that there are at least two types of coronary reactions: one in response to hypoxia, 'reactive hyperaemia', and another resulting from cardiac hyperactivity, 'metabolic coronary dilatation'. The latter, blocked by prostaglandin E2 and enhanced by diazoxide or papaverine, would be triggered by cyclic AMP while reactive hyperaemia would result from other mechanisms.

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

“…The mechanism responsible for the diminution in coronary resistance in response to increased cardiac metabolism, although it correlates with the levels of cardiac cyclic AMP, remains unknown (Sen et al, 1977). In the present paper, we give data confirming that MCD can be induced by NA, Ca2", tachycardia and also by glucagon.…”

“…Vasodilatation due to AA has also been reported by Needleman (1976) who explains its transient action to 'rapid washout' of the newly synthesized PGL produced by the heart. Although at the moment we do not have a better explanation to offer, Needleman's suggestion is not particularly convincing since AA, the availability of which is the rate-limiting step for prostaglandin synthesis, was continuously offered as a substrate; on the other hand we have already shown, and confirmed in the present paper, that prolonged exogenouLs administrationi of PGE2 also produced a coronary vasodilatation that subsided after some minutes of infusion (Sen et al, 1977).…”

“…Sudden increases in heart rate from the basic pacing of 210 beats/min to 270 or 300 beats/min for 30 s, were also followed by heart rate-dependent increases in coronary flow; the latter coronary reaction is also included under the term MCD (Sen et al, 1977). Reactive hyperaemia, induced by brief interruption of the inflow, was also tested and an example of the results obtained in these experiments is shown in Figure 1 Figure 1 and paired analysis of the results are shown in the bar graph of Figure 2.…”

“…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 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).…”