The inotropic actions of adrenaline on frog ventricular muscle: relaxing versus potentiating effects

Abstract

SUMMARY1. In frog ventricle, adrenaline increases the size ofthe action potential, potentiates twitch tension, and enhances relaxation. Because tension development is directly controlled by membrane potential in frog ventricle, experiments were designed to separate the effects of adrenaline on the action potential from its effects on the development of tension.2. Comparison of the tension-voltage relations in the presence and absence of adrenaline showed that during the initial portion of the voltage clamp step, adrenaline potentiated tension, but beyond 1 sec into the clamp pulse tension was depressed.3. The time and voltage dependence of the positive inotropic effect of adrenaline during voltage clamp pulses were compatible with the kinetics of the slow inward current, which is known to be augmented by adrenaline in frog and mammalian ventricle.4. Ni2+, which has been shown to block the slow inward current in frog ventricle, also inhibited the positive inotropic effect of adrenaline.5. The relaxant effect ofadrenaline was demonstrated to be present at least as early as 600 msec after the onset of membrane depolarization. However, generally 1 sec or more of membrane depolarization was required before the relaxant effect of adrenaline predominated over its positive inotropic effect.6. In catecholamine depleted strips, the augmentation of the action potential and twitch tension in the presence of adrenaline was found to occur at a sixty-fold lower concentration than the relaxant effect as judged by suppression of KCl-induced contractures.7. Pure fl-receptor agonists reproduced completely the electromechanical effects of adrenaline on the frog ventricle. a-receptor agonists or antagonists had no effect on action potential or development of tension.8. Cyclic AMP and dibutyryl cyclic AMP were found to augment the frog ventricular action potential and potentiate twitch tension in reserpinized or f-blocked 9. Theophylline produced changes in the action potential similar to those induced by adrenaline and mimicked both the positive inotropic and relaxant effects of the drug.10. The results suggest that the positive inotropic effects of adrenaline results mainly from changes induced in the action potential plateau. The changes are both time and voltage dependent, and if inhibited, leave the relaxant effect of adrenaline unopposed.11. The findings are consistent with a cyclic AMP-mediated mechanism of the positive inotropic effect of adrenaline. However, the role of cyclic AMP in mediating the relaxant effects of adrenaline is less clear.

A modulatory octopaminergic neurone increases cyclic nucleotide levels in locust skeletal muscle.

“…Increased levels of cyclic AMP have also been shown to be involved in the mediation of the actions of catecholamines on vertebrate muscle, including smooth muscle (Janis & Diamond, 1979;Schultz, Bohme, Kneye & Schultz, 1979), cardiac muscle (Reuter, 1974;Morad, Sanders & Weiss, 1981) and skeletal muscle (Bowman & Nott, 1974;Gonzalez-Serratos, Hill & Valle-Aguilera, 1981). The exact responses of vertebrate skeletal muscle, however, vary with the proportion of fast and slow muscle fibres in the muscle (see Bowman & Zaimis, 1958;Bowman & Nott, 1969;Bowman, 1982).…”

Regulation of cardiac sodium-calcium exchanger by beta-adrenergic agonists.

“…On the other hand, the phosphorylation of phospholamban and the subsequent stimulation of Ca2+ pump (5)(6)(7), in addition to decreased myofilament Ca2+ sensitivity (8)(9)(10), are thought to mediate the relaxant properties of 13-agonists. Quite similar to the mammalian myocardium, the frog heart also exhibits some of the characteristic features associated with the (3-agonist response, namely potentiation of phasic contraction (twitch) followed by enhanced inhibition of maintained (tonic) tension (11)(12)(13)(14). In light of recent reports suggesting low content of Ca-ATPase (15,16), absence of mRNA message for CaATPase (17), and lack of functionally significant Ca2+-release stores (18)(19)(20)(21)(22) in the frog heart, the (3-agonist tensionsuppressant effect is surprising and unexpected if its similarity to the mammalian heart is solely mediated by the cAMPinduced phosphorylation of the phospholamban.…”

“…This mechanism, which results in a decreased Ca2+1oad on the cardiac myocytes during experimentally or hormonally induced prolonged membrane depolarizations, may be responsible for catacholamine-induced suppression of KCl-induced contractures (11,13,14) and uncoupling of the duration of contraction and the action potential (11,13,14), resulting in enhanced relaxation of the twitch.…”

Myocardial relaxation. V. Postextrasystolic contraction-relaxation in the intact dog heart.

“…'8 Catecholamines promote deactivation and thus have a relaxing effect on cardiac muscle, presumably by augmenting calcium uptake by the sarcoplasmic reticulum. 19 In the intact dog heart, both systolic load and the deactivation process probably influence relaxation velocity. Because relaxation velocity was unchanged in the postextrasystolic beat under mechanical conditions that should have enhanced relaxation, it appears that deactivation must have been slowed in the postextrasystolic beat.…”