Actions of adenosine and isoproterenol on isolated mammalian ventricular myocytes.

Abstract

SUMMARY. We investigated the effects of adenosine and isoproterenol on enzymatically dispersed ventricular myocytes from bovine and guinea pig hearts. Inrracellular stimulation of relaxed myocytes with regular srriation patterns and normal resting potential resulted in action potentials with full plateaus accompanied by contractions. Adenosine in concentrations up to 0.2 HIM had no significant effect on any of the action potential parameters or on the basal contractility. In contrast, in the same cells, adenosine effectively antagonized the stimulatory effect of isoproterenol. Isoproterenol (1-10 nM) prolonged the action potentials by 34-41%, displaced the plateau to more positive potentials, and caused a 3-fold increase in the extent of myocyte sarcomere shortening. In the presence of adenosine (5-50 HM), isoproterenol increased the action potential duration by only 8-9%, the shift of the plateau was nearly abolished, and the increase in the extent of myocyte sarcomere shortening was less than 10%. In some of the myocytes, isoproterenol (1-10 nM) induced depolarizing afterpotentials accompanied by aftercontractions. The afterdepolarizations occasionally reached threshold resulting in triggered sustained rhythmic activity. Adenosine (20-50 HM) not only reduced the amplitude of the afterdepolarizarions and aftercontractions, but also abolished the sustained rhythmic activity. We conclude, first, that isolated ventricular myocytes respond to isoproterenol and adenosine; second, that adenosine has no direct effect, but effectively antagonizes the stimulatory actions of isoproterenol; third, that findings are consistent with the ones reported for multicellular ventricular preparations; fourth, that adenosine concentrations required to attenuate the actions of isoproterenol are in the range of adenosine concentrations released by cardiac cells when oxygen availability is limited and/or demand is increased; and fifth, that endogenously released adenosine may modulate the electrophysiological and contractile effects of catecholamines. (Circ Res 53: 287-297, 1983) RECENTLY, adenosine has been recognized to antagonize specifically the inotropic, and some of the electrophysiological and metabolic, effects of catecholamines in ventricular myocardium (Schrader et al., 1977;Dobson, 1978;Baumann et al., 1981, Belardinelli et al., 1982.The observation that adenosine antagonizes the inotropic effect of tyTamine, but not the tyramineinduced release of norepinephrine, has been assumed to indicate that adenosine acts postsynaptically (Schrader et al., 1979). However, adenosine has also been shown to inhibit the stimulationinduced release of norepinephrine from sympathetic nerve terminals in the heart (Hedquist and Fredholm, 1976;Wakade and Wakade, 1978). Consistent with this latter finding, in the dog, adenosine has been shown to reduce the increase in heart rate induced by electric stimulation of the right stellate ganglion (Horn and Lokhandwala, 1981). These observations suggest that the antagonism between adenosine and sympa...

Characterization of adenosine receptors in intact cultured heart cells

“…These responses include negative chronotropic, dromotropic and ionotropic effects on the heart [7,8]. A 1 adenosine receptors in the heart also appear to mediate the attenuation of the positive inotropic effects of catecholamine [12,13,[41][42][43][44][45]]. Thus, the increased level of adenosine receptors following catecholamine treatment might act as an inhibitory feedback to protect heart cells from excessive contractions.…”

“…These effects of adenosine occur also without prior catecholamine treatment [10]. Stimulation that enhances the cAMP content (catecholamines, forskolin, amrinone), makes the heart more sensitive to adenosine [11][12][13][14]. In addition, adenosine causes hyperpolarization by activation of K + channels [15] via G proteins [16, 17].…”

The anti‐adrenergic effect of adenosine and its blockade by pertussus toxin: a comparative study in myocytes isolated from guinea‐pig, rat and failing human hearts

“…However, endogenous adenosine is not a problem when using isolated superfused myocytes. Previous work on the effects of adenosine in isolated cardiac myocytes has mainly involved cells isolated from rat (Hazeki & Ui, 1981;Martens et al, 1987;Henrich et al, 1987), guinea-pig (Belardinelli & Isenberg, 1983) and bovine (Belardinelli & Isenberg, 1983) hearts but not myocytes isolated from human heart tissue. This earlier work has characterized the adenosine receptor mediating the anti-adrenergic effect of adenosine as being of the A, subtype.…”

Antiarrhythmic effects of BN‐063, a newly synthesized adenosine A1 agonist, on myocardial ischaemia in rats

“…There was a highly significant correlation between adenosine and the stimulation of catecholamines in in vitro studies. Adenosine not only antagonizes isoprenaline-induced increases in ICa but also inhibits catecholamine induced ITi and triggered activity (Belardinelli & Isenberg, 1983;Fedida et al, 1987). It is likely that adenosine antagonism of catecholamine stimulated increases in ICa resulted from effects on intracellular cyclic AMP levels (Lerman & Belardinelli, 1990).…”

“…High local noradrenaline (NA) levels may be achieved by either local nonexocytotic release (Abrahamsson et al, 1985;Schomig et al, 1987) or exocytotic NA release due to activa-_ tion of cardiac sympathetic nerves (Lombardi et al, 1983;Zaza & Schwartz, 1985). However, catecholamine-induced increases in the inward calcium current (ICa) and transient inward current (ITi) (Belardinelli & Isenberg, 1983;Fedida et al, 1987) which have been implicated in the genesis of afterdepolarization and triggered activity, are potentially arrhythmogenic in the ischaemic heart. Myocardial ischaemia facilitates adenosine release which may reduce the consequences of impaired myocardial tissue perfusion.…”