Effects of α‐adrenoceptor stimulation with phenylephrine in the presence of propranolol on force of contraction, slow inward current and cyclic AMP content in the bovine heart

Abstract

The mechanism of the cyclic AMP-independent positive inotropic effect of cardiac alpha-adrenoceptor stimulation was studied by analyzing the effects of phenylephrine on force of contraction, calcium-dependent slow action potentials and the slow inward current (Isi) in bovine ventricular trabeculae. The preparations were electrically driven at 0.3 Hz in the presence of propranolol 1 mumol 1(-1). Phenylephrine increased the force of contraction in a concentration-dependent manner (maximum about 200% of control at 30 mumol 1(-1). The effect was surmountably antagonized by phentolamine. The positive inotropic effect of phenylephrine was accompanied by a concentration-dependent increase in time to peak force and occurred without any detectable increase in cyclic adenosine 3',5'-monophosphate (cyclic AMP) levels. The positive inotropic effect of phenylephrine was accompanied by an increase in action potential duration both at 20% and 90% repolarization. Calcium-dependent slow action potentials were also prolonged by phenylephrine and there was a distinct increase in the maximal rate of depolarization (dV/dtmax) of these slow potentials. These effects were also completely reversible on washing and surmountably blocked by phentolamine. However, the increase in dV/dtmax was smaller than that of isoprenaline in concentrations producing similar inotropic effects. Voltage-clamp experiments with the single sucrose-gap method showed that the phenylephrine-induced increase in force of contraction was associated not only with an increase in peak slow calcium inward current, Isi max, but also with a delay in the inactivation of Isi. Outward currents were not detectably altered by phenylephrine. It is concluded that the alpha-adrenoceptor mediated, cyclic AMP-independent positive inotropic effects of phenylephrine in bovine cardiac muscle are associated with an increase in slow inward current. Additionally, the amount of calcium influx during excitation is probably increased by a delay in the inactivation of Isi. Both effects can explain the phenylephrine-produced prolongation of the action potential, and probably contribute to the positive inotropic effect of alpha-adrenoceptor stimulation. However, as the effect on dV/dtmax is smaller than that of isoprenaline, other (still unknown) mechanisms may also be involved.

Phorbol ester potentiates .ALPHA.1-adrenoceptor-mediated positive inotropic effect in rat papillary muscle.

“…2B). These results, thus, confirm the previous studies (13,14), showing that a, -adrenoceptor-mediated PIE occurs through potentiation of slow Ca2+ channels and further suggest that protein kinase C activation may be involved in this PIE. However, the fact that the increase in Ca2+ channel activity by PDBu requires concomi tant stimulation of a, -adrenoceptors suggests that coordinated interactions between IP3 and DAG-mediated signal transduction pathways may be necessary to elicit the full physiological response, as has been docum ented in other biological systems (15 …”

Selective and full β1‐adrenoceptor agonist action of a catechol derivative of denopamine (T‐0509) in the guinea‐pig cardiac muscle and trachea: comparison with denopamine, xamoterol and isoprenaline

“…Noradrenaline is a pI-selective agonist with potent a-adrenoceptor agonist activity, and this activity has been reported to induce positive inotropic action (Schumann et al, 1978;Bruchner et al, 1984) and cardiac hypertrophy (Simpson, 1985). Recently, P2-adrenoceptors in the human heart have been found to couple to adenylate cyclase and to mediate positive inotropic and chronotropic actions (Gille et al, 1985;Kaumann & Lemoine, 1987).…”

Role of α₁-Blockade in Congenital Long QT Syndrome

“…In animal models, the mechanism of the prolongation of the action potential caused by 1-adrenoceptor stimulation has been attributed to an increase in the L-type calcium current (ICa), 23 but subsequent studies have failed to demonstrate any effect of 1-adrenergic stimulation on ICa 24,25 and have instead demonstrated an 1-adrenergic inhibition of the outward (Ito) 24,26 and delayed rectifier potassium IK 24,27,28 currents. In the present study, the QT intervals in the stand- ing position and early recovery phase were prolonged, but that prolongation was inhibited by 1-blockade, which is consistent with studies in which 1-adrenergic stimulation prolonged the action potential duration.…”