Andreas Mügge

α-adrenoceptor-mediated positive inotropic effect of phenylephrine in isolated human ventricular myocardium

In isolated human ventricular myocardium the alpha-adrenoceptor agonist phenylephrine had a positive inotropic effect in preparations from 9 of 14 patients. This effect was seen in the presence of the beta-adrenoceptor-blocking agent propranolol but was nearly abolished by the alpha-adrenoceptor blocking agent prazosin. In contrast to the beta-adrenoceptor-mediated positive inotropic effect, the effect of phenylephrine was accompanied by a prolongation of the isometric contraction. The results suggest that alpha-adrenoceptors exist in human ventricular myocardium.

Functional evidence for the existence of adenosine receptors in the human heart

Adenosine added to isolated electrically driven preparations of human ventricular heart muscle antagonized the positive inotropic effect of isoprenaline (mean EC50 19 mumol 1(-1), n = 9). Similar effects were observed with the adenosine receptor agonist (-)-N6-phenylisopropyladenosine (mean EC50 0.5 mumol 1(-1), n = 7). These data provide functional evidence for the existence of adenosine receptors in the human myocardium which may modulate the force of contraction during beta-adrenergic stimulation and thus could be involved in the autoregulation of myocardial contractility.

Increased myocardial α1adrenoceptor density in rats chronically treated with propranolol

Abstract Chronic treatment with propranolol for 6 weeks resulted in a 16.6% increase, over the level in control rats, in myocardial α1-adrenoceptor density as measured by [3H]prazosin binding. The apparent affinity remained unaffected. No changes were observed in β-adrenoceptor density and apparent affinity as measured by [3H]dihydroalprenolol binding. It is concluded that myocardial α1-adrenoceptors might have a compensatory role under conditions where β-adrenergic effects are attenuated.

Effects of the beta2-adrenoceptor agonists fenoterol and salbutamol on force of contraction in isolated human ventricular myocardium

SummaryThe effects of fenoterol and salbutamol on isometric force of contraction were studied in isolated, electrically driven human papillary muscle preparations. Fenoterol increased force of contraction at concentrations of 1 µmol l−1 and higher. The maximally effective concentration of fenoterol (100 µmol l−1) increased force of contraction by about 130%. The positive inotropic effect of fenoterol was not influenced by 0.1 µmol l−1 prazosin. The beta1-selective antagonist atenolol (2 µmol l−1) and the beta2-selective antagonist ICI 118551 (1 µmol l−1) shifted the concentration-response curve of fenoterol to the right, indicating that beta1- and beta2-adrenoceptors may contribute to the positive inotropic effect of fenoterol. In contrast to fenoterol, salbutamol increased force of contraction only by about 11% at 100 µmol l−1. The results indicate that: (1) fenoterol exerts a direct positive inotropic effect in the human heart which may support the beneficial effects of the reduction of systemic vascular resistance in patients with congestive heart failure; (2) this positive inotropic effect of fenoterol is mediated by beta1- and beta2-adrenoceptors; (3) the clinically observed improvement of cardiac performance in the case of salbutamol is presumably not due to any direct positive inotropic effect.

Myocardial alpha-adrenoceptors and positive inotropy.

The positive inotropic effect (PIE) of beta-adrenoceptor stimulating agents in the mammalian heart is mainly due to an increase in slow Ca++ inward current (Isi) which in turn is probably the result of an increase in intracellular cAMP levels. The present paper is concerned with the alpha(probably alpha 1)-adrenoceptor-mediated PIE which differs from the response to beta-adrenoceptor stimulation in several points: it develops relatively slowly, is not accompanied by an abbreviation but instead by a prolongation of the contraction, is dependent on the frequency of stimulation, is increased in hypothyroidism and is not accompanied by detectable changes in cAMP and cGMP levels. In spite of the failure to elevate cAMP levels, alpha-adrenoceptor stimulation increases the magnitude, and decelerates the decay, of Isi. The alpha-adrenoceptor mediated increase in Isi is smaller than that of an equieffective (with respect to the PIE) concentration of isoprenaline. However, this effect conceivably contributes to the alpha-adrenoceptor-mediated PIE although other mechanisms (e.g. an increase in Ca++ sensitivity of the contractile proteins) are likely to be also involved. Recent experiments provide evidence that blockade of beta-adrenoceptors increases the density of myocardial alpha 1-adrenoceptors. This is in accord with the view that stimulation of alpha-adrenoceptors by endogenous catecholamines may serve as a reserve mechanism under conditions of impaired beta-adrenergic influence.

Alpha-Adrenozeptoren am Myokard: Vorkommen und funktionelle Bedeutung

Alpha-adrenoceptors mediating positive inotropic effects are well established in the heart of various species including human heart. The mechanism by which alpha-adrenoceptor stimulation increases force of contraction is not known. cAMP is unlikely to be involved as a mediator. Evidence has been presented that an increase in magnitude and duration of the slow Ca++ inward current may be partly responsible for the positive inotropic effect. In addition, stimulation of alpha-adrenoceptors may increase Ca++ sensitivity of the contractile proteins. Stimulation of alpha-adrenoceptors by endogenous catecholamines may serve as a reserve mechanism under various conditions of impaired beta-adrenergic influence, e.g. hypothyroidism, bradycardia or ischemia. Furthermore, alpha-adrenoceptors may be involved in the genesis of reperfusion arrhythmias in ischemic heart.SummaryAlpha-adrenoceptors mediating positive inotropic effects are well established in the heart of various species including human heart. The mechanism by which alpha-adrenoceptor stimulation increases force of contraction is not known. cAMP is unlikely to be involved as a mediator. Evidence has been presented that an increase in magnitude and duration of the slow Ca++ inward current may be partly responsible for the positive inotropic efffect. In addition, stimulation of alpha-adrenoceptors may increase Ca++ sensitivity of the contractile proteins. Stimulation of alpha-adrenoceptors by endogenous catecholamines may serve as a reserve mechanism under various conditions of impaired beta-adrenergic influence, e.g. hypothyroidism, bradycardia or ischemia. Furthermore, alpha-adrenoceptors may be involved in the genesis of reperfusion arrhythmias in ischemic heart.

Negative inotropic effects of aldosterone antagonists in isolated human and guinea-pig ventricular heart muscle

SummaryThe effects of K+-canrenoate (Aldactone® pro inj.) and its metabolite canrenone on isometric force of contraction were measured in isolated guinea-pig and human papillary muscle preparations driven electrically at a frequency of 1 Hz. In guinea-pig hearts both substances exerted a concentration-dependent negative inotropic effect; the IC50 of K+-canrenoate and canrenone were 129±22 µmol l−1 (n=5) and 85±11 µmol l−1 (n=12), respectively. At the maximally tested concentration canrenone (250 µmol l−1) and K+-canrenoate (1,000 µmol l−1) reduced force of contraction by 68±4% (n=12) and 83±3% (n=5), respectively. The negative inotropic effects of canrenone and K+-canrenoate were not affected by 10 µmol l−1 atropine. The negative inotropic effect of canrenone was also not affected by 14 µmol l−1 aldosterone, but canrenone (10 µmol l−1) diminished the maximal positive inotropic effect of dihydro-ouabain from 554±75% (n=4) to 269±39% (n=4) of the predrug value.In human heart muscles K+-canrenoate and canrenone also exerted a concentration-dependent negative inotropic effect. K+-canrenoate (1,000 µmol l−1) and canrenone (250 µmol l−1) reduced force of contraction by 57±7% (n=8) and 67±2% (n=6), respectively. A positive inotropic effect of both substances was never observed.It is concluded that the improvement of cardiac performance after application of aldosterone antagonists observed in patients cannot be explained by a direct effect on the heart. K+-canrenoate and canrenone are devoid of any direct cardiotonic action. Instead, K+-canrenoate and canrenone have direct negative inotropic effects at high concentrations.

Effects of (−)-Phenylephrine on force of contraction in the presence of cocaine and hydrocortisone in cat papillary muscle

SummaryThe positive inotropic effect of (−)-phenylephrine, in the presence of propranolol, was studied after inhibition of neuronal and extraneuronal uptake in isolated papillary muscles from reserpine-pretreated cats. An inhibition of extraneuronal uptake with hydrocortisone influenced the effect of (−)-phenylephrine neither when present alone nor in the presence of cocaine (additional inhibition of neuronal uptake). An inhibition of neuronal uptake with cocaine caused a small but significant increase in the potency of (−)-phenylephrine. We conclude that in cat ventricular cardiac muscle the extraneuronal compartment is apparently neither a “site of loss” nor a “site of gain” for (−)-phenylephrine with respect to force of contraction.