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Electrically driven (1 Hz) ventricular trabeculae from explanted failing human myocardium were indirectly examined for the localization of the alpha1-adrenoceptor population and the beta-adrenoceptor population in relation to sympathetic nerve endings. We examined the influence of neuronal uptake blockade by cocaine upon the horizontal position of the concentration-response curves for the inotropic effects exerted by noradrenaline in the presence and absence of appropriate adrenoceptor antagonists. Cocaine shifted the concentration-response curve for alpha1-adrenoceptor stimulation, but not that for beta-adrenoceptor stimulation, to lower concentrations of noradrenaline in a parallel manner. The concentration-response curve for combined adrenoceptor stimulation was shifted by cocaine to lower concentrations of noradrenaline in a nonparallel manner. In explanted allograft heart, cocaine had no effect upon the position of the concentration-response curve to alpha1-adrenoceptor stimulation. The data indicate that in the explanted native hearts the alpha1-adrenoceptor population is located close to or within the synaptic cleft, while the beta-adrenoceptor population remaining in the failing myocardium is located more distantly to the neuronal release sites.

The purpose of our study was to investigate the inotropic response to the endogenous agonist norepinephrine mediated through alpha-1 adrenoceptors and to compare this response to that mediated through beta-adrenoceptors in failing human ventricular myocardium. We studied ex vivo the inotropic effect of norepinephrine in isometrically contracting trabecular myocardium from both ventricles of explanted hearts. By studying influence of appropriate adrenoceptor blockers, qualitative characteristics of the inotropic response and sensitivity of the inotropic response to cholinergic stimulation, it was revealed that norepinephrine evoked both alpha-1 and beta adrenoceptor-mediated inotropic effects in failing human ventricle myocardium. Quantitatively the inotropic responses to norepinephrine varied markedly between preparations, but the mean responses elicited through the respective adrenoceptor systems were of comparable magnitude. Concomitant stimulation of alpha-1 and beta adrenoceptors by norepinephrine alone revealed a contribution of an alpha-1 adrenoceptor-mediated component to the final and unopposed inotropic response. Differential sensitivity of the two adrenoceptor systems to norepinephrine depending on etiology of heart failure and possibly also thyroid status was observed. It is concluded that norepinephrine evokes an alpha-1 adrenoceptor-mediated inotropic effect comparable to that evoked through the beta adrenoceptors in failing human ventricular myocardium, and that this alpha-1 adrenoceptor-mediated inotropic effect may be of functional importance.

It has been a matter of controversy whether alpha 1-adrenoceptor stimulation contributes to the final inotropic and lusitropic responses in mammalian myocardium to noradrenaline during concomitant and unopposed beta-adrenoceptor stimulation. In the present paper we report studies that compare time courses of the inotropic and lusitropic responses to separate and combined alpha 1- and beta-adrenoceptor stimulation, respectively, in electrically driven rabbit papillary muscles by a submaximal concentration of noradrenaline. Separate alpha 1- or beta-adrenoceptor stimulation (presence of appropriate receptor blocker) showed the characteristic slow and fast development, respectively, of the inotropic responses. Qualitatively, the respective characteristic changes were also observed: alpha 1-adrenoceptor stimulation caused a negative lusitropic effect giving a prolongation of the time to peak tension (TPT), while beta-adrenoceptor stimulation caused a pronounced positive lusitropic effect giving a shortening of TPT. The time course of the inotropic response to combined adrenoceptor stimulation had characteristics that deviated from the respective time courses to separate alpha 1- or beta-adrenoceptor stimulation thus indicating a contribution from both adrenoceptor populations to the final inotropic response. Combined alpha 1- and beta-adrenoceptor stimulation gave a pronounced positive lusitropic response as might be expected due to the obviously dominating role of the beta-adrenergic component. However, the maximal lusitropic effect and the shortening of TPT were both slightly less during combined adrenoceptor stimulation compared to separate beta-stimulation thus indicating an influence of the alpha 1-adrenoceptor mediated negative lusitropic effect. Quantitatively, the separate alpha 1- and the separate beta-adrenoceptor mediated inotropic effects were not additive. In accordance with other recent studies, this indicated an inhibitory interaction between the two adrenergic receptor populations in myocardium.

Earlier experiments have usually failed to demonstrate a competitively displaceable alpha adrenoceptor blocker-sensitive component in the dose-dependent inotropic response to norepinephrine in mammalian hearts. We reinvestigated if it was possible to reveal this phenomenon by carefully choosing a concentration of the alpha adrenoceptor blocker prazosin that would give a significant displacement while it still was possible to completely surmount the blockade by reasonable concentrations of norepinephrine. Both inotropic and lusitropic dose-dependent responses to norepinephrine in rabbit heart papillary muscles were recorded. In the presence of 3 X 10(-9) M prazosin there was a significant rightward shift of a component corresponding to about 20% of the total inotropic response to norepinephrine. The prazosin-sensitive component was shifted significantly more to the left by 3 X 10(-5) M cocaine than the nonsensitive component. The maximal inotropic response to norepinephrine was increased at lower prazosin-concentrations (3 X 10(-9) M), whereas at 10(-7) M prazosin the maximal response was unchanged compared to the absence of prazosin. The maximal lusitropic response to norepinephrine was increased monophasically and dose-dependently by prazosin. Thus, by carefully considering the relative potencies of the agonist and the antagonist it was possible to demonstrate an alpha adrenoceptor blocker sensitive component in the inotropic response to norepinephrine in rabbit heart. The effect of cocaine upon the prazosin-sensitive component would indicate that the alpha adrenoceptor population in rabbit myocardium is located more closely to the sympathetic nerve endings than the beta adrenoceptor population.(ABSTRACT TRUNCATED AT 250 WORDS)

The studies presented deal with the alpha 1-adrenoceptor mediated inotropic effects of noradrenaline obtained by exclusive ("pure") alpha 1-adrenoceptor stimulation or by concomitant stimulation of alpha 1- and beta-adrenoceptors in myocardium. The pure beta-adrenergic effects of noradrenaline were also quantified. Interactions between the two receptor systems were studied. The pure alpha 1- and beta-adrenergic effects of noradrenaline, respectively, were achieved separately in the presence of high concentrations of appropriate receptor blockers. The experiments were performed on isolated ventricular myocardium from rat, rabbit, and man. The pure alpha 1-adrenergic inotropic effects were about 35-50% of control (basal) and half the pure beta-adrenergic effects both in rat and rabbit myocardium. Ventricular myocardium from man exhibited an alpha 1-adrenergic inotropic effect of the same magnitude (50% of control [basal]) as did rabbit papillary muscle. Determination of the alpha 1-adrenergic inotropic component during concomitant beta-adrenoceptor stimulation was associated with difficulties. Several experimental approaches on rat and rabbit myocardium are presented and discussed. Some types of experimental approaches obviously underestimate the alpha 1-adrenergic component. The methods regarded as reliable revealed an alpha 1-adrenergic inotropic effect of about 20-30% during combined adrenoceptor stimulation by noradrenaline. Concomitant beta-stimulation reduced the alpha 1-adrenergic effect by about 50%, while alpha 1-stimulation attenuated the beta-effect to a lesser degree (about 20-25%). A model is presented on a mutual attenuation of the functional expression of the two receptor systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Other investigators have claimed that norepinephrine does not evoke a significant alpha adrenergic inotropic effect in rabbit ventricular myocardium in contrast to some other mammalian species, indicating an important functional limitation of the cardiac alpha adrenoceptors. We therefore characterized the inotropic effects of norepinephrine in isometrically contracting rabbit papillary muscles. We studied both contraction and relaxation by measuring developed tension and its first and second derivatives. Both the influence of propranolol and prazosin on concentration-effect curves of norepinephrine and the qualitative characteristics of the responses revealed that norepinephrine evoked both alpha and beta adrenergic inotropic effects. The alpha adrenergic response to norepinephrine was qualitatively markedly different from the beta adrenergic effect and qualitatively similar to the alpha adrenergic effect of phenylephrine which was also characterized for comparison. Although the alpha adrenergic response to norepinephrine was marked, the beta adrenergic effect was the dominating one when norepinephrine was administered alone. Thus, the beta adrenergic effect had to be extensively blocked to reveal the prazosin-sensitive alpha-1 adrenergic response. It is concluded that also in rabbit papillary muscles, norepinephrine evokes inotropic effects through both alpha and beta adrenoceptors.

It has been claimed by other investigators that norepinephrine does not evoke a significant alpha adrenergic inotropic effect in human atria in contrast to epinephrine and phenylephrine, indicating a limitation of a possible functional role of the cardiac alpha adrenoceptors. We therefore characterized the inotropic effects of norepinephrine in isometrically contracting muscle strips from human atria obtained during open heart surgery. Both contraction and relaxation were studied by measuring developed tension and its first and second derivatives. Both the influence of propranolol and prazosin upon the inotropic responses to norepinephrine and the qualitative characteristics of the responses revealed that norepinephrine evoked both alpha and beta adrenergic inotropic effects. The alpha adrenergic response to norepinephrine was qualitatively different from the beta adrenergic effect and qualitatively similar to the alpha adrenergic effect of norepinephrine observed in other mammalian species. Although the alpha adrenergic effect was marked, the beta adrenergic effect was the dominating one as has also been found in other species. It is concluded that also in human atria norepinephrine evokes inotropic effects through both alpha and beta adrenoceptors.