Notes: Summary Experiments on isolated organs-rabbit ileum, guinea-pig trachea and atrium — with different “β-receptor subtypes” were carried out in order to determine whether changes of the metabolic state or of the extracellular pH were able to alter the responsiveness of these receptors to sympathomimetic amines. 1. Guinea-Pig Atrium. Lowering of the pH of the bath fluid from 7.48 to 6.79 resulted in a significant decrease of the affinity of isoprenaline (IPN) calculated as the pD2-value. Metabolic inhibition induced by iodoacetic acid (IAA) (5×10−5 M) increased the affinity of Th 1165a. 2. Rabbit Ileum. The affinity of IPN was not changed by lowering the pH, even to values of 6.11. At this pH the spontaneous motility was already markedly impaired. IAA (2.4×10−5 M) caused a moderate increase in the affinity of IPN whereas those of Th 1165a and orciprenaline (OPN) were elevated 10-fold. 3. Guinea-Pig Trachea. Lowering of the pH caused a decrease of the pD2-values of IPN and in particular of Th 1165a. The metabolic inhibitor IAA had no influence upon the pD2 value of IPN. 4. The present results favour the existence of only one type of β-receptor which changes its sensitivity depending on the metabolic state. It seems therefore very likely that the affinity of sympathomimetic drugs depends not only on the structure of the β-receptor but also on the metabolic state of the tissue.

Notes: Summary In isolated electrically driven right auricular strips of human hearts (1 Hz at 37°C) the ability of the endogenous catecholamines noradrenaline, adrenaline, and dopamine to mediate positive inotropic effects by stimulation of myocardial α-adrenoceptors was investigated. 1. The concentration-response curve for the positive inotropic effect of noradrenaline was shifted to the right by pindolol, 10−8M, whereas the additional blockade by phentolamine, 3×10−6M, was without further effect; therefore, the positive inotropic effect of noradrenaline is mediated by β-adrenoceptors only. 2. In contrast, the positive inotropic effects of adrenaline as well as of dopamine are caused by stimulation of both, β- and α-adrenoceptors. 3. These results are discussed with respect to the possible physiological and pathophysiological function of myocardial α-adrenoceptors.

Notes: Summary The presence and distribution of myocardial α-adrenoceptors in different parts of the heart of various mammalian species was investigated. For this reason experiments were performed in isolated cardiac preparations of rats, guinea pigs and cats. In order to obtain more information about the nature of the cardiac α-adrenoceptors additional experiments were undertaken at different temperatures. These studies were aimed to show whether or not a conversion of β-to α-adrenoceptors or vice versa takes place. Moreover, we analyzed the influence of hypothyroidism on the sensitivity of α- and β-adrenoceptors of preparations from rats fed with propylthiouracil. Finally, we tried to find out whether stimulation of these α-adrenoceptors leads to the formation of the cyclic nucleotides cAMP and cGMP. The following results were obtained: 1. In right ventricular strips of rats, guinea pigs and cats phenylephrine stimulated α-adrenoceptors. After blockade of β-adrenoceptors the respective pD2-values of phenylephrine were 5.32, 5.99 and 5.33. The doseresponse curves obtained in the presence of α-adrenolytic drugs were shifted to the right without depression of the maximum. In the rat, in addition, the pA2-values for the α-adrenolytic drugs yohimbine (5.79) and phentolamine (7.85) were determined. They were at least 0.5 log units higher than those found in the rat for other α-adrenoceptors (Van Rossum, 1965) thus supporting the view that the population of cardiac α-adrenoceptors is different from that of other organs. In left ventricular strips of guinea pigs the pD2-value for the α-mimetic effect of phenylephrine was of the same order of magnitude as that obtained in the right ventricle. 2. In the papillary muscle of the right ventricle of guinea pigs and cats phenylephrine stimulated α-adrenoceptors. 3. In the left atrium of the rat, phenylephrine stimulated myocardial α-adrenoceptors (pD2: 5.58). Also in this preparation the pA2-values for yohimbine (6.36) and phentolamine (8.21) were different from those found for other α-adrenoceptors in the rat (Van Rossum, 1965). Likewise in strips from the left atrium of the cat myocardial α-adrenoceptors are present. 4. In spontaneously beating right atria of the rat a clear-cut positive chronotropic effect mediated by stimulation of α-adrenoceptors could not be demonstrated although in 6 out of 15 preparations a small positive chronotropic effect became evident. No positive chronotropic effect at all was obtained by stimulation of α-adrenoceptors in the cat right atrium. 5. In ventricular strips as well as in left atria from hypothyroid rats the pD2-value for the α-effect of phenylephrine was increased, in the atrium more than in the ventricle, while the pA2-values for yohimbine and phentolamine were not significantly different from the controls. Under these conditions a distinct positive chronotropic effect mediated by stimulation of α-receptors was found in the spontaneously beating rat atrium. 6. After stimulation of α-adrenoceptors in atria and ventricular strips of normal and propylthiouraciltreated rats, as well as in strips of guinea-pig ventricles or cat atria no elevation of cAMP and cGMP was observed. 7. The concept of a single adrenoceptor convertible from α- to β-type or vice versa was not supported by our experiments. These were carried out at different temperatures on left atria and on ventricular strips of rat hearts using the irreversible α-adrenoceptor blocking agent phenoxybenzamine. 8. The present experiments provide evidence for the existence of α-adrenoceptors in the myocardium of various mammalian species. Their stimulation produces positive inotropic effects without increases in heart rate.

Notes: Summary Under the conditions of altered temperature or metabolic inhibition experiments have been carried out on isolated organs with adrenergic α- and β-receptors, i.e., on rabbit ileum and guinea-pig vas deferens and atrium. Using phenylephrine as a selective α-adrenergic stimulant we were interested to determine whether or not an alteration of the metabolic conditions was capable of causing changes in the affinity of phenylephrine which were identical for the α- and β-receptors. 1. Rabbit Ileum. At 25°C the affinity of phenylephrine to the inhibitory adrenergic α-receptors was 100 times higher than to the β-receptors. Its affinity to the α-receptors was not influenced by raising the temperature or inhibiting the metabolic rate by iodoacetic acid (IAA), whereas that to the β-receptors was diminished to a great extent by raising the temperature. Preincubation at 42°C with the metabolic inhibitor IAA increased the affinity to β-receptors so that it was similar to that at 25°C. 2. Vas Deferens. The excitatory α-mimetic effect of phenylephrine was similarly unaltered by raising the temperature of the bath from 25° to 42°C. IAA did not affect responses to phenylephrine. 3. Guinea-Pig Atrium. An increase of the temperature from 25° to 42°C significantly decreased the affinity of phenylephrine to the β-receptors, whereas IAA at 42°C increased it almost to control values at 25°C. 4. The experiments show that the sensitivity of α-receptors is not altered by an increase of temperature irrespective of whether the α-receptors are mediating inhibitory or excitatory effects, whereas that of the β-receptors is depressed. These results favour the hypothesis that stimulation of α-receptors is independent of, while that of the β-receptors is strongly dependent on the metabolic rate.

Notes: Summary The β-sympathomimetic effect of phenylephrine was investigated on the electrically driven atrium, as well as on the tracheal chain of the guinea pig. 1. Phenylephrine (PE) was found to be less effective than isoprenaline (IPN) with regard to its positive inotropic effect on the guinea-pig atrium and to its relaxing action on the tracheal chain. The intrinsic activity for PE amounted to 0.75 on the tracheal chain and to 0.45 on the atrium, when compared with IPN. 2. From these low intrinsic activities, PE was assumed to be a partial β-agonist, exerting a competitive dualism in action to IPN. This dualism could be confirmed by dose-response curves for PE in the presence of IPN and vice versa: PE behaved as a β-agonist as well as a β-antagonist. 3. The intrinsic activity of PE steadily decreased with prolongation of the incubation period. After 1 h PE had almost lost its intrinsic activity. Under these conditions the dose-response curves for IPN on the tracheal chain, as well as on atrium, were shifted to the right in a parallel manner, i.e. PE behaved as a competitive β-antagonist. 4. High concentrations of PE (10−3 M) protected the electrically driven guineapig atrium against arrhythmias induced by k-strophanthoside. The onset of both the first extrasystoles and of heart standstill, which occurred after infusion of k-strophanthoside, were delayed after preincubation with PE. 5. Phentolamine was without any influence on these antiarrhythmic properties of PE. Therefore, it could be excluded that the antiarrhythmic effect of phenylephrine is due to a stimulation of myocardial α-adrenoceptors. 6. The local anaesthetic activity of phenylephrine, as tested on the rabbit cornea, was 4 times higher than that of propranolol. 7. The effective concentrations for the β-adrenolytic, antiarrhythmic, and local anaesthetic activities of PE were clearly different. We concluded, therefore, that the different actions produced by phenylephrine were not associated with each other.