H. J. Schümann

Wirkung von Angiotensin auf Funktion und Noradrenalinabgabe isolierter Kaninchenherzen in Ruhe und bei Sympathicusreizung

Summary1.The influence of angiotensin on the isolated rabbit heart perfused at constant pressure or constant flow was investigated at rest and during electrical stimulation of the postganglionic sympathetic nerves.2.In low concentrations (32–100ng/min or 1.4–5.3 ng/ml) angiotensin had considerable positive inotropic effects, while its chronotropic effects were weak and variable. High concentrations decreased the rate of beat, and an increase in the height of contraction was preceded by a transient phase of inhibition. In hearts perfused at constant pressure, angiotensin diminished coronary flow. The positive inotropic effect of angiotensin was not accompanied by the appearance of increased amounts of noradrenaline in the venous effluent.3.Angiotensin caused a dose-dependent increase in the output of noradrenaline induced by sympathetic nerve stimulation. The peptide was most potent in hearts perfused at constant flow; the threshhold dose of angiotensin for this procedure was 3.2 ng/min (128 pg/ml), and maximal effects (i.e., an increase by 81%) were observed with 32 ng/min (1.28 ng/ml). Doses about three times higher were required to obtain similar effects in hearts perfused at constant pressure. The reduction of coronary flow as seen under these conditions may be responsible for the weaker effect of angiotensin. Continuous infusion increased the output of noradrenaline during several successive stimulation periods.4.In most cases, the increase in output of noradrenaline induced by angiotensin did not lead to an increase in the response of the pacemaker or of the myocardium to sympathetic stimulation. Only in hearts perfused at constant flow during infusion of 32 ng/min of angiotensin the positive inotropic effect of sympathetic stimulation was significantly augmented.5.The results indicate that angiotensin may modulate the activity of the autonomic nervous system by influencing peripheral sympathetic nerves.

Interactions of angiotensin, phenoxybenzamine and propranolol on noradrenaline release during sympathetic nerve stimulation

Abstract In isolated rabbit hearts, angiotensin, phenoxybenzamine, cocaine and propranolol increased the overflow of noradrenaline caused by sympathetic nerve stimulation. After the outflow of transmitter had been raised by propranolol, angiotensin caused a further increase indistinguishable from that observed in non-pretreated hearts. The potentiation of overflow by cocaine was prevented in propranolol-treated hearts. After the outflow of noradrenaline had been augmented by phenoxybenzamine, addition of angiotensin did not result in a further increase. It is proposed that phenoxybenzamine and angiotensin share a common mechanism of action, i.e. an increase of the amount of the adrenergic transmitter liberated per stimulus from the nerve terminals.

Influence of temperature on the sensitivity of the -receptors and the contractility of guinea-pig atrium.

SummaryUsing electrically stimulated guinea-pig atria the influence of temperature on the contractility and on the efficacy of some β-sympathomimetic and-lytic drugs, was studied. The following results were obtained.1.Raising the temperature of the bath fluid from 25–42°C decreased significantly the developed amplitude of contraction under control conditions, whereas dT/dtmax values were not altered. The maximal developed tension induced by the sympathomimetic drugs decreased at 42°C. The corresponding dT/dtmax values, on the other hand, were increased by elevation of the temperature.2.The dose-response curves of the sympathomimetic drugs isoprenaline (IPN), Th 1165a and orciprenaline (OPN) were shifted to the right when the temperature was increased from 25–42°C. The affinity of IPN at 33°C was found about 30- and 100-times higher than that of Th 1165a and OPN, respectively.3.The β-adrenolytic drug pindolol (LB 46), as well as the cardioselective β-blocker, practolol, antagonized the β-sympathomimetic effects evoked by IPN and Th 1165a in a competitive manner. As indicated by the pA2 values, pindolol had a 100-times higher affinity than practolol. The present results lead to the conclusion that, on the guinea-pig atrium, the agonist β-receptor reaction depends on the metabolic rate of this organ.

Interactions of inhibitors of noradrenaline uptake and angiotensin on the sympathetic nerves of the isolated rabbit heart.

1 The interaction of angiotensin and several inhibitors of the uptake of noradrenaline across the neuronal membrane (cocaine, desipramine, protriptyline, and pronethalol) on the output of noradrenaline produced by sympathetic nerve stimulation has been studied in the isolated perfused rabbit heart. 2 Most of these drugs increased noradrenaline outflow—angiotensin, for example, by 175%. Cocaine (10−4m) did not change the amine overflow, probably because this very high concentration inhibited not only the re‐uptake but also the liberation of noradrenaline. 3 Desipramine, protriptyline, and pronethalol, although infused in concentrations which enhanced the noradrenaline output, were not able to impair the angiotensin‐induced increase of transmitter overflow. In the presence of cocaine (10−4m) the increase elicited by angiotensin was slightly reduced, though lower concentrations of cocaine, as previously described, do not interfere with the effect of angiotensin. 4 In contrast to the interaction between uptake inhibitors and angiotensin, the augmented output of noradrenaline caused by an uptake inhibitor could not be increased further by infusion of a second uptake inhibitor. 5 It is concluded that the increase of the outflow of noradrenaline during sympathetic nerve stimulation by small doses of angiotensin is not caused by an inhibition of re‐uptake. On the contrary, the transmitter liberation seems to be facilitated. This is a novel principle of drug action on the sympathetic nerve terminals.

The influence of angiotensin on the uptake of noradrenaline by the isolated heart of the rabbit

The influence of angiotensin on the removal of noradrenaline (10 ng/ml) from the perfusion medium and on the net‐uptake of noradrenaline (5 and 20 μg/ml) was examined in the rabbit isolated heart. Concentrations of angiotensin, known to augment the output of noradrenaline from rabbit heart during sympathetic nerve stimulation, did not inhibit the removal of infused noradrenaline from the perfusion fluid. Only very high concentrations of angiotensin (13 μg/ml) significantly diminished the loss of noradrenaline. The positive inotropic effect of noradrenaline was not potentiated by angiotensin. On the other hand, cocaine, in doses which enhance the output of noradrenaline during sympathetic stimulation greatly reduced the loss of noradrenaline from the perfusion fluid. Neither angiotensin (130 ng/ml) nor metanephrine (5 and 20 μg/ml) significantly influenced the net‐uptake of noradrenaline from high concentrations. The observations made support the assumption that an increase of transmitter liberation rather than inhibition of transmitter inactivation is responsible for the increase caused by angiotensin in the output of noradrenaline during stimulation of sympathetic nerves.

Influence of peptides on the output of noradrenaline from isolated rabbit hearts

Abstract In the isolated rabbit heart, the effects of angiotensin, vasopressin and mechanical reduction of coronary flow on the output of noradrenaline caused by sympathetic nerve stimulation were investigated. Both mechanical diminution of flow by 25–75% and infusion of Arg 8 -or Lys 8 -vasopressin (1–25 mU/min) decreased the output of noradrenaline. However, angiotensin (10 – 100 ng/min) augmented the output of transmitter. The regression equations relating changes of coronary flow to those of noradrenaline output were calculated for the three groups of hearts. Positive correlations with similar slopes were found for vasopressin and mechanical reduction of flow, while there was a negative correlation for angiotensin. - If coronary flow was diminished then the percentage of infused noradrenaline eliminated from the perfusion medium by the heart was significantly augmented. Vasopressin probably decreases the output of noradrenaline by reducing the coronary flow and consequently favouring the retention of the transmitter. Although the same mechanism may contribute to the effect of angiotensin, the output of noradrenaline is not reduced, but is enhanced by some specific interaction with adrenergic nerve function.

Sensitivity changes of adrenergic -receptors induced by alterations of the metabolic state of isolated organs.

SummaryExperiments 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.

Beeinflussung der Noradrenalinabgabe aus isolierten Kaninchenherzen durch Β-Adrenolytica unter sympathischer Nervenreizung

SummaryUsing isolated rabbit hearts with sympathetic nerve supply we have studied the influence of LB 46, (−)- and (+)-INPEA, (−) and (+)-propranolol on the output of noradrenaline evoked by electrical stimulation of the sympathetic nerves.1.LB 46, (−)-INPEA and the optical isomers of propranolol, drugs with differentΒ-receptor blocking potency, increase the noradrenaline output induced by electrical nerve stimulation.2.Likewise, (+)-INPEA, which lacksΒ-receptor blocking activity, enhances the noradrenaline output to the same extent as theΒ-receptor blocking (−)-isomer.3.High concentrations of both optical isomers of propranolol have a cardiodepressant action; they do not further augment the noradrenaline output but inhibit it.4.Additional experiments with the optical isomers of INPEA show an inhibition by these drugs of the uptake of noradrenaline by the rabbit heart. The latter observation favours the hypothesis that all drugs tested increase the noradrenaline output by an inhibition of re-uptake. The ability of these drugs to inhibit the noradrenaline re-uptake is independent of theirΒ-receptor blocking action.

Hemmung der Hormonfreisetzung aus dem Nebennierenmark durch BAY a 6781, eine antihypertensiv wirksame Substanz

SummaryIn vitro and in vivo experiments have been performed in order to study the effect of BAY a 6781 on the release of the adrenal medullary hormones.1.In the isolated perfused preparation of the bovine adrenal gland, injections of BAY a 6781 up to 100 Μg did not change the rate of spontaneous catecholamine release.2.In contrast, the increased hormone release induced by injections of carbachol andΒ-phenylethylamine was inhibited during an infusion of 1 Μg/ml BAY a 6781 by 68 and 48%, respectively.3.In experiments on anaesthetized cats the hormone release from the adrenal medulla into the blood of the adrenolumbar vein was determined fluorimetrically. Intraaortal injections of BAY a 6781 in doses of 1.6, 5 and 15 Μg/kg reduced the catecholamine release evoked by splanchnic nerve stimulation by 35, 46 and 47%, respectively.4.The hormonal secretion of the adrenal medulla under resting conditions was not altered by the above-mentioned doses of BAY a 6781; moreover the ratio of adrenaline to noradrenaline in the adrenal venous blood remained constant even after splanchnic stimulation.

Influence of the metabolic state on the action of phenylephrine on rabbit ileum, guinea-pig vas deferens and atrium

SummaryUnder 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.