Adrenaline in cardiovascular diseases--effect of beta-adrenoceptor antagonists

By subcutaneous insertion of osmotic minipumps leading to continuous infusion of l-adrenaline, we were able to induce hypertension in normotensive Wistar-Kyoto strain (WKY) rats which was shown to be completely reversible by application of the non-selective beta-adrenoceptor antagonist carvedilol. No consistent effect of adrenaline on heart rate could be observed. At least in rat heart, adrenaline replaced the original neurotransmitter noradrenaline in amine storage sites, the sum of all catecholamines remaining unchanged. By comparing tissue concentrations of endogenous amines of spontaneously hypertensive rats (SHR) and stroke-prone-SHR (SHR-SP) to the corresponding levels of their normotensive controls of the Wistar-Kyoto strain, we detected various differences in amine handling during the development of high blood pressure. Significant increases of adrenal gland catecholamines at the ages of 8 and 14 weeks are accompanied by striking alterations of catecholamine (CA) storage in other peripheral organs like the heart and kidneys. Most prominent increases, as compared to controls, were found in adrenaline concentrations in heart and kidney at all ages studied, with levels two to four times higher than the respective WKY concentrations. The results are compatible with a permissive role of adrenaline as a cotransmitter in the initiation and/or maintenance of hypertension. After incorporation into endogenous amine storage vesicles, e.g., of the heart, adrenaline is probably released, together with noradrenaline, upon nerve stimulation. By stimulating presynaptic beta 2-adrenoceptors, adrenaline is able to facilitate noradrenaline release and to enhance noradrenergic vasoconstriction. The resulting increase of peripheral sympathetic tone may be responsible for the pathogenesis of rat genetic and human essential hypertension, as well as for the triggering of myocardial infarction. The blockade of presynaptic beta-receptors is supposed to represent an important mechanism of action of non-selective beta-blocking agents. In the case of carvedilol, this effect is supported by additional antagonism at vascular alpha-adrenoceptors, leading to vasodilation.