Dehner R, Ikeda K, Yamori Y, Grobecker H
Department of Pharmacology, University of Regensburg.
Z Kardiol. 1990;79 Suppl 3:79-88.
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.
通过皮下植入渗透微型泵持续输注左旋肾上腺素，我们能够在正常血压的Wistar-Kyoto品系（WKY）大鼠中诱导高血压，结果显示应用非选择性β-肾上腺素能受体拮抗剂卡维地洛可使其完全逆转。未观察到肾上腺素对心率有一致的影响。至少在大鼠心脏中，肾上腺素取代了胺储存部位原有的神经递质去甲肾上腺素，所有儿茶酚胺的总量保持不变。通过比较自发性高血压大鼠（SHR）和易中风SHR（SHR-SP）的内源性胺类组织浓度与其Wistar-Kyoto品系正常血压对照的相应水平，我们在高血压发展过程中检测到胺类处理存在各种差异。8周和14周龄时肾上腺儿茶酚胺显著增加，同时心脏和肾脏等其他外周器官中的儿茶酚胺（CA）储存也发生了显著改变。与对照组相比，在所有研究年龄的心脏和肾脏中，肾上腺素浓度增加最为显著，其水平比相应的WKY浓度高两到四倍。这些结果与肾上腺素作为共递质在高血压起始和/或维持中起允许作用相一致。肾上腺素掺入内源性胺储存囊泡（如心脏的囊泡）后，可能在神经刺激时与去甲肾上腺素一起释放。通过刺激突触前β2-肾上腺素能受体，肾上腺素能够促进去甲肾上腺素释放并增强去甲肾上腺素能血管收缩。由此导致的外周交感神经张力增加可能是大鼠遗传性和人类原发性高血压发病机制的原因，也是心肌梗死触发的原因。突触前β受体的阻断被认为是非选择性β阻滞剂的重要作用机制。就卡维地洛而言，这种作用得到了对血管α-肾上腺素能受体的额外拮抗作用的支持，从而导致血管舒张。
