Study on the role of the kallikrein-kinin system in the cardiovascular diseases

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Studies have been undertaken to elucidate a role of the kallikrein-kinin system(KKS) in the cardiovascular diseases, such as the cardiac hypertrophy and hypertension. The abdominal aortic banding produced a transient reduction of the bradykinin B2-receptor mRNA in mouse heart before a development of the cardiac hypertrophy. The administration of angiotensin II(Ang II) type 1(AT1) receptor antagonist inhibited the pressure-overload-induced down-regulation of cardiac B2-receptor, suggesting a role of the renin-angiotensin system in regulating B2-receptor expression in cardiac tissue. Tisssue kallikrein was found to be synthesized and secreted by human endothelial cells, suggesting a presence of the local KKS,in vascular endothelium. The abdominal aortic banding produced an up-regulation of the Ang II type 2(AT2) receptor mRNA in pressure-overloaded thoracic aorta in rats and mice, and the administration of AT1-receptor antagonist inhibited the up-regulation of aortic AT2-receptor. The contractile response to Ang II was decreased in pressure-overloaded thoracic aorta in the endothelium-dependent manner, and the decreased response restored to sham-levels by either. AT2-receptor antagonist or B2-receptor antagonist. The aortic banding elicited a marked increase in cGMP content of pressure-overloaded thoracic aortas, and the administration of antagonists for either AT2-or B2-receptor reduced the elevated cGMP contents to sham levels. These results suggest that the aortic banding induced down-regulation of cardiac B2-receptor expression via the activation of AT1-receptor, while the up-regulation of the AT2-receptor in pressure-overloaded aorta through increased circulating Ang II via the AT1-receptor, thereby activating a vasodilatory pathway in vessels through the AT2-receptor via the kinin/cGMP system.