Involvement of β₂‐adrenoceptors in the regional haemodynamic responses to bradykinin in conscious rats

Abstract

1 Bradykinin can release neuronal calcitonin gene-related peptide (CGRP) and adrenal medullary catecholamines, both of which could contribute to its cardiovascular effects in vivo. Therefore, in the main experiment, regional haemodynamic responses to bolus injections of bradykinin (3 nmol kg- ', i.v.) were assessed in the same chronically-instrumented, conscious, Long Evans rats in the absence and in the presence of human a-CGRP or ICI 118551, antagonists of CGRPI-receptors and P2-adrenoceptors, respectively. The selected doses of these antagonists caused specific inhibition of responses mediated by exogenous human a-CGRP and P2-adrenoceptor agonists, respectively.2 Bradykinin administered alone as an i.v. bolus had a slight pressor effect accompanied by a marked tachycardia. There were early (at about 30 s) increases in flow and conductance in the mesenteric vascular bed, and delayed (at about 90 s), but qualitatively similar, changes in the hindquarters vascular bed. There were only slight increases in flow and conductance in the renal vascular bed. 3 Human a-CGRP had no statistically significant effects on the responses to bolus doses of bradykinin. However, in the presence of ICI 118551, the pressor effect of bradykinin was significantly enhanced while its tachycardic effect was significantly suppressed. The hindquarters vasodilator effect of bradykinin was converted to a vasoconstriction and there was a slight renal vasoconstriction, but the mesenteric vasodilator effect of bradykinin was unchanged by ICI 118551. 4 In subsidiary experiments, in other animals, it was found that infusion of bradykinin (36 nmol kg-' min-') elicited a pattern of haemodynamic responses similar to that seen with bolus injections and, as in the latter case, the hindquarters hyperaemic vasodilatation was inhibited by ICI 118551. In the presence of mecamylamine (at a dose sufficient to block reflex heart rate responses to rises or falls in arterial blood pressure) bolus injection or infusion of bradykinin still elicited increases in renal, mesenteric and hindquarters blood flow. However, in additional experiments in adrenal demedullated rats (n = 4) the hindquarters hyperaemic effect of bradykinin was absent, although the mesenteric hyperaemic effect remained. 5 The results indicate that the increase in hindquarters blood flow following administration of bradykinin in vivo is largely due to activation of P2-adrenoceptors by catecholamines released subsequent to direct stimulation of the adrenal medulla by the peptide. However, the bradykinin-induced increase in mesenteric blood flow does not depend on this mechanism.

Regional haemodynamic responses to acetylcholine, methoxamine, salbutamol and bradykinin during lipopolysaccharide infusion in conscious rats

“…We know that systemic administration of bradykinin causes r2-adrenoceptor mediated vasodilatation in the renal and hindquarters vascular beds (Gardiner et al, 1992b). It is therefore feasible that reduced P2-adrenoceptor sensitivity could reduce the bradykinin-induced renal vasodilator component, unmasking a vasoconstrictor component.…”

“…The experimental design meant that it was not possible to administer more than one dose of each of the vasoactive substances. The single doses were therefore chosen on the basis of our previous work (Gardiner et al, 1991;1992b (TheodorssonNorheim, 1987) or by Wilcoxon's signed rank test as appropriate. Inter-group changes were analysed using the Mann Whitney U test; a P value <0.05 was taken to indicate a significant difference.…”

Effects of Hoe 140, a bradykinin B2‐receptor antagonist, on renal function in conscious normotensive rats

“…Kinins are potent vasodilators, which acting as paracrine hormones, may be involved in the regulation of regional haemodynamics (Nolly et al, 1990;Saed et al, 1990;Wiemer et al, 1991;Gardiner et al, 1990;1992) and renal excretion of water and sodium (Willis et al, 1969;. Alteration of the function of locally formed kinins, leading to predominance of vasoconstrictor tone and retention of water and salt, may contribute to the pathogenesis of arterial hypertension.…”

The effect of captopril on the superior mesenteric artery and portal venous blood flow in normal man.

“…Captopril however has other actions such as inhibition of All formation in cardiac and vascular tissues and selective superior mesenteric vasodilatation either by scavenging superoxide radicals or by interacting with the dynamics of the L-arginine-nitric oxide system Muller et al, 1990;Swales & Heagerty, 1987;Westlin & Mullanc, 1988). Captopril is also known to augment the release of the vasodilator bradykinin, which may release prostacyclin or endothelium-derived relaxing factor (EDRF), which are potent vasodilators (Gardiner et al, 1992;Vanhoutte et al, 1989). Thus, studies using specific All antagonists will be needed to further define the role of angiotensin II on the splanchnic vascular bed in man.…”