Pharmacology of the kinin peptides: Role of kinin B1 and B2 receptors
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Description
Bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) is a naturally occurring nonapeptide released from substrate kininogen, by the serine protease kallikrein in both tissue and plasma during tissue injury and inflammation. The peptide is rapidly inactivated in the lung by kininase II, a dipeptidyl carboxypeptidase and other peptidases. Kininase II has been shown to be identical to angiotensin I-converting enzyme which produces the potent vasoconstrictor angiotensin II from angiotensin I Kinin receptors are classically divided into B$\sb1$ and B$\sb2$ receptor subtypes based on the activities of selective agonists. Kinin B$\sb1$ receptors are activated by des-Arg$\sp9$-bradykinin, located on vascular smooth muscle cells and are reported to mediate relaxation and contraction in the dog and rabbit via the release of prostaglandins. The role of the B$\sb1$ receptor is not well understood, and this receptor subtype may not be present under normal physiologic conditions. Although B$\sb1$ receptors have been shown to be induced following noxious stimuli in the rabbit carotid artery, recent studies in the dog systemic vascular bed and isolated renal artery have demonstrated B$\sb1$ receptor mediated vasodilation under physiologic conditions. The present study will attempt to characterize the kinin peptides in a single species within two vascular beds. Most of the biological activity of bradykinin is thought to be mediated by the B$\sb2$ receptor, including vasodilation, pain, inflammation, bronchoconstriction and increased vascular permeability These studies of the kinin peptides, bradykinin, kallidin (Lys-BK), des-Arg$\sp9$-bradykinin, des-Arg$\sp{10}$-kallidin, and T-kinin (Ile-Ser-BK) were designed to address the following specific aims: (1) to study the receptor subtype mediating responses to the kinin peptides in the hindquarters and mesenteric vascular beds of the cat. (2) to study the effect of locally derived factors such as nitric oxide and prostaglandins on responses to the kinin peptides in the regional vascular beds. (3) to study the effect of angiotensin-converting enzyme inhibitors on responses to bradykinin in the regional vascular beds. (4) to characterize reactive vasodilator responses to brief periods of occlusion under natural and controlled flow conditions and the mechanism of action of reactive vasodilator responses The results of these studies demonstrate that responses to bradykinin, kallidin and T-kinin are mediated by the activation of kinin B$\sb2$ receptors coupled to the release of nitric oxide. The results of these studies also demonstrate that angiotensin-converting enzyme activity in the hindlimb vascular bed occurs upstream at or near the site of action of bradykinin. The results also demonstrate that des-Arg$\sp9$-bradykinin and des-Arg$\sp{10}$kallidin produce vasodilator responses mediated by kinin B$\sb1$ receptors under normal physiologic conditions and that these B$\sb1$ receptors are coupled to the release of nitric oxide. This study demonstrates that reactive hyperemic responses to brief periods of occlusion are significantly reduced following K$\sp{+}$ATP channel blockade and suggest that the reactive vasodilator response in the hindquarters vascular bed of the cat is dependent in part on the opening of K$\sp{+}$ATP channels