des-Arg9-bradykinin produces tone-dependent kinin B1 receptor-mediated responses in the pulmonary vascular bed.

Abstract

Responses to des-Arg'-bradykinin, a selective kinin Bi receptor agonist, were characterized in the pulmonary vascular bed of the intact-chest cat. Injections of des-Arg'-bradykinin into the perfused lobar artery under low-resting tone conditions caused dose-related increases in lobar arterial pressure; whereas in the same experiment under elevated tone responses under elevated-tone conditions were inhibited by N'-nitro-L-arginine methyl ester, suggesting that des-Arg'-bradykinin stimulates the release of nitric oxide, whereas meclofenamate and U-37883A, a nonsulfonylurea ATP-sensitive K' channel antagonist, did not alter vasodilator responses to the Bi receptor agonist. These results suggest that vasoconstrictor responses to des-Arg'-bradykinin under low-tone conditions are mediated by the activation of kinin Bi receptors, the release of catecholamines within the lung, and the activation of a-adrenergic receptors, whereas vasodilator responses under elevated tone conditions are mediated by activation of Bi receptors and the release of nitric oxide from the endothelium. These data provide pharmacologic evidence for the existence of functionally active kinin Bi receptors that mediate tone-dependent vasoconstrictor and vasodilator responses in the pulmonary vascular bed of the cat. (Circ Res. 1994;75:1064-1072 Key Words * des-Arg9-bradykinin * Hoe 140 * pulmonary vascular bed * kinin Bi receptor * nitric oxideThere is considerable pharmacologic evidence in support of the concept of BK receptor heterogeneity.2'3'13'14The classic BK receptor subtypes have been characterized as B1 and B2, and the action of BK on the B2 receptor is thought to mediate the majority of physiological responses to the kinins.23 The Bi receptor is selectively stimulated by DABK on the basis of highaffinity contractile activity of the peptide in the rabbit aorta, mesenteric vein, and basilar artery; however, this receptor is not believed to play an important role under physiological conditions.314 The development of competitive, potent, selective kinin receptor antagonists has provided support for the identity of Bi receptors.2'3 DABK does not activate B2 receptors but stimulates kinin B1 receptors, and a change in the balance between levels of BK and its metabolite, DABK, could change the emphasis and effects of the kinin system.23"15Although Bi receptors are not thought to be physiologically important in mediating cardiovascular responses to kinins, such as increased vascular permeability, smooth muscle contraction, vasodilation, and hypotension, they have recently been shown to play a role in mediating decreases in systemic arterial pressure in the dog under physiological conditions.'6-19 Kinin

Stimulation of Bradykinin B 1 Receptors Induces Vasodilation in Conductance and Resistance Coronary Vessels in Conscious Dogs

“…26 The present study, using lisinopril, demonstrates a similar result in association with an increased CD response to bradykinin. However, lisinopril did not modify the coronary responses to des-Arg 9 -bradykinin, which is in accordance with observa- tions in the pulmonary circulation of cats, 10 indicating that in the coronary circulation in vivo, ACE plays only a small role in des-Arg 9 -[Leu 8 ]-bradykinin metabolism. Although it has been shown in vitro that ACE inhibitors may prevent the degradation of des-Arg 9 -bradykinin, 27 an in vivo experiment did not find an increased blood concentration of des-Arg 9 -bradykinin after enalapril administration.…”

“…11 In cats, the pulmonary vascular bed contains functional B 1 receptors; the stimulation of these receptors produces tone-dependent changes in pulmonary artery pressure. 10 In dogs, B 1 receptors are also present in the isolated renal artery and mediate vasorelaxation, 12 and in intact preparations, B 1 receptor stimulation by des-Arg 9 -bradykinin produces a hypotensive effect. 13,14 By use of a specific antibody directed to the peptide sequences of B 1 receptors, it has recently been shown in humans that B 1 receptors are present not only in vascular endothelial and smooth muscle cells of large elastic arteries but also in muscular arteries, such as coronary arteries and muscular arterioles.…”

“…4 -6 However, B 1 receptors are heterogeneously expressed depending on species and tissues. 7 B 1 receptors are constitutively and functionally expressed in the arterial vessels and glomerulus of rats, 8,9 in the pulmonary vascular bed of cats, 10 and in the arterial vessels of pigs 11 and dogs. [12][13][14] In humans, a recent in vitro study using immunolabeling techniques revealed the presence of B 1 receptors in vascular endothelial and smooth muscle cells of large elastic arteries, muscular arteries (such as coronary arteries), and muscular arterioles.…”

Kinin B2 receptor‐mediated contraction of tail arteries from normal or streptozotocin‐induced diabetic rats

“…In contrast, B 1 receptors exhibit high anities for kinin metabolites such as des-Arg 9 -BK and des-Arg 9 -kallidin, and are selectively antagonized by desArg 9 , [Leu 8 ]-BK and des-Arg 9 , [Leu 8 ]-kallidin. The constitutive expression of B 1 receptors is limited to certain types of tissues, such as dog coronary vessels (Nakhostine et al, 1993) and cat pulmonary vascular bed (DeWitt et al, 1994). B 1 receptors are also unique in that they can be up-regulated during certain pathophysiological situations, and a de novo synthesis of B 1 receptors occurs during in vitro incubation (Bouthillier et al, 1987;.…”

Des-Arg10-kallidin Engagement of the B1 Receptor Stimulates Type I Collagen Synthesis via Stabilization of Connective Tissue Growth Factor mRNA

“…Activation of the B1 receptor induces relaxation or contraction of various smooth muscle cell preparations, mediates chronic pain, and may be involved in chronic inflammation (1). Recent studies have demonstrated the expression of the B1 receptor in apparently healthy renal (13), intestinal (14), ocular (15), stomach (16), and pulmonary (17) tissues; however, the role of the B1 receptor in homeostasis and wound repair is not understood. Activation of the B1 receptor stimulates prostaglandin synthesis in fibroblasts, release of tumor necrosis factor ␣ and interleukin-1␤ from macrophages, and prostaglandin and platelet-activating factor synthesis in endothelial cells (1).…”