Cyclic AMP selectively enhances bradykinin receptor synthesis and expression in cultured arterial smooth muscle. Inhibition of angiotensin II and vasopressin response.

Abstract

Bradykinin receptors on vascular smooth muscle may play an important role in regulating the endogenous effects ofthe vascular kallikrein-kinin system. The present study examined the effect of cyclic nucleotides on bradykinin-stimulated responses in cultured arterial smooth muscle cells. Short term stimulation (1 min) with cyclic AMP produced a variable inhibition of bradykinin-stimulated calcium mobilization which was lost in later passaged cells. However, long-term stimulation (24 h) produced a consistent increase in bradykinin-stimulated calcium mobilization in both early and late passaged cells. Further analysis demonstrated that chronic exposure to cAMP produced a twofold increase in both the number of cell surface bradykinin receptors and in bradykinin-stimulated phosphoinositide hydrolysis. The increase in bradykinin receptors was time dependent (> 7 h) and blocked by protein synthesis inhibitors, suggesting that cAMP enhanced the synthesis of new bradykinin receptors. The increase in bradykinin receptor binding and calcium mobilization was also stimulated by cholera toxin, forskolin, and isobutylmethylxanthine, but not isoproterenol or prostaglandin E2. Of considerable interest, prolonged exposure to cAMP inhibited both angiotensin II and arginine vasopressinstimulated phosphoinositide hydrolysis and intracellular calcium mobilization. In summary, prolonged treatment with cAMP selectively stimulates the synthesis and expression of bradykinin receptors on arterial smooth muscle while decreasing the responsiveness to vasoconstrictor agonists such as angiotensin II and vasopressin. (J. Clin. Invest. 1994. 93:2535-2544.) Key words: intracellular calcium * phosphoinositides x vascular kallikrein-kinin system * cyclic nucleotides * rat mesenteric artery

Kallistatin is a potent new vasodilator.

“…Specific kallistatin-binding sites in the aortic membrane proteins were identified by analyzing saturation data with the EBDA program. Scatchard plot analysis revealed that rat aorta membrane proteins contained specific kallistatin-binding sites with a K d of 0.25Ϯ0.07 nM and B max of 47.9Ϯ10.4 fmol/mg protein (meanϮSEM, n ϭ 3), which are comparable with those of bradykinin and its B 2 -receptor binding in rat cultured arterial smooth muscle cells (21). These results support the notion of a receptor binding mechanism for kallistatin's effects on aortic smooth muscle cells.…”

PLA2 phosphorylation and cyclooxygenase-2 induction, through p38 MAP kinase pathway, is involved in the IL-1β-induced bradykinin B2 receptor gene transcription

“…The first evidence for its upregulation was proposed in human A 431 epidermoid carcinoma cells and in human synovial cells stimulated with TNFα or IL-1β, respectively (Bathon et al 1992;Sawutz et al 1992). The involvement of cAMP in the overexpression of B 2 receptors has been shown in arterial smooth muscle cells, rat mesangial cells and in human bronchial smooth muscle cells (Dixon 1994;Castano et al 1998;Schmidlin et al 1998a). …”

Cyclic AMP increases bradykinin receptor binding affinity in human endothelial cells

“…Cells were preincubated for 10 min in bradykinin binding buffer containing 140 mM NaCl (RiedeldeHaën AG, Seelze, Germany), 2 mM MgCl 2 (Merck, Darmstadt, Germany), 25 mM HEPES, 1 mM 1, 10 O-phenantroline and 0.03 mM captopril (Sigma) to inhibit bradykinin degradation by angiotensin converting enzyme (Dixon, 1994). For saturation experiments cells were incubated with increasing concentrations of 125 I-[Tyr 8 ]-bradykinin (25-700 pM) for 15 min at 37jC and for competition studies with increasing concentrations of bradykinin receptor agonists or antagonists with a fixed concentration of the radioactive ligand (approximately 90 pM).…”

“…The local concentration of kinins is regulated by proteases such as angiotensin converting enzyme, neutral endopeptidase-24.11, aminopeptidase and carboxypeptidases (Kasel et al, 1996;Dixon, 1994;Graf et al, 1993). The major regulator of bradykinin degradation in human endothelial cells is angiotensin converting enzyme and as a consequence, the hypotensive effect of angiotensin converting enzyme inhibitors in vivo may not only be due to inhibition of angiotensin II formation but also to accumulation of bradykinin (Kasel et al, 1996;Busse et al, 1993;Graf et al, 1993).…”

“…Upgrading of B 2 receptors in smooth muscle cells by platelet-derived growth factor has been reported (Dixon et al, 1996). Sustained elevation of cAMP has been reported to increase both bradykinin receptor number and bradykinin binding in vascular smooth muscle cells and fibroblasts (Dixon, 1994;Etscheid et al, 1991).…”