Bradykinin: potential for vascular constriction in the presence of endothelial injury

Abstract

Bradykinin (BK), a known vasodilator in vivo, and arginine vasopressin (AVP), a vasoconstrictor in vivo, both stimulate a rise in cytosolic free Ca2+ ([Ca2+]i) in vascular smooth muscle cells (VSMC). The present study was undertaken to investigate this apparent paradox. The following three possibilities were examined, namely, 1) signaling events other than [Ca2+]i are different for BK and AVP; 2) BK, but not AVP, stimulates prostaglandins in VSMC, thus resulting in divergent effects on VSMC tone; and 3) AVP and BK exhibit qualitatively similar effects on VSMC signal transduction but divergent effects on VSMC tone are mediated by endothelial events. The results demonstrated that BK stimulated a rise in inositol trisphosphate (IP3), [Ca2+]i, 45Ca2+ efflux, and Ca2+ influx and a biphasic change in intracellular pH when N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-buffered solution was used. The BK-induced VSMC contraction was also comparable to that observed with AVP. The cyclooxygenase inhibitor, meclofenamate, enhanced the effect of both BK and AVP on VSMC tone, as assessed by shape change, by a comparable degree. BK, but not AVP, stimulated endothelial cells to release a substance that blocked the contractile response of BK and AVP. Methylene blue, a blocker of cytosolic guanylate cyclase and therefore of the production of guanosine 3',5'-cyclic monophosphate (2nd messenger of endothelium-derived relaxing factor, EDRF), and nordihydroguaiaretic acid, an inhibitor of EDRF, both prevented this endothelium-dependent effect of BK. These results therefore indicate that BK is a constrictor of VSMC, an effect that can be overridden by the hormone's endothelial effect to stimulate the release of a vasodilator(s), which is most likely EDRF.

Plasma Kallikrein Promotes Epidermal Growth Factor Receptor Transactivation and Signaling in Vascular Smooth Muscle through Direct Activation of Protease-activated Receptors

“…Despite the generally salutary effects of BK, it is clear that dysregulation of the KKS is associated with progression of the vascular and renal complications of diabetes mellitus (40). In the setting of endothelial denudation, BK can act directly on B1 and B2 bradykinin receptors expressed by VSMC to promote vasoconstriction in a manner similar to angiotensin II (13). The complex roles of the KKS in health and disease and its potential as a therapeutic target underscore the importance of understanding its mechanisms of action in vascular tissue.…”

“…NO from endothelial cells also inhibits VSMC and renal mesangial cell proliferation (11,12). However, in the setting of vascular injury and endothelial denudation, BK can act directly on VSMC to induce their contraction and activate multiple signaling pathways in a manner similar to vasoconstrictors like angiotensin II (13).…”

Plasma Prekallikrein

“…Indeed, under normal physiological conditions, BK is a potent stimulator of nitric oxide release from renal and endothelial cells, which result in vasodilatation because of effects on underlying vascular smooth muscle cells (40,41). However, when the endothelium is denuded or dysfunctional, as is observed in disease states such as hypertension or diabetes, BK can act directly on mesangial and vascular smooth muscle cells (VSMCs) to induce contraction and to activate multiple signaling pathways, in a manner similar to those activated by vasoconstrictors, ultimately resulting in changes in cell proliferation and increased matrix deposition (42)(43)(44)(45)(46). Thus BK can protect from vascular disease associated with diabetes when there is an intact endothelium, but could aggravate vascular disease when endothelium is damaged.…”

Mechanisms of angiotensin II-induced expression of B2kinin receptors

“…BK causes relaxation of the VSMC through the synthesis and release of nitric oxide from the endothelium (44). In contrast, injury to the integrity of the endothelium enables BK to directly increase intracellular calcium levels and induce VSMC contraction in a manner similar to ANG II (3).…”