The mechanism of bradykinin‐induced endothelium‐dependent contraction and relaxation in the porcine interlobar renal artery

Abstract

The mechanism of endothelium‐dependent regulation of vascular tone of bradykinin was investigated by simultaneously monitoring the changes in the cytosolic Ca²⁺ concentration and the force of smooth muscle in fura‐2‐loaded strips of the porcine renal artery with endothelium. During phenylephrine‐induced sustained contraction, bradykinin (>3×10⁻⁹ M) caused endothelium‐dependent triphasic changes in the force of the strips, composed of an initial relaxation, a subsequent transient contraction and a late sustained relaxation. At low concentrations (10⁻¹⁰–10⁻⁹ M), bradykinin caused an endothelium‐dependent biphasic relaxation with no contraction. A thromboxane A₂ (TXA₂)/prostaglandin H₂ (PGH₂) receptor antagonist (10⁻⁵ M ONO‐3708) completely inhibited, while a TXA₂ synthase inhibitor (10⁻⁵ M OKY‐046) only partially inhibited, the transient contraction induced by bradykinin. Under conditions where the bradykinin‐induced contraction was inhibited by ONO‐3708 during the phenylephrine‐induced contraction, bradykinin induced only a transient relaxation in the presence of N^Ω‐nitro‐L‐arginine methyl ester (L‐NAME). This transient relaxation was inhibited when the precontraction was initiated by phenylephrine plus 40 mM extracellular K⁺. The removal of L‐NAME from this condition caused a partial reappearance of the initial relaxation and a complete reappearance of the sustained relaxation. In conclusion, bradykinin caused the endothelium‐dependent triphasic regulation of vascular tone in the porcine renal artery. The concentrations of bradykinin required to induce a contraction was higher than that required to induce relaxation. Both TXA₂ and PGH₂ were involved in the bradykinin‐induced contraction. The initial relaxation was mediated by nitric oxide and hyperpolarizing factors while the sustained relaxation depended on nitric oxide. British Journal of Pharmacology (2000) 129, 943–952; doi:10.1038/sj.bjp.0703141