KALLISTATIN IS A POTENT NEW VASODILATOR

Kallistatin is a serine proteinase inhibitor which binds to tissue kal likrein and inhibits its activity, The aim of this study is to evaluat e if kallistatin has a direct effect on the vasculature and on blood p ressure homeostasis. We found that an intravenous bolus injection of h uman kallistatin caused a rapid, potent, and transient reduction of me an arterial blood pressure in anesthetized rats. Infusion of purified kallistatin (0.07-1.42 nmoVkg) into cannulated rat jugular vein produc ed a 20-85 mmHg reduction of blood pressure in a dose-dependent manner . Hoe 140, a bradykinin B-2-receptor antagonist, had no effect on the hypotensive effect of kallistatin yet it abolished the blood pressure- lowering effect of kinin and kallikrein. Relaxation of isolated aortic rings by kallistatin was observed in the presence (ED50 of 3.4 x 10(- 9) M) and in the absence of endothelium (ED50 of 10(-9) M). Rat kallik rein-binding protein, but not kinin or kallikrein, induced vascular re laxation of aortic rings. Neither Hoe 140 nor N-omega-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, affected vasorelaxat ion induced by kallistatin. Kallistatin also caused dose-dependent vas odilation of the renal vasculature in the isolated, perfused rat kidne y, Specific kallistatin-binding sites were identified in rat aorta by Scatchard plot analysis with a K-d of 0.25+/-0.07 nM and maximal bindi ng capacity of 47.9+/-10.4 fmol/mg protein (mean+/-SEM, n = 3). These results indicate that kallistatin is a potent vasodilator which may fu nction directly through a vascular smooth muscle mechanism independent of an endothelial bradykinin receptor. This study introduces the pote ntial significance of kallistatin in directly regulating blood pressur e to reduce hypertension.