Kallistatin is a potent new vasodilator

J Clin Invest. 1997 Jul 1;100(1):11-7. doi: 10.1172/JCI119502.

Abstract

Kallistatin is a serine proteinase inhibitor which binds to tissue kallikrein and inhibits its activity. The aim of this study is to evaluate if kallistatin has a direct effect on the vasculature and on blood pressure homeostasis. We found that an intravenous bolus injection of human kallistatin caused a rapid, potent, and transient reduction of mean arterial blood pressure in anesthetized rats. Infusion of purified kallistatin (0.07-1.42 nmol/kg) into cannulated rat jugular vein produced a 20-85 mmHg reduction of blood pressure in a dose-dependent manner. Hoe 140, a bradykinin B2-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 kallikrein-binding protein, but not kinin or kallikrein, induced vascular relaxation of aortic rings. Neither Hoe 140 nor Nomega-nitro--arginine methyl ester, a nitric oxide synthase inhibitor, affected vasorelaxation induced by kallistatin. Kallistatin also caused dose-dependent vasodilation of the renal vasculature in the isolated, perfused rat kidney. Specific kallistatin-binding sites were identified in rat aorta by Scatchard plot analysis with a Kd of 0.25+/-0.07 nM and maximal binding capacity of 47.9+/-10.4 fmol/mg protein (mean+/-SEM, n = 3). These results indicate that kallistatin is a potent vasodilator which may function directly through a vascular smooth muscle mechanism independent of an endothelial bradykinin receptor. This study introduces the potential significance of kallistatin in directly regulating blood pressure to reduce hypertension.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology
  • Animals
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / physiology*
  • Blood Pressure / drug effects*
  • Bradykinin / analogs & derivatives
  • Bradykinin / pharmacology
  • Carrier Proteins / administration & dosage
  • Carrier Proteins / metabolism
  • Carrier Proteins / pharmacology*
  • Humans
  • In Vitro Techniques
  • Infusions, Intravenous
  • Injections, Intravenous
  • Kallikreins / pharmacology
  • Kinins / pharmacology
  • Male
  • Membrane Proteins / metabolism
  • Muscle Contraction / drug effects
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / physiology
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Rats
  • Rats, Inbred BN
  • Rats, Inbred Strains
  • Rats, Inbred WKY
  • Rats, Sprague-Dawley
  • Renal Circulation / drug effects*
  • Renal Circulation / physiology
  • Serpins / administration & dosage
  • Serpins / metabolism
  • Serpins / pharmacology*
  • Vasodilation
  • Vasodilator Agents*

Substances

  • Adrenergic beta-Antagonists
  • Carrier Proteins
  • Kinins
  • Membrane Proteins
  • Serpins
  • Vasodilator Agents
  • kallistatin
  • icatibant
  • Kallikreins
  • Bradykinin
  • NG-Nitroarginine Methyl Ester