Kallistatin is a potent new vasodilator.
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.
Chao
J
J
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Stallone
J N
JN
Liang
Y M
YM
Chen
L M
LM
Wang
D Z
DZ
Chao
L
L
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D002352:Carrier Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007610:Kallikreins / Q000494:pharmacology; D007705:Kinins / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D051381:Rats; D011914:Rats, Inbred BN; D011919:Rats, Inbred Strains; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects* / Q000502:physiology; D015843:Serpins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D014664:Vasodilation; D014665:Vasodilator Agents
D000319:Adrenergic beta-Antagonists; D002352:Carrier Proteins; D007705:Kinins; D008565:Membrane Proteins; D015843:Serpins; D014665:Vasodilator Agents; C051324:kallistatin; C065679:icatibant; D007610:Kallikreins; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester