Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Jul 1;100(1):11–17. doi: 10.1172/JCI119502

Kallistatin is a potent new vasodilator.

J Chao 1, J N Stallone 1, Y M Liang 1, L M Chen 1, D Z Wang 1, L Chao 1
PMCID: PMC508159  PMID: 9202051

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.

Full Text

The Full Text of this article is available as a PDF (200.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bhoola K. D., Figueroa C. D., Worthy K. Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev. 1992 Mar;44(1):1–80. [PubMed] [Google Scholar]
  2. Chai K. X., Chen L. M., Chao J., Chao L. Kallistatin: a novel human serine proteinase inhibitor. Molecular cloning, tissue distribution, and expression in Escherichia coli. J Biol Chem. 1993 Nov 15;268(32):24498–24505. [PubMed] [Google Scholar]
  3. Chao J., Chai K. X., Chen L. M., Xiong W., Chao S., Woodley-Miller C., Wang L. X., Lu H. S., Chao L. Tissue kallikrein-binding protein is a serpin. I. Purification, characterization, and distribution in normotensive and spontaneously hypertensive rats. J Biol Chem. 1990 Sep 25;265(27):16394–16401. [PubMed] [Google Scholar]
  4. Chao J., Chao L. A major difference of kallikrein-binding protein in spontaneously hypertensive versus normotensive rats. J Hypertens. 1988 Jul;6(7):551–557. doi: 10.1097/00004872-198807000-00006. [DOI] [PubMed] [Google Scholar]
  5. Chao J., Chao L. Biochemistry, regulation and potential function of kallistatin. Biol Chem Hoppe Seyler. 1995 Dec;376(12):705–713. [PubMed] [Google Scholar]
  6. Chao J., Schmaier A., Chen L. M., Yang Z., Chao L. Kallistatin, a novel human tissue kallikrein inhibitor: levels in body fluids, blood cells, and tissues in health and disease. J Lab Clin Med. 1996 Jun;127(6):612–620. doi: 10.1016/s0022-2143(96)90152-3. [DOI] [PubMed] [Google Scholar]
  7. Chen L. M., Chao L., Chao J. Adenovirus-mediated delivery of human kallistatin gene reduces blood pressure of spontaneously hypertensive rats. Hum Gene Ther. 1997 Feb 10;8(3):341–347. doi: 10.1089/hum.1997.8.3-341. [DOI] [PubMed] [Google Scholar]
  8. Chen L. M., Ma J. x., Liang Y. M., Chao L., Chao J. Tissue kallikrein-binding protein reduces blood pressure in transgenic mice. J Biol Chem. 1996 Nov 1;271(44):27590–27594. doi: 10.1074/jbc.271.44.27590. [DOI] [PubMed] [Google Scholar]
  9. Cooper C. L., Malik K. U. Mechanism of action of vasopressin on prostaglandin synthesis and vascular function in the isolated rat kidney: effect of calcium antagonists and calmodulin inhibitors. J Pharmacol Exp Ther. 1984 Apr;229(1):139–147. [PubMed] [Google Scholar]
  10. Dixon B. S. Cyclic AMP selectively enhances bradykinin receptor synthesis and expression in cultured arterial smooth muscle. Inhibition of angiotensin II and vasopressin response. J Clin Invest. 1994 Jun;93(6):2535–2544. doi: 10.1172/JCI117264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Linz W., Wiemer G., Gohlke P., Unger T., Schölkens B. A. Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev. 1995 Mar;47(1):25–49. [PubMed] [Google Scholar]
  12. Lu H. S., Lin F. K., Chao L., Chao J. Human urinary kallikrein. Complete amino acid sequence and sites of glycosylation. Int J Pept Protein Res. 1989 Apr;33(4):237–249. doi: 10.1111/j.1399-3011.1989.tb01277.x. [DOI] [PubMed] [Google Scholar]
  13. Ma J. X., Yang Z., Chao J., Chao L. Intramuscular delivery of rat kallikrein-binding protein gene reverses hypotension in transgenic mice expressing human tissue kallikrein. J Biol Chem. 1995 Jan 6;270(1):451–455. doi: 10.1074/jbc.270.1.451. [DOI] [PubMed] [Google Scholar]
  14. Malik K. U., McGiff J. C. Modulation by prostaglandins of adrenergic transmission in the isolated perfused rabbit and rat kidney. Circ Res. 1975 May;36(5):599–609. doi: 10.1161/01.res.36.5.599. [DOI] [PubMed] [Google Scholar]
  15. Margolius H. S. Theodore Cooper Memorial Lecture. Kallikreins and kinins. Some unanswered questions about system characteristics and roles in human disease. Hypertension. 1995 Aug;26(2):221–229. doi: 10.1161/01.hyp.26.2.221. [DOI] [PubMed] [Google Scholar]
  16. Margolius H. S. Tissue kallikreins and kinins: regulation and roles in hypertensive and diabetic diseases. Annu Rev Pharmacol Toxicol. 1989;29:343–364. doi: 10.1146/annurev.pa.29.040189.002015. [DOI] [PubMed] [Google Scholar]
  17. Moore P. K., al-Swayeh O. A., Chong N. W., Evans R. A., Gibson A. L-NG-nitro arginine (L-NOARG), a novel, L-arginine-reversible inhibitor of endothelium-dependent vasodilatation in vitro. Br J Pharmacol. 1990 Feb;99(2):408–412. doi: 10.1111/j.1476-5381.1990.tb14717.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Regoli D., Barabé J. Pharmacology of bradykinin and related kinins. Pharmacol Rev. 1980 Mar;32(1):1–46. [PubMed] [Google Scholar]
  19. Serveau C., Moreau T., Zhou G. X., ElMoujahed A., Chao J., Gauthier F. Inhibition of rat tissue kallikrein gene family members by rat kallikrein-binding protein and alpha 1-proteinase inhibitor. FEBS Lett. 1992 Sep 14;309(3):405–408. doi: 10.1016/0014-5793(92)80817-z. [DOI] [PubMed] [Google Scholar]
  20. Stallone J. N. Role of endothelium in sexual dimorphism in vasopressin-induced contraction of rat aorta. Am J Physiol. 1993 Dec;265(6 Pt 2):H2073–H2080. doi: 10.1152/ajpheart.1993.265.6.H2073. [DOI] [PubMed] [Google Scholar]
  21. Stallone J. N. Sex differences in nitric oxide-mediated attenuation of vascular reactivity to vasopressin are abolished by gonadectomy. Eur J Pharmacol. 1994 Jul 11;259(3):273–283. doi: 10.1016/0014-2999(94)90654-8. [DOI] [PubMed] [Google Scholar]
  22. Wang C., Tang C. Q., Zhou G. X., Chao L., Chao J. Biochemical characterization and substrate specificity of rat prostate kallikrein (S3): comparison with tissue kallikrein, tonin and T-kininogenase. Biochim Biophys Acta. 1992 Jun 24;1121(3):309–316. doi: 10.1016/0167-4838(92)90162-7. [DOI] [PubMed] [Google Scholar]
  23. Wassdal I., Hull R., Gerskowitch V. P., Berg T. Kallikrein rK10-induced kinin-independent, direct activation of NO-formation and relaxation of rat isolated aortic rings. Br J Pharmacol. 1995 May;115(2):356–360. doi: 10.1111/j.1476-5381.1995.tb15885.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Wirth K., Hock F. J., Albus U., Linz W., Alpermann H. G., Anagnostopoulos H., Henk S., Breipohl G., König W., Knolle J. Hoe 140 a new potent and long acting bradykinin-antagonist: in vivo studies. Br J Pharmacol. 1991 Mar;102(3):774–777. doi: 10.1111/j.1476-5381.1991.tb12249.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Xiong W., Tang C. Q., Zhou G. X., Chao L., Chao J. In vivo catabolism of human kallikrein-binding protein and its complex with tissue kallikrein. J Lab Clin Med. 1992 May;119(5):514–521. [PubMed] [Google Scholar]
  26. Zhou G. X., Chao L., Chao J. Kallistatin: a novel human tissue kallikrein inhibitor. Purification, characterization, and reactive center sequence. J Biol Chem. 1992 Dec 25;267(36):25873–25880. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES