This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mangiapane, M. L. Articles by Buchholz, R. A. Search for Related Content PubMed PubMed Citation Articles by Mangiapane, M. L. Articles by Buchholz, R. A.

Hypertension, Vol 23, 857-860, Copyright © 1994 by American Heart Association

ARTICLES

Vasoconstrictor action of angiotensin I-convertase and the synthetic substrate (Pro11,D-Ala12)-angiotensin I

ML Mangiapane, AL Rauch, JT MacAndrew, SS Ellery, KW Hoover, DR Knight, HA Johnson, WP Magee, DJ Cushing and RA Buchholz
Department of Cardiovascular and Metabolic Diseases, Pfizer Inc, Groton, CT 06340.

A chymase (also referred to as angiotensin I-convertase) specific for the conversion of angiotensin (Ang) I to Ang II has been identified in human heart. This serine protease is also present in dog and marmoset vasculature. We examined the vasoconstrictor effects of Ang II putatively generated from an angiotensin-converting enzyme (ACE)- resistant convertase synthetic substrate (SUB) in vivo and in vitro. In marmosets, SUB (7 to 700 micrograms/kg i.v.) or Ang I (0.1 to 30 micrograms/kg) caused similar dose-dependent increases in mean arterial pressure (10 to 100 mm Hg) and decreases in heart rate. Pressor effects of SUB were slightly attenuated at low (but not high) doses by captopril (CAP, 1 mg/kg i.v.) and blocked by losartan (5 mg/kg i.v.); in contrast Ang I pressor effects were substantially blocked by both. In isolated canine superior mesenteric artery, Ang I-induced contraction was eliminated by losartan and reduced but not eliminated by 10 mumol/L CAP. When combined with the serine protease inhibitor chymostatin, CAP eliminated Ang I-induced contraction, but chymostatin alone had no effect. SUB-induced contraction was not blocked by CAP but was equally blocked by chymostatin (25 mumol/L) alone or by the combination of CAP (10 mumol/L) and chymostatin (25 mumol/L); losartan (10 mumol/L) eliminated SUB-induced responses. Previous studies have suggested that Ang I-convertase is important for production of Ang II in the heart. Our results are consistent with a potential role for Ang I-convertase in the production of Ang II in the vasculature, resulting in Ang II-mediated vasoconstriction.

This article has been cited by other articles:

				S. A Doggrell and J. C Wanstall Vascular chymase: pathophysiological role and therapeutic potential of inhibition Cardiovasc Res, March 1, 2004; 61(4): 653 - 662. [Abstract] [Full Text] [PDF]

				C. F. Santos, M. A. V. Caprio, E. B. Oliveira, M. C. O. Salgado, D. N. Schippers, D. H. Munzenmaier, and A. S. Greene Functional role, cellular source, and tissue distribution of rat elastase-2, an angiotensin II-forming enzyme Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H775 - H783. [Abstract] [Full Text] [PDF]

				J. E. McDonald, N. Padmanabhan, M. C. Petrie, C. Hillier, J. M.C. Connell, and J. J.V. McMurray Vasoconstrictor Effect of the Angiotensin-Converting Enzyme-Resistant, Chymase-Specific Substrate [Pro11D-Ala12] Angiotensin I in Human Dorsal Hand Veins: In Vivo Demonstration of Non-ACE Production of Angiotensin II in Humans Circulation, October 9, 2001; 104(15): 1805 - 1808. [Abstract] [Full Text] [PDF]

				J. J. Saris, M. A. van Dijk, I. Kroon, M. A. D. H. Schalekamp, and A. H. J. Danser Functional Importance of Angiotensin-Converting Enzyme-Dependent In Situ Angiotensin II Generation in the Human Forearm Hypertension, March 1, 2000; 35(3): 764 - 768. [Abstract] [Full Text] [PDF]

				A. J. M. Roks, P. P. van Geel, Y. M. Pinto, H. Buikema, R. H. Henning, D. de Zeeuw, and W. H. van Gilst Angiotensin-(1–7) Is a Modulator of the Human Renin-Angiotensin System Hypertension, August 1, 1999; 34(2): 296 - 301. [Abstract] [Full Text] [PDF]

				N. Padmanabhan, A. G. Jardine, J. C. McGrath, and J. M. C. Connell Angiotensin-Converting Enzyme–Independent Contraction to Angiotensin I in Human Resistance Arteries Circulation, June 8, 1999; 99(22): 2914 - 2920. [Abstract] [Full Text] [PDF]

				H. Nishimura, H. Buikema, O. Baltatu, D. Ganten, and H. Urata Functional evidence for alternative ANG II-forming pathways in hamster cardiovascular system Am J Physiol Heart Circ Physiol, October 1, 1998; 275(4): H1307 - H1312. [Abstract] [Full Text] [PDF]

				E. A. Garrison, H. C. Champion, and P. J. Kadowitz [Pro11,D-Ala12]angiotensin I has rapid onset vasoconstrictor activity in the cat Am J Physiol Endocrinol Metab, December 1, 1997; 273(6): E1059 - E1064. [Abstract] [Full Text] [PDF]