Comparison of the Inhibitory Actions of Angiotensin AT1 Receptor Antagonists in the Peripheral Vascular Bed
The effects of nonpeptide angiotensin AT1 and AT2 receptor antagonists on pressor responses to the angiotensin peptides were investigated in the cat and the rat. Under constant flow conditions, injections of angiotensin (Ang) I, Ang II, Ang III, Ang I-(3-10), (Pro11,D-Ala12) Ang I and Ang IV into the hindlimb perfusion circuit caused dose-dependent increases in perfusion pressure, while Ang I-(4-8) was without effect. The order of potency was Ang I = Ang II = Ang III > (Pro11,D-Ala12) Ang I > Ang I-(3-10) = Ang IV. Losartan, EXP 3174, and candesartan decreased vasoconstrictor responses to Ang II in a selective manner. EXP 3174 (1 mg/kg iv) and candesartan (1 mg/kg iv) shifted the dose-response curve to Ang II to the right in a nonparallel manner, whereas losartan shifted the curve to the right in a parallel manner. The AT2 receptor antagonist PD 123,319 had no significant effect on vasoconstrictor responses to the angiotensin peptides in the regional vascular bed of the cat. In the rat, candesartan decreased pressor responses to Ang II, whereas PD 123,319 had no effect on the response to the peptide. These results indicate that vasoconstrictor responses to Ang peptides in the regional vascular bed of the cat and pressor responses to Ang II in the systemic vascular bed of the rat are mediated by the activation of AT1 receptors, whereas AT2 receptors play little, if any, role in the mediation or modulation of responses to Ang II in the cat or the rat.
KeywordsSystemic Arterial Pressure Angiotensin Peptide Nonpeptide Angiotensin Nonparallel Manner Full Intrinsic Activity
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- 1.Page III, Bumpus FM. 1974. Angiotensin: Handbook of experimental pharmacology. Berlin: Springer-Verlag.Google Scholar
- 9.Garrison EA, Santiago JA, Kadowitz PJ. 1995. Analysis of responses to angiotensin peptides in the hindquarters vascular bed of the cat. Am J Physiol 268:H2428-H2425.Google Scholar
- 28.Shibouta Y, Nada Y, Ojima M, Wada T, Noda M, Sanada T, Kubo K, Kohara Y, Naka T, Nishikawa K. 1993. Pharmacological profile of a highly potent and long-lasting angiotensin II receptor antagonist, 2-Ethoxy-l-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzim idazole-7-carboxylic Acid (CV-11974), and its prodrug, (+)-1-(Cyclohexyloxycarbonyloxy)-ethyl 2-Ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzim idazole-7-carboxylate (TCV-116). J Pharmacol Exp Ther 266:114–120.PubMedGoogle Scholar
- 30.Koh E, Morimoto S, Tomita J, Rakugi H, Jiang B, Inoue T, Nabata T, Fukuo K, Ogihara T. 1994. Effects of an angiotensin II receptor antagonist, CV-11974, on angiotensin II-induced increases in cytosolic free calcium concentration, hyperplasia, and hypertrophy of cultured vascular smooth muscle cells. J Cardiovasc Pharmacol 23:175–179.PubMedCrossRefGoogle Scholar
- 34.Snedecor GW, Cochran WG. 1967. Statistical Methods, Ames, Iowa: Iowa State University Press.Google Scholar
- 40.Stephenson RP. 1956. A modification of receptor theory. Br J Pharmacol 11:379–393.Google Scholar
- 41.Kaye AD, Nossaman BD, Smith DE, Ibrahim II, Imig JD, Kadowitz PJ. 1977. The effects of inhibition of phospholipase A2, 12-lipoxygenase and cyclooxygenase on vasoconstrictor responses in the pulmonary vascular bed of the cat. Am J Physiol, in press.Google Scholar
- 42.Kaye AD, Nossaman BD, Ibrahim II, Kadowitz PJ. 1995. Influence of phospholipase C and myosin light chain kinase inhibitors U73122 and KT5926, and the role of L-and N-calcium channels on vasoconstrictor responses in the pulmonary vascular beds of the cat and rat. Am J Physiol 269X532–L538.Google Scholar
- 43.Kaye AD, Nossaman BD, Ibrahim II, Kadowitz PJ. 1995. Influence of protein kinase C inhibitors on vasoconstrictor responses in the pulmonary vascular beds of the cat. Am J Physiol 268:L507–L513.Google Scholar