Effects of angiotensin metabolites in the coronary vascular bed of the spontaneously hypertensive rat: loss of angiotensin II type 2 receptor-mediated vasodilation.
Because angiotensin (Ang) metabolites mediate functions independent of Ang II, we investigated their effects on coronary flow in spontaneously hypertensive rats (SHRs). Results were compared with those in the iliac artery and abdominal aorta and the coronary circulation of the Wistar rat. Ang II, III, and IV decreased coronary flow in SHRs and Wistar rats, with Ang III and IV being approximately 10 and approximately 1000 times less potent than Ang II. Ang-(1-7) decreased coronary flow at concentrations >1 micromol/L in SHRs. The Ang II type 1 receptor antagonist irbesartan blocked the effects of Ang II, III, and IV, whereas the Ang II type 2 receptor antagonist PD123319 blocked the effects of Ang-(1-7). The maximal Ang II- and III-induced decreases in coronary flow in SHRs were twice as large as those in Wistar rats. PD123319 enhanced the constrictor effects of Ang II and III in Wistar rats so that, in the presence of this drug, their effects were comparable to those in SHRs. In contrast, PD123319 did not alter the Ang II- and III-induced responses in SHRs and blocked the constrictor effect of Ang II in iliac arteries. Ang II type 2 receptor-mediated relaxation did not occur in iliac arteries and abdominal aortas, and the constrictor effects of Ang metabolites in these vessels were identical in Wistar rats and SHRs. In conclusion, coronary constriction induced by Ang II, Ang III, and Ang-(1-7) is enhanced in SHRs as compared with Wistar rats. This is attributable to the absence of counterregulatory Ang II type 2 receptor-mediated relaxation and/or a change of the Ang II type 2 receptor phenotype from relaxant to constrictor.
Moltzer
Els
E
Division of Pharmacology, Erasmus MC, Rotterdam, The Netherlands.
Verkuil
Anna V A
AV
van Veghel
Richard
R
Danser
A H Jan
AH
van Esch
Joep H M
JH
D000704:Analysis of Variance; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D000805:Angiotensin III / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D007083:Iliac Artery / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D000077405:Irbesartan; D008297:Male; D011336:Probability; D011725:Pyridines / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D012016:Reference Values; D013777:Tetrazoles / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D000804:Angiotensin II; D000805:Angiotensin III; C073402:PD 123319; D000077405:Irbesartan