Published Online
on April 26, 2004

A more recent version of this article appeared on May 18, 2004

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Submitted on August 13, 2002
Revised on December 2, 2003
Accepted on February 18, 2004

Angiotensin II Type 2 Receptor-Mediated Vasodilation in Human Coronary Microarteries

Wendy W. Batenburg MSc, Ingrid M. Garrelds PhD, Catherine Chapuis Bernasconi MSc, Lucienne Juillerat-Jeanneret PhD, Jorge P. van Kats PhD, Pramod R. Saxena MD, PhD, and A.H. Jan Danser PhD^*

From the Department of Pharmacology (W.W.B., I.M.G., P.R.S., A.H.J.D.) and the Department of Thoracic Surgery and Heart Valve Bank (J.P.v.K.), Lausanne), Erasmus MC, Rotterdam, the Netherlands; and the University Institute of Pathology (C.C.B., L.J.-J.), Lausanne, Switzerland.

^* To whom correspondence should be addressed. E-mail: a.danser{at}erasmusmc.nl.

Background--Angiotensin (Ang) II type 2 (AT₂) receptor stimulation results in coronary vasodilation in the rat heart. In contrast, AT₂ receptor-mediated vasodilation could not be observed in large human coronary arteries. We studied Ang II-induced vasodilation of human coronary microarteries (HCMAs).

Methods and Results--HCMAs (diameter, 160 to 500 µm) were obtained from 49 heart valve donors (age, 3 to 65 years). Ang II constricted HCMAs, mounted in Mulvany myographs, in a concentration-dependent manner (pEC₅₀, 8.6±0.2; maximal effect [E_max], 79±13% of the contraction to 100 mmol/L K⁺). The Ang II type 1 receptor antagonist irbesartan prevented this vasoconstriction, whereas the AT₂ receptor antagonist PD123319 increased E_max to 97±14% (P<0.05). The increase in E_max was larger in older donors (correlation E_max versus age, r=0.47, P<0.05). The PD123319-induced potentiation was not observed in the presence of the NO synthase inhibitor L-NAME, the bradykinin type 2 (B₂) receptor antagonist Hoe140, or after removal of the endothelium. Ang II relaxed U46619-preconstricted HCMAs in the presence of irbesartan by maximally 49±16%, and PD123319 prevented this relaxation. Finally, radioligand binding studies and reverse transcription-polymerase chain reaction confirmed the expression of AT₂ receptors in HCMAs.

Conclusions--AT₂ receptor-mediated vasodilation in the human heart appears to be limited to coronary microarteries and is mediated by B₂ receptors and NO. Most likely, AT₂ receptors are located on endothelial cells, and their contribution increases with age.

Key words: angiotensin • bradykinin • microcirculation • nitric oxide • vasodilation

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