Comparison of the vascular and antiadrenergic activities of four angiotensin II type 1 antagonists in the pithed rat

Abstract

Background  

Angiotensin II is known to facilitate the release of catecholamines from peripheral sympathetic neurons by stimulating presynaptically located receptors. Although inhibitor studies have revealed these to be angiotensin II type 1 (AT₁) receptors, they do in fact appear to display peculiar susceptibilities to various AT₁ receptor antagonists, which might correspond to different neuronal and vascular receptor subtypes.

Objective  

A direct comparison of the pre- and postsynaptic potencies of four AT₁ antagonists was performed to characterize these receptors further.

Design  

We studied angiotensin II-induced catecholamine release and vasoconstriction in pithed, spontaneously hypertensive rats under the influence of candesartan, eprosartan, EXP 3174, and irbesartan. The effect of AT₁ blockade on postsynaptic vascular sensitivity to noradrenaline (NA) was also determined.

Methods  

Pithed rats received repeated intravenous applications of either angiotensin II or NA, preceded by cumulatively increasing doses of the AT₁ antagonists. Vasoconstriction and catecholamine release were quantified by the measurement of acute increases in blood pressure and plasma NA, respectively.

Results  

All AT₁ antagonists dose-dependently suppressed angiotensin II-induced vasoconstriction and release of NA. Although the antagonists differed greatly in their inhibitory potencies (ID₅₀ range 7–445 μg/kg), each displayed a similar potency at both neuronal and vascular angiotensin receptors. In a higher dose range, all AT₁ antagonists attenuated the blood pressure increase in response to NA by up to 70%. The order of potencies for all inhibitory effects was: candesartan > eprosartan > EXP 3174 > irbesartan.

Conclusion  

The AT₁ antagonists tested do not discriminate between presynaptic neuronal and postsynaptic vascular angiotensin II receptors – a fact that refutes the existence of tissue-specific AT₁ receptor subtypes. A marked reduction in vascular sensitivity to NA may contribute to the antihypertensive and cardioprotective mechanisms of AT₁ antagonists.