Evidence for a functional cardiac interaction between losartan and angiotensin‐(1–7) receptors revealed by orthostatic tilting test in rats

Abstract

1 Studies have shown that the angiotensin II (Ang II) AT 1 receptor antagonist, losartan, accentuates the orthostatic hypotensive response in anesthetized rats, and there is evidence indicating that this effect is not exclusively mediated by AT 1 receptors. 2 We investigated whether the pronounced orthostatic cardiovascular response observed in losartantreated rats involves an interference with angiotensin-(1-7) (Ang-(1-7)) receptors. 3 Urethane-anesthetized rats were submitted to orthostatic stress (901 head-up tilt for 2 min). Intravenous injection of losartan (1 mg kg À1 , n ¼ 9) significantly accentuated the decrease in mean arterial pressure (MAP) induced by head-up tilt (À3376% after losartan vs À1578% control tilt). This effect was accompanied by a significant bradycardia (À873% after losartan vs À373% control tilt). Another AT 1 antagonist, candesartan, did not potentiate the decrease of MAP and did not change the cardiac response induced by head-up tilt. Strikingly, administration of the Ang-(1-7) antagonist, A-779 (10 nmol kg À1 , n ¼ 5), totally reversed the bradicardiac effect caused by losartan and this effect was accompanied by a tendency towards attenuation of the hypotensive response caused by losartan. 4 These findings indicate that the marked orthostatic cardiovascular response is specific for losartan, and that it may be due, in part, to an interaction of this antagonist with Ang-(1-7) receptors, probably at the cardiac level.

Cardiovascular reactivity after blockade of angiotensin AT1 receptors in the experimental model of tilting test in conscious rats

“…Previous reports using anaesthetized preparations showed a clear difference between the effects of losartan and other AT 1 antagonists on the cardiovascular response to orthostatic stress, showing a pronounced hypotensive response only in the losartan-treated rats (Ohlstein et al, 1992;Hashimoto et al, 1999;de Moura et al, 2005). In contrast, the present data in conscious rats reveal that the effect produced by losartan on the cardiovascular reactivity to orthostatic stress exhibits a profile similar to that of a highly specific AT 1 antagonist (Maillard et al, 2002).…”

“…Therefore, the development of animal models that might, as closely as possible, reproduce the cardiovascular effects produced by orthostatic challenges would be useful to the investigation of the mechanisms involved. A model for predicting orthostatic hypotension during antihypertensive drug therapy in rats was first reported by Humphrey and McCall (1982) and has been validated by different laboratories (Ohlstein et al, 1992;Hashimoto et al, 1999) including ours (de Moura et al, 2005). However, different anaesthetics might importantly influence the level of peripheral sympathetic outflow or sympathetic reactivity (Weaver and Stein, 1989;Shimokawa et al, 1998), and the sympathetic reactivity is the only mechanism responsible for the maintenance of normal levels Changes in MAP and HR caused by orthostatic stress (tilt) in conscious rats after oral treatment with losartan (1 mg kg À1 , n ¼ 6), telmisartan (1 mg kg À1 , n ¼ 5) or vehicle (0.9% NaCl, 1 ml kg…”

“…Previous studies have shown that the AT 1 receptor antagonist, losartan, accentuated the orthostatic hypotensive response in the orthostatic stress model carried out in rats (Ohlstein et al, 1992;Hashimoto et al, 1999;de Moura et al, 2005). The same effect was not observed with other highly selective AT 1 receptor antagonists, suggesting that at least peripherally, the orthostatic hypotensive effect caused by losartan was due to effects other than the antagonism of AT 1 receptors.…”

“…The same effect was not observed with other highly selective AT 1 receptor antagonists, suggesting that at least peripherally, the orthostatic hypotensive effect caused by losartan was due to effects other than the antagonism of AT 1 receptors. However, in all these studies, the orthostatic stress test was performed in anaesthetized rats (Ohlstein et al, 1992;Hashimoto et al, 1999;de Moura et al, 2005). Although the use of anaesthesia is sometimes necessary in different experimental approaches, it is also known that anaesthetics alter the central sympathetic output (Shimokawa et al, 1998).…”

Involvement of the paraventricular nucleus (PVN) of hypothalamus in the cardiovascular alterations to head up tilt in conscious rats

“…The head up tilt is an accepted methodology to induce orthostatic challenge in anesthetized rats (Ohlstein et al, 1992;Hashimoto et al, 1999;De Moura et al, 2005), and has been also published a model developed for conscious rats (Bedette et al, 2008), which was used in this study. To test the efficacy of the method of tilt test in conscious rats in detecting orthostatic hypotension, a group of rats was injected with prazosin plus atenolol (0.1 and 2.5 mg/kg, intravenous).…”