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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Blockade of AT₁ receptors in the rostral ventrolateral medulla increases sympathetic activity under hypoxic conditions

Department of Physiology and Institute for Biomedical Research, University of Sydney, New South Wales, Australia

Submitted 9 June 2005 ; accepted in final form 3 October 2005

The role of ANG type 1 (AT₁) receptors in the rostral ventrolateral medulla (RVLM) in the maintenance of sympathetic vasomotor tone in normotensive animals is unclear. In this study, we tested the hypothesis that AT₁ receptors make a significant contribution to the tonic activity of presympathetic neurons in the RVLM of normotensive rats under conditions where the excitatory input to these neurons is enhanced, such as during systemic hypoxia. In urethane-anesthetized rats, microinjections of the AT₁ receptor antagonist candesartan in the RVLM during moderate hypoxia unexpectedly resulted in substantial increases in arterial pressure and renal sympathetic nerve activity (RSNA), whereas under normoxic conditions the same dose resulted in no significant change in arterial pressure and RSNA. Under hypoxic conditions, and after microinjection of the GABA_A receptor antagonist bicuculline in the RVLM, subsequent microinjection of candesartan in the RVLM resulted in a significant decrease in RSNA. In control experiments, bilateral microinjections in the RVLM of the compound [Sar¹,Thr⁸]ANG II (sarthran), which decreases sympathetic vasomotor activity via a mechanism that is independent of AT₁ receptors, significantly reduced arterial pressure and RSNA under both normoxic and hypoxic conditions. The results indicate that, at least under some conditions, endogenous ANG II has a tonic sympathoinhibitory effect in the RVLM, which is dependent on GABA receptors. We suggest that the net effect of endogenous ANG II in this region depends on the balance of both tonic excitatory and inhibitory actions on presympathetic neurons and that this balance is altered in different physiological or pathophysiological conditions.

brain stem; angiotensin receptors; arterial pressure; chemoreceptor reflex; sympathetic vasomotor tone; angiotensin type 1 receptor

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