Chronic ethanol administration attenuates imidazoline I 1 receptor- or a 2 -adrenoceptor-mediated reductions in blood pressure and hemodynamic variability in hypertensive rats Mahmoud M. El-Mas, Abdel A. Abdel-Rahman * Department of Pharmacology, School of Medicine, East Carolina University, Greenville, NC 27858-4353, USA Received 26 August 2003; received in revised form 20 November 2003; accepted 28 November 2003 Abstract Our previous studies have demonstrated that acute ethanol administration counteracts imidazoline I 1 receptor but not a 2 -adrenoceptor- mediated hypotension in spontaneously hypertensive rats (SHR). In the present study, we investigated the effect of chronic ethanol administration on hypotensive responses elicited by acute administration of selective imidazoline I 1 receptor (rilmenidine) or a 2 -adrenoceptor (a-methyldopa) agonist along with ethanol effects on: (i) locomotor activity and (ii) time-domain indices of variability in blood pressure (standard deviation of mean arterial pressure) and heart rate (standard deviation of beat-to-beat intervals and root mean square of successive differences in R – R intervals). Hemodynamic and locomotor responses elicited by rilmenidine or a-methyldopa were assessed in radiotelemetered ethanol-fed (2.5% or 5% w/v, 12 week) and control SHR. In control SHR, i.p. rilmenidine (600 Ag/kg) or a-methyldopa (100 mg/kg) significantly reduced blood pressure. Rilmenidine had no effect on heart rate whereas a-methyldopa elicited a biphasic response (tachycardia followed by bradycardia). Blood pressure and heart rate oscillations were also reduced by both drugs, which may conform to sympathoinhibition. The hypotensive effect of rilmenidine or a-methyldopa was significantly attenuated by ethanol feeding (2.5% or 5%) in a concentration-dependent manner. In addition, ethanol attenuated a-methyldopa-evoked reduction in heart rate, but not blood pressure, variability in marked contrast to attenuating rilmenidine-evoked reductions in blood pressure, but not heart rate, variability. These findings demonstrate that, unlike its acute effects, chronic ethanol attenuates both imidazoline I 1 receptor and a 2 -adrenoceptor-mediated hypotension whereas its effect on hemodynamic variability depended on the nature of the hypotensive stimulus. D 2003 Elsevier B.V. All rights reserved. Keywords: Ethanol; Rilmenidine; a-Methyldopa; Hypotension; Hemodynamic variability; Time-domain analysis 1. Introduction Experimental findings from our laboratory have shown that ethanol compromises the hypotensive effect of centrally acting antihypertensive agents such as clonidine and guana- benz (Abdel-Rahman, 1989; El-Mas et al., 1994b). These findings are clinically relevant as ethanol intake has been associated with inadequate blood pressure control in treated hypertensive patients (Volicer et al., 1978; Puddey et al., 1987). The adverse effect of ethanol on centrally mediated hypotensive responses is demonstrated in conscious aortic barodenervated (El-Mas et al., 1994b) and spontaneously hypertensive rats (SHR; Abdel-Rahman, 1989; Abdel-Rah- man et al., 1992). In contrast, peripherally mediated hypo- tensive responses (e.g. hydralazine, nitroprusside, or hexamethonium) are not affected by ethanol (Abdel-Rah- man, 1989; Abdel-Rahman et al., 1992; El-Mas and Abdel- Rahman, 1997b). These findings suggest that the adverse effect of ethanol on centrally mediated hypotensive responses involves, at least in part, the central nervous system. This view is further supported by ethanol counter- action of the centrally mediated sympathoinhibition elicited by clonidine. Ethanol counteracted clonidine-evoked reduc- tions in plasma norepinephrine levels (Abdel-Rahman et al., 1992; El-Mas et al., 1994b) and in norepinephrine electro- chemical signal in the rostral ventrolateral medulla (Mao and Abdel-Rahman, 1998). Nonetheless, the possible involve- ment of the peripheral hemodynamic effects of ethanol, e.g. vasodilatation of cutaneous blood vessels (Turlapaty et al., 0014-2999/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2003.11.075 * Corresponding author. Tel.: +1-252-744-3470; fax: +1-252-744- 3203. E-mail address: abdelrahmana@mail.ecu.edu (A.A. Abdel-Rahman). www.elsevier.com/locate/ejphar European Journal of Pharmacology 485 (2004) 251 – 262