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Differential modulation by estrogen of ₂-adrenergic and I₁-imidazoline receptor-mediated hypotension in female rats

Department of Pharmacology, School of Medicine, East Carolina University, Greenville, North Carolina 27858

Submitted 15 April 2004 ; accepted in final form 14 May 2004

We have recently shown that estrogen negatively modulates the hypotensive effect of clonidine (mixed ₂-/I₁-receptor agonist) in female rats and implicates the cardiovascular autonomic control in this interaction. The present study investigated whether this effect of estrogen involves interaction with ₂- and/or I₁-receptors. Changes evoked by a single intraperitoneal injection of rilmenidine (600 µg/kg) or -methyldopa (100 mg/kg), selective I₁- and ₂-receptor agonists, respectively, in blood pressure, hemodynamic variability, and locomotor activity were assessed in radiotelemetered sham-operated and ovariectomized (Ovx) Sprague-Dawley female rats with or without 12-wk estrogen replacement. Three time domain indexes of hemodynamic variability were employed: the standard deviation of mean arterial pressure as a measure of blood pressure variability and the standard deviation of beat-to-beat intervals (SDRR) and the root mean square of successive differences in R-wave-to-R-wave intervals as measures of heart rate variability. In sham-operated rats, rilmenidine or -methyldopa elicited similar hypotension that lasted at least 5 h and was associated with reductions in standard deviation of mean arterial pressure. SDRR was reduced only by -methyldopa. Ovx significantly enhanced the hypotensive response to -methyldopa, in contrast to no effect on rilmenidine hypotension. The enhanced -methyldopa hypotension in Ovx rats was paralleled with further reduction in SDRR and a reduced locomotor activity. Estrogen replacement (17-estradiol subcutaneous pellet, 14.2 µg/day, 12 wk) of Ovx rats restored the hemodynamic and locomotor effects of -methyldopa to sham-operated levels. These findings suggest that estrogen downregulates ₂- but not I₁-receptor-mediated hypotension and highlight a role for the cardiac autonomic control in -methyldopa-estrogen interaction.

rilmenidine; -methyldopa; blood pressure; hemodynamic variability

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