CARDIOVASCULAR EFFECTS OF RILMENIDINE, A NEW α₂‐ADRENOCEPTOR AGONIST, AND CLONIDINE IN CONSCIOUS SPONTANEOUSLY HYPERTENSIVE RATS

Abstract

1. The acute and chronic effects of rilmenidine, a partial agonist of alpha 1- and alpha 2-adrenoceptors with antihypertensive properties, were compared to those of clonidine on blood pressure (BP), heart rate (HR) and the urinary excretion of catecholamines, which was used as an index of sympathetic activity. 2. As these drugs are known to interfere centrally and peripherally with the sympathetic nervous system, long-term arterial blood pressure recordings in freely moving unstressed adult spontaneously hypertensive rats (SHR) were used. 3. Acute i.v. administrations of rilmenidine (0.3 mg/kg at 1200 h, 1.2 mg/kg at 1700 and 2200 h) and clonidine (12 micrograms/kg at 1200 h, 50 micrograms/kg at 1700 and 2200 h) induced short-lasting increases in BP associated with a decrease in HR, which were followed by prolonged, dose-dependent decreases in BP without bradycardia. The pressor effect was less marked and the associated bradycardia was more marked in active SHR with physiologically high sympathetic activity than in resting SHR. 4. A 12-day oral treatment with rilmenidine (6.0 mg/kg daily) or clonidine (150 micrograms/kg daily) induced moderate decreases in BP without change in HR. Rilmenidine but not clonidine decreased normetanephrine (NMN) excretion in active but not in resting SHR. 5. Finally, during the 24 h following the cessation of the treatments, BP returned to normal, without significantly exceeding that of untreated controls. However, upswings in BP or HR were observed, more markedly and frequently after clonidine than after rilmenidine. 6. In conclusion the effects of alpha 2-adrenoceptor agonists appear to be influenced by the pre-existing sympathetic tone. The general agreement between these data and those observed in patients demonstrates that the use of conscious unstressed animals is of value to determine the cardiovascular effects of drugs which act on the sympathetic nervous system.

Influence of anaesthesia on the cardiovascular effects of rilmenidine and clonidine in spontaneously hypertensive rats

“…However, the precise site(s) of action of clonidine remains unclear (Jarrott et al, 1987) and it has recently been suggested that the receptors involved differ from a2-adrenoceptors and are more specific for the imidazole structure (Meeley et al, 1986;Lachaud et al, 1988;Ernsberger et al, 1990). Furthermore, in previous experiments (Sannajust et al, 1989), we observed that in conscious SHRs, rilmenidine like clonidine induced significant but mild decreases in BP and HR, associated with a slight reduction in the urinary excretion of catecholamines taken as an index of the peripheral SNS activity. The discrepancy between these results and most of those of the literature prompted us to assess the importance of a central site of action and the effects of anaesthesia on the cardiovascular effects of rilmenidine and clonidine.…”

“…In previous experiments, we observed that in conscious freely moving SHRs, rilmenidine and clonidine, administered i.v., exhibited moderate antihypertensive activity and that this effect was more marked in active rats, i.e. with an activated SNS, than in resting animals (Sannajust et al, 1989). Therefore, the purpose of the present work was to evaluate the effects of anaesthesia on the cardiovascular effects of rilmenidine and clonidine given by i.v.…”

“…per animal. The ascertainment of the stability of the preparations during the course of the experiments was previously described (Sannajust et al, 1989); therefore two series of experiments were designed.…”

Sympathoinhibitory effects of rilmenidine may be mediated by sites located below the brainstem

“…Although the mechanism proposed for the antihypertensive action of rilmenidine in SHRs is a reduction in peripheral sympathetic tone (Van Zwieten, 1988), to our knowledge, no studies have demonstrated its direct action on the peripheral SNS activity in anaesthetized or conscious SHRs. Previous studies in conscious, unrestrained (Sannajust et al, 1989) and pentobarbitone-anaesthetized (Sannajust et al, 1992) SHRs have shown that the ability of rilmenidine and clonidine to lower BP could be related to the level of the sympathetic drive and conversely to the integrity of the cardiac baroreflex. The absence of antihypertensive effects of rilmenidine or clonidine administered by the i.c.v.…”

“…Moreover, although one mechanism proposed for the antihypertensive action of rilmenidine in spontaneously hypertensive rats (SHRs) has been a reduction in peripheral sympathetic tone (Van Zwieten, 1988), to our knowledge, no studies have been able to demonstrate the direct action of rilmenidine on the peripheral sympathetic nervous system activity in anaesthetized or conscious SHRs. Otherwise, previous studies in conscious unrestrained (Sannajust et al, 1989;1992) and pentobarbitone-anaesthetized (Sannajust et al, 1992) SHRs suggested that rilmenidine did not act primarily and exclusively on the central nervous system (forebrain/ brainstem) to lower arterial blood pressure (BP) and heart rate (HR).…”