Cardiovascular responses to intrathecal dopamine receptor agonists in conscious DOCA‐salt hypertensive rats

Abstract

Previous studies have demonstrated that in conscious deoxycorticosterone acetate (DOCA)-salt hypertensive rats, the hypotensive action of intravenous (i.v.) bromocriptine, a selective dopamine D2 receptor agonist, was mediated partly by peripheral and partly by spinal dopamine D2 receptor stimulation, and that this effect was greater and longer-lasting than that in uninephrectomized control rats. To determine whether this amplification results partly from a putative spinal hypersensitivity phenomenon, cardiovascular responses to intrathecal (i.t.) administration of apomorphine and quinpirole were studied in conscious, 4-week DOCA-salt hypertensive rats and compared with those in uninephrectomized control rats. In both groups, upper thoracic (T2-T4) i.t. injections of apomorphine (9.1, 45.5 and 91.1 microg/rat) induced immediate and dose-dependent decreases in mean aortic pressure (MAP) and heart rate (HR), while i.t. quinpirole (38.4 microg/rat) induced only bradycardia. Neither magnitude nor duration of these responses was enhanced in DOCA-salt hypertensive rats when compared to control rats. In DOCA-salt hypertensive rats, apomorphine-induced hypotension and bradycardia remained unaffected by i.v. (500 microg/kg) pretreatment with domperidone, a selective dopamine D2 receptor antagonist that does not cross the blood-brain barrier. However, i.t. (40 microg/rat at T2-T4) pretreatment with domperidone significantly reduced apomorphine-induced hypotension, but fully suppressed bradycardia elicited by either apomorphine or quinpirole. These results demonstrated that in conscious DOCA-salt hypertensive rats, intrathecally-injected apomorphine or quinpirole decreased MAP and/or HR through a spinal D2 dopaminergic mechanism, as previously demonstrated in normotensive intact rats. Since both magnitude and duration of these responses were unchanged with respect to uninephrectomized control rats, enhancement of the hypotensive effect of intravenously-administered bromocriptine in DOCA-salt hypertensive rats does not appear to involve spinal dopamine D2 receptors.

Blockade of Spinal Dopamine D2 Receptors Enhances the Pressor Effect of Intravenous Quinpirole in Normotensive, Conscious Rats

“…Thus, it seems most likely that systemic quinpirole stimulates spinal dopamine D 2 receptors to decrease blood pressure via withdrawal of sympathetic outflow to the vasculature. Finally, the fact that blockade of spinal dopamine D 2 receptors by intrathecally injected domperidone failed to alter the baseline mean aortic pressure values in conscious normotensive rats, agrees with the previous concept that spinal dopaminergic pathways controlling blood pressure are not activated under normal conditions, at least in Wistar rats (Lahlou et al 1990;Lahlou & Demenge 1991;Lahlou 1998Lahlou & 1999.…”

“…In fact, blockade of low thoracic spinal dopamine D 2 receptors by intrathecal domperidone in conscious intact rats significantly enhances the maximal pressor response to intravenous quinpirole. Diffusion of intrathecal domperidone by the circulation seems unlikely, since this antagonist, which does not cross the blood-brain barrier, was shown to counteract the cardiovascular responses to intrathecal dopamine D 2 receptor agonists (Petitjean et al 1984;Lahlou 1998Lahlou & 1999. Furthermore, diffusion of intrathecal domperidone into brain stem structures by direct central spreading also seems unlikely since it was unable to prevent the quinpirole-induced stereotyped movements, which results from activation of brain dopamine D 2 receptors (metoclopramide did block the quinpirole-induced stereotypy).…”

“…Previous studies from our laboratory show that stimula- tion of spinal dopamine receptors by intrathecal dopamine receptor agonists decreased mean aortic pressure and heart rate in either normotensive (Petitjean et al 1984;Lahlou et al 1990;Lahlou & Demenge 1993) or hypertensive DOCAsalt conscious rats (Lahlou 1999). These hypotensive and bradycardic effects are of spinal dopaminergic origin and appear to result from withdrawal of spinal sympathetic outflow to the vasculature and to the heart, respectively (Lahlou et al 1990;Lahlou & Demenge 1993;Lahlou 1999).…”

“…These hypotensive and bradycardic effects are of spinal dopaminergic origin and appear to result from withdrawal of spinal sympathetic outflow to the vasculature and to the heart, respectively (Lahlou et al 1990;Lahlou & Demenge 1993;Lahlou 1999). Blockade of spinal dopamine D 2 receptors by intrathecal domperidone, a selective dopamine D 2 receptor antagonist that does not cross the blood-brain barrier (Laduron & Leysen 1979;Sved & Fernströ m 1980;Kohli et al 1983;Champion 1988), reduces partially, but significantly, the depressor action of the dopamine D 2 receptor agonist, bromocriptine, when administered intravenously to either normotensive (Lahlou & Demenge 1991) or DOCA-salt hypertensive conscious rats (Lahlou & Pinto Duarte 1998).…”

Central Bromocriptine‐Induced Tachycardia is Reversed to Bradycardia in Conscious, Deoxycorticosterone Acetate‐Salt Hypertensive Rats

“…On the other hand, it is possible that a putative hypersensitivity of spinal dopamine D 2 receptors might account for the blunted tachycardiac effects of bromocriptine in deoxycorticosterone acetate-salt hypertensive rats. However, this seems also unlikely since it was recently shown that bradycardiac responses to intrathecally-administered dopamine receptors in deoxycorticosterone acetate-salt hypertensive rats did not differ significantly from those in uninephrectomized, control rats, either in magnitude or in duration (Lahlou 1999).…”