Central modulation of baroreceptor reflex response to phenylephrine by dihydropyridines in rats.

The effects of two dihydropyridine derivatives, the calcium channel agonist BAY k 8644 or the antagonist PN 200-110, on the central nervous components of the baroreceptor reflex control of heart rate during activation of baroreceptors by phenylephrine (2 micrograms i.v.) were studied in pentobarbital-anesthetized normotensive (Wistar) rats and spontaneously hypertensive rats (SHR). To rule out an effect on peripheral vessels or on the sinoauricular node (or on both), BAY k 8644 and PN 200-110 were administered intracerebroventricularly (i.c.v.) at doses that did not change blood pressure. Baroreceptor reflex sensitivity was calculated as the slope of the relationship between systolic arterial pressure and heart period. Baroreceptor reflex sensitivity increased with time following the onset of anesthesia. In SHR, injection of BAY k 8644 (3 micrograms/kg i.c.v.) suppressed the time-dependent increase in baroreceptor reflex sensitivity. The inhibitory effect of BAY k 8644 (3 micrograms/kg i.c.v.) on the time-dependent increase in baroreceptor reflex sensitivity was suppressed by pretreatment with PN 200-110 (0.6 microgram/kg i.c.v.) but not with the solvent, indicating that the central effect of BAY k 8644 occurred at the level of specific dihydropyridine binding sites. In addition, the inhibitory effect of BAY k 8644 (3 micrograms/kg i.c.v.) on the time-dependent increase in baroreceptor reflex sensitivity was suppressed by pretreatment with the muscarinic antagonist atropine methylnitrate (80 micrograms/kg i.c.v.) but not with the solvent. In normotensive rats, the time-dependent increase in baroreceptor reflex sensitivity was not significantly altered by BAY k 8644 (3 micrograms/kg i.c.v.).(ABSTRACT TRUNCATED AT 250 WORDS)

Central cardiovascular action of penicillin in anaesthetized dogs and rats.

Penicillin (2-3 mg X kg-1) administered into the cisterna magna (i.c.) of dogs anaesthetized with alpha-chloralose induced a significant increase in mean blood pressure (MBP) and bradycardia, whereas intravenous injections of the same doses had negligible effects. Moreover, dogs receiving central injections of penicillin showed seizures abolished by administration of decamethonium bromide (100 micrograms X kg-1, i.v.). In urethane anaesthetized rats, intracerebroventricular (i.c.v.) injections of penicillin (0.3-3 mg X kg-1) caused dose-dependent increases in mean blood pressure while the intravenous route led to opposite effects. gamma-aminobutyric acid (GABA) (1 mg X kg-1), its agonist muscimol (2 micrograms X kg-1) and the alpha 2-adrenoceptor agonist clonidine (1 micrograms X kg-1) injected intracisternally induced hypotension and bradycardia in dogs. These effects were abolished in animals pretreated with penicillin. In rats, the same agents injected intraventricularly respectively at 0.5 mg X kg-1, 0.5 micrograms X kg-1 induced also hypotension. The effect of clonidine only, was antagonized by pretreatment with penicillin, while penicillin administered at the peak of the hypotensive effect caused by GABA or muscimol reversed it. It is suggested that penicillin acts centrally as a GABA-antagonist, and that the cardiovascular effects of clonidine seem to be mediated, at least in part, by the stimulation of a GABAergic pathway controlling the autonomic nervous system.

Interaction between central alpha 1- and alpha 2-adrenoceptors on sympathetic tone in rats.

The interaction between piperoxan and alpha 2-agonists on sympathetic tone was studied in rats. The sympatho-inhibitory effect of alpha 2-agonists (clonidine, guanfacine, B-HT 933) was assessed by recording heart rate in normotensive bilaterally-vagotomized rats. Clonidine (3 micrograms/kg, i.c.v.) and B-HT 933 (100 micrograms/kg, i.c.v.) induced a bradycardia which was fully reversed by piperoxan (30 micrograms/kg, i.c.v.). However, in rats treated with guanfacine, piperoxan induced a partial recovery of the bradycardic effect. The injection of a small dose of the specific alpha 1-adrenoceptor blocking drug, AR-C 239 (10 micrograms/kg, i.c.v.) which, by itself did not modify heart rate, completely inhibited the reversal effect of piperoxan in rats treated with clonidine, B-HT 933 or guanfacine. In rat brainstem membranes, B-HT 933 was found to bind to both alpha 1- and alpha 2-adrenoceptors and was as potent as clonidine in competing for alpha 1-sites bound by [3H]prazosin. On the other hand, in bilaterally vagotomized rats, piperoxan (30 micrograms/kg, i.c.v.) induced an increase in blood pressure and heart rate which was inhibited by previous administration of AR-C 239 (10 micrograms/kg, i.c.v.). These data suggest that, by inhibiting central alpha 2-adrenoceptors, piperoxan unmasks central alpha 1-adrenoceptor stimulation by endogenous catecholamines leading to an increase in the sympathetic tone, but a full recovery in heart rate could be observed only with the mixed alpha 1- and alpha 2-adrenoceptor agonists, clonidine and B-HT 933. In addition, these data further indicate that alpha 1-adrenoceptors are implicated in a tonic control of the sympathetic nerve activity in normotensive rats.

Pulse pressure gradient along the aortic tree in normotensive Wistar-Kyoto and spontaneously hypertensive rats: effect of nicardipine.

BACKGROUND: In large animals pulse pressure increases from central to peripheral arteries whereas mean arterial pressure decreases slightly. This haemodynamic pattern has not been verified in small animals, particularly in hypertensive rats before and after administration of antihypertensive drugs. DESIGN: The intra-arterial blood pressure of normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) was determined along the aorta in anaesthetized and conscious rats. In anaesthetized rats the study was performed before and after acute intravenous nicardipine administration (30 micrograms/kg). RESULTS: Mean arterial pressure was significantly higher in untreated SHR than in WKY rats, and within each strain was quite similar along the aortic tree. Pulse pressure increased significantly from the central to the terminal aorta in WKY rats, principally due to an increase in systolic blood pressure. In SHR pulse pressure did not differ along the aortic tree. Compared with in WKY rats, aortic pulse pressure in SHR was significantly elevated whereas femoral pulse pressure was quite similar. Acute nicardipine administration re-established the pulse pressure gradient in SHR, due to a significant decrease in central aortic pulse pressure with no significant change in femoral pulse pressure. CONCLUSIONS: These results suggest, first, that since there are large differences in pulse pressure in the proximal aorta of SHR and WKY rats but only small or negligible differences in the distal aorta, the measurement of pulse pressure may be an available index to differentiate normotensive and hypertensive rats, and secondly, that increased aortic pulse pressure in SHR participates in the increase in cardiac afterload independently of mean arterial pressure, and may be a preferential site of action of antihypertensive agents.

Reversal of the central hypotensive effect of clonidine by intracisternal curare-like agents.

Administration of tubocurarine, pancuronium, gallamine, or decamethonium into the cisterna magna of chloralosed dogs induced a rise in blood pressure. Clonidine (3 micrograms/kg) administered into the cisterna magna after tubocurarine, pancuronium, or gallamine significantly increased blood pressure; no significant change was found after decamethonium. The pressor response to clonidine after tubocurarine was antagonized by injection of the alpha 1-adrenoceptor-blocking agents AR-C 239 or prazosin into the cisterna magna at low doses prior to injection of clonidine. Yohimbine, a preferential alpha 2-adrenoceptor-blocking agent was ineffective. It is suggested that the pressor response to intracisternal clonidine after intracisternal tubocurarine is due to stimulation of alpha 1-adrenoceptor stimulation.

Is the pressor response to strychnine centrally mediated?

Intravenous administration of strychnine (0.003-0.300 mg . kg-1) to curarized, chloralosed dogs induced hypertension and tachycardia. In spinal cord-transected dogs, intravenous administration of strychnine no longer elicited a rise in blood pressure and heart rate. Intracisternal injections of strychnine also produced hypertension and tachycardia but at lower doses. Similar results were obtained after intrathecal administration of strychnine in doses significantly different from those effective on intravenous and intracisternal administration. These findings suggest that the central nervous system may be involved in the haemodynamic changes induced by strychnine, but did not allow the site of action to be located.

Central cardiovascular actions of d-tubocurarine and inhibition of the hypotensive effect of clonidine.

Intracisternal (i. cist.) administration of d-tubocurarine (0.025-0. 100 mg. kg-1) in alpha-chloralose-anaesthetized dogs caused a dose-related increase in blood pressure associated with seizures. When injected in dogs pretreated with guanethidine (15 mg. i.v.), d-tubocurarine elicited the same effect while bilateral adrenalectomy abolished the pressor response. The hypotensive effect of clonidine (0.003 mg. kg-1 i. cist.) was reversed when clonidine was given after the alkaloid. These results suggest possbile interactions of the drugs at central GABA-ergic, glycinergic or cholinergic synapses.

Central and peripheral cardiovascular effects of the enantiomers of the calcium antagonist PN 200-110.

The negative inotropic effects and the central and peripheral hypotensive effects of (+) and (-) PN 200-110 were investigated in cultured chick heart cells and in spontaneously hypertensive rats, respectively. There was a large difference in negative inotropic potency between the two enantiomers in cultured chick embryo ventricular cells: the (+) enantiomer was 140 fold more potent (IC50 = 1.1 +/- 0.2 nM) than the (-) enantiomer (IC50 = 160 +/- 20 nM). (+) PN 200-110 was 10 fold more potent than (-) PN 200-110 in lowering blood pressure after intravenous injection and only three fold more potent after intra-cerebroventricular injection (i.c.v.) into pentobarbital-anaesthetized spontaneously hypertensive rats. I.c.v. administered (+) PN 200-110 (1 microgram/kg) partially antagonized the hypertensive response to i.c.v. administered BAY K 8644 (30 micrograms/kg), a calcium channel agonist, while the same dose of the (-) enantiomer did not change the i.c.v. BAY-induced increase in blood pressure. These results suggest that the dihydropyridine calcium channel antagonist, PN 200-110, may act centrally and stereoselectively at the level of the dihydropyridine receptor sites involved in the control of blood pressure in spontaneously hypertensive rats.

[Central control of the baroreflex response to phenylephrine by dihydropyridines in the anesthetized rat]. / Contrôle central de la réponse baroréflexe à la phényléphrine par les dihydropyridines chez le rat anesthésié.

We have previously shown that a calcium channel activator (BAY K 8644) and a calcium channel inhibitor (CCI) (nifedipine), both dihydropyridine derivatives (DHP), can modulate in opposite fashion calcium dependent mechanisms involved in the central control of blood pressure and heart rate in SHR but not in Wistar rats. These results suggested that central DHP receptor sites might modulate baroreflex function. Therefore, we studied in pentobarbital anaesthetized SHR, the effects of BAY K 8644 and PN (200-110) (CCI) on central integration of baroreflex function (ramp method: phenylephrine 2 microgram i.v.). In order to rule out peripheral vascular effects, BAY and PN were administered intracerebroventricularly (i.c.v.) at doses which did not change BP. Baroreflex sensitivity (BRS) increased with time following the onset of anesthesia. In SHR, i.c.v. injection of BAY (3 microgram/kg) but not PN (0.6 micrograms/kg) suppressed the time dependent increase in BRS. The inhibitory effect of BAY on the time-dependent increase in BRS was suppressed by a pretreatment with PN (0.6 micrograms/kg i.c.v.) and by a pretreatment with the muscarinic antagonist atropine methylnitrate (80 micrograms/kg i.c.v.). BAY i.c.v. dit not change BRS in Wistar rats. These results indicate that DHP may centrally modulate BRS in SHR and suggest a central sympatho-excitatory effect for BAY mediated by an enhanced release of acetylcholine.

Furter investigations on the interaction between alpha-adrenoceptor antagonists and the central hypotensive effect of clonidine in rats, rabbits and dogs.

1. The interactions between five alpha-adrenoceptor blocking agents and clonidine have been studied in rats, rabbits and dogs after intracisternal injections. 2. Dibozane, ethomoxane, azapetine, dibenamine and thymoxamine reduced blood pressure in rats and an antagonism of the hypotensive effects of clonidine was detected for the first four drugs. 3. In rabbits, azapetine, dibenamine, dibozane and ethomoxane were hypotensive while thymoxamine had no effect on blood pressure. Dibozane and dibenamine reduced the hypotensive effect of clonidine. 4. In dogs, azapetine, dibozane and ethomoxane reduced blood pressure, while dibenamine induced an increase in blood pressure and thymoxamine was without effect. Only dibenamine antagonized the blood pressure lowering effect of clonidine. A definite conclusion could not be drawn with azapetine due to its long duration of action of action in both rabbits and dogs. 5. These results suggest that the central receptors involved in the hypotensive effect of clonidine differ from many other central receptors and vary according to the animal species. In addition the alpha-adrenoceptor blocking agents appear not to have a unique site and mechanism of action on central cardiovascular control.