Henri Schmitt

Role of α1-and α2-adrenoceptors in the modulation of the baroreflex vagal bradycardia

Yohimbine (100 μg/kg), an α2-adrenoceptor blocking agent when injected into the vertebral artery of anaesthetized dogs decreased the vagally mediated bradycardia induced by carotid sinus nerve stimulation. Intracisternal administration of phenylephrine (30 μg/kg) an α1-adrenpceptor agonist decreased, whereas AR-C 239 (5 μg/kg) and prazosin (5 μg/kg) two potent α1-adrenoceptor antagonists injected into the vertebral artery, potentiated the bradycardic response. These results suggest the presence of two types of α-adrenoceptors to modulate the baroreceptor pathway: α1-adrenoceptors inhibit and α2-adrenoceptors facilitate the transmission of baroreceptor impulses.

Ventrolateral medullary pressor area: site of hypotensive and sympatho-inhibitory effects of (±)8-OH-DPAT in anaesthetized dogs

Injections of 8-OH-DPAT (0.1-6 micrograms/kg) into the vertebral artery or into the cisterna magna (5 micrograms/kg) produced a dose-dependent decrease in blood pressure, heart rate and renal sympathetic nerve activity in intact anaesthetized dogs and baroreceptor-denervated dogs. 8-OH-DPAT reduced the renal sympathetic nerve activity without changing the blood pressure or heart rate in catecholamine-depleted animals. Methiothepin (0.2 mg/kg) injected into the vertebral artery reduced the blood pressure without changing the heart rate or renal sympathetic nerve activity in baroreceptor-denervated dogs. The pressor response to i.v. phenylephrine was largely attenuated. Subsequent administration of 8-OH-DPAT (3 micrograms/kg) into the vertebral artery failed to alter the sympathetic discharge. Methiothepin (0.2 mg/kg) injected into the vertebral artery reversed the sympatho-inhibitory effect of 8-OH-DPAT (3 micrograms/kg) injected by the same route without changing the blood pressure. (+/-)Pindolol (0.2 mg/kg) injected into the vertebral artery of baroreceptor-denervated dogs reduced the blood pressure and heart rate without changing renal sympathetic activity. Subsequent administration of 8-OH-DPAT (3 micrograms/kg) failed to alter the sympathetic discharge. Bilateral microinjection of 8-OH-DPAT (1 microgram) into the nucleus tractus solitarii or into the medullary raphe nuclei failed to alter the blood pressure, heart rate or renal sympathetic activity. In contrast, bilateral microinjections of 8-OH-DPAT into the ventrolateral pressor area (VLPA) (0.2 microgram) produced a marked decrease in blood pressure, heart rate and renal sympathetic nerve activity. These effects were prevented or reversed by microinjections of methiothepin (10 micrograms) at the same sites. These results indicate that the central sympatho-inhibitory effects of 8-OH-DPAT were due to the stimulation of 5-HT1A receptors located in the ventrolateral pressor area. 5-HT autoreceptors did not seem to be involved.

Central sites and mechanisms of the hypotensive and bradycardic effects of the narcotic analgesic agent fentanyl.

SummaryIn dogs, anaesthetized with chloralose, fentanyl (5 μg/kg i.v.) augmented the bradycardia produced by electrical stimulation of the carotid sinus nerves. In contrast, the same dose of the drug did not change the bradycardic response to stimulation of the nucleus of the solitary tract (NTS) indicating that a central facilitation of baroreceptor impulses occurs within the NTS, probably at the first synapse of baroreceptor reflex fibres.Bilateral destruction of the NTS caused a ful-minating hypertension and tachycardia similar to that after cutting the baroreceptor afferent fibres. After both procedures, fentanyl (20 μg/kg i.v.) produced marked hypotension and bradycardia. The bradycardic effect was abolished by cutting both vagal nerves when the dogs were pretreated with a β-adrenoceptor blocking agent (S 2395, 50 μg/kg i.v.).The results provide evidence that the NTS is not the main site of action either for the hypotensive effect or for the vagally mediated bradycardia of fentanyl. Since the dorsal nucleus of the vagal nerve was destroyed together with the NTS, this nucleus does also not appear to be a major site of the action of fentanyl.Blockade of dopamine receptors by haloperidol or pimozide or of serotonin receptors by methysergide did not change the hypotensive, bradycardic and sympathoinhibitory effects of fentanyl.

Central and peripheral sites for cardiovascular actions of dynorphin-(1–13) in rats

Dynorphin-(1-13) (i.v.) induced bradycardia and hypotension in artificially ventilated anaesthetized rats. These effects were prevented by MRZ 2266 BS. The bradycardia was inhibited by bilateral vagotomy whereas the fall in blood pressure was not sensitive to bilateral vagotomy and chlorpheniramine treatment. In pithed rats, dynorphin-(1-13) reduced heart rate. This bradycardia was prevented by MRZ 2266 BS but not by tertatolol and cimetidine. It is suggested that the dynorphin-(1-13)-induced effects result from the stimulation of central and cardiac kappa-opiate receptors.

Effects of some α-adrenoceptor agonists and antagonists on the guinea-pig ileum

SummaryThe purpose of the present study was to further characterize the α-adrenoceptors located on parasympathetic fibres. Segments of guinea-pig ileum were stimulated by transmural electrical pulses, and the ensuing contractions, which are due to the release of acetylcholine from postganglionic parasympathetic fibres, were monitored. Clonidine and tramazoline, which are thought to act preferentially on presynaptic α-adrenoceptors, reduced the contractions, whereas phenylephrine and methoxamine, postsynaptic α-adrenoceptor agonists, were ineffective. Contractions induced by acetylcholine were not changed by clonidine but were abolished by atropine. Yohimbine, piperoxan, phentolamine and thymoxamine reversed or prevented the inhibitory effect of clonidine. Prazosin and AR-C239 did not antagonize this effect. The inhibitory effect of tramazoline was antagonized by piperoxan but not by AR-C239 or by prazosin. Naloxone did not alter the action of clonidine, and piperoxan did not change the inhibitory effect of morphine.In conclusion, these experiments suggest the presence on cholinergic postganglionic fibres of both opiate receptors and α-adrenoceptors. The latter appear to resemble more closely α1-adrenoceptors than α1-adrenoceptors.

Cardiac slowing induced by peripheral κ-opiate receptor stimulation in rats

Abstract The cardiovascular effects of ethylketocyclazocine were studied in rats anaesthetized with pentobarbital and artificially ventilated. Ethylketocyclazocine (1 mg·kg −1 i.v.) induced a fall in heart rate and blood pressure. The bradycardia and the hypotension were not altered by bilateral vagotomy and atropine, but were inhibited by naloxone and Mr 2266 BS. Ethylketocyclazocine always induced bradycardia in β-adrenoreceptor-blocked and pithed animals. This bradycardia was prevented by Mr 2266 BS. These results would suggest that a direct peripheral action may occur at κ-sites, located on the heart after intravenous injection of ethylketocyclazocine in the rat.

Characterization of DOI, a putative 5-HT2 receptor agonist in the rat

DOI (1-100 micrograms/kg i.v.) induced an increase in mean blood pressure in the anaesthetized rat. Similarly, in the pithed rat, DOI (1-100 micrograms/kg i.v.) induced a dose-dependent increase in mean blood pressure, as did 5-HT. However, in contrast to 5-HT, DOI did not change the heart rate in either intact or pithed rats. In the pithed rat, the dose-pressor response curves to both 5-HT and DOI were unaffected by MDL 72222 (5-HT3 receptor antagonist), spiroxatrine or (+/-)-pindolol (5-HT1A receptor antagonists), idazoxan (alpha 2-adrenoceptor blocking agent) and AR-C 239 (alpha 1-adrenoceptor blocking agent). Only the selective 5-HT2 receptor antagonist. LY 53857, significantly and dose dependently shifted to the right the dose-response curves to both 5-HT and DOI. These results indicated that DOI possesses 5-HT2 agonistic properties and that the pressor response induced by DOI in the pithed rat is mediated via 5-HT2 receptors.

Central interactions between dihydropyridines and cholinergic systems in the control of blood pressure in rat

Intracerebroventricular (i.c.v.) injection of the 1,4-dihydropyridine (DHP) calcium channel agonist, Bay K8644 (30 micrograms/kg) increased mean blood pressure and the K+-evoked release of [3H]acetylcholine ([3H]ACh) from hippocampal slices in spontaneously hypertensive rats (SHR). The Bay K8644-induced hypertension was inhibited by a pretreatment with methylatropine (80 micrograms/kg i.c.v.). In SHR, nicardipine, a DHP calcium channel antagonist, reduced mean blood pressure when i.c.v. injected (10 micrograms/kg). The nicardipine-induced hypotension was reduced by a pretreatment with hemicholinium-3 (20 micrograms, i.c.v.). Nicardipine (1 microM) did not modify, in SHR, the K+-evoked release of [3H]ACh, but inhibited the Bay K8644-induced increase in the ACh release. In normotensive rats, neither Bay K8644 nor nicardipine modify blood pressure, when centrally injected, or the stimulated release of [3H]ACh from hippocampal slices. The participation of central DHP sites in the cholinergic transmission in genetic hypertension is discussed.

Effects of Nicergoline on the Cardiovascular System of Dogs and Rats

Summary In pentobarbitalized closed-chest dogs, nicergoline (10–100 μg/kg, i.v.) reduced blood pressure, heart rate, and splanchnic nerve activity. Intra-cisternal administration of nicergoline (3 μg/kg) only reduced splanchnic nerve activity. In open-chest dogs, nicergoline reduced blood pressure, cardiac output, and total peripheral resistance but did not change heart rate. In pithed rats treated with a β-adrenoceptor-blocking agent, nicergoline reduced the pressor responses to noradrenaline and adrenaline. Nicergoline slightly attenuated the pressor responses of dogs to noradrenaline and tyramine and, in addition, reversed the hypertension induced by adrenaline and dimethylphenyl-piperazinium. Nicergoline (100 μg/kg) increased the tachycardia induced in dogs by stimulation of the right cardiovascular nerve and prevented the inhibitory effect of clonidine on this response. However, nicergoline only partially antagonized the effect of clonidine once it was fully established. Nicergoline did not antagonize the hypotensive and bradycardic effects of clonidine when they were established. Nicergoline did not affect the vagally mediated bradycardia evoked by carotid nerve stimulation in β-adrenoceptor-blocked dogs. The compound did not change blood pressure in C1 spinal cord transected dogs. In conclusion, nicergoline appears to decrease blood pressure by blocking α-adrenoceptors and, at least at some doses, by a central inhibition of the sympathetic tone. Nicergoline appears to be a preferential α1-adrenoceptor-blocking agent.

Central α1-adrenoceptors and cardiovascular control in normotensive and spontaneously hypertensive rats

Intracerebroventricular (i.c.v.) injection of AR-C239 (30 μg/kg), a selective α1-adrenoceptor blocking drug, did not modify the heart rate in normotensive control (without pretreatment), bilaterally vagotomized and β blocked rats and in spontaneously hypertensive (SH) bilaterally vagotomized rats. Intracisternal (i.c.) administrations of AR-C 239 (30 μg/kg) however decreased the heart rate in normotensive β blocked and in SH bilaterally vagotomized rats. The differential effect of heart rate on i.c.v. versus i.c. administration of AR-C 239 suggests a brainstem localization of the α1-adrenoceptors involved. The binding of [3H]prazosin was significantly higher in homogenates from whole brain and in membranes from the cerebral cortex and hypothalamus of SH rats as compared to normotensive rats. In addition, the binding of [125I]BE 2254, a new iodinated radioligand of high specific radioactivity used to characterize α1-adrenoceptors, was significantly increased in membranes from the NTS of SH rats. These results suggest that central α1-adrenoceptors localized in the brainstem and in the hypothalamus and the cortex play a role in the control of vagal tone in normotensive rats and of sympathetic activity in SH animals. Thus, it is postulated that central α1-adrenoceptors may participate in either the genesis or the maintenance of genetic hypertension.