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Blood pressure responses to LBNP in nontrained and trained hypertensive rats.

To study the influences of 16 wk of endurance training on the reflex regulation of resting blood pressure, nontrained (NT) and trained (T) female hypertensive rats (SHR) were subjected to conditions of lower body negative pressure (LBNP). Measurements of muscle cytochrome oxidase activity and run time to exhaustion indicated that the animals were endurance trained. The rats (NT = 6, T = 7) were tranquilized with 300-600 micrograms.kg-1 diazepam (IV) before heart rates and blood pressures were measured over a range of 2.5-10.0 mm Hg of negative pressure. When subjected to conditions of LBNP, the reflex tachycardia of the T group was greater than the NT at the lower (-2.5 and -5.0 mm Hg) negative pressures. Although arterial pressure declines were similar in both groups, the T group experienced significantly less of a decline in central venous pressure than the NT animals. When chlorisondamine was used as a ganglionic blocker (2.5 mg.kg-1, IV), the fall in CVP at 10 mm Hg negative pressure was greater for the NT group while the fall in the initial systemic arterial pressure was more for the T group. From these results we concluded that training had altered the interaction between cardiopulmonary and arterial baroreflexes in these hypertensive rats and a nonneural component had been altered such as cardiac function.

Animals↗

Pathophysiological and pharmacological mechanisms of acute cocaine toxicity in conscious rats.

In conscious rats, continuous i.v. infusion of cocaine (2 mg/kg/min) produced a marked increase in blood pressure, an initial moderate increase followed by a decrease in heart rate, tonic-clonic convulsions and, finally, a lethal episode of status epilepticus. No change in rectal temperature was observed. Infusion of cocaine methiodide (2 mg/kg/min), a quaternary derivative of cocaine, also produced a lethal episode of status epilepticus, but it was 6 times less potent than cocaine on a molar basis. In pentobarbital-anesthetized, spontaneously breathing rats, cocaine produced death by respiratory failure. Artificial ventilation of pentobarbital-anesthetized rats elevated the lethal dose of cocaine by 15-fold and these animals died of marked hypotension. In conscious rats, pretreatment with dl-, d- or l-propranolol or the alpha 2-selective adrenoceptor antagonist yohimbine enhanced the convulsive and lethal effects of cocaine. In contrast, the alpha 2-selective adrenoceptor agonist clonidine or the alpha 1-selective adrenoceptor antagonist prazosin attenuated these effects. Yohimbine antagonized the protective effect of clonidine. The nonselective alpha adrenoceptor antagonist phentolamine, the autonomic ganglionic blocker chlorisondamine and various calcium channel blockers had no effect on the convulsive or lethal doses of cocaine. The pressor response to cocaine was attenuated by calcium channel blockers, clonidine, phentolamine and dl- or l-propranolol, but not by d-propranolol. The pressor response to cocaine was abolished by chlorisondamine, reversed to a depressor response by prazosin and enhanced by yohimbine. The initial tachycardiac response to cocaine was reversed to bradycardia by dl- and l-propranolol, prazosin, yohimbine or high doses of the calcium channel blockers, but was unaffected by phentolamine, d-propranolol, clonidine or chlorisondamine. These results indicate that in spontaneously breathing animals, acute i.v. infusions of lethal doses of cocaine produce death primarily by central effects, namely by status epilepticus in conscious rats and by respiratory arrest in pentobarbital-anesthetized rats. In artificially ventilated, pentobarbital-anesthetized rats, however, cocaine produces death by effects on the cardiovascular system. In conscious rats, endogenous alpha 1 adrenoceptors exert a deleterious influence on cocaine-induced convulsive and lethal effects, whereas alpha 2 adrenoceptors provide protective influence. Propranolol appears to enhance cocaine-induced acute lethality through a mechanism independent of beta adrenoceptors. Calcium channel blockers appear ineffective in antagonizing cocaine's lethality.

Animals↗

[Pulmonary hemorrhages of different etiology: diagnosis and treatment].

Hemorrhage is one of the most pressing problems in lung diseases. The paper analyzes the results of medical and surgical treatments for pulmonary hemorrhages. A total of 724 patients with hemoptysis and bleedings of various etiology were treated at the Thoracic Unit in 1985-2003. Pulmonary hemorrhages occurred in 442 (61%) patients with pulmonary tuberculosis and in 282 (39%) patients with nonspecific lung diseases. X-ray study revealed right-sided lung lesions in 268 (37%) patients; left-sided lung lesions in 203 (28%), bilateral lesions in 170 (23.5%). The visible X-ray changes were not found in 83 (11.5%) patients. Destructive pulmonary parenchymal changes were detected in 366 (50.5%) patients. Bronchological study was conducted in 703 patients with pulmonary hemorrhage: 377 (53.7%) and 214 (30.4%) patients were found to have its direct and indirect signs, respectively. Neither changes nor hemorrhagic traces were detected in 112 (15.9%) patients since they underwent bronchoscopy in a later period when bleeding had already stopped. Foam rubber sponge tamponade of the main and lobar bronchi was made in 75 (10.4%) patients with profuse bleeding; a positive effect was achieved in 61 (81.3%) patients. The treatment policy for pulmonary hemorrhage is determined by its severity and etiology and the health status of the patient. A major role was assigned to medical hemostatic therapy in the treatment of pulmonary hemorrhages. If it was ineffective, surgical treatment was used. The use of hypotension controlled by ganglionic blockers (more commonly pentamine): bleedings were suppressed in 359 (74%) of 485 patients with second- and third-degree hemorrhages yielded good results. They were medically stopped in 558 (77%) patients; death occurred in 14 (2.4%) cases. A hundred and fifty two (20.9%) were operated on; of them 8 patients underwent segmentectomy; 85 had lobectomy. Pulmonectomy, cavernostomy, and thoracoplasty were performed in 48, 4, and 7 patients, respectively. Twenty-six patients were operated on at the peak of hemorrhage. Bleedings were suppressed in 140 (92%) patients (they recovered; 12 (7.9%) patients died. In the postoperative period different complications were noted in 30 (19.7%) patients. The final results of medical and surgical treatment were as follows: bleedings were stopped in 698 (96.4%) patients (they recovered) and 26 (3.6%) died.

Adolescent↗

[Paticipation of cannabinoid receptors in the regulation of cardiac rhythm and cardiac contractility].

It has been found that i. v. administration of cannabinoid receptor (CB) agonists (HU-210, ACPA, anandamide, methanandamide) induced a decrease in the heart rate (HR) in anesthetized rats. Pretreatment with CB1 receptor antagonist SR141716A completely abolished a negative chronotropic effect of CB receptor agonist HU-210. The CB2 receptor antagonist SRI 44528 did not prevent a HU-210-induced decrease in the HR. Pretreatment with the ganglion blocker hexamethonium had no effect on the negative chronotropic action of HU-210. Addition of HU-210 (100 nM) to perfusion solution induced a decrease in the HR, left ventricular development pressure, rate of contractility and relaxation of isolated perfused rate heart without change in end diastolic pressure. These data suggest that cardiac CBI receptor activation induces a decrease in the HR both in vivo and in vitro. An occupancy of the same receptors mediates a negative inotropic effects of cannabinoids.

Animals↗

Hypotensive and regional hemodynamic effects of the dopamine receptor agonist SK & F 85174 in the anesthetized rat.

The effects of the D1/D2 dopamine receptor agonist SK & F 85174, an N-allyl derivative of fenoldopam, on blood pressure and regional hemodynamics were studied in anesthetized normotensive rats. SK & F 85174 reduced blood pressure and enhanced blood flow in the renal, superior mesenteric and the hindquarters vascular beds. Calculated vascular resistances were reduced. The nonselective dopamine receptor antagonist RS-sulpiride abolished, while SCH 23390 (D1 antagonist), domperidone (D2 antagonist) and hexamethonium (ganglion blocker) each partly blocked the hypotensive effect. SCH 23390 antagonized the vasodilator effect more in the renal and superior mesenteric vascular beds, whereas domperidone antagonized the response more in the hindquarters vascular bed. RS-sulpiride antagonized vasodilatation in the three vascular beds. Hexamethonium abolished vasodilatation in the hindquarters vascular bed only. These results indicate that the hypotensive effect of SK & F 85174 is due to stimulation of both postsynaptic D1 and neuronal D2 receptors. The vasodilator effect in the renal and superior mesenteric vascular beds is mediated by D1 receptor stimulation, the vasodilator response in the hindquarters vascular bed is due to neuronal D2 receptor stimulation.

Animals↗

Changes in clinical characteristics and drug treatment of hypertension over 40 years at the Dunedin Hypertension Clinic.

The clinical characteristics of the 4,170 hypertensive patients referred to the Dunedin Clinic from 1950 to 1989 have been compared for eight successive 5-year periods. A gradual decrease in the severity of referred hypertension and an increase in the proportion of patients already on treatment at the time of referral (currently 50%) were noted. For male patients, mean +/- SD initial lying blood pressure was 179 +/- 27/116 +/- 19 mm Hg in 1950-1954 and 158 +/- 25/91 +/- 14 mm Hg in 1985-1989. Corresponding prevalence data for target organ damage among male patients were retinal grade 3 or 4, 49% and 3%; cardiomegaly on chest radiograph, 60% and 26%; electrocardiogram left ventricle strain pattern, 28% and 3%; and serum urea levels greater than 10 mmol/L, 16% and 5%, respectively. For women there was a similar trend. The number of patients on drugs in each of nine categories and the percent use of each drug category for each year during 1950-1989 was recovered from computerized data files. The percentage peak usage of ganglion blockers was in 1950-1958, adrenergic neuron blockers in 1963-1970, centrally acting drugs in 1965-1968, diuretics in 1960-1982, beta-blockers in 1974-1987, alpha-blockers in 1980-1987, and angiotensin converting enzyme inhibitors and calcium antagonists in 1989. The diuretics have been the most enduring drugs, followed by the beta-blockers.

Ambulatory Care Facilities↗

The choice of controlled hypotension during repair of intracranial aneurysms: techniques and complications.

Induced hypotension is frequently used during cerebral aneurysm dissection and clipping to reduce the risk of rupture. The ideal hypotensive agent does not exist and many drugs are currently used for the purpose of inducing hypotension. When used correctly serious complications are rare. These complications are either related to (1) the physiological effects of hypotension on the vital organs, namely, the brain, the heart, the lungs, the liver and the kidneys, or (2) the pharmacology of the respective hypotensive agent used which currently include the direct vasodilators-sodium nitroprusside and nitroglycerin; inhalation agents--isoflurane, enflurane and halothane; ganglionic blocker--trimethaphan; alpha/beta blockers- labetalol, esmolol; calcium channel blockers; and the experimental compound adenosine. Familiarity with both the physiology and pharmacology of induced hypotension will reduce the risk of complications of this useful technique.

Adrenergic beta-Antagonists↗

Vasoconstriction of the isolated rabbit ear artery caused by nicotinic agonists acting on adrenergic neurons.

In the perfused isolated central ear artery of the rabbit, nicotine, acetylcholine (ACh), tetramethylammonium (TMA) and carbachol (CCh) at high concentrations (greater than 1 mug/ml) produced transient vasoconstriction. The order of potency was: nicotine greater than ACh greater than TMA greater than CCh. Over the concentration range used, all of the agonists except ACh gave bell-shaped log concentration-response curves. Methacholine did not cause vasoconstriction. The response to ACh, TMA or CCh, but not to nicotine, was potentiated by atropine (0.1-1.0 mug/ml). Tetraethylammonium, hexamethonium, mecamylamine and d-tubocurarine blocked the response to the nicotinic agonists and to nerve stimulation. Ear arteries from reserpine-treated rabbits gave no, or very little, constrictor response to the nicotinic agonists or to nerve stimulation. These findings support the conclusion that the vasoconstriction produced by the nicotinic agonists is mediated by norepinephrine released from adrenergic nerve terminals as a result of the action of the agents on neuronal nicotinic receptors located at or near the terminals. The potentiation by atropine of the constrictor response to ACh, TMA and CCh is attributed to the blockade by atropine of neuronal muscarinic receptors on which these agonists act to inhibit the release of norepinephrine.

Acetylcholine↗

Cardiovascular effects of spinal cord substance P: studies with a stable receptor agonist.

The role of spinal cord substance P (SP) in regulating sympathetic outflow to the cardiovascular system was assessed with the stable active analog [pGlu5,MePhE8,MeGly9]-SP(5-11) (DiME-SP). The interaction of DiME-SP with spinal cord SP receptors was evaluated initially in binding studies. Saturable, high-affinity binding of [125I]Bolton-Hunter-SP to rat spinal cord membranes was dose-dependently inhibited by DiME-SP (IC50 = 1.5 microM). Intrathecal (i.t.) injections of DiME-SP (1.0-33 nmol) in anesthetized rats produced dose-dependent increases in blood pressure and heart rate that were accompanied by increases in plasma epinephrine and norepinephrine. Intravenous injections of the ganglionic blocker pentolinium blocked the cardiovascular and plasma catecholamine responses to i.t. injections of DiME-SP. Bulbospinal sympathoexcitatory pathways originating in the ventral medulla and their mediation by SP were also assessed. As demonstrated previously, application of bicuculline, the gamma-aminobutyric acid receptor antagonist, to the ventral surface of the medulla produced sympathetic mediated increases in blood pressure and these effects were blocked by i.t. injection of the SP receptor antagonist [D-Arg1,D-Pro2,D-Trp7,9,Leu11]-SP. In this study, we studied the specificity of the SP antagonist for SP receptors by attempting to alter the actions of the SP antagonist with a SP agonist. Administration of DiME-SP (33 nmol i.t.) blocked the effects of [D-Arg1,D-Pro2,D-Trp7,9,Leu11]-SP (3.3 nmol i.t.). Specifically, the SP agonist countered the SP antagonist-mediated 1) hypotensive response and 2) inhibitory effect on bicuculline-induced sympathoexcitatory responses elicited from the ventral surface of the medulla. These data provide further evidence that SP transmits excitatory information to the cardiovascular system via spinal sympathetic pathways.

Animals↗

Effect of clonidine on myocardial cyclic GMP content in the mouse-activation of central and peripheral alpha adrenoceptors.

Clonidine (0.23-3.77 mumol/kg i.p.) produced a dose-dependent increase in mouse myocardial cyclic GMP (cGMP) content. This effect was antagonized by yohimbine (0.03-1 mg/kg i.p.), but not by prazosin (1 mg/kg i.p.). The inhibition by yohimbine was biphasic. The cGMP response to clonidine was inhibited by atropine (5 mg/kg i.p.) and methylatropine (0.2-5 mg/kg i.p.). In mice pretreated with the ganglionic blocker hexamethonium, the cGMP response to clonidine persisted. St-91 [(2,6-diethylphenylamino)-2-imidazoline] (0.39-3.94 mumol/kg i.p.), a cogener of clonidine which does not cross the blood-brain barrier, also increased myocardial cGMP content. The potency of clonidine was similar in mice pretreated and nonpretreated with hexamethonium. Methylatropine did not affect the cGMP response to St-91 and to clonidine in ganglionectomized mice and yohimbine was a less potent antagonist. These results indicate that systemic administration of clonidine produces an increase in myocardial cGMP content by both a central and a peripheral action. The increase in cGMP can be due to a direct activation of cardiac prejunctional alpha-2 adrenoceptors and to stimulation of cardiac muscarinic receptors, a response secondary to an action of clonidine on central alpha-2 adrenoceptors.

Animals↗

Blood pressure and heart rate responses to intracerebroventricular infusion of sodium chloride solution in normotensive and hypertensive rats.

An increased central salt sensitivity is thought to be basically involved in hypertension. Therefore, in anaesthetized normotensive (Wistar, WKY) and hypertensive (SHR) rats, small amounts (10 microliters in 20 min) of both isotonic and hypertonic NaCl solutions (0.154 M, 0.3 M, 0.6 M and 1.0 M) were i.c.v. applied and blood pressure (BP) and heart rate (HR) responses registered. Central administration of hypertonic NaCl solution caused an elevation in BP and HR in both strains. The response magnitude was positively correlated to the NaCl concentration used. This increase could be interrupted by i.v. injection of a ganglionic blocker (tetraethylammoniumbromide). Despite of differences in time course, the magnitude of the BP and HR increases were much more elevated in SHR and WKY than in Wistar rats, suggesting strain differences. Considering the results obtained with 1.0 M NaCl solution, the following values were reached: in Wistar: delta syst. BP +15.7 mm Hg, delta HR +23.3 bpm; in WKY: delta syst. BP +40.2 mm Hg, delta HR +51.6 bpm; in SHR: delta syst. BP +46.0 mm Hg, delta HR +48.0 bpm. On the contrary, isotonic NaCl solution, when centrally applied, caused an elevation in HR (+25 bpm) and BP (delta syst. BP +6.2 mm Hg) only in SHR. These results support the idea that an exaggerated central sensitivity to sodium chloride may participate in hypertension.

Animals↗

Effects of nicotine bitartrate on mucociliary activity.

The in vivo effect of nicotine bitartrate on mucociliary (mc) activity in the rabbit maxillary sinus was investigated. An animal model was used, which permitted administration of drugs directly into the artery feeding the sinus and simultaneous recording of changes in the mc activity. When nicotine was given ia (0.5-10.0 micrograms/kg) it resulted in a brief (1 min at most) acceleration of the mc wave frequency. The response was dose-dependent and a maximum increase of 34.9% was recorded at a dose of 10.0 micrograms/kg. The response was inhibited by a preceding injection of the ganglionic blocker hexamethonium (0.2 mg/kg) or the cholinergic antagonist atropine (0.2 mg/kg). The alpha and beta-adrenoceptor antagonists phentolamine (0.2 mg/kg) and propranolol (0.2 mg/kg) did not influence the response to nicotine injection. It is concluded that the acceleration of mc wave frequency after nicotine administration is probably mediated via stimulation of nicotinic receptors on postganglionic parasympathetic nerve cells.

Adrenergic Agonists↗

[Effect of cholinergic compounds on spontaneous quantal mediator release at the neuromuscular synapse of the frog].

The action of cholinergic drugs on spontaneous quantal transmitter release has been investigated in the frog sartorius muscle. Acetylcholine and carbacholine decreased the miniature end-plate potential frequency. These presynaptic effects had no dependence on the potassium concentration in the bath solution. Nicotinic agonists--nicotine, tetramethylammonium and suberyldicholine had a similar effect, while muscarinic agents--methylfurmetide, oxotremorine and F-2268 (L- and D-stereoisomers) did not affect the transmitter release. The presynaptic effects of carbacholine and acetylcholine were abolished neither by atropine nor by d-tubocurarine and bensohexonium. It is suggested that there are nicotinic receptors on the frog motor nerve terminals that modify spontaneous quantal transmitter release and differ pharmacologically from nicotinic end-plate, ganglionic and presynaptic receptors of higher vertebrates.

Acetylcholine↗

Renal effects of selective alpha-1 and alpha-2 adrenoceptor agonists in conscious, normotensive rats.

The effects of the selective alpha-1 adrenoceptor agonist, cirazoline, and the selective alpha-2 adrenoceptor agonist, B-HT 933, were assessed on renal hemodynamics and on water and solute excretion in conscious, chronically instrumented rats. Infusion (i.v.) of equipressor doses of cirazoline and B-HT 933, 0.04 and 4 mg/kg/hr, respectively, decreased renal plasma flow without changing glomerular filtration rate. Cirazoline infusion did not affect urinary excretion of water, electrolytes or total solutes. In marked contrast, B-HT 933 increased urine flow and sodium excretion significantly (P less than .01) but did not significantly alter potassium and urea excretion. Urine osmolality decreased to hyposmotic levels (from 613 +/- 86 to 172 +/- 8 mOsmol/kg of H2O) during the infusion of B-HT 933, suggesting a possible interaction between the alpha-2 adrenoceptor agonist and the vasopressin system. This diuretic action of the selective alpha-2 adrenoceptor agonist was also observed after the i.v. infusion of a subpressor dose (0.4 mg/kg/hr) of B-HT 933. In rats treated with the ganglionic blocker, hexamethonium (10 mg/kg i.v.), the B-HT 933-induced diuresis was not affected, confirming an action in the periphery, possibly at the level of the kidney. These results suggest that stimulation of renal alpha-2 adrenoceptors in conscious, euvolumic rats modulates the reabsorption of water and sodium at the site of the renal nephron.

Adrenergic alpha-Agonists↗

The bronchial effects of adenosine in the rat.

The in vivo intravenous administration of adenosine caused bronchoconstriction in the rat. There were significant differences between inbred rat strains with regard to bronchial reactivity to adenosine. Inosine caused bronchoconstriction in the rat but was a less potent bronchoconstrictor than adenosine and there was no correlation between the bronchial reactivity to inosine and the reactivity to adenosine. Theophylline, DSCG and nedocromil were potent inhibitors of the adenosine-induced bronchoconstriction. Bilateral vagotomy and the ganglion blocker hexamethonium had no effect on the adenosine-induced bronchoconstriction. High doses of atropine had a small inhibitory effect. The bronchial adenosine receptor has the characteristics of the A2 type.

Adenosine↗

Marked up-regulation of the beta-bungarotoxin site in adrenal chromaffin cells by specific nicotinic antagonists.

The effect of nicotinic antagonists was studied on various parameters of adrenal medullary chromaffin cells in culture. Incubation of the cells in culture with d-tubocurarine or mecamylamine for 0.5-6 days resulted in up to an 8-fold increase in the binding of alpha-bungarotoxin (alpha-BGT) to the cells; other ganglionic blockers, on the other hand, such as hexamethonium and dihydro-beta-erythroidine, had no effect. This enhanced binding was due to an increase in the number of alpha-BGT sites with little change in affinity of the ligand for the receptor. The nature of the increase in the number of toxin-binding sites in chromaffin cells observed after treatment with d-tubocurarine or mecamylamine was subsequently investigated. A direct interaction of the drug with the alpha-BGT recognition site was not required for the increase in receptor number to occur; mecamylamine did not affect binding of alpha-BGT to chromaffin cells in culture in competition binding experiments, although d-tubocurarine did compete with alpha-BGT for binding to its recognition site. The reversal of the antagonist-induced increase in the alpha-BGT-binding sites by nicotine and carbachol suggested it was mediated through an interaction at an acetylcholine receptor recognition site. The depolarizing agent veratridine greatly attenuated the increase in the number of toxin-binding sites in response to antagonists; this effect of veratridine could be reversed by tetrodotoxin. These latter findings indicate that neuronal excitability can influence the observed increase in the number of alpha-BGT sites after exposure of the cultures to nicotinic antagonists. The antagonist-induced increase in the alpha-BGT sites in the cells was not associated with an increased functional responsiveness of the cells to acetylcholine. The present results demonstrate that the number of alpha-BGT-binding sites in adrenal medullary chromaffin cells can increase dramatically in response to some, but not other, nicotinic antagonists by an interaction at a nicotinic acetylcholine recognition site. The differential effect of antagonists at the nicotinic-like alpha-BGT site and the functional nicotinic receptor suggests these two parameters are distinct. The unusually large alteration in receptor number may be related to the unique localization of the adrenal medulla and could infer that these receptors have a role in this tissue.

Adrenal Medulla↗

Role of the sympathetic nervous system in the maintenance of hypertension in rats harboring pheochromocytoma.

Hypertension due to pheochromocytoma is generally considered to be a straightforward, direct consequence of the elevated concentrations of circulating catecholamines. However, clonidine, a centrally acting antihypertensive drug, has been reported to lower blood pressure in patients with pheochromocytoma, suggesting the possibility that the sympathetic nervous system is involved in the maintenance of hypertension in this disease. We have investigated this possibility in New England Deaconess Hospital rats harboring a transplantable pheochromocytoma that secretes norepinephrine and dopamine. Both clonidine and chlorisondamine, a ganglionic blocker, markedly decreased blood pressure in tumor-bearing rats. However, in other rats made acutely hypertensive with a norepinephrine infusion, neither clonidine nor chlorisondamine decreased blood pressure. This result indicates that in an acute model of hypertension, where baroreflex mechanisms have likely withdrawn sympathetic tone, neither clonidine nor chlorisondamine had nonspecific antihypertensive effects. A central nervous system site of action for the antihypertensive effect of clonidine in the rats harboring pheochromocytoma was suggested by the observation that the opiate antagonist naloxone both reversed and prevented clonidine's effect on blood pressure. Prazosin and yohimbine were utilized to determine the respective contributions of alpha-1 and alpha-2 adrenergic receptors in the maintenance of hypertension in rats harboring pheochromocytoma. Both drugs markedly lowered blood pressure in these rats. Our data suggest that both the sympathetic nervous system and circulating catecholamines are involved in the maintenance of hypertension due to pheochromocytoma.

Adrenal Gland Neoplasms↗

Heterogeneity of nicotine actions in the rat cerebellum: an in vivo electrophysiologic study.

Much controversy surrounds the actions of nicotine on mammalian central neurons, especially with respect to the question of presence of multiple nicotine receptors and with respect to similarities of responses to those induced by acetylcholine (ACh). To resolve some of these complexities, the authors determined the effects of pressure-ejected nicotine on identified neurons in the cerebellar cortex of Sprague-Dawley rats under urethane anesthesia. Purkinje cells and interneurons were identified by their anatomical localization, discharge characteristics and responses to electrical stimulation of superficial parallel fibers. Locally applied nicotine altered single-unit activity in a manner strictly dependent on cell type. Pressure-ejected nicotine inhibited Purkinje cells (50/51) and excited cerebellar interneurons (22/22). The effects of nicotine on cell discharge rate were probably receptor mediated because "classical" nondepolarizing nicotinic antagonists selectively blocked the agonistic actions of nicotine. A curare-sensitive site (neuromuscular type) was found to mediate the excitatory effects of nicotine, and a hexamethonium-sensitive site (ganglionic type) was found to mediate the inhibitory effects of nicotine. ACh mimicked the effects of nicotine on both cell classes although muscarinic interactions were also observed. The inhibitory effects of ACh on Purkinje cells were antagonized by the ganglionic blocker hexamethonium only if muscarinic receptors were simultaneously blocked via systemic administration of scopolamine. The excitatory effects of ACh on interneurons, on the other hand, were antagonized by the neuromuscular blocker curare even in the absence of a muscarinic antagonist. No interactions of curare and hexamethonium were observed with the amino acid transmitters gamma-aminobutyric acid (Purkinje cells) and glutamate (interneurons).

Acetylcholine↗