Nicotine cue in rats: effects of central administration of ganglion-blocking drugs.
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In rats trained to discriminate nicotine from saline, a single intraventricular injection of a small dose of the quaternary ganglion-blocking drug chlorisondamine blocked the response to nicotine for four weeks. pentolinium was only weakly active and hexamethonium was inactive as a nicotine antagonist under the conditions used, even in doses that were just below those producing myoclonic jerks. Chlorisondamine had no blocking effect in rats trained to discriminate the non-nicotinic drugs midazolam or morphine from saline. Intraventricular injections of chlorisondamine have a specific and unusually persistent nicotine-blocking action, the mechanism of which requires further investigation. (+info)
Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. V. Role of pharmacokinetics and the autonomic nervous system in the interactions between verapamil and inhalational anesthetics.
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To assess the role of both pharmacokinetics and the autonomic nervous system in the interaction between inhalational anesthetics and verapamil, dogs were chronically instrumented to measure heart rate, PR interval, dP/dt, cardiac output, and aortic blood pressure. In a first group of seven dogs, studied awake and during halothane (1.2%), enflurane (2.5%), and isoflurane anesthesia (1.6%), verapamil was infused for 30 min in doses calculated to obtain similar plasma concentrations (83 +/- 10, 82 +/- 6, 81 +/- 10, and 77 +/- 9 ng.ml-1, respectively). For the latter purpose, the infusion dose was 3 and 2 micrograms.kg-1.min-1 awake and during anesthesia, respectively, preceded by a loading dose of 200, 150, and 100 micrograms.kg-1, awake, during isoflurane, and halothane and enflurane, respectively. In awake dogs, verapamil induced an increase in heart rate (24 +/- 5 bpm) and PR interval (35 +/- 9 msec) and a decrease in mean arterial pressure (-5 +/- 2 mmHg) and dP/dt (-494 +/- 116 mmHg/s). Although plasma concentrations were similar in awake and in anesthetized dogs, the only statistically significant changes induced by verapamil were an increase in heart rate and a decrease in dP/dt during halothane and enflurane, while left atrial pressure increased only with enflurane. In a second group of six dogs, verapamil pharmacokinetics were determined in the presence and absence of a ganglionic blocking drug (chlorisondamine, 2 mg.kg-1 iv). Blockade of ganglionic transmission resulted in a decrease in both initial volume of distribution and total clearance of verapamil--changes similar to those previously reported with inhalational anesthetics.(ABSTRACT TRUNCATED AT 250 WORDS) (+info)
Hemodynamic and neural mechanisms of action of thyrotropin-releasing hormone in the rat.
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The mechanisms mediating the effects of thyrotropin-releasing hormone (TRH) on the cardiovascular system were studied in the conscious rat. Intracerebroventricular (i.c.v.) injection of TRH (8 pmol-80 nmol/kg) induced dose-dependent increases in mean arterial pressure, heart rate, and cardiac index. Hindquarter blood flow increased due to vasodilation, while an increase in renal and mesenteric vascular resistance caused a decrease in blood flow in the respective organs. The plasma levels of norepinephrine and epinephrine were increased by TRH, while there was no change in plasma renin activity or vasopressin. The cardiovascular actions of i.c.v. TRH were not influenced by blockade of the renin-angiotensin system or vasopressin receptors. The ganglion blocker chlorisondamine and the alpha 1- and alpha 2-adrenoreceptor antagonist phentolamine (2 mg/kg i.v.) abolished the increase in blood pressure and mesenteric vasoconstriction after i.c.v. TRH. Propranolol (2 mg/kg i.v.) blocked the TRH-induced increase in cardiac index, heart rate, and hindquarter blood flow. The hindquarter vasodilation induced by TRH was also blocked by the selective beta 2-adrenoceptor antagonist ICI 188,551 (1 or 2 mg/kg i.v.), while the beta 1-adrenoceptor blocker practolol (10 mg/kg i.v.) had no effect on the hindquarter vasodilation produced by TRH but totally blocked the increase in cardiac index. In adrenal demedullated rats, the systemic hemodynamic effects of i.c.v. TRH were diminished along with the decrease in renal blood flow and increase in renal vascular resistance; however, the increase in hindquarter blood flow was attenuated only in adrenal demedullated rats pretreated with the sympathetic blocker bretylium. The renal vasoconstriction induced by i.c.v. TRH was not abolished by renal denervation. In sinoaortic debuffered rats, the pressor, tachycardic, and mesenteric vasoconstrictor responses to centrally administered TRH were significantly potentiated. Taken together, these data suggest that the putative neurotransmitter TRH may play a role in central regulation of cardiac functions and organ blood flow distribution through both the sympathetic nerves and the adrenal medulla. A pivotal role for beta 2-adrenoceptors in mediation of hindquarter vasodilation is also demonstrated. (+info)
Effects of chronic nicotine administration on the denervated rat adrenal medulla.
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1 The effects of chronic nicotine administration (1 or 10 mg/kg, s.c., twice daily) were studied in intact and denervated rat adrenal glands to determine the relative roles of central input and direct actions on catecholamines. 2 Catecholamine depletion was obtained in the intact glands from 1-7 days of treatment with 10 mg/kg, with recovery by 14 days of treatment; catecholamines were not decreased in denervated adrenal glands. 3 Catecholamine depletion was accompanied by a decline in functional storage vesicles (determined by [3H]-adrenaline uptake per gland) in the intact side, while no change was seen in the denervated side; the proportion of newly synthesized vesicles increased markedly during 1-7 days of treatment with 10 mg/kg in the intact side, while a much smaller increase of shorter duration was seen in the denervated adrenal gland. 4 Chronic nicotine administration at either dose level induced tyrosine hydroxylase in both intact and denervated glands, but the increase occurred more slowly in the denervated glands. 5 Dopamine beta-hydroxylase levels increased similarly in both sides during treatment with nicotine (10 mg/kg). 6 These studies suggest that although long-term adrenal denervation eliminates the catecholamine depletion caused by chronic administration of nicotine, the mechanisms for induction of catecholamine synthesizing enzymes are still capable of responding to the drug. (+info)
Glycine microinjected in the rat dorsal vagal nucleus increases arterial pressure.
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Microinjections (25 nl) of glycine into the dorsal motor nucleus of the vagus in 21 rats elicited dose-dependent increases of arterial pressure and heart rate that were not seen with injections adjacent to the dorsal motor nucleus of the vagus. The responses to glycine were neurally mediated and could be blocked either by local pretreatment with strychnine or by combined vagotomy and ganglionic blockade. The data suggest that glycine receptors on, or in the region of, neurons of the dorsal motor nucleus of the vagus may have a role in the regulation of arterial pressure and heart rate. (+info)
Trapping of an open-channel blocker at the frog neuromuscular acetylcholine channel.
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At the ganglionic nicotinic acetylcholine channel (Gurney, A. M., and H. P. Rang, 1984, Br. J. Pharmacol., 82:623-642) and on some cholinergic neuromuscular synapses of Crustacea (Lingle, C., 1983a, J. Physiol. (Lond.), 339:395-417; Lingle, C., 1983b, J. Physiol. (Lond.), 339:419-437), some agents that block cholinergic currents by an open-channel block mechanism appear to become trapped within the channel when it subsequently closes. It is unknown whether trapping of some open-channel blockers might also occur at the neuromuscular nicotinic acetylcholine channel. Here we show that the long-lived cholinergic blocking action of chlorisondamine, a ganglionic nicotinic blocker, can in part be most simply explained by an open-channel block mechanism followed by a subsequent trapping of the blocking molecule within the closed ion channel. Unique structural characteristics of the chlorisondamine molecule place several provocative constraints on the mechanism by which trapping may be occurring. (+info)
Role of renal prostaglandins in sympathetically mediated renin relase in the rat.
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Renal prostaglandins (PG) appear to mediate renin release due to stimulation of the intrarenal baroreceptor, but not that due to activation of the macula densa. However, as the role of PG in sympathetically mediated renin release remains unclear, a possible interrelationship between these factors was examined in conscious rats. Hydralazine increased the serum renin levels from 3.1+/-0.8 to 16.7+/-3.0 ng/ml per h at a dose of 1 mg/kg. Indomethacin (5 mg/kg) suppressed urinary PGE(2) and PGF(2alpha) excretion by 89 and 74%, respectively, arachidonate hypotension by 82%, and inhibited the elevated renin levels from hydralazine by 100% without altering the hypotensive effect of the drug. Another PG synthetase inhibitor, meclofenamate, was also effective in attenuating hydralazine-induced renin release, urinary PGE(2) and PGF(2alpha) excretion, and arachidonate hypotension. Isoproterenol, a nonselective beta-adrenergic agonist, increased heart rate, lowered blood pressure, and also stimulated the release of renin when administered intraperitoneally. However, intrarenal infusion of the drug only resulted in increased renin release. Indomethacin inhibited isoproterenol-induced renin release by 66 and 67%, respectively, without altering the hemodynamic effects associated with the intraperitoneal administration of the drug. The selective beta(1) agonist, H133/22, increased the release of renin and heart rate in a dose-related manner without altering blood pressure. H133/22-induced renin release was inhibited by 80% by indomethacin pretreatment. Finally, intrarenal infusions of dibutyryl cyclic AMP (3 mg/kg per min) increased the serum activity from 4.1+/-0.2 to 20.4+/-3.9 ng/ml per h without altering mean arterial pressure. Indomethacin inhibited this renin response to dibutyryl cyclic AMP by 96%. Thus, renal PG appear to be important mediators of sympathetically stimulated renin release acting as a site distal to the beta-adrenergic receptor. (+info)
Plasticity of expression of a synaptic vesicle antigen in adult rat superior cervical ganglion.
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The effects of deafferentation and alterations of synaptic activity on levels of a synaptic vesicle-specific membrane protein (SV) were studied in the adult rat superior cervical ganglion (SCG) in vivo, using a monoclonal antibody directed against the protein. Levels of SV were quantified by radioimmunoassay. Deafferentation of the SCG results in a transient increase in SV levels in the SCG on days 7 and 10 after surgery, with levels then dropping below control levels on days 14, 21, and 30 after surgery. Immunohistochemical labeling of deafferented ganglia indicates that the increase is confined to the perikarya of principal ganglionic neurons. Levels of SV in an SCG target tissue, the iris, do not differ from control levels on day 7 after deafferentation, but are elevated at days 10, 14, and 30 after surgery. After reinnervation of the SCG, levels of SV in the SCG are elevated above control values, but do not differ from control values in the iris. Treatment with chlorisondamine, which blocks synaptic transmission in sympathetic ganglia, produces a significant increase in SV levels in the SCG after 7 d of treatment. Long-term chlorisondamine treatment results in reductions in SV in the SCG after 14 and 28 d. Treatment with phenoxybenzamine for 6 d, which reflexly increases synaptic activity, produces a marked decrease in SV in the SCG. These results suggest that activity, mediated by transsynaptic factors, contributes to the regulation of synthesis of a synaptic vesicle protein in the SCG. The results further suggest that accumulation of synaptic vesicles in terminals of the principal ganglion neurons may help regulate the maintenance of normal synaptic vesicle pools within sympathetic neurons. (+info)