The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Nov 1982
Comparative StudyEffects of phenoxybenzamine or N-methyl chlorpromazine on regional cerebral blood flow: comparison of central and peripheral alpha adrenergic receptor antagonism.
A comparison of the central and peripheral effects of alpha adrenergic receptor antagonism on regional cerebral blood flow was examined utilizing N-methyl chlorpromazine, an alpha adrenergic receptor antagonist which does not cross the blood-brain barrier, or phenoxybenzamine, an alpha adrenergic receptor antagonist which does enter the brain when injected systemically. Regional cerebral blood flow was monitored in 17 brain regions of 16 pentobarbital-anesthetized New Zealand White rabbits using radioactively tagged microspheres (15 +/- 3 micrometer in diameter). There was a significant overall difference in regional cerebral blood flow distribution in the control state. ⋯ There were no significant effects of N-methyl chloropromazine on average global cerebral blood flow or its regional distribution. Central alpha adrenergic receptor blockade probably decreased regional cerebral blood flow in brain regions rich in neuronal alpha adrenoreceptors by decreasing regional metabolic and/or neuronal activity, while increasing metabolic and/or neuronal activity in the pons and substantia nigra via a positive feedback mechanism causing an increased flow rate in these regions. Peripheral alpha adrenergic receptor blockade appears to have little or no effect on regional cerebral blood flow.
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J. Pharmacol. Exp. Ther. · Sep 1982
Inhibition of acetylcholine turnover rate in rat hippocampus and cortex by intraventricular injection of adenosine analogs.
The effects of i.c.v. administration of adenosine receptor agonists and antagonists on the turnover rate of acetylcholine (TRACh) in various areas of the rat brain were examined in an effort to better understand the role of adenosine as a neuromodulator or cotransmittr. TRACh was determined by gas chromatographic-mass fragmentographic analysis of the rate of deuterium incorporation into ACh and choline during a constant rate infusion of deuterated phosphorylcholine. The i.c.v. administration of the adenosine receptor agonist, 2-chloroadenosine (2-CIAdo), in a dose of 82 nmol failed to change the ACh or choline content of any of the brain areas examined. ⋯ The i.c.v. administration of L-PIA (65 nmol) elicited a 79% reduction in the TRACh in the hippocampus, whereas D-PIA (65 nmol i.c.v.) had no significant effect on hippocampal TRACh. This finding supports the view that these effects on TRACh may be mediated by adenosine A1 receptors, but not by A2 receptors, because the former, but not the latter, display marked stereoselectivity toward PIA. It also was demonstrated that intraseptal injections of L-PIA or theophylline failed to reduce the TRACh in the hippocampus, suggesting that adenosine receptors located in the septum are not operative in mediating the i.c.v. action of PIA.
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J. Pharmacol. Exp. Ther. · Oct 1981
Relationship between cyclic guanosine 3':5'-monophosphate formation and relaxation of coronary arterial smooth muscle by glyceryl trinitrate, nitroprusside, nitrite and nitric oxide: effects of methylene blue and methemoglobin.
The purpose of the present study was to determine time course relationship between cyclic GMP accumulation and relaxation in bovine coronary artery and evaluate the effects of recently identified inhibitors, methylene blue and methemoglobin, on these relationships. Arterial strips were suspended in specially mounted tissue baths which permitted continuous recording of isometric tension until rapid freeze-clamping for subsequent determination of cyclic GMP levels by radioimmunoassay. Relaxation and cyclic GMP levels were measured in submaximally contracted strips at zero time (untreated) or 5-sec to 5-min intervals after exposure to 0.5 microliter of nitric oxide, 1 microM glyceryl trinitrate, 1 microM sodium nitroprusside of 1 mM sodium nitrite in the absence or presence of 10 mM methylene blue or 1 microM methemoglobin. ⋯ Methylene blue simultaneously inhibited cyclic GMP accumulation and relaxation induced by all four relaxants. In contrast to methylene blue, methemoglobin abolished cyclic GMP accumulation and relaxation elicited by nitric oxide without altering responses to glyceryl trinitrate, sodium nitroprusside and sodium nitrite. These findings are consistent with and strongly support an involvement of cyclic GMP formation in vascular smooth muscle relaxation elicited by nitrogen oxide-containing vasodilators.
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J. Pharmacol. Exp. Ther. · Sep 1981
Drug effects on multiple and alternating mixed-schedule performance.
The effects of d-amphetamine, pentobarbital, morphine, chlorpromazine and triflupromazine were determined on key pecking by pigeons maintained under multiple and alternating-mixed fixed-ratio 30, fixed-interval 5-min schedules of grain presentation. Similar schedule performances were maintained under both the multiple and alternating mixed schedules. The effects of d-amphetamine and pentobarbital were similar under the multiple and alternating mixed schedules. ⋯ The effects of morphine, chlorpromazine and triflupromazine on fixed-interval rates of responding did not differ between the multiple and alternating mixed schedules. However, morphine, chlorpromazine and triflupromazine decreased responding under the alternating mixed fixed-ratio without affecting responding under the multiple fixed-ratio component. This selective decrease in fixed-ratio responding under the alternating mixed schedule by morphine, chlorpromazine and triflupromazine appears to be functionally similar to the effects of these drugs to decrease avoidance responding without affecting escape responding.
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J. Pharmacol. Exp. Ther. · Sep 1981
Effects of d-amphetamine on responding of squirrel monkeys maintained under second-order schedules of food presentation, electric shock presentation or stimulus-shock termination.
The effects of d-amphetamine (0.01-5.6 mg/kg i.m.) were studied on lever pressing of squirrel monkeys maintained under various second-order schedules by a visual stimulus (S) that, with separate monkeys, was occasionally paired with the presentation of either food, electric shock or with the termination of a stimulus in the presence of which shocks occurred. Under one condition, the first response after 5 min produced a 3-sec stimulus change and the fourth stimulus change was followed immediately by food delivery, electric shock presentation or by the termination of a stimulus in the presence of which shocks occurred [fixed-ratio (FR); fixed-interval (FI) [FR 4 (FI 5-min:S)]. ⋯ Low to intermediate doses of d-amphetamine (0.03-0.3 mg/kg) generally increased and higher doses (0.56-5.6 mg/kg) decreased responding under all conditions. The effects of d-amphetamine on responding maintained by brief stimuli under different types of second-order schedules are generally similar, regardless of the type of reinforcing event or particular second-order schedule.