The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Jan 1987
Activation of cholinergic mechanisms in the medulla oblongata reverse intravenous opioid-induced respiratory depression.
The role of cholinergic mechanisms in opioid-induced respiratory depression was investigated in isoflurane-anesthetized rats. In these animals, the i.v. administration of fentanyl, a clinically useful potent opioid analgesic/anesthetic, induced a prolonged period of apnea and subsequent rise in the end-tidal CO2, hypotension and bradycardia. The centrally acting anticholinesterase, physostigmine, significantly decreased fentanyl-induced respiratory and circulatory depression. ⋯ In conclusion, opioid-induced respiratory depression after systemic administration is obtunded greatly by facilitation of muscarinic mechanisms in the ventrolateral medulla. Inhibition of a cholinergic link in the central chemosensor may underlie opioid-induced respiratory depression. Manipulation of this cholinergic link could lead to the use and development of analgesics devoid of respiratory depression.
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J. Pharmacol. Exp. Ther. · Jan 1987
Differential effects of the imidazole derivatives etomidate, ketoconazole and miconazole and of metyrapone on the secretion of cortisol and its precursors by human adrenocortical cells.
The direct effects of etomidate, ketoconazole, miconazole and metyrapone were investigated on the secretion of cortisol and its precursors by dispersed cells from the adrenal cortex of a normal individual and four patients with Cushing's syndrome. The drugs interfered with adrenocorticotropic hormone-stimulated cortisol secretion in a dose-dependent way. Desoxycortisol concentrations in the medium were increased after the addition of metyrapone and low doses of etomidate but were suppressed with higher doses of etomidate. ⋯ It is concluded that etomidate at a low concentration (IC50, 10(-8) M) inhibits 11 beta-hydroxylase, whereas, at higher concentrations (10(-7)-10(-6) M), the side-chain cleavage enzyme system is also inhibited; metyrapone is a weaker (IC50, 10(-7) M) but pure 11 beta-hydroxylase inhibitor; miconazole inhibits adrenal 21-hydroxylase at 10(-6) M; and ketoconazole inhibits 17-hydroxylase. Etomidate, ketoconazole, miconazole and metyrapone inhibit cortisol biosynthesis in the human adrenal gland in different manners, which appear to involve the four cytochrome P-450-dependent monooxygenase reactions. Interestingly, these drugs affect corticosteroidogenesis by normal, hyperplastic and adenomatous adrenal cells in a similar manner.
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J. Pharmacol. Exp. Ther. · Oct 1986
Anticonvulsant drugs effective against human temporal lobe epilepsy prevent seizures but not neurotoxicity induced in rats by quinolinic acid: electroencephalographic, behavioral and histological assessments.
Intrahippocampal injection of quinolinic acid (QUIN) in rats caused an epileptic-like syndrome reminiscent of human temporal lobe epilepsy. By electroencephalographic (EEG) analysis, the authors assessed whether QUIN seizures were responsive to anticonvulsants effective in the treatment of the human disease. Anticonvulsants used in clinical practice to control partial seizures, such as carbamazepine, diphenylhydantoin, sodium phenobarbital, sodium valproate and diazepam, prevented QUIN-induced EEG seizures, whereas ethosuximide, which is specifically used to control absence attacks, and chlorpromazine, a sedative with no anticonvulsant properties, were ineffective. ⋯ Animals injected with QUIN displayed chewing, sniffing and rearing; no clear correlation was found between the ability of drugs to prevent QUIN-induced EEG seizures and effects on stereotypies, suggesting that these behavioral signs are not sensitive measures of anticonvulsant activity in this model. The anticonvulsants that protected animals from QUIN seizures did not prevent nerve cell degeneration induced by the excitotoxin, thus indicating that nerve cell death can occur even in the absence of sustained seizure activity. The data show that, in this animal model of epilepsy, the EEG seizure activity is specifically sensitive to anticonvulsants effective in partial epilepsy, thus suggesting that it could be used to test potential new drugs for this human disorder.
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J. Pharmacol. Exp. Ther. · Aug 1986
Development of high sodium renal hypertension during chronic blockade of the vascular effects of vasopressin.
Studies in sodium-dependent models of hypertension have shown that arginine-vasopressin (AVP) plays an important role in the maintenance of blood pressure, predominantly through its vasoconstrictor action. In addition to AVP, the sympathetic nervous system (SNS) also acts to maintain blood pressure in high sodium one-kidney, figure-8 renal wrap hypertension. The purpose of this study was to determine if chronic blockade of vascular AVP (V1) receptors affected the induction of high sodium renal hypertension and the contribution of the SNS to the maintenance of blood pressure. ⋯ In renal-wrapped rats, ganglionic blockade caused a greater fall in blood pressure in animals treated with d(CH2)5Tyr(Me)AVP than in vehicle-treated animals. However, this apparent increase in SNS function was not responsible for the hypertension in d(CH2)5Tyr(Me)AVP-treated, renal-wrapped rats, inasmuch as ganglionic blockade lowered blood pressure a similar amount in normotensive d(CH2)5Tyr(Me)AVP-treated, sham-operated rats and blood pressure remained elevated after combined blockade of the SNS, AVP and the renin-angiotensin systems. These results indicated that chronic blockade of V1 receptors did not alter the induction of high sodium renal hypertension and the mechanism of the elevated blood pressure was not through an activation of the SNS or other neurohumoral mechanisms.
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J. Pharmacol. Exp. Ther. · May 1986
Central opioid receptors and baroreflex control of sympathetic and cardiovascular function.
The effect of central opioid receptor activation and blockade on arterial baroreflex regulation of cardiovascular function was studied. Baroreceptor reflexes were elicited in urethane-anesthetized rats by graded electrical stimulation of the aortic nerve while mean arterial pressure, heart rate and sympathetic nerve activity were recorded simultaneously. Baroreflex response curves were constructed after intracisternal administration of saline vehicle, after intracisternal infusion of the relatively selective mu and delta opioid receptor agonists D-Ala2-MePhe4-Gly(ol)5 enkephalin (DAGO), or D-Ala2-D-Leu5 enkephalin (DADLE) respectively, and again after i.v. naloxone. ⋯ These results suggest that the effect of DADLE on baroreflexes was mediated by activation of mu rather than delta opioid receptors. No evidence was obtained to suggest a role for endogenous opioid modulation of baroreflexes because i.v. naloxone was without effect. These results demonstrate that activation of central mu opioid receptors significantly impairs baroreflex control of sympathetic and cardiovascular function.