The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Jul 1997
Impaired contractile response to beta adrenoceptor stimulation in diabetic rat hearts: alterations in beta adrenoceptors-G protein-adenylate cyclase system and phospholamban phosphorylation.
The aim of this study was to explore the cellular mechanisms underlying the impaired contractile response to beta adrenoceptor stimulation in diabetic hearts. Chronic diabetes was induced in rats by a streptozotocin injection. Four to six weeks later, papillary muscles isolated from diabetic hearts exhibited marked reductions in the positive inotropic responses to isoproterenol, norepinephrine and epinephrine. ⋯ The abilities of isoproterenol, sodium fluoride, 5'-guanylyl imidodiphosphate and forskolin to stimulate adenylate cyclase were preserved well in membranes prepared from diabetic hearts. Nevertheless, neither stimulation of beta adrenoceptors with isoproterenol nor direct activation of adenylate cyclase with forskolin evoked any significant increase in the degree of phosphorylation of phospholamban in diabetic hearts. These results suggest that impaired contractile response to beta adrenoceptor stimulation is not caused by an alteration in the beta adrenoceptors-Gs-adenylate cyclase system, but is possibly caused by an alteration in cellular function beyond the step of adenylate cyclase activation.
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J. Pharmacol. Exp. Ther. · Jul 1997
Enhancement of analgesia from systemic opioid in humans by spinal cholinesterase inhibition.
Intravenous opioids cause analgesia and increase release of ACh in spinal cord dorsal horn in animals, and these effects are enhanced by intrathecal neostigmine injection. The purpose of the current study was to test whether intrathecal neostigmine enhanced analgesia and increased cerebrospinal fluid concentrations of ACh over those induced by i.v. alfentanil in volunteers, and also to test whether neostigmine enhanced alfentanil-induced side effects. After human studies committee approval, 40 healthy volunteers received an intrathecal injection of saline or neostigmine (50, 100 or 200 microg) followed in 60 min by a computer-controlled, stepped i.v. infusion of alfentanil to escalating targeted plasma concentrations. ⋯ Intravenous alfentanil increased cerebrospinal fluid ACh concentration, and neostigmine enhanced this change. These data in humans are consistent with a spinal cholinergic mechanism of i.v. opioid analgesia. Because neostigmine enhances both analgesia and side effects induced by i.v. alfentanil, the clinical utility of their use in combination will depend on the relative strength of these interactions.
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J. Pharmacol. Exp. Ther. · Jul 1997
S 15535, a novel benzodioxopiperazine ligand of serotonin (5-HT)1A receptors: II. Modulation of hippocampal serotonin release in relation to potential anxiolytic properties.
In these studies, we characterized the influence of the novel benzodioxopiperazine serotonin (5-HT)1A ligand, S 15535, on the release of 5-HT in rat hippocampus and compared its potential anxiolytic properties with those of the 5-HT1A receptor partial agonist, buspirone, the 5-HT1A antagonist, WAY 100,635 and the benzodiazepine, diazepam (DZM). (Doses are in milligrams per kilogram s.c., unless otherwise specified.) S 15535 dose-dependently (0.3-3.0) reduced dialysate concentrations of 5-HT in the hippocampus of anesthetized rats. This action of S 15535 (3.0) was blocked by WAY 100,635 (0.3), (-)-penbutolol (2.0) and (-)-tertatolol (8.0), antagonists at 5-HT1A autoreceptors. In rats, fear-induced ultrasonic vocalizations (USVs) were dose-dependently abolished by S 15535 (0.16-2.5 s.c. and 0.63-10.0 p.o.), an action mimicked by buspirone (0.02-2.5) and DZM (0.16-10.0). ⋯ In addition, it displays antiaggressive (and antidepressant, accompanying paper) properties. Further, S 15535 does not compromise motor behavior at doses over which it expresses its anxiolytic properties. Thus, S 15535 represents a promising candidate for the treatment of anxious states in man.