The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Jan 1999
Levosimendan, a calcium sensitizer in cardiac muscle, induces relaxation in coronary smooth muscle through calcium desensitization.
Levosimendan is a pyridazinone-dinitrile derivative belonging to a new class of cardiac inotropic drugs, Ca++ sensitizers. Levosimendan is also a vasodilator both in vitro and in vivo, but its mechanism is not well understood. The cardiac target protein of levosimendan, troponin C, is a Ca++-binding EF-hand protein. ⋯ Levosimendan relaxes coronary arteries and lowers [Ca++]i by mechanisms different than milrinone. Our results indicate a lowering of [Ca++]i by levosimendan consistent with opening of potassium channels and a relaxation that is independent of [Ca++]i. Our evidence points to a novel mechanism that might involve the direct effect of levosimendan on the smooth muscle contractile or regulatory proteins themselves.
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J. Pharmacol. Exp. Ther. · Jan 1999
Differences in degree of trapping of low-affinity uncompetitive N-methyl-D-aspartic acid receptor antagonists with similar kinetics of block.
This study characterizes the trapping of block of N-methyl-D-aspartic acid (NMDA)-induced currents by three structurally distinct, use-dependent NMDA receptor antagonists with similar rapid on-off rates. The antagonism of whole-cell currents in cultured rat cortical neurons by AR-R15896AR, ketamine, and memantine was examined. All three compounds produced a steady-state block after a 30-s coapplication, which was fully relieved after 50 s of NMDA exposure. ⋯ Higher antagonist concentrations produced larger initial blocks, but the degree of trapping block was not significantly different from that at lower antagonist concentrations. The results demonstrate that differences in the degree of trapping exist among use-dependent NMDA receptor antagonists even when on and off rates are similar. These differences are correlated with measures of therapeutic index.
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J. Pharmacol. Exp. Ther. · Dec 1998
OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats.
The pharmacological profile and the acute and chronic aquaretic effects of OPC-41061, a novel nonpeptide human arginine vasopressin (AVP) V2-receptor antagonist, were respectively characterized in HeLa cells expressing cloned human AVP receptors and in conscious male rats. OPC-41061 antagonized [3H]-AVP binding to human V2-receptors (Ki = 0.43 +/- 0.06 nM) more potently than AVP (Ki = 0. 78 +/- 0.08 nM) or OPC-31260 (Ki = 9.42 +/- 0.90 nM). OPC-41061 also inhibited [3H]-AVP binding to human V1a-receptors (Ki = 12.3 +/- 0.8 nM) but not to human V1b-receptors, indicating that OPC-41061 was 29 times more selective for V2-receptors than for V1a-receptors. ⋯ As the result of aquaresis, hemoconcentration was seen at 4 hr postdosing although, no differences were seen in serum osmolality, sodium, creatinine and urea nitrogen concentrations at 24 hr postdosing. Furthermore, there was no difference in serum AVP concentration, pituitary AVP content or the number and affinity of AVP receptors in the kidney and liver at trough throughout the study period. These results demonstrate that OPC-41061 is a highly potent human AVP V2-receptor antagonist and produces clear aquaresis after single and multiple dosing, suggesting the usefulness in the treatment of various water retaining states.
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J. Pharmacol. Exp. Ther. · Dec 1998
Delta-opioid ligands reverse alfentanil-induced respiratory depression but not antinociception.
Evidence suggests both opioid mu and delta receptors may participate in the regulation of respiration at different central nervous system sites. In the past, the overlapping receptor specificity of various opioid drugs has made it difficult to dissect the receptor subtype-specific activities involved in respiratory regulation. The new family of delta receptor selective agents such as cyclic[D-Pen2, 5]enkephalin, deltorphins, (+)-4-((alpha-R)-alpha-((2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide, naltrindole and H-Tyr-Tic(psi)[CH2NH]Phe-Phe-OH have now made it feasible to more clearly define the role of delta receptors in respiratory control. ⋯ The reversal of alfentanil-induced hypercapnia by these delta ligands was antagonized by a novel synthetic delta antagonist cis-4-(alpha-(4-((Z)-2-butenyl)-3, 5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide. We propose that in this experimental respiration model, the delta antagonists naltrindole and H-Tyr-Tic(psi)[CH2NH]Phe-Phe-OH behave like delta agonists with low but sufficient intrinsic activities to reverse alfentanil-induced hypercapnia in rats. The results suggest that a function of the delta receptor is to modulate or counteract the respiratory depression induced by the mu receptor.
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J. Pharmacol. Exp. Ther. · Nov 1998
Pharmacological characterization of nicotinic receptor-stimulated GABA release from mouse brain synaptosomes.
Several recent electrophysiological studies have demonstrated that nicotinic agonists stimulate the release of gamma-aminobutyric acid (GABA) from rodent brain tissue. Our studies used a neurochemical approach to characterize nicotinic receptor-stimulated [3H]-GABA release from mouse brain synaptosomes. Nicotine increased [3H]-GABA release from synaptosomes preloaded with [3H]-GABA in a concentration-dependent manner. ⋯ Differences in [3H]-GABA release were detected in 12 brain regions and maximal release was significantly correlated with [3H]-nicotine binding. The pharmacological and regional comparisons suggest that the nAChR that stimulates [3H]-GABA release is the one that binds [3H]-nicotine with high affinity (alpha4beta2). Unequivocal evidence that the receptor that modulates nicotine-stimulated [3H]-GABA release contains a beta2 subunit was obtained in a study using wild-type, heterozygous and homozygous beta2 null mutant mice. [3H]-GABA release and [3H]-nicotine binding decreased along with the number of copies of the null mutant gene.