The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Oct 1995
Zatebradine, a specific bradycardic agent, alters the hemodynamic and left ventricular mechanical actions of levosimendan, a new myofilament calcium sensitizer, in conscious dogs.
The cardiovascular and left ventricular (LV) functional effects of levosimendan were examined (LSM; 0.5, 1.0, 2.0 and 4.0 micrograms.kg-1.min-1) in conscious, chronically instrumented dogs (n = 8) in the presence and absence of heart rate control with zatebradine (ZAT) or ZAT alone (0.25, 0.5 and 1.0 mg.kg-1). LSM increased heart rate (HR) cardiac output (CO), diastolic coronary blood flow velocity (DCBFV) and pressure-work index (PWI; calculated myocardial oxygen consumption) and decreased mean arterial, LV systolic and end-diastolic pressures, systemic vascular resistance and diastolic coronary vascular resistance (DCVR). ZAT alone decreased HR and PWI and increased stroke volume. ⋯ LSM increased the maximal rate of segment lengthening to a similar degree in ZAT-treated versus -untreated dogs. ZAT alone had minimal effects on LV function. Control of LSM-induced tachycardia with ZAT decreases myocardial oxygen consumption but also partially attenuates the positive inotropic and lusitropic effects of LSM.
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J. Pharmacol. Exp. Ther. · Oct 1995
Comparative StudySpinal opioid receptors and adenosine release: neurochemical and behavioral characterization of opioid subtypes.
Release of adenosine from the spinal cord contributes to spinal antinociception by morphine. Morphine induces a Ca(++)-dependent release of adenosine from dorsal spinal cord synaptosomes, which is augmented under partially depolarizing conditions. The present study examined the opioid receptor subtypes involved in this release, and determined whether adenosine is an important mediator of antinociception induced by the spinal administration of selective opioid agonists in rats. ⋯ Caffeine did not block the antinociceptive response to delta agonists, but in fact augmented antinociception when combined with DPDPE and DELT. This augmentation was dose-dependent. This study demonstrates that activation of the mu receptor subtype is responsible for the opioid-induced release of adenosine from the spinal cord, that such release contributes to the spinal antinociception by mu agonists and that only release evoked by low doses of opioids is behaviorally relevant.
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J. Pharmacol. Exp. Ther. · Oct 1995
Effects of cholinesterase inhibitors and clonidine coadministration on rat cortex neurotransmitters in vivo.
In previous investigations, we have demonstrated that cholinesterase inhibitors such as physostigmine (PHY) and heptylphysostigmine (HEP) elicit a significant and simultaneous increase in acetylcholine (ACh) and norepinephrine (NE) levels in the rat cortex. This effect is enhanced by idazoxan, a selective alpha-2 antagonist. These data suggest that a combination of cholinergic and adrenergic drug may improve the pharmacological effect of the cholinesterase inhibitor on cortical neurotransmitters such as ACh-NE. ⋯ Comparison between the two treatment combinations shows that, although CLO coadministration reduces the effect of PHY on ACh levels, HEP administered to animals pretreated with CLO produces a stronger effect than HEP alone. A possible explanation for this difference is the variation in duration of the two drugs on ACh elevation and muscarinic receptor desensitization. As a result of the alpha-2 agonist cholinesterase inhibitor coadministration, our data suggest that such a combination does not represent an advantage as a therapeutical alternative for treatment of cognitive impairment in Alzheimer disease patients.
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J. Pharmacol. Exp. Ther. · Oct 1995
Peptide structural requirements for antagonism differ between the two mammalian bombesin receptor subtypes.
Recently it has been established that both a gastrin-releasing peptide (GRP) receptor and a neuromedin B (NMB) receptor mediate the actions of bombesin-related peptides in mammals. Five different classes of peptides that function as GRP receptor antagonists have been identified; however, it is unknown whether similar strategies will yield antagonists for the closely related NMB receptor. In the present study we have used either native cells possessing only one bombesin (Bn) receptor subtype or cells stably transfected with one subtype to determine whether using the strategies that were used successfully for GRP receptors would allow NMB receptor antagonists to be identified. [DPhe12]Bn analogs; des Met14 amides, esters and alkylamides; psi 13-14 Bn pseudopeptides; and D-amino acid-substituted analogs of substance P (SP) or SP(4-11) were all synthesized and each functioned as a GRP receptor antagonist. ⋯ These results demonstrate that none of the known strategies used to prepare peptide GRP receptor antagonists are successful at the NMB receptor, suggesting that a different strategy will be needed for this peptide, such as the formation of somatostatin octapeptide or D-amino acid-substituted substance P analogs. These results suggest that even though there is a close homology between GRP and NMB and their receptors, their structure-function relations are markedly different. These results indicate that the development of receptor subtype-specific peptide agonists or peptide antagonists for newly discovered receptor subtypes of gastrointestinal hormones/neurotransmitters may be difficult because the strategies developed for one well-studied subtype may not apply to the other even though it is structurally closely related.