The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Oct 1988
Cardiovascular effects of rat calcitonin gene-related peptide in the conscious rat.
The role of rat calcitonin gene-related peptide (CGRP), a recently characterized vasoactive neuropeptide, in cardiovascular regulation was studied in the conscious rat. Mean arterial pressure (MAP), heart rate, cardiac output (thermodilution technique) and regional blood flow (directional pulsed Doppler velocimetry) were monitored after i.v. or i.c.v. administration of CGRP. Systemic administration of CGRP (0.1-10 nmol/kg i.v.) decreased MAP and increased heart rate in a dose-related manner. ⋯ CGRP, i.c.v. (0.1-10 nmol/kg), induced a modest tachycardia in both intact and sinoaortic denervated rats, but was devoid of any other cardiovascular effects. The results indicate that CGRP is a potent vasodilator of mesenteric, renal and hindquarter skeletal muscle blood vessels in the conscious rat. The hypotensive and vasodilator actions of circulating CGRP are likely to be mediated by direct peripheral interaction with CGRP receptors on vascular smooth muscle, whereas its tachycardic effect seems to involve reflex activation of the sympathetic nervous system.
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J. Pharmacol. Exp. Ther. · Aug 1988
Randomized Controlled Trial Clinical TrialCigarette brand-switching: effects on smoke exposure and smoking behavior.
This study examined the effects of cigarette yield (Federal Trade Commission-determined deliveries of nicotine, tar and CO) on both biological exposure to smoke constituents and smoking behaviors. Smokers (N = 10) of high-yield cigarettes were switched in random order among five different commercially available cigarette brands with nicotine yields of 0.1, 0.4, 0.7, 1.1 (altered brand) and 1.0 (usual brand) mg and smoked each cigarette type for 5 days while a wide variety of assessments were performed. Steady-state cotinine and CO levels were substantially lower after 5 days of smoking ultra-low yield cigarettes (cotinine, 152 ng/ml; CO, 25 ppm) than when smoking usual-brand high-yield cigarettes (cotinine, 252 ng/ml; CO, 38 ppm). ⋯ However, filter vent-blocking of ultra-low yield cigarettes did not appear to occur on a consistent basis. Subjective reports indicated poor acceptability of lower-yield cigarettes. We conclude that switching to lower-yield cigarettes brings about substantial alterations in smoking behavior which are at least partially responsible for the observed biological compensation associated with these cigarettes.
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J. Pharmacol. Exp. Ther. · May 1988
Intrathecal morphine and clonidine: antinociceptive tolerance and cross-tolerance and effects on blood pressure.
The effects of acute and chronic intrathecal (i.t.) administration of the opioid receptor agonist, morphine, or the alpha-2 adrenoceptor agonist, clonidine, on nociception and blood pressure were examined in rats. In rats lightly anesthetized with pentobarbital, morphine produced dose-dependent inhibition of the nociceptive tail-flick reflex (ED50 = 10.0 micrograms) and small, non-dose-related pressor effects. These effects were antagonized by pretreatment with the opioid receptor antagonist naloxone (30.0 micrograms i.t.), whereas the alpha-2 adrenoceptor antagonist yohimbine (30.0 micrograms i.t.) potentiated the pressor effects and did not alter the antinociceptive effects of morphine. ⋯ These results indicate that the antinociceptive effects of acute i.t. morphine and clonidine are mediated by spinal opioid and alpha-2 adrenergic receptors, respectively. However, tolerance to and cross-tolerance between i.t. morphine and i.t. clonidine suggest that spinal opioid and alpha-2 adrenergic systems interact in producing antinociception. These systems also appear to interact in complex ways to exert effects on blood pressure.
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J. Pharmacol. Exp. Ther. · Jan 1988
Nalbuphine: an autoradiographic opioid receptor binding profile in the central nervous system of an agonist/antagonist analgesic.
Nalbuphine is a potent agonist/antagonist analgesic with a low side effect profile and low abuse potential. Previous studies have shown that nalbuphine produces predominantly agonist (analgesic) effects at kappa receptors and antagonist (morphine-reversal) effects at mu receptors in vivo. The present study was designed to localize the sites of nalbuphine binding to mu, delta and kappa opioid receptors in the central nervous system (CNS) using in vitro labeling light microscopic autoradiography. ⋯ The autoradiographic distribution of [3H]nalbuphine binding sites in the CNS corresponds well to the distribution of mu and kappa opioid receptors. In addition, CNS areas (deep layers of the cerebral cortex, laminae I and II of the spinal cord, substantia gelatinosa of the trigeminal nerve, periaqueductal gray and thalamic nuclei) that mediate analgesia contain high concentrations of [3H]nalbuphine binding sites. In summary, these data demonstrate that nalbuphine acts on mu and kappa opioid receptors and identify anatomical loci in the CNS in which nalbuphine may produce its actions.
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J. Pharmacol. Exp. Ther. · Sep 1987
Pharmacological analysis of the cardiac actions of xamoterol, a beta adrenoceptor antagonist with partial agonistic activity, in guinea pig heart: evidence for involvement of adenylate cyclase system in its cardiac stimulant actions.
The pharmacological effects of xamoterol, a beta adrenoceptor antagonist with partial agonistic activity, were examined in guinea pig cardiac preparations and compared with those of isoproterenol to assess possible mechanisms of its cardiac stimulant actions. Xamoterol produced a positive inotropic effect in the papillary muscles and a positive chronotropic effect in the spontaneously beating right atria in a concentration-dependent manner. The maximum inotropic and chronotropic effects of xamoterol were about 33 and 35% of those of isoproterenol, respectively. ⋯ In papillary muscles the increases in contractile force induced by xamoterol and isoproterenol were depressed markedly in the presence of carbachol or adenosine. In all of left atria, right atria and papillary muscles obtained from reserpine-pretreated animals, xamoterol caused a significant elevation in cyclic AMP levels, while inhibiting the isoproterenol-induced increase in cyclic AMP levels. Computer-assisted analysis of concentration-response curves for the inhibition by xamoterol of the binding of [125I]iodocyanopindolol in the membranes from guinea pig ventricles showed the existence of the 5'-guanylylimidodiphosphate sensitive, highly affinity site of beta adrenoceptors for xamoterol, suggesting that xamoterol may induce the formation of a ternary complex with the beta adrenoceptor and a stimulatory guanine nucleotide regulatory protein.(ABSTRACT TRUNCATED AT 250 WORDS)