Hypothermia produces marked changes in cardiac activity and response to different anesthetic interventions. Isolated spontaneously beating right, or electrically stimulated left rat atria were examined while heart rate, sinus node recovery time, developed force, and effective refractory period were measured at 35 and 20 degrees C. Thus, we wanted to investigate the influence of low temperature on the cardiac effects of midazolam. The preparations were exposed to seven progressively increasing concentrations of midazolam. At 35 degrees C, midazolam produced a concentration-dependent positive inotropic effect and had a biphasic effect (shortening followed by lengthening) on the effective refractory period. These effects are best explained as due to a release of endogenous catecholamines, since the positive inotropy was completely blocked by propranolol. In reserpinized animals, there was no effect of midazolam. Midazolam, however, significantly decreased heart rate and increased the sinus node recovery time; these responses are believed to be direct effects. At 20 degrees C, midazolam had no effect on the developed force but, when a high concentration was administered, it significantly reduced the effective refractory period. Heart rate values were first increased and the reduced to control values. No effect on the sinus node recovery time was observed. Thus, hypothermia may reduce the catecholamine release and mask the effect of midazolam on cardiac tissue by mechanisms not yet fully understood.
The present study was undertaken to examine the possible therapeutic effects on nebracetam on the energy metabolism of rat brain regions in microsphere-induced, sustained ischemia. Microsphere embolism was induced by injection of 900 microspheres (48 microns in diameter) into the right internal carotid artery of rats, and changes in the energy metabolism of the cerebral cortex, striatum and hippocampus of the right hemisphere were determined without and with nebracetam treatment. Microsphere embolism induced increases in lactate and glucose contents and decreases of ATP and creatine phosphate contents in these regions, suggesting that sustained impairment of cerebral energy metabolism occurred. These changes were gradually reversed with time after the operation. Treatment of microsphere-injected rats with 30 mg/kg of nebracetam, p.o., twice a day, was started one day after the onset of cerebral ischemia. The effects of treatment with nebracetam on cerebral energy metabolites were determined on the 3rd and 7th day after operation. Treatment of microsphere-injected rats with nebracetam significantly improved these variables on the 3rd day after the onset of ischemia, but the improvement was small on the 7th day, except for reversal of the hippocampal ATP content. These results suggest that nebracetam is a possible therapeutic agent for the restoration of cerebral energy metabolism against microsphere-induced, sustained cerebral ischemia.
The aims of the present study were to determine (1) the β1-blocking potency and (2) the β1 adrenoceptor selectivity of nebivolol in man after repeated dosing (7 days) compared with that after a single oral intake and with that after atenolol for 7 days. In addition, it was investigated whether (3) nebivolol has α1-blocking properties which might at least in part explain the vasodilating property of the compound.
The effects of histamine H1 receptor antagonists (H1 antagonists) on action potentials in guinea-pig isolated papillary muscles were examined using a microelectrode technique. Terfenadine (0.03 microM) prolonged the action potential duration at 90% repolarization, without affecting the resting membrane potentials, the action potential amplitude or the maximal upstroke velocity, although its metabolite, terfenadine carboxylate, did not affect any action potential parameters. Astemizole, (+)-chlorpheniramine, and clemastine prolonged the action potential duration at 90% repolarization at 0.03, I and 10 microM, respectively. The action potential duration-prolonging effects of terfenadine and astemizole correspond to the reverse use-dependence phenomenon. However, ebastine and its metabolite, carebastine, did not affect the action potential parameters at 3 microM. Mequitazine, diphenhydramine, epinastine, ketotifen and oxatomide were also without effect at 10 microM. These H1 antagonists suppressed the histamine-induced contractions in guinea-pig isolated ileum longitudinal muscles. However, the potency order was inconsistent with that for prolonging the action potential duration. Terfenadine or astemizole prolonged the action potential duration at concentrations lower than each IC50 value for H1 receptor antagonism. Cimetidine, a H2 receptor antagonist, and thioperamide, a H3 receptor antagonist, had little effect on the action potentials. These results suggest that, in guinea-pig isolated papillary muscles, blockade of histamine receptors does not cause prolongation of the action potential duration, leading to prolongation of electrocardiographic QT intervals, and that H1 antagonists may be classified into three groups: (1) drugs causing prolongation of the action potential duration at concentrations producing H1 antagonism and (2) at concentrations higher than those producing H1 antagonism, and.
Fractionation of the rat lung yielded a 54,000 g supernate, and DOC-solubilized 775 g, 3100 g and 54,000 g sediments, each of these preparations displaying an increasing angiotensin-converting enzyme activity with increasing dilution, suggesting the presence of freely reversible angiotensin-converting enzyme inhibitors. The solubilized 775 g sediment was applied to an immobilized captopril column, eluted successively with 20 mM Pi(K+), pH 7.8 buffer, buffer/0.5 M NaCl, and buffer/0.01M cysteine to obtain four major protein bands, two of which appeared with the cysteine eluant. The first two protein peaks were each pooled and subjected to ultrafiltration with 10,000 molecular weight cutoff filters. The pooled peaks, retentates and ultrafiltrates each inhibited the angiotensin-converting enzyme activity, suggesting the presence of large and small molecular weight reversible angiotensin-converting enzyme inhibitors in association with the solubilized (membranous) particulate angiotensin-converting enzyme fraction. These results expand upon earlier observations on the existence of angiotensin-converting enzyme inhibitors in mammalian serum by observing an increasing angiotensin-converting enzyme activity with increasing dilution. This activity was eluted in multiple peaks, including elution with the cysteine eluate, suggesting that the angiotensin-converting enzyme, as well as other proteins, may react covalently with the sulfhydryl functional group of the immobilized captopril in a transsulfhydration reaction cleaving the disulfide bonds in proteins. Subsequent elution with cysteine affects an additional transsulfhydration reaction, releasing the proteins from the column. It is further postulated that air oxidation of the proteins permits reformation of disulfide bonds, yielding some active angiotensin-converting enzyme. Having in mind the possibility of lipophilic angiotensin-converting enzyme inhibitors crossing the blood-brain barrier as a means of treatment of alcohol abuse, the intriguing presence of a naturally occurring angiotensin-converting enzyme inhibitors in the particulate, lipid-rich fraction of the lung cell raises the theory that inhibitors such as these might cross the blood-brain barrier to serve as downregulators of alcohol consumption.
The antispasmogenic effects of nicorandil on epicardial coronary artery vasoconstriction were compared with those of a K+ channel opener, cromakalim, and a nitrovasodilator, nitroglycerin, in open-chest dogs. Intracoronary administration of U46619 (0.5-1.0 micrograms), a stable thromboxane A2 analogue, reduced the external diameter of the left circumflex coronary artery with no marked alternations in systemic hemodynamics. This U46619-induced vasoconstriction of large epicardial coronary arteries was dose-dependently prevented by the intracoronary infusion of nicorandil (1-10 micrograms/kg/min), cromakalim (0.03 micrograms/kg/min) and nitroglycerin (1 micrograms/kg/min). After pretreatment with glibenclamide (3 mg/kg, i.v.), and ATP-sensitive K+ channel blocker, these effects of nicorandil and cromakalim were inhibited significantly, whereas the response to nitroglycerin remained unchanged. Nicorandil (3 micrograms/kg/min), cromakalim (0.03 micrograms/kg/min) and nitroglycerin (1 micrograms/kg/min) increased coronary blood flow. However, the inhibitory effects of each drug on the U46619-induced vasoconstriction were not influenced by the partial occlusion of the left circumflex coronary artery, which kept coronary blood flow constant. This indicates a direct antispasmogenic effect of K+ channel openers, which is independent of that mediated by the response to flow. Furthermore, our results suggest that, by this effect, nicorandil protects large coronary arteries from U46619-induced vasoconstriction.
Anesthetized guinea-pigs were intravenously injected with Evans blue. After intracutaneous injection of agonists (lys-plasminogen, histamine, platelet-activating factor, thrombin, bradykinin), the resulting wheals appeared blue in a dose-dependent manner, due to an enhanced capillary permeability, alpha 1-Acid glycoprotein, given i.v. in different doses (3.125-50 mg/kg) and at different times (30-180 min) before Evans blue administration, antagonized the effects of all agonists listed above. This was shown by a parallel shift of the agonist dose-response curves to the right. The effect was time-dependent (tmax: mainly 120 min) and dose-dependent. alpha 1-Acid glycoprotein antagonized the agonists in the following order: lys-plasminogen > histamine = platelet-activating factor > thrombin > bradykinin. As all agonist mentioned are suggested to play a major role in the shock-related increase in vascular permeability, a putatively beneficial role of alpha1-acid glycoprotein in shock is discussed.
The action of the adenosine agonist, 5'-(N-ethylcarboxamido)-adenosine (NECA), at extracellular A(2), receptors of guinea-pig and rabbit aortic rings was investigated. A near-maximum relaxant concentration (10(-5) M) of NECA was determined from cumulative concentration-response curves in aortae precontracted with noradrenaline. The effects of this concentration of NECA upon the noradrenaline-induced contractions were measured as the ratio of the contractions obtained before and, in the same tissue, after addition of NECA. This ratio was compared with the control ratio obtained in paired tissues after adding vehicle between the first and second contraction. The roles of intracellular Ca2+ mobilization and influx of extracellular Ca2+ were examined using normal Ca2+ and Ca2+-free media. In normal Ca2+ medium, where both sources of Ca2+ are involved in the contraction to noradrenaline, NECA inhibited the contractions. In Ca2+-free conditions, the phasic contraction to noradrenaline was mediated via the intracellular Ca2+ pool and was not inhibited by NECA. The contractions of the guinea-pig aorta to angiotensin II (10(-6) M) in both normal and Ca2+-free media, which are mediated via release of intracellular Ca2+, were also not inhibited by NECA. These results indicate that the activation of extracellular A(2) adenosine receptors by NECA does not cause vasorelaxation by interfering with the release of intracellular Ca2+ by noradrenaline. The effects of NECA on contractions, due to influx of extracellular Ca2+, were examined in guinea-pig aortae in Ca2+-free medium and after exposure to angiotensin to deplete intracellular Ca2+ stores. Contractions were then induced by restoring the Ca2+ to the medium. These contractions were not inhibited by NECA, but when noradrenaline was present during the restoration of Ca2+, NECA was inhibitory. This and the evidence in normal Ca2+ medium, suggests that NECA causes vasorelaxation in the aorta by interfering with the Ca2+ influx via receptor-operated channels induced by noradrenaline.
The effects of the antimalarial drug, mefloquine, on the uptake and release of Ca2+ by crude microsomes from dog brain were investigated using a spectrophotometric method. Mefloquine inhibited the inositol-1,4,5-phosphate (IP3)-induced Ca2+ release with an IC50 of 42 microM, but was a weaker inhibitor of the uptake of Ca2+ into the vesicles (IC50: 272 microM). These effects of mefloquine are in contrast to its actions on Ca2+ uptake and release by skeletal muscle microsomes, where its predominant effect was seen to be the inhibition of Ca2+ uptake into the vesicles. Mefloquine was found to be more potent than quinine as a specific inhibitor of Ca2+ release from IP3-sensitive stores in dog brain microsomes. The possibility of the drug affecting cellular IP3-linked signal transduction processes should be considered.
Results obtained in the prevention of ventricular fibrillation secondary to myocardial ischaemia are unexpected. Profibrillatory properties might be manifested by Class I antiarrhythmic drugs, normally antifibrillatory. Clear antifibrillatory properties might be manifested by calcium channel blockers, the antifibrillatory effects of which are normally questionable. Therefore, the action of a Class I antiarrhythmic drug, flecainide, and of a calcium channel blocker, verapamil, on the vulnerability to ischaemic ventricular fibrillation was assessed in anaesthetized, open-chest pigs by ventricular fibrillation threshold. Ventricular fibrillation threshold was determined with trains of diastolic stimuli of 100 msec duration, delivered at a rate of 180 beats/min (near that of the ventricular tachycardia), by a subepicardial electrode inserted into the area that could be subjected to ischaemia. Before determining this threshold, ventricles were paced at the same rate, particularly during the ischaemic periods. Ischaemia was produced by complete occlusion of the left anterior descending coronary artery, either at its origin or half-way from it, over increasing periods. The monophasic action potential and conduction time were recorded in the ischaemic area. Before ischaemia, flecainide was adapted to rais the ventricular fibrillation threshold, in spite of a lengthening of the conduction time. Verapamil was devoid of any influence on these parameters. The antifibrillatory effect of flecainide disappeared with ischaemia, which reduced the ventricular fibrillation threshold down to near 0 mA, with triggering of the spontaneous fibrillation at this level: this reduction was no longer counteracted and even hastened by flecainide, becomes finally profibrillatory. Verapamil, on the contrary, delayed the fall in ventricular fibrillation threshold, maintained far from 0 mA, with prevention of fibrillation, unless the occlusion was maintained over a much longer period. Verapamil similarly delayed the shortening of the monophasic action potential duration and the lengthening of the conduction time, preceding fibrillation and leading to it. Consequently, ischaemic depolarization is apparently responsible for the loss of antifibrillatory activity in a sodium blocker, such as flecainide, and the development of antifibrillatory activity in a calcium blocker, since the sodium channel is activated only at high potentials, whereas the calcium channel is activated at lower potentials.
We investigated the role of the 5-hydroxytryptamine3 (5-HT3) receptor in the regulation of gastric emptying in rats using various 5-HT3 receptor antagonists, including GK128, a novel and selective 5-HT3 receptor antagonist. GK128 dose-dependently accelerated gastric emptying in rats. The accelerating effect of GK128 on gastric emptying was more potent than that of the other 5-HT3 receptor antagonists used in this study. However, the rank order of potency of the selective 5-HT3 receptor antagonists, except for the benzamide derivatives, on the accelerating effect of gastric emptying, was not consistent with that of their 5-HT3 receptor-binding affinity in the rat cortex. GK128 improved the gastric emptying delayed by m-chlorophenylbiguanide, a 5-HT3 receptor agonist, and by cisplatin, which is known to cause damage to the small intestine and to release 5-HT from enterochromaffin cells. Furthermore, 5,7-dihydroxytryptamine, an indoleamine neurotoxin known to destroy 5-HT-containing neurons, significantly accelerated gastric emptying, and no further acceleration was observed after administration of GK128. These results may suggest that 5-HT3 receptor antagonists induce, at least in part, the acceleration of gastric emptying in rats via a peripheral mechanism, and that endogenous serotonin has an inhibitory regulatory effect on gastric emptying in rats. Furthermore, the difference in rank order between the accelerating effect of gastric emptying and the 5-HT3 receptor antagonistic potencies in the cortex suggests that the 5-HT3-like receptor, modulating gastric emptying, is not identical to the classically defined 5-HT3 receptor.
The effects of R-84760 [(3R)-3-(1-pyrrolidinylmethyl)-4-[(1S)-5,6-dichloro-l-indancarb onyl] tetrahydro-1,4-thiazine hydrochloride] on nociception, locomotion and respiration were examined in rats. R-84760 induced a potent antinociceptive effect in the formalin test. The potency was 930 and 1500 times higher than that of U-50488 and morphine, respectively, when injected subcutaneously. Intracerebroventricular and intrathecal injection, as well as subcutaneous administration of naloxone antagonized the antinociceptive effect of R-84760, suggesting the sites of action of R-84760 were at the spinal and supraspinal levels. R-84760 disturbed the rotarod performance at doses 16 times higher than those needed for antinociception. R-84760 did not affect the arterial blood Pco2, Po2 and pH at a supramaximal dose for antinociception.
The aim of this study was to assess the pharmacokinetics and subsequent pharmacodynamic interaction of MPC-1304, a dihydropyridine Ca2+ antagonist, with other drugs in animal experiments. We measured the systolic blood pressure and heart rate of conscious spontaneously hypertensive rats implanted with battery-operated biotelemetry devices after combined administration of various drugs. Cimetidine (10 mg/kg) did not affect the reduction in systolic blood pressure and the increase in heart rate induced by MPC-1304, whereas it significantly increased the plasma concentration of a metabolite of MPC-1304 (M-1) compared to that detected when MPC-1304 was administered alone. When MPC-1304 was consecutively administered in combination with rifampicin (400 mg/kg) for 9 days, the plasma concentrations of MPC-1304 and of M-1 significantly decreased compared to those found when MPC-1304 alone was given. In spite of these reductions in plasma concentrations, rifampicin did not attenuate the hypotensive action induced by MPC-1304. When prazosin, reserpine, or methyldopa was administered in combination with MPC-1304, the hypotensive action was enhanced as compared to that by MPC-1304 alone or to that by the co-administered drug used alone (prazosin, reserpine, or methyldopa). Quinidine (10 mg/kg) affected neither the hypotensive action induced by MPC-1304 nor the plasma concentrations of MPC-1304 and M-1. These results indicate that cimetidine and rifampicin interact with MPC-1304 pharmacokinetically, without apparently changing the hypotensive action of MPC-1304, whereas quinidine does not affect the metabolism of MPC-1304, and that other hypotensive drugs, such as prazosin, reserpine, and methyldopa, potentiate the hypotensive action of MPC-1304.
The pharmacological properties of a newly synthesized 3-acetoxy-6 beta-acetylthio-10-oxo-N-cyclopropylmethyl-dihydronormorphine (KT-95) were examined. This compound, as well as (-)-3-acetyl-6 beta-acetylthio-N-cyclopropylmethylnormorphine (KT-90) and morphine, inhibited the twitch response to electrical stimulation of the guinea-pig ileal preparation that contains mu- and kappa-receptors. The inhibitory effect of KT-95 was about 17 times more potent than morphine, and about 4 times more potent than KT-90. In the guinea-pig ileal preparation, KT-95 behaved as a mu-antagonist against morphine in the presence of norbinaltorphimine (3 x 10(-8) M). In the rabbit vas deferens, containing kappa-opioid receptors, KT-95 inhibited the twitch response to electrical stimulation in a concentration-dependent manner. Norbinaltorphimine concentration-dependently caused parallel rightward shifts of the concentration-response curves to KT-95 in the guinea-pig ileum and in the rabbit vas deferens after electrical stimulation, suggesting that KT-95 behaved as an agonist for the kappa-opioid receptor. In the mouse vas deferens, that contains delta-receptors. KT-95 behaved also as a delta-antagonist against Leu-enkephalin in the presence of norbinaltorphimine. KT-95, KT-90 and morphine were examined for their potencies in displacing the specific binding of [3H]naloxone (mu-selective ligand), [3H]U69593 (kappa-selective ligand), and [3H]D-Ala2-D-Leu5-enkephalin (delta-selective ligand) to synaptosomal fractions from rat brain. Although KT-95 had a higher nonselective affinity to mu-receptors than KT-90 and morphine, the affinity of KT-95 to kappa-receptors was about 18 times higher than that of morphine, and about 5 times higher than that of KT-90. In the acetic acid-induced writhing test, subcutaneously injected KT-95 was more potent than morphine. Furthermore, the analgesic effect, induced by KT-95 (0.062 mumol/kg, s.c.), was abolished by simultaneous administration of norbinaltorphimine (0.020 mumol/mouse, s.c.), suggesting that the analgesic action of KT-95 is mediated through the kappa-opioid receptor. In the pressure test, KT-95 was 20.17 times more potent than morphine. The analgesic action, induced by KT-95 (2.05 mumol/kg, s.c.), was also in this test abolished by simultaneous administration of norbinaltorphimine (0.14 mumol/rat, s.c.), suggesting that this action of KT-95 is mediated through the kappa-opioid receptor. These results indicate that KT-95 behaves as a kappa-agonist with mu- and delta-antagonistic activities, and suggest that analgesia, induced by KT-95, is mainly mediated through kappa-receptors.
The effect of lidocaine on brain lipid peroxidation, as reflected by jugular vein malondialdehyde concentrations, and of polymorphonuclear leukocyte activation in peripheral venous blood samples following transient global cerebral ischemia, were studied. In normothermic dogs subjected to a 10 min elevation of cerebrospinal fluid pressure and a subsequent 60 min reperfusion, the malondialdehyde concentration during the first 3 min of reperfusion increased significantly (p < 0.05) in the jugular vein. Lidocaine (10 mg/kg, i.v.), administered 10 min before ischemia, not only prevented the elevation of the malondialdehyde concentrations during ischemia, but also provoked a significant transient decrease 10 min after the start of reperfusion. A 10 min ischemia and a 60 min reperfusion caused no significant changes in the polymorphonuclear leukocyte radical production, neither following ischemia nor after addition of lidocaine. These results suggest that lidocaine exerts a scavenging action on free radical processes but that it has no direct effect on the polymorphonuclear leukocyte activation in the early phase of reperfusion following ischemia.
The effect of MET-88 [3-(2, 2, 2-trimethylhydrazinium) propionate], a gamma-butyrobetaine hydroxylase inhibitor, on the ischemic changes of energy metabolism was studied in the anesthetized dog. In the dog pretreated orally with MET-88 (50, 100 or 200 mg/kg/day) or placebo for 10 days, the left anterior descending coronary artery was occluded for 60 min, and the myocardium was taken from the left anterior descending coronary area (ischemic area) and left circumflex area (nonischemic area) for metabolic analysis. In the ischemic area, occlusion of the left anterior descending coronary artery decreased the tissue levels of adenosine triphosphate, adenosine diphosphate and creatine phosphate, increased the tissue levels of adenosine monophosphate and lactate, and decreased the value of the energy charge potential. These metabolic alterations, induced by occlusion of the left anterior descending coronary artery, were dose-dependently attenuated by MET-88. In the nonischemic area, MET-88 did not markedly change either the tissue levels of energy metabolites or the value of the energy charge potential. These results indicate that MET-88 attenuates the derangement of the energy metabolism in the ischemic myocardium, without affecting the energy metabolism in the nonischemic myocardium.
We analyzed the displacement activity of sarpogrelate and its active metabolite (M-1) in the radiolabeled ligand binding to various 5-hydroxytryptamine (5-HT) receptor subtypes using rat brain cortical membranes. Sarpogrelate was shown to have the same affinity as ritanserin for 5-HT2A receptors, with a Ki value of 8.39 nM. The active metabolite of sarpogrelate, M-1, was more active than sarpogrelate itself and of ritanserin, with a Ki value of 1.70 nM. Both sarpogrelate and M-1 had no affinity for 5-HT1A receptors, but these substances, at a concentration of 10 microM, displaced the specific binding to the 5-HT1B receptors of [125I]iodocyanopindolol, resulting in Ki values of 0.881 and 0.859 microM, respectively. The Ki values of sarpogrelate and M-1 are almost the same as that of ritanserin, a specific 5-HT2 receptor antagonist. Sarpogrelate and M-1, as well as ritanserin, are shown to have very low affinity for 5-HT1B receptors. Both sarpogrelate and M-1 had no affinity for 5-HT3 receptor subtypes. In the 5-HT4 receptor binding experiments, sarpogrelate exhibited almost no affinity, while M-1, at the concentration of 10 microM, displaced the binding activity, resulting in a Ki value of 0.838 microM. Both drugs had a weak antagonistic effect on a 5-HT4 receptor-mediated function, i.e., the 5-HT-induced relaxation of rat isolated esophageal tunica muscularis mucosae. In conclusion, sarpogrelate and M-1 have high affinity for 5-HT2A receptors with a relatively high selectivity.
The association between torsade de pointes and experimentally induced early afterdepolarizations in isolated fibres is well documented. The effect of eight beta-adrenoceptor-blocking drugs (sotalol, nifenalol, acebutolol, dichloroisoproterenol, propranolol, oxprenolol, pindolol, atenolol), and of amiodarone, was studied in isolated spontaneously beating guinea-pig Purkinje fibres by the intracellular microelectrode technique. Phase 3 early afterdepolarizations were initiated by nifenalol hydrochloride (n = 18; 10 mumol/l: 0/18, 40 mumol/l: 3/18, 80 mumol/l: 8/18, 160 mumol/l: 11/18), rac.-(+/-)-sotalol hydrochloride (n = 28; 20 mumol/l: 0/28, 40 mumol/l: 9/28, 80 mumol/l: 20/28), (R)(+)-sotalol hydrochloride (n = 12; 40 mumol/l: 1/12, 80 mumol/l: 4/12), and (S)(-)-sotalol hydrochloride (n = 10, 40 mumol/l: 1/10, 80 mumol/l: 4/10). The arrhythmogenic effect was reversible after a washout period of one hour and early after-depolarizations could be terminated by tetrodotoxin (0.4-1.6 mumol/l, n = 6). Amiodarone only induced early afterdepolarizations at a low extracellular potassium concentration of [K+]o = 1.35 mmol/l (n = 5; 150 mumol/l: 0/5, 300 mumol/l: 1/5). The initiation of early after-depolarizations by sotalol and nifenalol might be induced by an imbalance of sodium inward current and potassium outward currents, and early afterdepolarizations are blocked by tetrodotoxin.
The present study explored the role of the dopaminergic transmission in the mouse writhing test analgesia by examining the relative analgesic activity of indirect dopaminergic agonists (amphetamine and cocaine), a mixed D1/D2 direct agonist (apomorphine), and a direct D1 (SKF38393) and D2 (bromocriptine) dopaminergic agonist. Amphetamine (1, 3 and 10 mg/kg, s.c.), cocaine (3 and 10 mg/kg, s.c.), apomorphine (0.3, 1 and 3 mg/kg, s.c.) and bromocriptine (30 mg/kg, s.c.) induced a significant decrease of the number of writhes. SKF38393 (1, 3, 10 and 30 mg/kg, s.c.) had no effect on writhing. The antinociceptive effect of amphetamine and cocaine was not reversed by naltrexone, haloperidol or SCH23390. The apomorphine- and bromocriptine-induced analgesia was not reduced by naltrexone or SCH23390 but was attenuated by haloperidol; the apomorphine-induced analgesia was not modified by domperidone. The present results suggest an involvement of the dopaminergic transmission in visceral nociception. This dopaminergic component appears to involve exclusively the central D2 receptor system, and does not seem to be influenced by opioid mechanisms.
The difference between the responses of phenylephrine (1 microM)-precontracted vascular (endothelium-denuded rat or rabbit aortic strips) and nonvascular (rat anococcygeus muscle) smooth muscles to acetylcholine (0.1-100 microM) was investigated when they were mounted co-axially inside the tracheas isolated from normal or ovalbumin-sensitized guinea-pigs. Acetylcholine produced concentration-dependent relaxations in both types of bioassay tissues. These relaxations, previously shown to be due to the release of airway epithelium-derived relaxing factor(s), were significantly attenuated when the epithelial layer of the tracheas was removed mechanically (as confirmed by histological examination). There were no significant differences in responsiveness to acetylcholine between vascular strips mounted inside the epithelium-intact normal or sensitized tracheas. The phenylephrine-induced precontraction was significantly more pronounced in rat anococcygeus muscles mounted inside sensitized tracheas as compared to tissues mounted inside control tracheas. The acetylcholine-induced relaxations were significantly decreased but this effect disappeared when the concentration of phenylephrine was reduced to obtain a similar precontraction level as in tissues mounted inside control tracheas. The responsiveness of both vascular strips and anococcygeus muscles to acetylcholine was attenuated when they were mounted inside sensitized tracheas and incubated with ovalbumin for 20 min, which may be explained by the epithelial damage induced by ovalbumin challenge. This attenuation was absent when co-axial pairs, utilizing normal tracheas, were used. These results indicate a difference in response patterns of the rat anococcygeus muscle and vascular strips in ovalbumin-sensitized tracheas, which should be taken into consideration in co-axial bioassay studies.
