European journal of pharmacology
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To examine the role of vasopressin V1 and V2 receptors, nitric oxide and prostanoids in the coronary vascular effects of [Arg8]vasopressin, coronary blood flow was measured with an electromagnetic flow transducer placed around the left circumflex (23 goats) or anterior descending (11 goats) coronary artery and vasopressin (0.03-1 microg) was intracoronarily injected in 34 anesthetized, open-chest goats. Basal mean values for coronary blood flow, mean systemic arterial pressure and heart rate, were 34 +/- 2.38 ml/min, 89 +/- 3.34 mmHg and 80 +/- 3.06 beats/min, respectively. Vasopressin produced dose-dependent decreases in coronary blood flow and the maximal reduction of this flow, attained with 1 microg of vasopressin, was 14 +/- 1.49 ml/min (42 +/- 2.64% of basal flow) (P < 0.01). ⋯ During this treatment the reduction in coronary blood flow produced by vasopressin was higher than under control (the effects of 1 microg of vasopressin were increased by 28%, P < 0.01). Intravenous administration of the inhibitor of cyclooxygenase, meclofenamate (5 mg/kg, 7 animals), neither modified resting coronary blood flow, arterial pressure and heart rate nor the effects of vasopressin on this flow. These data indicate that vasopressin produces marked coronary vasoconstriction and suggest that: (a) it may be mediated by vasopressin V1 receptors, without involvement of vasopressin V2 receptors, (b) it is probably inhibited by nitric oxide under normal conditions and (c) it may be not modulated by prostanoids.
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Endothelial cells play an important role in the regulation of vascular activity through the release of endothelium derived relaxing factor (EDRF) now believed to be nitric oxide (NO). NO and the NO donor drug nitroglycerin relax vascular smooth muscle by stimulating soluble guanylyl cyclase leading to elevation of intracellular levels of cyclic guanosine 3',5'-monophosphate (cGMP). Halothane has been shown to inhibit the action of NO on blood vessels. ⋯ Halothane, in combination with methylene blue or LY 83583, produced inhibition equivalent to the sum of their individual effects. The present study demonstrates that the halothane, methylene blue and LY 83583 attenuate nitroglycerin and NO-induced relaxations of endothelium-denuded rat aortic rings. This suggests that halothane, methylene blue and LY 83583 may act through competitive antagonism at a common site of action on soluble guanylyl cyclase in the EDRF/NO relaxation pathway.
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We investigated the effects of SNC 80 ((+)-4-[alphaR)-alpha-((2S,5R)-4-ally1-2,5-dimethyl-1-pipera zinyl)-3-methoxybenzyl]-N,N-diethylbenzamide), a new highly selective, non-peptidic and systemically active delta-opioid receptor agonist, on gastrointestinal and colonic propulsion in mice. Intraperitoneally (i.p.) SNC 80 (1, 10 and 30 mg/kg) significantly decreased gastrointestinal propulsion measured as transit of an orally administered charcoal meal. Pretreatment with the delta-opioid receptor antagonist, naltrindole (1 mg/kg) subcutaneously (s.c.), with the non-selective opioid antagonist, naloxone (5 mg/kg, s.c.) or the mu1-opioid receptor antagonist, naloxonazine (10 mg/kg, i.p.), significantly decreased the antitransit effect of SNC 80 but pretreatment with the non-selective opioid antagonist, naloxone methiodide (5 mg/kg, s.c.), a quaternary salt of naloxone that does not cross the blood-brain barrier, did not. ⋯ It does so mainly through a central mechanism. Although the gastrointestinal antitransit effect of SNC 80 is naltrindole- and naloxonazine-sensitive, we cannot exclude an opioid-independent mechanism. The colonic antipropulsive effect of SNC 80 confirms the inhibitory role of the central delta-opioid receptor system on colonic motility.
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This study tested whether a 5-HT3 receptor antagonist could reverse the signs of precipitated opioid withdrawal. Rats were treated with either saline or morphine for 4 days. After the four days, half of the rats in each group received naloxone and half received saline. ⋯ Administration of ondansetron to rats receiving naloxone after chronic morphine decreased the intensity of withdrawal signs such as increased defecation, jumping and wet-dog shakes, elevated the nociceptive threshold values which were decreased by precipitated withdrawal, but produced no change in urination, rectal temperature or salivation. The effects exhibited by ondansetron administration may be explained through interference of its 5-HT3 receptor antagonist activity with serotoninergic mechanisms involved in the regulation of these withdrawal symptoms. The use of this drug is thus suggested as a possible treatment of opioid withdrawal signs in heroin addicts.
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The effect of inhibition of nitric oxide synthesis and guanylate cyclase on the peripheral antinociceptive effect of morphine was assessed by using the formalin test in the rat. Saline, N(G)-monomethyl-L-arginine, a nitric oxide synthesis inhibitor (50 microg) and methylene blue, a guanylate cyclase inhibitor (500 microg), did not exhibit any antinociceptive activity. However, morphine (10 microg) produced a significant antinociceptive effect in phases 2a and 2b, which was reduced by pretreatment with either N(G)-monomethyl-L-arginine or methylene blue. These results suggest that the local administration of morphine induces antinociception by the activation of the L-arginine-nitric oxide-cGMP pathway.