Blockade of neuronal tryptamine receptors by metoclopramide.

Metoclopramide (0.13, 0.51, 2.0 and 8.1 X 10(-6) M) caused parallel, rightward, shifts in the dose response curves to 5-HT on the isolated rabbit heart. A significant straight line relationship was found between log (5-HT dr--1) and log [metoclopramide] (molar) with a slope of 1.08 +/- 0.13 and giving a pA2 value of 7.20. Metoclopramide did not significantly alter responses to noradrenaline and was 575 times less effective as an inhibitor of DMPP than of 5-HT. The results indicate that metoclopramide is a potent, surmountable and selective antagonist of tryptamine receptors on rabbit cardiac sympathetic nerves.

Dual mechanism of the stimulant action of N,N-dimethyl-5-hydroxy-tryptamine (bufotenine) on cardiac sympathetic nerves.

The indirect sympathomimetic effects of N,N-dimethyl-5-hydroxytryptamine (bufotenine) have been analysed on the rabbit heart perfused in vitro by the Langendorff technique. Comparisons have been made with the effects of 5-hydroxytryptamine (5-HT), which activates tryptamine receptors, and dimethylphenylpiperazinium (DMPP), which stimulates nicotine receptors. Bufotenine, 5-HT and DMPP stimulated the rate and force of cardiac contraction but whereas all were powerful stimulants of cardiac rate, bufotenine and DMPP were much stronger stimulants of atrial and particularly ventricular tension than 5-HT. Responses to 5-HT were markedly reduced by perfusion of hearts with an excess of 5-HT, and those to DMPP, during perfusion with hexamethonium. A combination of 5-HT with hexamethonium was necessary to abolish the effects of bufotenine. The data suggest a dual mechanism of stimulant action of bufotenine on the cardiac sympathetic nerves of the rabbit heart involving activation of receptors sensitive to 5-HT and nicotine receptors.

Blockade of serotonin receptors on autonomic neurones by (-)-cocaine and some related compounds.

The interaction between (--)-cocaine and responses to 5-HT elicited through serotonin receptors on autonomic neurones has been investigated on the rabbit heart and the guinea-pig ileum. Low concentrations of (--)-cocaine or its stereoisomer, (4)-pseudococaine, produced shifts to the right of the 5-HT dose-response curves on heart and ileum with no depression of the maximum responses to electrical stimulation or dimethylphenylpiperazinium remained unaffected. A Schild analysis of data obtained on heart and ileum indicated competitive antagonism of 5-HT by (--)-cocaine. Antagonism of 5-HT by the cocaine isomers cannot be ascribed to local anaesthesia per se since neither lignocaine, tetracaine, benzocaine nor bu tacaine were selective antagonists of 5-HT. Similarly, inhibition of monoamine uptake seems of minimal relevance since desipramine proved only a weak antagonist of 5-HT on the heart and did not influence the 5-HT antagonist potency of (--)-cocaine. Selective blockade of 5-HT neuronal responses is a property shared by several structural analogues of (--)-cocaine and (+)-pseudococaine; nor-(--)-cocaine proved the most potent of these, being active at a concentration of 2 x 10(-8) M. These data indicate that (--)-cocaine and several of its derivatives inhibit 5-HT stimulation of both adrenergic and cholinergic autonomic neurones through competition with the agonist at serotonin receptor sties. Since morphine, the tool normally used to identify responses mediated through neuronal serotonin receptors, acts only at certain "morphine-sensitive" junctions and then, non-discriminately, the cocaine analogues, and particularly nor-(--)-cocaine would seem to offer real advantages as tools for differentiating such responses.

Enhancement of antithrombotic effect of aspirin by metoclopramide in rats.

The potential antithrombotic effect of aspirin and metoclopramide were studied in a model of arterial thrombosis in rats. Thrombosis was produced in the abdominal aorta by the combination of local partial obstruction and intravenous administration of hypotonic saline containing 5-HT. The resulting aortic occlusion and the effects of drugs were quantified by measuring rectal temperature. Metoclopramide as well as ketanserine effectively reversed while zacopride failed to alter thrombotic effect. Metoclopramide or ketanserine when combined with aspirin enhanced the antithrombotic effect of the latter. On the other hand, co-administration of metoclopramide with ketanserine failed to show any synergistic effect. As with ketanserine, the antithrombotic effect of metoclopramide appeared to be mediated through the blockade of 5-HT2 receptors in the platelets.

Natural honey prevents ethanol-induced increased vascular permeability changes in the rat stomach.

The effect of honey on ethanol-induced increased vascular permeability changes was studied in the rat stomach. Sucralfate and allopurinol were used as standard gastroprotective and antioxidant drugs, respectively. Extravasation of intravenously administered Evans blue dye into the stomach following 30 min exposure to ethanol was used as an indicator of vascular permeability. The amounts of the extravasated dye were quantified spectrophotometrically. Ethanol produced concentration and time-dependent increase in the extravasation of Evans blue. Oral administration of honey (0.078-0.625 g/kg) 30 min before ethanol dose-dependently attenuated ethanol-induced increased vascular permeability. Pretreatment with a sulfhydryl blocker, N-ethylmaleimide (0.050 g/kg, subcutaneously), caused enhancement of ethanol-induced vascular permeability changes. Treatment with N-ethylmaleimide before honey reduced the protective effects of honey. Similarly, sucralfate (0.031-0.250 g/kg) orally and allopurinol (0.025-0.050 g/kg) intravenously inhibited vascular permeability caused by ethanol and treatment with N-ethylmaleimide before sucralfate or allopurinol reduced their inhibitory effects. These results suggest that the protective effect of honey may be mediated through sulfhydryl-sensitive processes and it may also possess antioxidant properties. It is also suggested that endogenous sulfhydryl may facilate and mediate beneficial effects of gastroprotective and antioxidant drugs.

Natural honey exerts its protective effects against ethanol-induced gastric lesions in rats by preventing depletion of glandular nonprotein sulfhydryls.

The role of nonprotein sulfhydryls (NP-SH) in the protective effects of honey against absolute ethanol-induced gastric lesions was studied in rats. Sucralfate and ranitidine were used as known standard gastroprotective agents. Honey orally and drugs orally or subcutaneously were administered to 24 h fasted rats 30 or 90 min before oral administration of ethanol. Mucosal damage and the glandular NP-SH levels were measured 1 h after ethanol. Both honey and sucralfate dose-dependently afforded protection against gastric damage and reversed the changes in glandular NP-SH levels induced by ethanol. Ranitidine was ineffective in this model. Pretreatment with indomethacin (IND) did not alter the protective effects of honey or the NP-SH levels, but significantly reduced the protective effects of sucralfate. On the other hand, pretreatment with N-ethylmaleimide (NEM) significantly reduced the protective effects of both honey and sucralfate and lowered the NP-SH levels. Combined IND and NEM treatment caused a significant reduction of the protective effects of honey and the NP-SH levels, but the values were not significantly different from those obtained with NEM alone. In contrast, combined IND plus NEM treatment completely abolished the protective effects of sucralfate and significantly lowered the NP-SH levels. Although these results suggest the involvement of prostaglandins (PGs) -- sensitive process in the protective effects of sucralfate, but honey and sucralfate (partially) share a common mechanisms of action in mediating the gastroprotective effects through NP-SH sensitive processes.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of non-protein sulphydryls in the protective effects of antioxidants against ethanol-induced vascular permeability changes in the rat stomach.

Increased vascular permeability has been reported to preceed the development of ethanol-induced gastric lesions. Both generation of oxygen-derived free radicals and depletion of non-protein sulphydryls may be involved in the ethanol-induced vascular permeability. Thus, this study aimed to examine the effect of antioxidants, allopurinol and dimethylsulphoxide, and a sulphydryl blocker, N-ethylmaleimide, on ethanol-induced vascular permeability changes and to evaluate the possible interactions between antioxidants and endogenous sulphydryls. Extravasation of intravenously administered Evans blue into the stomach of rats following 30 min exposure to ethanol was used as an indicator of vascular permeability. The glandular non-protein sulphydryl and extravasated Evans blue were determined spectrophotometrically. Increased vascular permeability and a significant depletion of non-protein sulphydryl contents of the gastric mucosa were observed following 30 min exposure to 50% ethanol. Treatment with N-ethylmaleimide (50 mg/kg subcutaneously) caused enhancement of ethanol-induced vascular permeability and further depletion of non-protein sulphydryls. Intraperitoneal pretreatment with either allopurinol (12.5-50 mg/kg) or dimethylsulphoxide (20-40 mg/kg) attenuated ethanol-induced vascular permeability changes and restored the non-protein sulphydryl levels towards control. In contrast, treatment with N-ethylmaleimide before allopurinol (50 mg/kg) or dimethylsulphoxide (40 mg/kg) reduced the protective effect of both and are also associated with corresponding depletion of non-protein sulphydryl contents. These results suggest that oxygen-derived free radicals may be involved in the pathogenesis of ethanol-induced vascular permeability changes and endogenous sulphydryls may facilitate and mediate beneficial effects of antioxidants.

Enhancement of anti-inflammatory effects of calcium channel blockers by allopurinol and dimethylsulphoxide.

The effects of the calcium channel blockers, nifedipine, verapamil and flunarizine, and the antioxidants, allopurinol and dimethylsulphoxide, were investigated on carrageenan-induced rat paw oedema and changes in vascular permeability. Paw volume was measured by using a plethysmometer and vascular permeability was quantified by measuring the extravasated Evans blue dye 3 h after injecting the phlogistic agent. Intraperitoneal administration of nifedipine (1,2 and 4 mg/kg), verapamil (5, 10 and 20 mg/kg), flunarizine (2.5, 5 and 10 mg/kg), allopurinol (6.25, 12.5 and 25 mg/kg) and dimethylsulphoxide (20, 40 and 80 mg/kg) 30 min before carrageenan, dose dependently inhibited oedema formation and increased vascular permeability. Co-administration of the lowest doses of calcium channel blockers with the lowest doses of antioxidants produced synergistic inhibitory effects. These results indicate that both calcium influx and oxygen-derived free radicals are involved in carrageenan-induced inflammatory responses. Thus, the synergistic effects of their combination may be due to the blockade of calcium entry and reduction in the generation of oxygen-derived free radicals.