Involvement of 5-hydroxytryptamine in the intestinal motor disturbances induced by mast cell degranulation in rats.

Fasted rats with chronically implanted electrodes were used for investigation of the effects of mast cell degranulation induced by compound 48/80 and BrX-537A and their antagonism by previous administration of 5-hydroxytryptamine (5-HT) antagonists on duodenal and jejunal myoelectric activity. Administered i.p., both 48/80 (1 mg/kg i.p.) and BrX-537A (2 mg/kg i.p.) abolished the intestinal spiking activity of duodeno-jejunum with a progressive recovery, BrX-537A being less active. These effects were dose-related. Injected prior to 48/80, methysergide (1 mg/kg) reduced by about 80% both duodenal and jejunal inhibition of spiking activity with early recovery of a normal pattern. In contrast, ketanserin (1 mg/kg) had selective reducing effects on the duration of the spiking inhibition induced by 48/80 and BrX-537A on the duodenum only. Zacopride (1 mg/kg) and ICS 205-930 (50 micrograms/kg) shortened and suppressed, respectively, the inhibition of intestinal spiking activity with early restoration of intestinal motility in both duodenum and jejunum. We conclude that, in fasted rats (i) the degranulation of peritoneal mast cells induces alterations in intestinal myoelectric activity through the release of 5-HT (ii) these effects are mainly mediated through both 5-HT1 and 5-HT3 receptors.

Studies on the mechanism of an antibiotic ionophore, R02-2985 (X537A) in the conscious chronically instrumented dog: involvement of the prostaglandin synthetic pathway.

Conscious dogs were pretreated with a large dose of indomethacin in order to test the hypothesis that prostaglandin synthesis may be involved in the mechanism of action of the inophore R02-2985. The increase in renal blood flow and decrease in renal vascular resistance usually produced by R02-2985 were inhibited by indomethacin. In fact, the calculated renal resistance doubled. In contrast to the effects on renal circulation, indomethacin did not affect coronary blood flow increases which occur independent of contractility changes produced by this ionophore. Effects associated with facilitated release of catecholamines, ie, increases in heart rate, central aortic pressure, and dP/dt were prolonged in comparison to the control study published earlier where these parameters returned to control levels within 2.5 h, thus suggesting that prostaglandin synthesis may somehow potentiate the effects of R02-2985 on the release of catecholamines in vivo.

The action of the ionophores, X-537A and A-23187, on smooth muscle.

The cation ionophore X-537A in the concentration range of 10(-6) to 3 X 10(-5) M produced contractions in the rat and guinea-pig vas deferens. No contractile effect was produced in either of the vasa deferentia preparations by the ionophore A-23187 in the concentration range of 10(-7) to 5 X 10(-5) M. In contrast, X-537A had no contractile effect on the guinea-pig ileal longitudinal smooth muscle while A-23187 produced a dose and [Ca2+] dependent contraction. The contractile effect of X-537A in the vasa deferentia preparations is abolished by phenoxybenzamine or prior reserpine treatment and is therefore attributed to the release of norepinephrine. The effect of A-23187 in the intestinal smooth muslce is attributed to a direct Ca2+ transporting action since its contractile effect is unaffected by histamine, acetylcholine, or 5-hydroxytryptamine antagonists.

Human platelet secretion and aggregation induced by calcium ionophores. Inhibition by PGE1 and dibutyryl cyclic AMP.

Ca2+, Mg2+-ionophores X537A and A23,187 (10(-7)-10(-6) M) induced the release of adenine nucleotides adenosine diphosphate (ADP, adenosine triphosphate (ATP), serotonin, beta-glucuronidase, Ca2+, and Mg2+ from washed human platelets. Enzymes present in the cytoplasm or mitochondria, and Zn2+ were not released. The rate of ATP and Ca2+ release measured by firefly lantern extract and murexide dye, respectively, was equivalent to that produced by the physiological stimulant thrombin. Ionophore-induced release of ADP, and serotonin was substantially (approximately 60%) but not completely inhibited by EGTA, EDTA, and high extracellular Mg2+, without significant reduction of Ca2+ release. The ionophore-induced release reaction is therefore partly dependent upon uptake of extracellular Ca2+ (demonstrated using 45Ca), but also occurs to a significant extent due to release into the cytoplasm of intracellular Ca2+. The ionophore-induced release reaction and aggregation of platelets could be blocked by prostaglandin E1 (PGE1) or dibutyryl cyclic AMP. The effects of PGE1, and N6, O2-dibutyryl adenosine 3':5'-cyclic monophosphoric acid (dibutyryl cAMP) were synergistically potentiated by the phosphodiesterase inhibitor theophylline. It is proposed that Ca2+ is the physiological trigger for platelet secretion and aggregation and that its intracellular effects are strongly modulated by adenosine 3':5'-cyclic monophosphoric acid (cyclic AMP).