Türker Rk

Endothelium-dependent relaxing effect of histamine on the isolated guinea-pig main pulmonary artery strips

Contribution of endothelial cells (ECs) to the effects of histamine (HA) was investigated on the isolated guinea-pig main pulmonary artery (GPPA) strips precontracted with noradrenaline (NA). HA caused a dose-dependent relaxation at the concentrations ranged between 10−8 to 10−6M but produced a contraction when a relatively higher concentration (10−5M) was used in unrubbed strips. Cimetidine partially inhibited the relaxing effect of HA without altering its constrictive action. In rubbed strips, however, HA produced a dose-dependent contraction. The constrictive effect of HA in rubbed strips enhanced after addition of cimetidine to the incubation medium. HA elicited a concentration-dependent relaxation in both unrubbed and rubbed strips in the presence of mepyramine. Impromidine produced a relaxation in the strips with and without endothelium.These data was taken as an evidence indicating that HA caused a relaxation in the isolated GPPA strips, first causing the release of endothelium derived relaxing factor (EDRF) which is triggered by H1-receptors and secondly by the direct stimulation of H2-receptors.

Protective effect of iloprost and UK 38 485 against gastric mucosal damage induced by various stimuli

This study was undertaken to evaluate the efficacy of iloprost and UK 38485 in the prevention of gastric lesions due to restraint-cold stress, ethanol or indomethacin. Prior injection of iloprost to the rats significantly prevented the increase in ulcer index by restraint- cold stress or indomethacin but nonsignificantly reduced the ulcer index induced by ethanol. UK 38 485 at lower doses caused a highly significant decrease in the ulcer index induced by all noxious stimuli used in this study. UK 38 485 also reduced the increased 3H back diffusion due to restraint-cold stress. Higher doses of the compound, however, failed to decrease the mucosal damage due to restraint-cold stress. Combination of iloprost and UK 38 485 produced a further significant decrease in the ulcer index induced by all noxious stimuli and increased 3H back diffusion induced by restraint-cold stress. In relation to these results the importance of PGI2/TXA2 ratio in the production of gastric mucosal lesions is discussed.

Modulation by endothelium of the vascular effects of angiotensin II

Modulation by vascular endothelium of the effects of AII was studied in the isolated rabbit aortic and superior mesenteric artery strips. The contractile effect of AII was enhanced in rubbed aortic strips. Similar enhancement was obtained in hydroquinone pretreated unrubbed strips. The relaxing effect of acetylcholine in AII-induced precontracted aortic strips was abolished after rubbing and hydroquinone pretreatment. However, no significant changes were observed in the contractile response to AII on aspirin and nicotine pretreated strips.In the isolated mesenteric artery strips AII produced a biphasic responses. The contractile effect of AII was enhanced in rubbed strips. Similar potentiation was also obtained in hydroquinone, aspirin and nicotine pretreated unrubbed strips. The relaxation phase of AII response was completely abolished in rubbed strips but partially inhibited in hydroquinone, aspirin and nicotine preatreated unrubbed strips.From these results it was concluded that EDRF is the main endothelial humoral factor which modulates the effect of AII in the rabbit aorta while both EDRF and PGI2 are involved for the modulation of the effects of octapeptide in the mesenteric artery.

Possible prostacyclin-mediated vascular effect of angiotensin II in the isolated perfused rat lung.

Angiotensin I (A I) and angiotensin II (A II) when injected through the pulmonary artery caused an increase in perfusion pressure (PP) of the isolated perfused rat lung and a contraction when the venous outflow was superfused over rat ascending colon (RC). Nicotine (N) when added to the perfusion medium caused a significant increase in PP to A II without altering that to A I. Further addition of ZK 36374, a stable analog of prostacyclin (PGI2), to the medium prevented the potentiating effect of N on the A II pressor response. Neither N nor ZK 36374 altered the superfused RC responses to A I and A II-injected venous effluent. Lysine acetylsalicylate (ASA), however, caused a potentiation in the pressor response to A I. The response of venous effluent superfused RC to A I was also found to be potentiated by ASA. ASA failed to alter the responses to A II. These results were taken as evidence that A II is a potent activator for the biosynthesis of PGI2 in the pulmonary vascular bed. Moreover, PGI2 does not affect angiotensin converting enzyme activity in the lung circulation while other stable metabolites of arachidonic acid can inhibit the conversion of A I to A II.

The effects of nocloprost, nileprost, iloprost and (15 S)-15-Methyl-PGE2 on gastric mucosal damage induced by stress, indomethacin and ethanol

The preventive effects of nocloprost, nileprost, iloprost and (15S)-15-Methyl-prostaglandin E2 were studied in the rat gastric mucosal damage induced by restraint-cold stress, indomethacin and ethanol. Nocloprost was found to be the most potent orally active compound against rat mucosal damage induced by all noxious stimuli used in this study. Both nocloprost and iloprost were more effective on stress-induced ulcers than on those induced by indomethacin and ethanol. Nocloprost and 15-methyl prostaglandin E2 were also more active on ethanol-induced mucosal damage than on induced by indomethacin. No significant differences were obtained with iloprost and nileprost on indomethacin and ethanol-induced mucosal injury. These results indicate a more potent oral antiulcer activity of nocloprost.

Possible involvement of endogenous histamine in the myotropic effect of clonidine on the isolated rabbit aorta.

Clonidine has a contractile effect in the isolated rabbit aorta which can be blocked by alpha-adrenergic antagonist, phentolamine. Histamine H1-receptor blocker, mepyramine, partly antagonizes its myotropic effect and histamine H2-blocker, metiamide, potentiates it, implying a histaminergic component in the response. Inhibition of histamine synthesis by histidine decarboxylase inhibitor, GYKI 11.121, reduces clonidine-induced contraction in this preparation, while diamine oxidase inhibition by aminoguanidine potentiates it. This is indirect evidence of the possibility ofde novo histamine synthesis by clonidine, which may take part on the contractile effect of the drug in the rabbit aorta.

A comparative study with impromidine (SKF 92676), a potent agonist for histamine H2-receptors

Histamine, dimaprit and impromidine caused a relaxation on the isolated cat tracheal muscle contracted by acetylcholine or serotonin. Mepyramine partially inhibited the relaxing effect of histamine without altering that of impromidine and dimaprit. Both impromidine and dimaprit produced a dose-dependent fall in perfusion pressure of the isolated perfused guinea-pig lung while histamine has a pressor effect in this preparation which reversed into a depressor one in the presence of mepyramine. Both dimaprit and impromidine also produced a fall in perfusion pressure and urine flow of the isolated perfused rabbit kidney. A rapid tachyphylaxis developed to the effect of impromidine in the kidney but not to dimaprit. A cross-tachyphylaxis was also observed between impromidine and dimaprit. The agonistic potency of impromidine was found to be very much higher than histamine and dimaprit. Metiamide has a competitive inhibitory effect against impromidine and dimaprit on the isolated perfused lung, kidney and tracheal muscle. It was concluded that impromidine is a very potent pure histamine H2-receptor agonist when compared with histamine and dimaprit on the investigated tissues.

Possible involvement of eicosanoids in alpha-naphthylthiourea-induced pulmonary oedema and alteration of angiotensin-converting enzyme activity.

alpha-Naphthylthiourea (ANTU) when injected intraperitoneally to rats at a dose of 10 mg/kg elicited lung oedema indicated by an increase in lung weight/body weight (LW/BW) ratio and pleural effusion. The injection of acetylsalicylic acid, which is a cyclo-oxygenase inhibitor, and BW 755C, a cyclo-oxygenase and lipoxygenase inhibitor, prior to ANTU produced a significant inhibition in pleural fluid accumulation without changing the LW/BW ratio. BW A4C, a selective 5-lipoxygenase inhibitor, however, caused a highly significant inhibition in pleural effusion and a slight but significant decrease in LW/BW ratio. Thromboxane A2 synthetase inhibitor, UK 38485, caused a slight but significant inhibition in pleural fluid accumulation without altering the LW/BW ratio. Iloprost, however, produced a slight but significant inhibition in the LW/BW ratio without reducing the pleural effusion rate. A significant decrease in angiotensin-converting enzyme (ACE) activity in the isolated perfused lungs of ANTU-treated rats was noted. This observation was thought to be an evidence of a functional alteration of the lung vascular endothelium. The possible role of eicosanoids in lung oedema induced by ANTU and the related mechanisms of decreased ACE activity are discussed.

Iloprost (ZK 36374) modulates the responses to beta-adrenoceptor agonists in guinea-pig airways and pulmonary vasculature

The effect of iloprost on airway smooth muscles and its influence on the actions of beta-agonists and histamine were studied in the isolated perfused lung and isolated tracheal strips from guinea-pigs. Bolus injection of iloprost into the pulmonary artery elicited a concentration-dependent decrease in pulmonary perfusion pressure and an increase in airway resistance. These effects are not mediated through cholinergic, serotoninergic and histaminergic receptors. A rapid tachyphylaxis affected the effect of iloprost in airway resistance but not in pulmonary perfusion pressure. Iloprost did not induce a response in the isolated tracheal strips and did not alter the effect of histamine in both tracheal strips and airway resistance. This compound, however, caused an inhibition in the airway resistance-reducing effect of adrenaline and isoprenaline in the isolated perfused lung and a potentiation in the perfusion pressure-increasing effect of adrenaline. Iloprost also inhibited the relaxing effect of adrenaline and isoprenaline in the isolated tracheal strips precontracted with histamine and potentiated the inhibitory effect of propranolol against adrenaline and isoprenaline. From these results it was concluded that: Iloprost, a stable analogue of prostacyclin, modulates the beta-adrenoceptor blocking effect of propranolol in both airway smooth muscles and pulmonary vasculature.