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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-plasminogenhistamine = platelet-activating factorthrombinbradykinin. 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.

Intracerebroventricular injection of alpha-fluoromethylhistidine caused a significant decrease of the histamine content of the hypothalamus as well as of plasma adrenocorticotropic hormone and corticosterone concentrations. A high correlation was observed between the histamine content of the hypothalamus and the plasma corticosterone concentration. When the histamine content of the hypothalamus decreased, the plasma concentration of corticosterone diminished. Almost the same result was obtained when the posterior hypothalamus was lesioned electrically. The increases in plasma adrenocorticotropic hormone and corticosterone concentrations, induced by intracerebroventricular injection of histamine in sham-operated rats, were abolished after hypothalamic lesioning. When electrical stimulations were applied to the posterior hypothalamus, plasma adrenocorticotropic hormone and corticosterone concentrations increased significantly and, at the same time, evoked potentials were recorded on the adrenal nerve. An increase in plasma corticosterone concentration, induced by hypothalamic stimulation, was also observed even after hypophysectomy, suggesting that another corticosterone-secreting pathway exists apart from the hypophysis-adrenocortex system. The increase in plasma adrenocorticotropic hormone and corticosterone concentrations was inhibited not only by pyrilamine and cimetidine, but also by (R)-alpha-methyl-histamine, and H3 agonist. In addition, the effect of this latter product was inhibited by thioperamide, an H3 antagonist. These results indicate that hypothalamic histamine plays an important role in the stimulation of the corticosterone release in rats.

The presence of the platelet-activating factor (PAF) in peritoneal exudate, induced by zymosan, was investigated in rats. Intraperitoneal injection of zymosan induced an extravasation of plasma proteins and an accumulation of polymorphonuclear leukocytes in the peritoneal cavity. Zymosan induced a release of immunoreactive PAF in peritoneal exudate which reached maximum levels at 30 min and then declined slowly. Immunoreactive PAF was evenly distributed in the fluid and cellular fractions of the exudate. A PAF-acetyltransferase activity was found as well in the exudate as in plasma. Histamine levels, measured by bioassay, increased after injection of zymosan, reached a peak at 15 min and declined to a normal level within 4 hr. Protein extravasation was inhibited by WEB 2086, a PAF antagonist, during the 6 hours of the study, whereas the accumulation of leukocytes was suppressed at 2 hour by WEB 2086 and SM 12502, two PAF antagonists. PAF is present in the peritoneal exudate induced by zymosan in rats, and plays a role in the development of the inflammatory response. Its main origin might be resident macrophages and polymorphonuclear leukocytes.

In vivo and in vitro studies have demonstrated that beta-adrenoceptor blockers enhance the airway smooth muscle contraction to antigen, but the mechanisms are not fully understood. In the present work, we corroborated that propranolol (3.9 x 10(-6) M, 30 min incubation) induces hyperreactivity to antigenic challenge (cumulative concentration-response curve to ovalbumin, 0.01 to 100 micrograms/ml) in lung parenchyma strips from sensitized guinea-pigs. This hyperreactivity was enhanced by indomethacin (3.2 x 10(-5) M) and was unaffected by the lipoxygenase/cyclooxygenase inhibitor phenidone (1 x 10(-4) M). However, the histamine H1 receptor antagonist pyrilamine (1 x 10(-6) M) reduced the potentiation effect of propranolol. These results suggest that bronchoconstrictor prostaglandins, thromboxane A2 and leukotrienes, are not involved in the propranolol-induced lung parenchyma strips hyperreactivity to antigen in vitro, and that histamine may account, at least in part, for such propranolol effect.

In vitro studies indicate that the intact endothelium prevents the access of circulating endothelin to vascular smooth muscle cells. Disease states like diabetes, that are associated with endothelium dysfunction, might facilitate the access of endothelin to vascular smooth muscle, causing increased vasoconstriction. To investigate whether differences between diabetic and nondiabetic subjects could be detected on superficial veins, venous diameter changes in response to local infusions of endothelin (1.53, 3.11 and 6.22 pmol/min) were compared in type 2-diabetics with albuminuria (greater than 300 mg/day) and borderline hypertension (diastolic blood pressure 90-95 mmHg), and in healthy volunteers. In addition, we studied the effect of histamine on the endothelin-induced venoconstriction. The dorsal hand vein compliance technique was employed. Endothelin caused a dose-dependent, slow-onset constriction of the hand vein in all subjects, without any difference in endothelin responsiveness between diabetic and control subjects. The maximal venoconstriction at 6.22 pmol endothelin/min was 29 +/- 26% (% of venous diameter at base line) in diabetics and 23 +/- 22% in controls (p greater than 0.02). Co-infusion of endothelin and a dose of histamine with minimal venodilatory effect ("ED5-ED20") had no influence on the endothelin responsiveness of the hand veins, in that the maximal venoconstriction after 6.22 pmol endothelin/min was 25 +/- 23% without, and 23 +/- 16% with added histamine. Submaximally venodilating histamine doses ("ED60-ED90") markedly attenuated the endothelin-induced venoconstriction (maximal venoconstriction: 63 +/- 43%). These data, obtained in veins, argue against a generalized defect in vascular responsiveness to endothelin associated with diabetes.

The effect of histamine on the endothelial and smooth muscle cells of isolated rings of the rat femoral artery and the receptor type involved in its development were examined. Relaxed rings did not respond to histamine (10(-8)-10(-4) mol/l). However, when contraction had been produced by phenylephrine, histamine (3 x 10(-7)-10(-4) mol/l) caused a concentration-dependent relaxation. The relaxant effect of histamine on the rat femoral artery was abolished by metiamide, but it was not affected by removal of the vascular endothelium, pyrilamine, atropine, sotalol, hemoglobin or methylene blue. In contrast, under the same experimental conditions, the relaxant effect of histamine on the rat mesenteric artery was strongly reduced by removal of the vascular endothelium, hemoglobin or methylene blue. These findings indicate that, in the rat femoral artery, unlike in several other rat large peripheral arteries, the histamine-induced relaxation is endothelium-independent and results from the activation of smooth muscle histamine H2-receptors. It is tentatively suggested that histamine H1-receptors are not present on the endothelial and smooth muscle cells of the rat femoral artery.

Adjuvant arthritis was induced in 30 male Wistar rats by injection into the tail of heat-killed Mycobacterium butyricum. Three weeks later, 14 of these rats exhibited severe arthritic lesions. Their thoracic aortae were studied in parallel with those isolated from a control group. On rings precontracted with phenylephrine (0.1 microM), the endothelium-dependent relaxations produced by acetylcholine and histamine were significantly diminished in the arthritic group as compared to the control group. Moreover, the increase in tone induced by incubation with methylene blue (10 microM) (a nonspecific inhibitor of endothelium-derived relaxing factor) was significantly less pronounced in preparations isolated from the arthritic group. On the other hand, relaxations produced by the endothelium-independent vasodilators verapamil and nitroprusside were similar in both groups. It is concluded that adjuvant arthritis modifies the endothelium-derived relaxing factor-mediated responses of rat aorta.

High concentrations of methylxanthines induce contraction in many smooth muscle types, but relax guinea-pig trachealis. We examined this discrepancy by studying the interaction of caffeine and spasmogens in the isolated guinea-pig trachealis. We extended our observations to the isolated human trachealis. In the guinea-pig trachealis, 25 mM but not 2.5 mM caffeine totally blocked any contractile effect of methacholine or histamine, but not of KCl, whose contractile effect relies on extracellular Ca++. The beta-adrenergic agent isoprenaline (10(-3)M) only partially blocked the spasmodic effect of methacholine and histamine. In the human trachealis, 25 mM but not 2.5 mM caffeine induced an initial contraction followed by a relaxation. After this latter relaxation, methacholine (10(-5) M) and histamine (10(-5) M) were without effect, while KCl caused a contraction. In the guinea-pig, a contractile effect of 25 mM but not 2.5 mM caffeine was uncovered by switching to a high K+, Ca(++)-free solution prior to adding the caffeine. The source of the Ca++ promoting the contraction thus must be intracellular stores. Accordingly, ryanodine, an inhibitor of Ca++ storage, blocked this contraction. Similarly histamine (10(-5) M) and methacholine (10(-5) M) in the Ca(++)-free solution induced a contraction. The histamine contraction was completely blocked by ryanodine, the methacholine contraction, 79% blocked. We conclude that caffeine appears to surpass the antispasmodic effects of beta-adrenergic stimulation, at least in part, by depleting intracellular stores of Ca++.

Tioxamast, an anti-allergic compound inhibiting the release and synthesis of certain mediators of allergy and having no major antagonist effect towards such mediators, was experimented on various models of anaphylactic shock, hyperreactivity and bronchial inflammation in guinea-pigs. Tioxamast does not reduce passive pulmonary anaphylactic shocks induced in anaesthetized or conscious guinea-pigs by i.v. challenge of antigen. Likewise, the compound has no effect on systemic hyperreactivity towards i.v. histamine induced in anaesthetized guinea-pigs after a passive anaphylactic shock caused by i.v. challenge of antigen. On the other hand, tioxamast inhibits passive pulmonary anaphylactic shock induced in guinea-pigs by antigen aerosol in conscious guinea-pigs. Likewise, tioxamast decreases hyperreactivity to inhalation of histamine or carbamylcholine obtained after an active or passive anaphylactic shock by aerosol in conscious guinea-pigs. The oxamate derivative attenuates the increase in number of eosinophils and mononuclear cells obtained in the bronchoalveolar lavage fluid 24 hr after an active anaphylactic shock induced by aerosol. The anti-allergic activity of tioxamast on the various models carried out in guinea-pigs thus appears when these models are induced by a challenge of antigen or mediator by inhalation.

The effects of berberine on the contractions of the longitudinal muscle of the guinea-pig isolated ileum were investigated. Lower concentrations of berberine (less than or equal to 5 x 10(-5) M) induced a parallel rightward shift of the dose-response curve of acetylcholine, suggesting that berberine is antagonizing the actions of acetylcholine at the receptors competitively. At higher concentration, berberine (1 x 10(-4) M) facilitated a rightward shift of the dose-response curve of acetylcholine with a reduction of maximum response, indicating that the interactions of the two agents changed from competitive to noncompetitive antagonism. The competitive antagonism is due to the actions of acetylcholine at the muscarinic receptors, while the noncompetitive antagonism is probably due to the action of berberine at other sites in addition to the muscarinic receptor sites. Berberine dose-dependently antagonized the effects of muscarine, a specific muscarinic receptor agonist, in a fashion similar to the antagonism of acetylcholine, providing evidence that the site of action of berberine is at the muscarinic receptors. Hexamethonium (7.5 x 10(-4) M) did not influence the effect of berberine on the concentration-response curve of acetylcholine and berberine had no effects on the contractions of the preparation elicited by histamine, suggesting its specificity for muscarinic receptors. Berberine also concentration-dependently reduced electrically induced cholinergic contractions, corresponding with its effects at the muscarinic receptor sites. Berberine had no effects on the contractions elicited by KCl, which acts at postreceptor sites. The action of berberine was reversible and dependent on the duration of incubation with the preparation; the longer the time of incubation with the tissues, the slower the recovery. The results of this series of experiments support the hypothesis that berberine blocks muscarinic receptors and this might be part of the explanation of its efficacy in the reduction of intestinal motility and in the treatment of diarrhea.

Measurements were made of the effects of methoxyphenamine hydrochloride on histamine-, acetylcholine- and U46619-induced bronchoconstriction in pentobarbitone-anaesthetized guinea-pigs, and on histamine- and acetylcholine-induced contractions of guinea-pig ileum in vitro. Methoxyphenamine (20 mg/kg, i.v.) did not affect bronchoconstriction induced by acetylcholine or the thromboxane A2-mimetic U46619. However, it produced a parallel rightward shift [2.94-(1.79, 4.41) fold, 95% confidence limits in parentheses] of the curve relating bronchoconstrictor responses to log-dose of histamine at a total dose of 13 mg/kg, i.v., which was not significantly different from the shift [3.30-(1.93, 5.56) fold] produced by 3 micrograms/kg, i.v., of the histamine antagonist mepyramine maleate. Histamine-induced contractions of the isolated guinea-pig ileum were antagonized by methoxyphenamine (10(-5) to 10(-3) M). The histamine log-concentration-response curve was shifted to the right in a parallel manner by methoxyphenamine (10(-5) to 10(-4) M), without depression of maximum responses. However, at higher concentrations, maximum responses were reduced. The slope of the Schild plot was significantly different from -1. The degree of the rightward shift of the concentration-response curves to histamine, produced by 10(-5) M of methoxyphenamine [3.90-(2.83, 4.97) fold], was not significantly different from that produced by 3 x 10(-9) M of mepyramine [4.60-(2.86, 6.52) fold]. Methoxyphenamine, at concentrations of 10(-5) to 3 x 10(-4) M, had no significant effect on responses of guinea-pig ilea to acetylcholine (10(-9) to 10(-5) M). These results indicate that methoxyphenamine antagonizes the effects of histamine both in vivo and in vitro. In vitro studies indicate a noncompetitive antagonism.

In this study we examined the desensitization of guinea-pig parenchymal lung strips after excessive stimulation of the histamine H1-receptor. After stimulation with maximal effective concentrations of the selective H1-receptor agonist 2-pyridylethylamine (1 mM) for 30 min, subsequent 2-pyridylethylamine responses were inhibited as shown in a depression of the maximal response with approximately 40%. This desensitization was time- and concentration-dependent. Besides H1-receptor responses, potassium chloride (50 mM)-induced responses were also affected. Treatment of lung strips with 1 mM of 2-pyridylethylamine for 30 min resulted in an inhibition of the potassium-induced contraction with 26.1 +/- 8.7% of the control response. Desensitization of the lung strip preparation could not be prevented by the cyclooxygenase inhibitor indomethacin (20 microM), indicating that the observed inhibition is not due to an elevated production of relaxing prostaglandins. Desensitization was also not dependent on the influx of extracellular calcium. Stimulation of guinea-pig parenchymal lung strips with 1 mM of 2-pyridylethylamine in a calcium-free buffer, supplemented with the calcium chelator EGTA, did not lead to observable contractions. However, desensitization still developed under these conditions. These data indicate that guinea-pig parenchymal lung strips exhibit a desensitized state after prolonged H1-receptor stimulation. Because this effect is not only limited to H1-receptor responses, as KCl effects are reduced as well, it should, at least partly, be explained by an interference with processes which occur distally to the H1-receptor itself.

As acetylcholine (ACh) is claimed to be a possible mediator of cholinergic urticaria, the potency of acetylcholine (ACh) in increasing vascular permeability was tested by skin perfusion technique in rats and by dye extraction method from the skin of rabbits. The potency of vascular permeability increase of ACh was much lower than that of histamine (Hist) and bradykinin (BK) in rats and rabbits. The higher dose of ACh (10 mg in 0.1 ml of saline), however, produced slight increase of vascular permeability in rabbits, which was inhibited by the antihistamine, pyrilamine maleate. Furthermore, ACh did not potentiate the responses to BK or Hist, when injected simultaneously. It seems unlikely that ACh did increase or potentiate vascular permeabilitay in physiological doses.

The influence of pretreatment with the antihistaminic, mepyramine, or with the histamine liberator 48/80 was studied on the volume and the histamine content of pleural exudates induced in rats by intrapleural injection of turpentine, silver nitrate or carrageenan. The fluorometric determination of histamine was performed in the exudates collected at different times after injection of the irritant. In control animals the histamine levels were different from those previously found by the authors using biological assays. In rats pretreated with mepyramine or compound 48/80, the effects observed varied according to the nature of the irritant used to induce pleurisy.

The effects of bolus and infusion of ciramadol, dezocine, morphine and pentazocine were examined in anesthetized dogs. Cardiopulmonary parameters, blood PCO2, PO2 and pH and plasma histamine determinations were made. Ciramadol (2 and 8 mg/kg) did not exhibit any major activity. Dezocine produced slight respiratory depression at 2 mg/kg but no cardiopulmonary effects were observed at this dose. At 8 mg/kg there were also reductions in pulmonary compliance (Cdyn) and resistance (RL), tidal volume (VT) and a marked arterial hypotension. Morphine (2 mg/kg) elicited significant effects on all parameters examined: marked bronchoconstriction, increased arterial PCO2 and pH and corresponding decrease in PO2, slight increase in heart rate and dramatic arterial hypotension. Morphine was the only agent studied to elevate plasma histamine. Histamine (0.015 mg/kg) mimicked the cardiopulmonary actions of morphine but was virtually devoid of effect on blood gases and pH. Pentazocine (8 mg/kg) did not produce bronchoconstriction but did increase VT and reduce respiratory frequency. It produced increases in arterial PCO2 and reductions in pH and PO2. There was a slight bradycardia and hypotension within this dose. These results demonstrate that both ciramadol and dezocine possess less potential than either morphine or pentazocine for producing bronchoconstriction, respiratory depression, hypotension and histamine release.

4-Methylhistamine relaxed potassium-constricted perfused rabbit middle cerebral arteries at low concentrations (3 X 10(-11) - 3 X 10(-8) M) and constricted them at high concentrations (3 X 10(-7) - 10(-4) M). The relaxation was antagonized by either cimetidine (3 X 10(-7) or 10(-6) M) or mepyramine (3 X 10(-8) M) given 20 min before testing a series of increasing concentrations of 4-methylhistamine, whereas the constriction was slightly potentiated by cimetidine and reversed by mepyramine. The reduction of relaxation was enhanced by a combination of both blockers. These results suggest the involvement of both H1- and H2-receptors in the 4-methylhistamine-induced relaxation. When dimaprit was compared with 4-methylhistamine, it acted only as a relaxing agent, not as a constricting agent. The dimaprit-induced relaxation was antagonized by either cimetidine (3 X 10(-7) M) or mepyramine (3 X 10(-8) M). The inhibition of relaxation was enhanced with a combination of both blockers. This supports the hypothesis that the dimaprit-induced relaxation in the rabbit cerebral artery is also mediated through both H1- and H2-receptors. The H1-agonists 2-methylhistamine and 2-pyridyl ethylamine induced two kinds of responses: an initial relaxation at low concentrations which was reversed by mepyramine (3 X 10(-8) or 10(-6) M) but not by cimetidine (10(-6) or 10(-5) M); this relaxation was followed at higher concentrations by a vasoconstriction which was antagonized by mepyramine (3 X 10(-8), 3 X 10(-7) or 10(-6) M) but not by cimetidine (10(-6) or 10(-5) M). Relaxation by these agents therefore seems to involve the participation of H1-receptors. The pharmacological effects of the histaminergic agonists and antagonists used could be explained by assuming that a distinction exists in the rabbit middle cerebral artery between the receptors concerned in H1-mediated relaxation and H1-mediated constriction.

N,N-Dimethyl-N'-(2-diisopropylaminoethyl)-N-(4,6-dimethyl-2-pyridyl)urea (L-634,366) was selected from a series of pyridylurea compounds with antisecretory activity as a potential therapeutic agent for the treatment of ulcer disease. L-634,366 was an effective inhibitor of gastric secretion evoked by gastrin, histamine and 2-desoxy-D-glucose (2-DG) in conscious dogs. Orally, L-634,366 was slightly less potent than the reference H2 receptor blocker, cimetidine as an inhibitor of secretion evoked by histamine, but was equipotent as an inhibitor of secretion evoked by gastrin and 2-DG. In vitro L-634,366 was a weak antagonist of histamine (H2) receptor responses in the guinea-pig atria and rat uterus; in the atria the antagonism appeared to be noncompetitive. In the anesthetized dog, L-634,366 possessed weak anticholinergic activity as compared to atropine in reducing vagally mediated cardiovascular, antral motor responses and with regard to antagonizing the pressor response to the muscarinic stimulant, McN 343-A. The anticholinergic activity of L-634,366 was lower and more selective than that of pirenzepine or atropine in producing mydriasis in mice, in antagonizing acetylcholine induced bradycardia in guinea-pig atria, methacholine and acetylcholine elicited contractions in the guinea-pig ileum and QNB binding to muscarinic receptors. L-634,366, like carbenoxolone, increased incorporation of 3H-glucosamine in gastric mucous indicating an increase in synthesis or turnover of mucous. L-634,366 is a novel compound possessing a broad spectrum of antisecretory activity; in vitro studies suggested a weak noncompetitive inhibition of the histamine-H2 receptor in atria.

SC-19220 has been studied for its ability to antagonize the contractions produced by prostaglandins E1, E2 and F2 alpha (PGE1, PGE2, PGF2 alpha) on isolated guinea-pig gastric muscle. At concentrations of 1 X 10(-6) M to 3 X 10(-4) M SC-19220 inhibited reversibly in a dose-dependent manner both the spontaneous tone and the phasic activity. At the same concentrations the compound had no effect on the inhibitory responses of circular muscle strips to PGE1, PGE2 and PGF2 alpha. In contrast, SC-19220 antagonized the excitatory responses of longitudinal muscle strips to PGE1, PGE2 and PGF2 alpha. The concentration-effect curves for PGE1, PGE2 and PGF2 alpha were shifted to the right. Analysis of the data ( Arunlakshana and Schild, 1959) gave the pA2 values of PGE2, PGE1 and PGF2 alpha 4.90, 6.28 and 4.16, the slopes of the Schild plots being 1.05, 1.18 and 1.11 respectively. This suggests that SC-19220 is a competitive antagonist. Moreover, the antagonistic action of SC-19220 appeared to be a specific one since at concentrations of 3 X 10(-6) M to 3 X 10(-4) M the compound had a little, if any, effect on the responses of the gastric muscle to acetylcholine and histamine. This favors the suggestion that the longitudinal layer of the guinea-pig stomach contains prostaglandins receptors which are the same for PGE1, PGE2 and PGF2 alpha. SC-19220 specifically blocks these prostaglandin receptors characterized by the order of agonist potency PGE2 greater than PGE1 greater than PGF2 alpha.

The release of noradrenaline accompanying positive inotropic and chronotropic actions of isoprenaline and histamine was investigated in rabbit atria in which the transmitter stores were labelled with (2H)-noradrenaline. Propranolol (3 microM) significantly reduced the isoprenaline (1 microM)-induced release of radioactivity and positive inotropic and chronotropic actions. Cimetidine (30 microM) significantly reduced the histamine (25 microM)-induced release of radioactivity and positive inotropic and chronotropic actions. Tetrotoxin (0.9 microM) significantly reduced the release of radioactivity by both isoprenaline and histamine but did not affect the positive inotropic and chronotropic actions of these drugs. The results suggest that conducted action potentials are associated with isoprenaline- and histamine-induced release of noradrenaline and it is possible that the sympathetic nerves are ephaptically stimulated by increased myocardial activity.

The effects of selective histamine receptor stimulation on relaxation to norepinephrine (NE) were determined in four sizes of spirally cut porcine coronary arteries. The four sizes of porcine coronary artery were designated very large (greater than 4.0 mm o.d.), large (1.5-2.5 mm o.d.), medium (0.8-1.2 mm o.d.), and small (less than or equal to 0.5 mm o.d.). Histamine, dimaprit, 2-pyridylethylamine, and histamine plus either mepyramine or metiamide did not alter the concentration-response curve to NE. Thus histamine receptor stimulation does not change relaxations of porcine coronary arteries to NE.

Dopamine, 5-hydroxytryptamine and 4-methylhistamine facilitated whereas noradrenaline and 2-pyridylethylamine inhibited footshock aggression (FSA) in rats. Dopamine increased FSA in cyproheptadine and cimetidine but not in pimozide pretreated animals; 5-hydroxytryptamine potentiated FSA in cimetidine and pimozide but not in cyproheptadine pretreated rats; 4-methylhistamine facilitated FSA in pimozide and cyproheptadine but not in cimetidine pretreated groups. Also 2-pyridylethylamine inhibited FSA in phenoxybenzamine but not mepyramine pretreated animals. These effects were not significantly different from those seen with dopamine, 5-hydroxytryptamine, 4-methylhistamine and 2-pyridylethylamine, alone, respectively on FSA. It is inferred that each of the neurotransmitters involved in the modulation of footshock aggression acts through an independent mechanism which is not under the regulatory control of the other.

Metoclopramide [(Mcp)-N-diethylaminoethyl-2-methoxy-4-amino-5-chloro-benzamide] was shown by the authors (This Journal 1973, 204, 239) to stimulate the isolated guinea-pig ileum, mainly by an indirecr cholinergic mechanism, to increase responses to acetylcholine (Ac) and transmural stimulation, and to inhibit responses to serotonin (5 HT) and histamine (H). Four structuraly related benzamide derivative (1211, 1265, 1308 and 1347) also stimutated the ileum, 1211 being the most active, and 1347 the least active, and resembled Mcp with regard to the responses to Ac, transmural stimulation and histamine. However, serotonin contractions were enhance by 1265 and 1347, while 1308 and 1211 were inhibitory. These observations suggest that a 4-amino group does not seem to be essential for the stimulant effect or the interference with Ac responses (1211, 1265, 1347), whereas a methylsulfonyl group (1347) and, to a lesser degree, a flour in 5 position (1265) sensitize the ileum towards 5 HT contractions.

Histamine and acetylcholine administered simultaneously to anaesthetized guinea-pigs result in a bronchoconstriction greater than that of the sum of the individual bronchoconstrictor effects of histamine and acetylcholine administered separately, i.e., a supra-additive interaction. In contrast, a supra-additive effect of acetylcholine and histamine on the isolated tracheal strip did not occur. At a pretreatment concentration of acetylcholine of 5 microM, histamine concentration-response curves were shifted rightwards, i.e., a less than additive interaction, suggesting that, at higher concentrations, histamine and acetylcholine do not act as independent agonists on guinea-pig tracheal smooth muscle. There was no supra-additive interaction between histamine and acetylcholine on tracheal segment tension when measured in situ. These observations suggest that there is no direct interaction between histamine and acetylcholine on the airways smooth muscle cell capable of explaining the supra-additive interaction in vivo. Hexamethonium pretreatment did not alter the magnitude of this supra-additive interaction indicating that an indirect interaction involving autonomic control of airways calibre does not contribute to this phenomenon. The selectivity of the supra-additive interaction for changes in airways resistance rather than compliance, together with the negative evidence for either a direct or an indirect pharmacological interaction between histamine and acetylcholine, suggest that the interaction may result from the physical relationship between airways resistance and airways calibre.

The effects of nicotine on histamine-induced contractions in the aortic strip from rabbit and in the intestinal and airway smooth muscles from guinea-pig were examined. Nicotine inhibited the contractile effects of histamine in a concentration-dependent manner in all investigated smooth muscle preparations having identical pA2 values. Data obtained in this study indicate that nicotine has a histamine H1-receptor antagonistic property with a lower activity than mepyramine for H1-receptors as verified by the calculated pA2 values.

The effects of metiamide on 14C-histamine movements and on contractions induced by histamine were studied in rabbit aortic smooth muscle. Low temperature (0 degrees C) and pretreatment with aminoguanidine or chloroquine markedly reduced the uptake of 14C. Component analysis of 14C efflux curves indicated that this decrease occurred mainly within the slower of two washout components. Addition of metiamide (but not pyrilamine) to the bathing solution decreased 14C-histamine uptake, and exposure to metiamide during the washout of 14C-histamine decreased the rate of efflux. These effects of metiamide on 14C-histamine movements can be explained in terms of an altered ability of rabbit aortic smooth muscle to accumulate histamine at some cellular site or store.

On isolated electrically stimulated left and spontaneously beating right guinea-pig atria the interaction between PDE-inhibitors and the positive inotropic and chronotropic action of orciprenaline, forskolin and histamine in dose-response curve was examined. The experiments led to the following results: triamterene (20-120 mumol/l) and papaverine (10-100 mumol/l) inhibit the positive inotropic and chronotropic action of orciprenaline, whereas theophylline (10-100 mumol/l) and isobutyl-methyl-xanthine (0.1-10 mumol/l) only inhibit the inotropic action of orciprenaline. Amrinone (100-316 mumol/l) increases the positive inotropic and chronotropic action of orciprenaline; the positive inotropic and chronotropic action of forskolin is inhibited by triamterene but not by theophylline and IBMX. The positive chronotropic action of forskolin and histamine is inhibited by triamterene, whereas the positive inotropic action of histamine is not influenced; our experimental results suggest that triamterene and papaverine antagonize orciprenaline action by inhibition of adenylate cyclase. For this there is further evidence in the antagonism between triamterene and the inotropic action of forskolin and the tachycardic action of histamine. As theophylline and IBMX inhibit only the inotropic action of orciprenaline, there might be a different mechanism for their interaction regarding the chronotropic action of orciprenaline compared to triamterene and papaverine. The amrinone mechanism differs from that of the other PDE-inhibitors as it increases the positive inotropic and chronotropic action of orciprenaline.

The cardiovascular effects of morphine were determined in anesthetized dogs at 37 and 30 degrees C. Intravenous (i.v., 1 mg/kg) but not intracisternal (i.c., 0.1 mg/kg) morphine produced a significant cardiovascular depression only at 30 degrees C. These effects were antagonized by i.v. naloxone (1 mg/kg) suggesting a peripherally mediated opiate mechanism. Moreover, hypothermia significantly increased plasma and cerebrospinal fluid morphine levels and enhanced the morphine-induced histamine release. The results suggest that opiates could have detrimental effects in patients with poor cardiovascular reserve in which high doses of opiates and hypothermia may be used concomitantly.

The influence of a histidine decarboxylase (HD) inhibitor, GYKI 11.121, on the action of angiotension II (AII) was investigated in the isolated continuously superfused rabbit aortic strip and perfused rat lung. An A II analog, Sar1-Ile5-A II, was also used only in aortic strip experiments. The myotropic effects of both peptides on the rabbit aorta were found to be inhibited when GYKI 11.121 was added to the superfusion medium. However, the vasoconstrictor effect of A II was found to be enhanced in the isolated rat lung following the addition of GYKI 11.121 to the perfusion medium. These findings are explained by the presence of a histaminergic component in the myotropic action of A II peptides.

We have studied the effects of 17 beta-estradiol on the left ventricular pressure and on the coronary perfusion pressure in isolated rabbit heart, in order to evaluate the action of this hormone on the myocardial contractility and on the coronary resistances. 17 beta-Estradiol has induced a negative inotropic effect starting from a concentration of 10(-6) M and a vasodilation starting from 10(-7) M when administered on a vasopressin-induced coronary spasm. These effects are not related to sex or to alpha-, beta-adrenergic, histaminergic, anaesthetic-like mechanisms, but seem to interfere with calcium transport.

Many physiological important substances elicit a relaxing effect on blood vessels which is mediated by (a) substance(s) [EDRF(s)] released from the endothelial cells. EDRF(s) stimulate(s) guanylate cyclase, increasing cGMP at the smooth muscle level, resulting in relaxation. Since this mechanism of action is very similar to that of nitrovasodilator substances, we investigated whether EDRF(s) would act via the "organic nitrate receptor", which is thought to be the common site of action for organic nitrovasodilator substances. The relaxation effect of EDRF-mediated substances (histamine and acetylcholine) was investigated on contracted rat aorta preparations in which the affinity of the organic nitrate receptor was lowered by a treatment with high doses of nitroglycerin. The dose-relaxation curve of nitroglycerin on aorta preparations of pre-treated animals showed a highly significant shift to the right compared to preparations of control rats, proving the nitrate-receptor tolerance. However, when the same preparations were tested for their reactivity to acetylcholine or histamine, no differences could be demonstrated. These results indicate that, although it is known that organic nitrates and EDRF relax vascular smooth muscle cells by stimulating guanylate cyclase, this stimulation is mediated by a different mechanism.

The roles of histamine H1 and H2 receptors in histamine skin wheals were studied in the guinea-pig. Intradermal injections of histamine, 0.125--2 micrograms/0.1 ml, produced wheals in a dose dependent manner. Pyrilamine maleate (3.2 mg/kg p.o., pretreatment for 1 hour) produced a dose dependent shift of the histamine wheal dose-response curve to the right in a parallel fashion. Metiamide, 3, 10 or 30 mg/kg p.o., had no effect on the histamine dose-response curve. However, a combination of metiamide (10 or 30 mg/kg) and pyrilamine (3.2 mg/kg) further increased the effect of pyrilamine. It is concluded that both H1 and H2 receptors are involved in histamine-induced wheals in the guinea-pig.

The effects of metoclopramide (Mcp), sulpiride (Sp) and some of their derivatives: bromopride (Br), tiapride (Ti) and sultopride (Stp) have been compared on the guinea-pig isolated ileum. 1. Br and Ti have, like Mcp, and indirect cholinergic stimulating effect on the intestinal smooth muscle. Sp and Stp are devoid of such an effect. 2. At high doses, all the benzamides have a direct inhibitory effect on the ileum. 3. Mcp, Br and Ti (10(-5)M) potentiate the responses of the ileum to acetylcholine (ACh). At high doses (10(-4)M) the effects of all benzamides on the responses to ACh as well as to histamine (H) are mostly inhibitory. 4. Mcp and Br (10(-5)M) inhibit the responses of the ileum to serotonin (5HT) while Ti, Sp and Stp potentiate them. 5. Neural pathways and calcium mechanisms are involved in the potentiations of ACh and 5HT responses since the enhancements observed are abolished in the presence of tetrodotoxin or in the absence of Ca++.

The phenomenon of histamine tachyphylaxis in vitro previously observed in the airway smooth muscle from adult dogs was investigated in airway smooth muscle from young dogs (age 72-96 days; mean: 91 days). Tachyphylaxis was demonstrated by repetitive exposure to 10(-4) M histamine (4th contractile response was 53.0 +/- 4.9% of the initial histamine contraction; n = 6, P less than 0.01). This result was similar to that previously reported (Anderson et al., 1979) in adult canine tracheal smooth muscle. Tachyphylaxis to histamine was demonstrated also by repetitive exposure to histamine (10(-4) M) in the small airway smooth muscle (2 mm diameter), (4th contractile response was 59.6 +/- 7.2% of the initial histamine contraction; n = 6, P less than 0.01). This tachyphylaxic response is not present in the small airways from adult animals. The development of histamine tachyphylaxis in both tracheal and small airway smooth muscle could be prevented or reversed by preincubation of the tissue with indomethacin (2.8 x 10(-6) M). The composite information thus implicates prostaglandins as the most probable mediators of the process. These results suggest that the variable phenomenon of histamine tachyphylaxis is dependent on the maturity of the animal and on the size of the airway.

Histamine-induced paw oedema and anaphylactic shock were studied simultaneously in ovalbumin-sensitized guinea-pigs and cinnarizine and flunarizine were evaluated quantitatively with regard to protection from the two types of challenge. Both compounds were markedly more active in preventing lethal anaphylaxis (ED50's of 0.67 and 0.53 mg/kg OR) than in reducing histamine oedema (ED50's of 2.77 and 1.54 mg/kg OR). The high anti-anaphylactic potency after oral administration may be an important finding in view of the therapeutic applications of cinnarizine and flunarizine.

The anaphylactic mediators, histamine and leukotrienes, stimulate arachidonic acid (AA) metabolism in the guinea-pig lungs, leading to the synthesis and release of thromboxane A2 (TxA2) and other cyclo-oxygenase products. Since TxA2 is a potent bronchoconstrictor, it is possible that the activation of AA metabolism by histamine may contribute to the pulmonary manifestations of anaphylaxis. In the present experiments, histamine-induced release of TxA2 was inhibited by mepyramine (10(-8)-10(-6) M) but not by cimetidine (5 X 10(-5) M) indicating that the release was mediated by H1-receptors. The beta-adrenoceptor agonists, fenoterol (10(-6) M) and isoprenaline (10(-6) M) inhibited the histamine-induced release of TxA2. This effect was partially reversed by propranolol. These results suggest that if histamine-induced TxA2 release is involved in guinea-pig pulmonary anaphylaxis then inhibition of this release may be a factor in the anti-anaphylactic effect of beta-adrenoceptor agonists.

Etintidine is a potent competitive antagonist of histamine H2-receptors. It is 4.6 and 2.2 times more potent than cimetidine in the isolated guinea pig atrium (pA2 = 7.18) and the isolated rabbit parietal cell (pA2 = 6.51), respectively. Etintidine is 2.0 (ED50 = 1.8 mg/kg, i.g.) times more potent than cimetidine at inhibiting betazole-stimulated total acid output in the chronic gastric fistula dog. In the 4 hr pylorus-ligated rat etintidine is a potent inhibitor of total acid output (ED50 = 22 mg/kg, i.d.), total pepsin output, and is well absorbed from the gastrointestinal tract. Additional pharmacological and biochemical studies indicate that etintidine displays minimal competition with appropriate ligands for the alpha 1, alpha 2, cholinergic and neuroleptic receptors in vitro, and has minimal effects on the immunological, autonomic and central nervous systems at doses much higher than antisecretory doses. While high doses of both cimetidine and etintidine increase serum prolactin levels in rats, the effect of etintidine is less than that of cimetidine. Similarly, the prolongation of hexobarbital-induced sleep time in rats is less than with cimetidine. These data indicate that etintidine may be potentially useful and safe in the treatment of peptic ulcer disease and may offer some advantages over cimetidine in terms of less potential for side effects.

The effects of theophylline (10(-5)M, 10(-4)M and 10(-3)M) on the contractile responses of the guinea-pig urinary bladder to nerve stimulation, adenosin 5' triphosphate (ATP) and histamine have been investigated. Contractile responses were unaffected by 10(-5)M and 10(-4)M therophylline but were significantly reduced by 10(-3)M theophylline. Since responses to histamine were reduced to a similar extent as responses to ATP, it is suggested that theophylline is not a specific antagonist of ATP in this tissue and that the ATP receptors in the bladder differ from those in other smooth muscle preparations.

F 1865 (ethyl-3-methoxyphenyl-4-thiazolyl-2-oxamate) has powerful oral anti-allergic properties in immediate hypersensitivity models in rats. In IgE-dependent passive cutaneous anaphylaxis (PCA) the ED50 was of 0.8 mg/kg. In IgG-dependent PCA the ED50 was of 0.6 mg/kg. This oxamate derivative inhibited the liberation of histamine during passive peritoneal anaphylaxis in rats at concentrations of 1 X 10(-6) M or higher. Doses of F 1865, active in PCA, had only weak anti-histamine and anti-serotonin effects, as measured by the increase of cutaneous capillary permeability. Likewise, its inhibitory effect on the bronchospasm due to histamine or serotonin in guinea-pigs was apparent only at doses of 1 mg/kg on i.v. administration. At doses of 100 mg/kg (X2) p.o., F 1865 was inactive against reverse passive Arthus pleurisy induced in rats by rabbit anti-bovine-albumin serum.

Astemizole (R 43 512), a chemically novel compound, has been studied for its in vivo histamine H1-antagonizing properties in laboratory animals. The test models used were: in rats, protection from compound 48/80-induced lethality and inhibition of histamine-induced skin reactions; in guinea-pigs, protection from histamine-induced fatality and bronchoconstriction and in dogs, inhibition of histamine-and Ascaris allergen-provoked skin oedema formation. When compared to standard antihistamines, astemizole showed a higher oral potency and a longer duration of action in all animal models studied. Astemizole's activity was highly specific: it exerted only weak antiserotonin and no anticholinergic actions. Behavioral and drug interaction studies showed that it was devoid of depressant or stimulatory effects on the central nervous system (CNS). Astemizole was very atoxic: safety margins were greater than 25,000 in rats and mice, 30,800 in guinea-pigs and greater than 2000 in dogs. The data of this study indicate that astemizole can be described as a potent, exceptionally long-acting and selective histamine H1-antagonist, free of central and toxic effects.

The effect of contraction and Ca2+ on the indomethacin mediated increased tracheal reactivity to histamine was studied in swine isolated tracheal smooth muscle. The potentiating effect of indomethacin was not directly related to the size of muscle contraction. Histamine, but not acetylcholine-induced contractions were partially inhibited in a zero-Ca2+ Krebs solution and almost abolished in zero-Ca2+ Krebs solution containing 0.1 mM EGTA. Indomethacin potentiated histamine but not acetylcholine-induced contractions in the zero-Ca2+ medium. Re-addition of Ca2+ ions caused a further potentiation of the histamine-induced response. The histamine response with indomethacin when EGTA was present was further reduced. Indomethacin had no effect on Ca2+-contractures of tissues bathed in zero-Ca2+ solution containing 80 mM K+. The results demonstrate that histamine-induced tone is largely dependent on labile Ca2+, whereas its potentiation by indomethacin, is only partly dependent on this cation pool.

The effects of the newly isolated antihistamine (KC-18) from the Hungarian oak gall extracts on some actions of histamine have been investigated. Intraperitoneally administered KC-18 into guinea pigs and cats in doses of 2.5-16 mg/kg exerted a significant dose-related inhibition of histamine-induced bronchoconstriction, increase in capillary permeability and hypotension. In guinea pigs, actively sensitized with ovalbumin, 4 mg/kg KC-18 administered intraperitoneally prevented the development of anaphylactic shock following antigenic challenge. Histamine-induced gastric acid secretion in the rat was also dose-relatedly reduced by the intravenous administraton of 72 and 120 mg/kg KC-18. However, KC-18 in doses up to 100 mug/ml did not modify the histamine-induced contraction of the isolated guinea pig ileum.

In rat isolated anococcygeus muscle, dopamine (2.6 x 10(-11) M to 8.3 x 10(-10) M) produced a concentration-dependent inhibitory effect on field stimulated contractions. The effect of dopamine was blocked by pimozide (2.2 x 10(-8) M) but not by yohimbine (2.6 x 10(-10) M) or propranolol (1.0 x 10(-7) M), suggesting a specific prejunctional inhibitory effect. Higher concentrations of dopamine (1.4 x 10(-7) M to 1.4 x 10(-4) M) elicited concentration-dependent contractions which were blocked competitively with higher concentrations of pimozide (2.2 x 10(-7) M to 1.4 x 10(-4) M) and 2.2 x 10(-6) M), suggesting a postjunctional activity. ACh in very low concentrations (2.8 x 10(-11) M to 4.4 x 10(-10) M) blocked the field stimulated contractions. Atropine (2.6 x 10(-9) M) per se augmented them and also antagonized the inhibitory effects of ACh, suggesting a prejunctional activity of ACh. Higher concentrations of ACh (5.5 x 10(-7) M to 7.0 x 10(-5) M) produced contractions which were not altered by atropine in a concentration (2.6 x 10(-9) M) which antagonized the prejunctional activity of ACh. Histamine, in a wide range (3.1 x 10(-12) M to 2.6 x 10(-8) M), did not modify field stimulated contractions. Very low concentrations of 5-HT (1.2 x 10(-11) M to 3.8 x 10(-10) M) had an inhibitory effect on field stimulated contractions. Methysergide (2.8 x 10(-9) M) enhanced the responses to electrical stimulation and antagonized the 5-HT-induced inhibitory effect. Still higher concentrations of 5-HT (1.9 x 10(-6) M to 1.0 x 10(-3) M) produced concentration-dependent contractions. Methysergide (8.5 x 10(-7) M) failed to antagonize, whereas phentolamine (1.0 x 10(-6) M) antagonized 5-HT competitively. Dopamine (8.3 x 10(-10) M), ACh (4.4 x 10(-10) M) or 5-HT (3.9 x 10(-10) M), in concentrations which produced a maximal prejunctional inhibitory effect, did not alter the EC50 value of NA, ruling out a post-junctional effect. Moreover, the concentration ratios of these agents for EC50 pre to EC50 post were less than 1, suggesting their preferential prejunctional site of action. It is concluded that multiple prejunctional site of action. It is concluded that multiple prejunctional receptor activities for DA, ACh (muscarinic) and 5-HT, which modify the release of neurotransmitter, may be operative in this preparation.

Butorphanol, levo-N-cyclobutylmethyl-3, 14beta-dihydroxy-morphinan, is a new agonist-antagonist type analgetic agent which is 4 times more potent than morphine in experimental animals. Equianalgetic doses of butorphanol and morphine were compared, following rapid intravenous injection to anesthetized dogs, for their effects on pulmonary resistance, dynamic compliance, arterial blood pressure and venous plasma histamine levels. Butorphanol, 0.75 mg/kg, had no effect on pulmonary resistance, dynamic compliance or venous plasma histamine levels. Morphine, 3 mg/kg, increased pulmonary resistance, decreased dynamic compliance and elevated venous plasma histamine levels. Both drugs decreased arterial blood pressure but the hypotensive effect of butorphanol was significantly less in magnitude than that of morphine. Pretreatment with chlorpheniramine antagonized the effects of morphine on pulmonary resistance, dynamic compliance and arterial blood pressure. These results suggest that in man butorphanol may have less potential than morphine for causing airway constriction, hypotension and histamine release.

The effect of five neuromuscular blocking agents on histamine levels of various tissues was studied. Blood and tissue samples were taken from male rats previously treated intravenously with neuromuscular blocking agents. d-Tubocurarine proved to be the most potent histamine liberator. Alcuronium, gallamine and succinylcholine were only moderate histamine liberators, whereas pancuronium released practically no histamine. The results from the individual tissues suggest that the possible sources of increased blood histamine concentrations are tongue and skin with high histamine content. No release of histamine was found from the lung.