Effects of calcium-antagonistic drugs on the stimulation by carbamoylcholine and histamine of phosphatidylinositol turnover in longitudinal smooth muscle of guinea-pig ileum. (1/32)

A number of drugs classed as calcium antagonists, spasmolytics, non-specific receptor antagonists or receptor antagonists with multiple sites of action were tested to determine whether they prevent the stimulation of phosphatidylinositol turnover caused in various tissues by the activation of receptors which increase cell-surface Ca2+ permeability. The experiments were done with fragments of longitudinal smooth muscle from guinea-pig ileum; these were incubated in vitro with 32Pi and either 100 muM-carbamoylcholine or 100 muM-histamine, in the presence of antagonistic drugs at concentrations at least sufficient to cause complete blockade of smooth-muscle contraction. The phosphatidylinositol response to carbamoylcholine was not changed by cinchocaine, papaverine, nifedipine, dibenamine, amethocaine, cinnarizine, lidoflazine, methoxyverapamil, prenylamine or two antimuscarinic alkane-bis-ammonium compounds, and the response to histamine was unaffected by the first four drugs. In contrast, phenoxybenzamine prevented the increase in phosphatidylinositol labelling caused by either carbamoylcholine or histamine. The insensitivity of the phosphatidylinositol response to most of the drugs provides further experimental support for the conclusion that the receptor-stimulated phosphatidylinositol breakdown which initiates the increase in phosphatidylinositol turnover is not caused by an increase in intracellular Ca2+. The simplest interpretation of the available information appears to be that phosphatidylinositol breakdown plays a role in the coupling between the receptor-agonist interaction and the opening of cell-surface Ca2+ gates [Michell, R. H. (1975) Biochim. Biophys. Acta 415, 81-147]. If this is correct, then phenoxybenzamine must exert its inhibitory effects on phosphatidylinositol breakdown early in this sequence of events, but the drugs must act at a stage later than phosphatidylinositol breakdown. The unexpected difference in the effects of dibenamine and phenoxybenzamine, which are chemically very similar, may provide a useful experimental tool with which to explore the way in which activated receptors provoke the opening of cell-surface Ca2+ gates.  (+info)

Studies on the mode of antagonism between adrenergic beta-mimetics and beta-blocking agents (III). Functional antagonism between beta-mimetics and spasmogens. (2/32)

New equations which can explain the following characteristic phenomena in the functional antagonism between isoproterenol (ISO) and spasmogens in guinea-pig trachea are proposed: (1) The amplitude of relaxation of the muscle induced by ISO varied depending on the concentration of a spasmogen used (histamine or carbachol). (2) The dose-response curves for the relaxation by ISO shifted to the right in a parallel manner as the concentration of the spasmogen increased, and became stationary at high concentrations of the spasmogen. (3) The slope of the dose-response curve became steeper with increasing concentrations of the spasmogen. When the saturable uptake process of ISO was taken into consideration, a satisfactory parallel was seen between the theoretical dose-response curves and the present experimental results.  (+info)

Discrimination by SZL49 between contractions evoked by noradrenaline in longitudinal and circular muscle of human vas deferens. (3/32)

The effects of irreversible alpha1-adrenoceptor antagonists, SZL-49 (an alkylating analogue of prazosin), dibenamine and benextramine on contractions to noradrenaline (NA) in longitudinal and circular muscle of human epididymal vas deferens were investigated. Competitive alpha1-adrenoceptor antagonists were also used to further characterize the alpha1-adrenoceptor subtype stimulated by NA in longitudinal and circular muscle. NA evoked concentration-dependent contractions of both muscle types (pD2; 5.4 and 5.2 respectively). The contraction of circular muscle was comparatively more sensitive than that of longitudinal muscle to pretreatment with SZL-49. In contrast, dibenamine or benextramine produced comparable effects in both muscle types. The relationship between receptor occupancy and contraction in either longitudinal or circular muscle was nonlinear, with half-maximal response requiring similar receptor occupancy (longitudinal muscle 14%, circular muscle 16%). Maximal response in both muscle types occurred with little or no receptor reserve (<10%). The competitive alpha1-adrenoceptor antagonists produced dextral shifts of the dose-response curves to NA in longitudinal and circular muscle. The inhibitory potencies, estimated from the apparent pKB values were significantly different in longitudinal and circular muscle respectively for either WB 4101 (pKB, 8.6 and 9.5) or RS-17053 (pKB, 7.1 and 9.0) but not for Rec 15/2739 (pKB, 9.2 and 9.8) or HV 723 (pKB, 8.3 and 8.4). In conclusion, the potency profile of the competitive alpha1-adrenoceptor antagonists and the lack of different receptor reserves for NA in the muscle types suggest that the discriminatory effects of SZL-49 is primarily due to a predominance of the alpha1L-adrenoceptor subtype in longitudinal muscle and alpha1A-subtype in circular muscle.  (+info)

Selective alpha-adrenoceptor blocking actions of a new derivative of 2-halogenotheylamine: 6-(2-bromoethyl)-10,11-methylenedioxy-5,6,7,8-tetrahydrodibenz[c,e]azocine. (4/32)

A new compound, 6-(2-bromoethyl)-10,11-methylenedioxy-5,6,7,8-tetrahydrodibenz [c,e] azocine (DA-VIII-MBr) was found to have a more selective alpha-adrenergic blocking action than dibenamine or phenoxybenzamine. From dose-response curves for adrenaline and 5-hydroxytryptamine (5-HT) obtained in strips of rat aorta before and after incubation with each of the three blocking agents, the fractions of receptors remaining active for adrenaline and 5-HT, respectively, were estimated. After blockade with DA-VIII-MBr the receptors for adrenaline were blocked considerably, but those for 5-HT were little affected. Dibenamine blocked the receptors to adrenaline and 5-HT almost equally. The effective dose of phenoxybenzamine for adrenaline receptors was less than one hundredth that of dibenamine or DA-VIII-MBr, but specificity for these receptors was intermediate between those of dibenamine and DA-VIII-MBr. The structure of DA-VIII-MBr is an analog of apogalanthamine and its nitrogen atom bears the 2-halogenoethylamine group in part of an eight membered ring.  (+info)

ACTIONS OF SYMPATHOMIMETIC DRUGS ON THE SMOOTH MUSCLE AT THE JUNCTION OF THE BILE DUCT AND DUODENUM STUDIED IN SITU. (5/32)

The actions of adrenaline, noradrenaline, phenylephrine and isoprenaline have been examined on flow through the terminal bile duct and on the tone of the duodenum in the vicinity of the terminal bile duct. These drugs were injected intravenously, or intra-arterially into the blood supply of the junction of the bile duct and duodenum. The effects of the antagonistic drugs, dibenamine and dichloroisoprenaline, were also tested. Isoprenaline always relaxed the duodenum and increased the flow through the bile duct. Adrenaline, noradrenaline and phenylephrine relaxed the duodenum, but had variable effects on the flow through the bile duct. It is concluded that adrenaline acts directly on the smooth muscle of the bile duct to contract it, but the influence of the neighbouring duodenal muscle may nevertheless result in an increase in flow through the duct.  (+info)

STUDIES ON THE HYPERGLYCAEMIA INDUCED BY CHLORPROMAZINE IN RATS. (6/32)

Chlorpromazine induces in rats a marked and long-lasting hyperglycaemia which (a) is more marked at low than high room temperatures, (b) is inhibited by phentolamine but not by dibenamine, and (c) is prevented by adrenalectomy, by removal of the adrenal medullae and by treatment of the rats with reserpine. Other experimental results suggest that there is a correlation between the hyperglycaemia and the hypothermia induced by chlorpromazine and by its congeners. The hyperglycaemia seems to be the result of at least two factors: an activation of the adrenergic mechanisms and an impaired peripheral utilization of glucose.  (+info)

DISTRIBUTION OF (2-BROMOETHYL)ETHYL(NAPHTH-1-YMETHYL-(14C))AMINE HYDROBROMIDE IN THE RAT. (7/32)

(2-Bromoethyl)ethyl(naphth-1-ylmethyl)amine hydrobromide (SY28) is a halogenoalkylamine related to dibenamine. A dose of 10 mg/kg injected intravenously into rats antagonizes the pressor response to adrenaline for 36 hr. If this amount of SY28 labelled with (14)C in the 1-methyl position is administered, specific radioactivity is present in blood and tissues many days after the antagonism of adrenaline is relieved. The (14)C is excreted in bile and in urine, but not in expired air. It is present in fat but not to a greater extent than it is in other tissues. It does not cross the placental barrier. There is no evidence that slow release from a lipid depot accounts for the long duration of action.  (+info)

Comparison of alpha 1-adrenoceptors between rat brain and spleen. (8/32)

Scatchard analyses of 3H-prazosin binding in rat brain membranes showed biphasic curves, which identified the presence of alpha 1High- and alpha 1Low-affinity sites. The alpha 1High-affinity site was completely inhibited by 0.1 microM phenoxybenzamine. On the other hand, 3H-prazosin binding in rat spleen membranes resulted in linear curves that were identical to the binding curve for the alpha 1High-affinity site in the brain. The displacement potencies of alpha 1-adrenergic antagonists were characterized by 3H-prazosin binding to alpha 1High-affinity sites in the rat spleen and brain and alpha 1Low-affinity sites in the brain in the presence of 0.1 microM of phenoxybenzamine. The affinities of WB-4101, phenoxybenzamine, phentolamine, chlorpromazine, labetalol and nifedipine for brain alpha 1High-affinity sites were significantly higher than those in the spleen. The affinities of most ligands for alpha 1Low-affinity sites were significantly lower than those for both alpha 1High-affinity sites in the brain and spleen, but chlorethylclonidine was significantly selective for alpha 1Low-affinity sites, and bunazosin, dibenamine and 5HT had the same affinities for the alpha 1Low- and both alpha 1High-affinity sites. These results show that two alpha 1-adrenoceptor subtypes, alpha 1High- and alpha 1Low-affinity, are present in the rat brain and that a different alpha 1High-subtype, exists in the rat spleen.  (+info)

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