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Biomedical subjects

G Allan

Publications and source records attributed to G Allan.

120 records · Page 7Linked to original sources
PubMed1981

Thromboxane and prostacyclin release during cardiac immediate hypersensitivity reactions in vitro.

Cardiac immediate hypersensitivity reactions in vitro are characterized by tachycardia, arrhythmias and coronary constriction. Whereas endogenous cardiac histamine release is responsible for the generation of arrhythmias, metabolites of arachidonic acid mediate the fall in coronary flow. In the present study, we have shown that antigenic challenge of sensitized guinea-pig hearts results in the release into the coronary effluent of immunoreactive thromboxane B2, 6-keto prostaglandin (PG) F1 alpha and PGF2 alpha. Thromboxane B2 was the predominant metabolite generated. After the administration of histamine (1-100 micrograms) or a partially purified preparation of slow-reacting substance of anaphylaxis (5-100 U) to the sensitized heart there was no detectable release of thromboxane B2 into the coronary effluent. After the administration of sodium arachidonate (3 X 10(-6) M) to the sensitized heart 40 min after antigenic challenge, there was a predominant release of 6-keto PGF1 alpha into the coronary effluent. Pretreatment of sensitized hearts with aspirin (5.5 X 10(-5) M), indomethacin (1.4 X 10(-5) M) or 1-(2-isopropylphenyl)imidazole (5.4 X 10(-5) M) resulted in inhibition of antigen-induced thromboxane B2 release and coronary vasoconstriction. These results suggest that during immediate hypersensitivity reactions, the coronary vasculature may be predisposed to ischemic and thrombotic episodes as a result of thromboxane release. Thromboxane formation occurs independently of the actions of histamine and slow-reacting substance of anaphylaxis and, since it is not generated preferentially by the coronary circulation of the sensitized heart in response to arachidonate infusion, it is plausible to suggest that it is of mast cell origin.

6-Ketoprostaglandin F1 alpha↗
PubMed1980

Inhibition of thromboxane A2 biosynthesis in human platelets by burimamide.

1 Burimamide selectively inhibited the formation of thromboxane A2 from prostaglandin endoperoxides by human platelet microsomes in a dose-dependent manner (IC50 = 2.5 x 10(-5) M). Burimamide was found to be equipotent to imidazole as a thromboxane synthetase inhibitor. 2 Metiamide, cimetidine and a series of compounds either bearing a structural or pharmacological relationship to histamine caused little or no inhibition of thromboxane A2 biosynthesis by human platelet microsomes. 3 Burimamide (5 x 10(-4) to 2.3 x 10(-3) M) did not inhibit either the cyclo-oxygenase or the prostacyclin synthetase of sheep seminal vesicles or the prostacyclin synthetase of dog aortic microsomes. 4 Burimamide (2.5 x 10(-5) to 1.2 x 10(-4) M) inhibited sodium arachidonate-induced human platelet aggregation; the degree of inhibition was dependent upon the concentration of arachidonic acid used to aggregate the platelets.

Blood Platelets↗
PubMed1980

The cardiac effects of prostaglandins and their modification by the prostaglandin antagonist N-0164.

The cardiac actions of a number of prostaglandins and their modification by the prostaglandin antagonist sodium p-benzyl-4-[1-oxo-2-(4-chlorobenzyl)-3-phenyl propyl]phenyl phosphonate (N-0164) was studied in the isolated guinea-pig heart. Arachidonic acid, prostaglandin (PG)E2 (0.01--1 micrograms) and prostacyclin (0.01--10 micrograms), administered by bolus injection, caused dose-dependent increases in coronary flow rate, whereas PGD2, PGF2 alpha and the stable PG enderoperoxide analog U46619 (0.01--100 micrograms) caused dose-dependent decreases in coronary flow rate. Over the dose range studied, PGE2, arachidonic acid, prostacyclin and PGF2 alpha increased the sinus rate and PGD2 decreased the sinus rate, whereas U46619 had no consistent effect. Arachidonic acid, PGF2 alpha, PGD2 and U46619 produced a decrease in ventricular contractile force, whereas PGE2 had no effect and prostacyclin produced a modest increase in ventricular contractile force. N-0164 (10 ng and 100 ng/ml) selectively antagonized the coronary vasoconstrictor effects of PGD2 and PGF2 alpha. N-0164, at higher concentrations (1 micrograms/ml), antagonized the coronary vasodilator actions of PGE2; however, it did not modify the coronary vasodilator action of prostacyclin. N-0164 (10--100 ng/ml) also antagonized as a function of its concentration sinus rate changes produced by either PGD2 or PGF2 alpha, whereas at higher concentrations (1 microgram/ml), rather than antagonizing it potentiated sinus rate increases produced by either PGE2 or prostacyclin. These results suggest that the cardiac actions of prostaglandins are complex and are not readily elucidated by the use of the prostaglandin antagonist, N-0164.

Animals↗
PubMed1976

Cardiac histamine receptors.

Current evidence pertinent to the identification of cardiac histamine receptors in the guinea pig is reviewed. Pharmacological characterization has been aided by the use of selective agonists and antagonists for both types of histamine receptors. It appears that both H1 and H2 receptors mediate the cardiac effects of histamine. Histamine H2 receptors mediate the positive chronotropic and ventricular inotropic effects. H1 receptors mediate the negative dromotropic effect of histamine and possibly the atrial inotropic effect. Histamine-induced arrhythmias involve H1 receptors (arrhythmias of conduction) or H2 receptors (arrhythmias of automaticity), or both. The receptors mediating the histamine-induced increase in coronary flow are not as clearly defined: both H1 and H2 receptors might be implicated.

Animals↗
PubMed1975

Selective impairment of atrioventricular conduction by 2-(2-pyridyl)-ethylamine and 2-(2-thiazolyl)-ethylamine, two histamine H1-receptor agonists.

To further characterize the receptor mediating histamine-induced impairment of atrioventricular conduction, the effects of two selective histamine H1-receptor agonists, 2-(2-pyridyl)-ethylamine (PEA) and 2-(2-thiazolyl)-ethylamine (ThEA), were investigated using the isolated guinea pig heart. These effects were compared with those of histamine and other selective agonists. PEA and ThEA produced a weak stimulation of cardiac rate and contractility; however, they produced a marked prolongation of atrioventricular conduction. The orders of relative potencies observed substantiate the hypothesis that H2-receptors mediate the positive inotropic and chronotropic effects and H1-receptors mediate the negative dromotropic effect of histamine.

Animals↗
PubMedDate not supplied

Pharmacokinetic/pharmacodynamic assessment of the effects of E4031, cisapride, terfenadine and terodiline on monophasic action potential duration in dog.

1. Torsades de pointes (TDP) is a potentially fatal ventricular tachycardia associated with increases in QT interval and monophasic action potential duration (MAPD). TDP is a side-effect that has led to withdrawal of several drugs from the market (e.g. terfenadine and terodiline). 2. The potential of compounds to cause TDP was evaluated by monitoring their effects on MAPD in dog. Four compounds known to increase QT interval and cause TDP were investigated: terfenadine, terodiline, cisapride and E4031. On the basis that only free drug in the systemic circulation will elicit a pharmacological response target, free concentrations in plasma were selected to mimic the free drug exposures in man. Infusion regimens were designed that rapidly achieved and maintained target-free concentrations of these drugs in plasma and data on the relationship between free concentration and changes in MAPD were obtained for these compounds. 3. These data indicate that the free ED50 in plasma for terfenadine (1.9 nM), terodiline (76 nM), cisapride (11 nM) and E4031 (1.9 nM) closely correlate with the free concentration in man causing QT effects. For compounds that have shown TDP in the clinic (terfenadine, terodiline, cisapride) there is little differentiation between the dog ED50 and the efficacious free plasma concentrations in man (< 10-fold) reflecting their limited safety margins. These data underline the need to maximize the therapeutic ratio with respect to TDP in potential development candidates and the importance of using free drug concentrations in pharmacokinetic/pharmacodynamic studies.

Action Potentials↗
PubMedDate not supplied

Myeloperoxidase activity as a quantitative marker of polymorphonuclear leukocyte accumulation into an experimental myocardial infarct--the effect of ibuprofen on infarct size and polymorphonuclear leukocyte accumulation.

The accumulation of polymorphonuclear leukocytes (PMN) into a canine occlusion/reperfusion model of myocardial infarction (MI) has been quantitated using a spectrophotometric assay for the PMN-specific enzyme myeloperoxidase (MPO). In anaesthetized beagle dogs subjected to 1 h of occlusion of the left anterior descending coronary artery followed by coronary reperfusion for 1 h, MPO activity was found in fourfold greater amounts in infarcted myocardium as opposed to normal myocardium. MPO activity in infarcted myocardium increased with coronary reperfusion in a time-related manner, the greatest accumulation occurring at 5 h of coronary reperfusion. The time-related increase in MPO activity in ischemic myocardium was closely correlated with the observed accumulation of PMN as assessed by histological sectioning, thus supporting the specificity of the method. Pretreatment of dogs with ibuprofen (12.5 mg/kg i.v.) did not alter the MPO content and therefore PMN invasion of infarcted myocardium, a finding confirmed by light microscopy. However, pretreatment with ibuprofen increased myocardial infarct size (from 11.5 to 37.4%, p less than 0.01) and increased the incidence of haemorrhagic infarction and ventricular fibrillation. In conclusion, our studies demonstrate that MPO can be used as a sensitive and quantitative marker of PMN accumulation into an evolving MI. Furthermore, we have demonstrated that PMNs rapidly infiltrated injured myocardium in a time dependent manner and this accumulation was unaffected by ibuprofen pretreatment.

Animals↗