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The myocardium of animals and man possesses alpha 1-adrenoceptors in addition to beta-adrenoceptors. Ischemia increases sympathetic tone, and ventricular arrhythmias can occur by beta- and alpha 1-adrenoceptor stimulation. I believe that alpha 1-adrenoceptor blocking drugs have antifibrillatory effects and will review the data that support this condition. The effect of alpha 1-adrenoceptor blocking drugs on the incidence of ventricular fibrillation in acute coronary artery occlusion and (or) reperfusion has been determined in 24 studies in conscious and anesthetized dogs and rats, anesthetized cats and pigs, and rat and guinea-pig isolated hearts. The drugs reduced the incidence of fibrillation from 35 to 24% in coronary occlusion and from 61 to 29% in reperfusion.

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In addition to beta-adrenoceptors (beta ARs), cardiac myocytes of animals and man possess alpha 1ARs, but not alpha 2ARs. Norepinephrine and epinephrine have a higher affinity for myocardial alpha 1ARs than for beta ARs. Unlike beta AR stimulation, myocardial alpha 1AR stimulation does not increase the slow inward current. The alpha 1AR-mediated positive inotropic effect seen in isolated heart preparations appears to involve increased Ca sensitivity of myofibrils and production of inositol triphosphate (IP3) and diacylglycerol (DAG), but the functions of IP3 and DAG are not clear. Myocardial alpha 1AR stimulation reduces rate of isolated atria and Purkinje fibers and lengthens refractory period and action potential duration. Hypoxia increases alpha 1AR density in cardiomyocytes. alpha 1AR-mediated arrhythmias occur in isolated Purkinje fibers during hypoxia, following infarction, and in the presence of Ba2+ or high Ca2+. In animals, coronary artery occlusion and/or reperfusion increase myocardial alpha 1AR density and responsiveness, and alpha AR blocking drugs attenuate arrhythmias. However, an antiarrhythmic effect of alpha AR blocking drugs mediated by action on coronary vascular alpha ARs cannot be excluded. Presently available drugs do not differentiate between myocardial and vascular alpha ARs and thus affect the coronary and systemic circulations and, indirectly, the heart. Additional myocardial alpha 1AR-mediated effects include production of cardiac hypertrophy, stimulation of glucose uptake and phosphofructokinase and cyclic AMP phosphodiesterase activity, and release of atrial natriuretic peptide.

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Open-chest dogs and pigs anaesthetized with pentobarbitone were used to evaluate the anti-arrhythmic effect of prazosin and propranolol during a 30 min period of occlusion of the left anterior descending coronary artery followed by 15 min of re-perfusion. In dogs, both prazosin and propranolol reduced the incidence of ventricular premature depolarizations and ventricular tachycardia during the occlusion period. During the 45 min period of occlusion and re-perfusion, the incidence of ventricular fibrillation was significantly reduced in the prazosin-treated and propranolol-treated dogs. In pigs prazosin reduced the incidence of ventricular premature depolarizations during occlusion and propranolol reduced the incidence of both ventricular premature depolarizations and ventricular tachycardia during occlusion, but the incidence of ventricular fibrillation was not significantly reduced in the prazosin- and propranolol-treated pigs. Prazosin reduced arterial pressure and propranolol lowered heart rate in both dogs and pigs, but a comparison of mean arterial pressure and heart rate in animals surviving and those not surviving the 30 min of coronary artery occlusion and 15 min of re-perfusion showed no significant difference.

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Inotropic effects of isoprenaline, phenylephrine and calcium were studied in left atria of 5 weeks old rats fed a low (5%) or a normal (21%) protein diet for 3 weeks. Rats maintained on a low (5%) protein diet consume about half the amount of food eaten by the same rats maintained on a normal (21%) protein diet and thus suffer from protein-calorie malnutrition (PCM). Body weight did not increase in PCM, but heart weight adjusted to body weight was slightly increased compared to normal rats. Atrial resting tension and peak developed tension in response to isoprenaline, phenylephrine or calcium were not diminished by PCM. The number of alpha and beta-adrenoceptors and the receptor affinity in ventricular membranes were not reduced by PCM.

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1 The activity of the irreversible alpha-adrenoceptor blocking drug, benextramine, was determined in human platelets. 2 Compared to its postsynaptic and presynaptic alpha-adrenoceptor blocking potency, benextramine had a very low potency as an antagonist of adrenaline-induced platelet aggregation. 3 The results confirm the previous observation with the irreversible alpha-adrenoceptor blocking drug, phenoxybenzamine, that platelet alpha-adrenoceptors differ from postsynaptic and presynaptic alpha-adrenoceptors.

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1 Benextramine (N,N1-bis[o-methoxybenzylamino)-n-hexyl]cystamine), which irreversibly blocks alpha-adrenoceptors and does not inhibit the H1-receptor-mediated contractile effect of histamine on guinea-pig isolated ileum, also did not inhibit the H1-receptor-mediated inotropic effect of histamine on guinea-pig isolated atrium. 2 Benextramine irreversibly inhibited the H2-receptor-mediated chronotropic effect of histamine on guinea-pig isolated atrium. 3 Since its combination with the competitive H2-receptor blocking drug cimetidine had a additive blocking effect, benextramine appears to act directly on the chronotropic H2-receptor.

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1 The presynaptic alpha-adrenoceptor blocking activity of the newly synthesized alpha-adrenoceptor blocking drug, benextramine, was evaluated in the isolated left atrium of the guinea-pig heart. 2 High-voltage stimulation increased the force of contraction of electrically driven atrial strips, presumably by releasing noradrenaline from sympathetic nerve endings. Like phentolamine, benextramine increased the effect of high-voltage stimulation, presumably by blocking presynaptic alpha-adrenoceptors. 3 Clonidine reduced the effect of high-voltage stimulation, presumably by stimulating presynaptic alpha-adrenoceptors. The inhibitory effect of clonidine was antagonized noncompetitively by benextramine and competitively by phentolamine. 4 Combined administration of benextramine and phentolamine only resulted in the competitive phentolamine antagonism. Thus phentolamine protected the presynaptic alpha-adrenoceptors against benextramine blockade.

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The tetramine disulfide benextramine irreversibly blocked the noradrenaline-induced contraction of the isolated rabbit aorta in a manner similar to that observed with phenoxybenzamine. Cysteamine abolished the benextramine blockade but not the phenoxybenzamine blockade. Incubation of aortic tissue with benextramine prior to phenoxybenzamine exposure and followed by cysteamine treatment led to a recovery of the noradrenaline response that depended on the dose of benextramine. Thus benextramine protected the alpha adrenoceptors against phenoxybenzamine blockade.

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Inotropic effects of phenylephrine, carbachol, and butyrylcholine were used in the rabbit left atrium to evaluate respectively alpha adrenoceptor blocking, muscarinic blocking, and nicotinic blocking effects of tetramine disulfides ((RNH(CH2)nNH(CH2)2S-)2 x 4HX). The alpha adrenoceptor blocking potencies of newly synthesized derivatives R = 3',4'-(OH)2-benzyl, n = 5-9, were similar to those of compounds R = 2'-OCH2-benzyl, n = 5-7. Muscarinic blocking and nicotinic blocking potencies of tetramine disulfides were correlated with alpha adrenoceptor blocking potency. Compounds R = 3',4'-(OH)2-benzyl had relatively low muscarinic blocking potencies and compounds R = 2'-OCH3-benzyl had relatively low nicotinic blocking potencies.

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In low concentrations (0.3-3 muM) the tetramine disulfide benextramine (BHC; N,N'-bis[6-(o-methoxybenzylamino)-n-hexyl]cystamine) potentiated the contracture of the isolated frog rectus abdominis muscle caused by acetylcholine but in the presence of physostigmine or in a higher concentration (10 muM) it inhibited. Benextramine only inhibited the contracture caused by carbachol or butyrylcholine. The all-carbon analog of benextramine only inhibited the effect of acetylcholine. The inhibitory effects of benextramine and its carbon analog were noncompetitive and readily reversible but the potentiating effect of benextramine was not readily reversible.

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The purpose of this study was to test the adrenoceptor interconversion hypothesis of Kunos and Nickerson (Brit. J. Pharmacol. 59: 603--614, 1977) which claims that lowering temperature from 31 to 17 degrees C converts inotropic beta adrenoceptors in rat atria to alpha adrenoceptors. If lowering temperature transforms the adrenoceptor from a beta type to an alpha type, one should expect that the sympathomimetic drug phenylephrine would be more potent at the low than at the high temperature, that the reverse would be true for the sympathomimetic drug isoproterenol, and that the blocking ability of the beta adrenoceptor blocking drug propranolol might be reduced and that of the alpha adrenoceptor blocking drug phentolamine increased by lowering temperature. This was not observed. It was impossible to obtain satisfactory inotropic effects at 17 degrees C and the calcium concentration in the incubation medium had to be reduced, which lowered contractility and permitted strong inotropic effects. At 17 degrees C the sympathomimetic drug effects were inhibited only by propranolol and not by phentolamine, and there was no evidence of "adrenoceptor interconversion."

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The newly synthesized alpha-adrenoceptor blocking drug BHC (N,N'-bis[6-(10-methoxybenzyl-amino)-a-hexyl]cystamine) was found to block irreversibly the positive inotropic effect of the sympathomimetic drug phenylephrine on the isolated rat left atrium. BHC was used to test the adrenoceptor interconversion hypothesis which claims that low temperature converts inotropic beta-adrenoceptors in rat atrium and frog ventricle to alpha-adrenoceptors. There was no evidence of adrenoceptor 'interconversion.' In the rat atrium low temperature did not increase the BHC antagonism of phenylephrine and did not cause BHC to inhibit the inotropic effect of noradrenaline or isoprenaline. In the perfused frog heart low temperature did not lead BHC to inhibit the inotropic effect of phenylephrine, adrenaline, or isoprenaline.

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Since many alpha-adrenoceptor blocking drugs were known to have muscarinic blocking activity, BHC, a newly synthesized tetramine disulfide with alpha-adrenoceptor blocking activity, and two of its analogs were tested for muscarinic blocking activity in the isolated guinea pig atrium and ileum. BHC had muscarinic blocking activity. Its potency was higher in the atrium than in the ileum. The cardiac muscarinic blocking potency of the analog that contained carbon atoms instead of sulfur atoms was similar to that of BHC. Lower concentrations of the drugs antagonized inotropic effects of acetylcholine competitively, but higher concentrations had a smaller effect than expected for competitive antagonism. In the atrium BHC competitively inhibited the muscarinic blocking effect of atropine. Its atropinic blocking potency was similar to the muscarinic blocking potency. Quinidine and gallamine also had muscarinic blocking and atropinic blocking effects in the atrium but were about 10 times less potent than BHC.

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Isolated heart preparations of frog and rat were used to test the validity of the adrenoceptor interconversion hypothesis. This hypothesis claims that low temperature converts the inotropic beta-adrenoceptors in isolated frog and rat heart to alpha-adrenoceptors. The present results do not support the adrenoceptor interconversion hypothesis. In the isolated frog ventricle, lowering the temperature from 24 C to 14 C did not significantly alter the inotropic potency of the sympathomimetic drugs isoprenaline, epinephrine, and phenylephrine and did not reduce the potency of the beta-adrenoceptor blocking drug propranolol as an epinephrine antagonist. In the isolated rat left atrium, lowering the temperature from 31 C to 17-19 C did not significantly change the inotropic potency of isoprenaline, norepinephrine and phenylephrine, did not diminish the potency of propranolol, and did not increase the potency of the alpha-adrenoceptor blocking drug phentolamine.--Benfey, B. G. Cardiac adrenoceptors at low temperature; what is the experimental evidence for the adrenoceptor interconversion hypothesis?

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