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Biomedical subjects

E Malta

Publications and source records attributed to E Malta.

49 records · Page 3Linked to original sources
PubMedDate not supplied

Biphasic relaxant curves to glyceryl trinitrate in rat aortic rings. Evidence for two mechanisms of action.

The concentration-effect curve for the relaxant effects of glyceryl trinitrate (GTN) in rat aortic rings consisted of two phases with IC50 values of 0.1 microM for Phase I and 14 microM for Phase II. Incubation of tissues with oxyhaemoglobin or the induction of tolerance to GTN abolished responses occurring in Phase I but were without effect on Phase II relaxant responses. Both phases of the relaxant curve appeared to involve cyclic GMP since responses were (i) potentiated by the cyclic GMP phosphodiesterase inhibitor zaprinast (M & B 22948) and (ii) inhibited by methylene blue and LY83583, agents which inhibit soluble guanylate cyclase. The latter agents inhibited Phase I responses in a non-surmountable manner while Phase II responses were shifted to the right without effect on the maximal response. Neither phase of relaxation involved stimulation of the Na+/K+ ATPase pump since treatment of tissues with ouabain or K+-free solutions did not alter the GTN biphasic curve. Phase I relaxant responses to GTN resembled those to the endothelium-dependent relaxant acetylcholine, since oxyhaemoglobin and methylene blue were non-surmountable antagonists; however there was no cross tolerance to acetylcholine in GTN tolerant tissues. Phase II relaxant responses resembled those obtained with sodium nitroprusside (SNP) since neither oxyhaemoglobin nor the induction of tolerance to GTN altered the response to SNP. These results indicate that there are two distinct mechanisms of relaxation for GTN in rat aortic rings; however both mechanisms appear to involve cyclic GMP as the second messenger.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMedDate not supplied

Effects of some catecholamines on the cat cardiovascular system: interactions with adrenoceptor antagonists.

The effects of intravenous infusions of norepinephrine, epinephrine, isoproterenol, N-t-butylnorepinephrine, oxymethyleneisoproterenol, and RO363 on heart rate, mean arterial blood pressure, cardiac output, total peripheral resistance, and stroke volume were evaluated in chloralose-anaesthetized cats before and after phentolamine, propranolol, atenolol, and butoxamine. Pressor responses to both norepinephrine and epinephrine largely resulted from alpha-receptor-mediated increases in total peripheral resistance. Vasomotor reversal was noted with both drugs in the presence of alpha-receptor blockade. Dilator responses to norepinephrine were abolished by the beta 1-receptor selective antagonist atenolol, as were those to the beta 1-receptor selective agonists oxymethyleneisoproterenol and RO363. Dilator responses to epinephrine were abolished by the beta 2-receptor selective antagonist butoxamine, as were those to N-t-butylnorepinephrine (beta 2-selective) and isoproterenol (nonselective). These results indicate that in addition to beta 2-receptors, beta 1-receptors subserving vasodilatation occur in the cat vasculature. Atenolol displayed agonist-dependent inhibition of the cardiac responses. Responses to noradrenaline, RO363, and oxymethyleneisoproterenol were blocked to a greater extent than were those to epinephrine, N-t-butylnorepinephrine, and isoproterenol. Butoxamine did not display any marked agonist-dependent inhibition of cardiac responses. Nevertheless, the results are in accord with previous suggestions that cardiostimulant beta 2-receptors exist in the cat heart. Interpretation of the actions of catecholamines may be complicated by mixed beta-adrenoceptor populations in the cat cardiovascular system.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Cardiovascular actions of xamoterol (ICI 118,587) in anaesthetized cats, rats, and guinea pigs.

The maximal increases in heart rate produced by intravenous xamoterol in anaesthetized cats and rats are less than that of (-)-isoprenaline. In cats, blood pressure was slightly raised, while in rats, supramaximal cardiac-stimulant doses produced reductions in blood pressure. In anaesthetized guinea pigs, cardiac-stimulant effects of xamoterol were evident only after treatment with hexamethonium. In all three species cardiovascular responses to xamoterol were antagonized by beta-adrenoceptor antagonists. Thus, xamoterol is a partial agonist which displays beta 1-adrenoceptor selectivity. In cats, infusions of xamoterol elicited beta-adrenoceptor-mediated increases in heart rate, blood pressure, and cardiac output, while calculated total peripheral resistance was little affected and, unexpectedly, stroke volume was reduced. These cardiovascular effects were unaffected by hexamethonium or captopril. Both xamoterol and (-)-isoprenaline elevated left ventricular dP/dtmax and reduced central venous pressure. When cat heart rate was paced over a range (175-250 beats/min) corresponding to the beta-receptor-mediated chronotropic effects, an inverse relationship between rate and stroke volume was observed. The rate-induced reduction in stroke volume offers the best explanation for the decrease in stroke volume produced by xamoterol. In general, the effects of beta-adrenoceptor agonists on stroke volume in the anaesthetized cat appear to represent a balance between a rate-related reduction and a drug-induced elevation of this parameter.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Influence of changes in amine substitution on the beta-adrenoceptor stimulant activity of soterenol and related compounds in the anaesthetized cat.

1. Three 3-methanesulphonamido, 4-hydroxy ring substituted phenylethanolamines with N-isopropyl (soterenol), N-t-butyl (MJ7999-1) and N-(1-phenyl-t-butyl)(MJ9184-1) amine substituents have been compared with ()-isoprenaline for their ability to produce beta-receptor mediated reductions in serotonin-induced increases in pulmonary resistance, decreases in soleus muscle contractility, and increases in heart rate in anaesthetized cats. For each parameter, the dose of a compound required to produce 50% of its maximal response (ED50) was calculated. 2. For all three parameters ()-isoprenaline was the most potent of the compounds studied, and the rank order of potency of the methanesulphonanilides was MJ9184-1 (N-(1-phenyl-t-butyl))congruent to MJ7999-1 (N-t-butyl) greater than soterenol (N-isopropyl). 3. For each individual drug, molar dose-ratios [drug:()-isoprenaline] were calculated. Ratios for the effects of the compounds on the soleus muscle and in the bronchi were similar. With each compound higher dose-ratios were found in the heart. The rank order for relative beta2-selectivity was soterenol (N-isopropyl) greater than MJ7999-1 (N-t-butyl) congruent to MJ9184-1 (N-(1-phenyl-t-butyl)).

Adrenergic beta-Agonists↗
PubMedDate not supplied

Comparison of the effects of (--)-isoprenaline, orciprenaline terbutaline, and Me506 on heart rate, soleus muscle contractility and pulmonary resistance of anaesthetized cats.

1. Three resorcinol derivatives with N-isopropyl (orciprenaline), N-t-butyl (terbutaline) and N-p-hydroxypheny-t-butyl (Me506) amine substituents have been compared with (--)-isoprenaline for their ability to produce beta-receptor mediated reductions in serotonin-induced increases in pulmonary resistance, decreases in soleus muscle contractility and increases in heart rate in anaesthetized cats. 2. For all parameters studied the four compounds produced similar maximal responses and dose-response curves were close to parallel. From the graphs doses of the compounds producing 50% of the maximal response (ED50) were interpolated, and from these dose-ratios with respect to (--)-isoprenaline [drug ED50:(--)-isoprenaline ED50] were calculated on a molar basis. 3. Increasing the size of the amine substituent from N-isopropyl to N-t-butyl led to an increase in beta-receptor stimulant activity in bronchial and skeletal muscle, but not in the heart. The change from N-t-butyl to N-p-hydroxyphenyl-t-butyl did not further affect stimulant activity in any of the parameters studied. 4. Calculation of selectivity ratios [molar dose-ratio (heart): molar dose-ratio (pulmonary resistance)] showed that orciprenaline was non-selective, and that terbutaline and Me506 showed a similar degree of selectivity for beta2- as opposed to beta1-receptor mediated actions.

Airway Resistance↗
PubMedDate not supplied

Leakage of catecholamines from rabbit cerebrospinal fluid following intracerebroventricular injection.

The intracerebroventricular (i.c.v.) injection of (-)-isoprenaline and the selective beta 1-adrenoceptor agonist, RO363, elicited reproducible dose-related increases in heart rate in unanaesthetized and anaesthetized rabbits. (-)-Isoprenaline produced vasodepressor effects in unanaesthetized animals, whereas both catecholamines decreased blood pressure in anaesthetized rabbits. Pretreatment with guanethidine sulphate (5 mg/kg i.v.) reduced but did not abolish the tachycardia elicited by i.c.v. RO363, whereas heart rate responses to i.c.v. (-)-isoprenaline were unaffected. Pretreatment of anaesthetized rabbits with hexamethonium bromide (10 mg/kg i.v.) did not markedly affect the tachycardia elicited by i.c.v. RO363 and reduced the response to i.c.v. (-)-isoprenaline in only one out of five experiments. The results suggest that there is a marked leakage of centrally administered catecholamines into the peripheral circulation and that the rabbit may be unsuited for examining centrally mediated cardiovascular effects of catecholamines.

Adrenergic beta-Agonists↗
PubMedDate not supplied

Effects of phenoxybenzamine on responses to some receptor agonists and calcium in vitro.

Noradrenaline-induced contractions of the rabbit and rat isolated aorta and guinea-pig spleen strips were inhibited by concentrations of phenoxybenzamine which did not affect responses to calcium. This may suggest a specific action on alpha-adrenoceptors. However, analysis of noradrenaline concentration-effect curves in guinea-pig spleen indicated that 1 mumol/l phenoxybenzamine should have reduced the available receptor population to 6% of control, but data from radioligand binding experiments on the same tissues using [3H]-prazosin indicated a reduction of the receptor population to only 82% of control. The reduced responsiveness observed in the organ bath study after phenoxybenzamine pretreatment, whilst not apparently related to effects on voltage-dependent calcium channels, could be due to the actions of phenoxybenzamine on other (non-receptor) processes such as receptor-operated calcium channels. Maximal contractile responses to histamine in rabbit isolated aorta but not those in guinea-pig isolated ileal preparations, were depressed by concentrations of phenoxybenzamine which depressed responses to calcium. Phenoxybenzamine produced parallel rightward shifts of curves to carbachol in guinea-pig ileal preparations but only depressed maximal responses to the agonist in higher concentrations which reduced responses to calcium. On the basis of the results obtained with calcium it is possible that the effects of phenoxybenzamine on receptor-mediated responses could be produced through the actions of this antagonist at less specific sites such as voltage-dependent calcium channels for histamine in rabbit aorta and carbachol in guinea-pig ileum. For alpha-receptor mediated responses in aortic and splenic strip preparations and for histamine-mediated responses in guinea-pig ileum, the actions of phenoxybenzamine may reflect an interaction of the antagonist with receptor-operated calcium channels.

Animals↗
PubMedDate not supplied

Beta-adrenoceptor selectivity of dobutamine: in vivo and in vitro studies.

We compared the beta-adrenoceptor stimulant actions of dobutamine and (-)-isoprenaline in isolated tissue preparations (atria, trachea, and uterus) from the guinea pig and in chloralose-anaesthetized, vagotomized cats (arterial blood pressure, heart rate, hindlimb perfusion pressure, and soleus muscle contractility). The results obtained in these experiments indicate that, on a dose basis, dobutamine shows little selectivity in producing alpha-, beta 1-, and beta 2-adrenoceptor-mediated effects. In phentolamine-treated cats, reductions in arterial pressure and total peripheral resistance produced by infusions of dobutamine were little affected by the beta 2-adrenoceptor-selective antagonist butoxamine, but were antagonized by atenolol. The rise in cardiac output produced by dobutamine involved increases in both heart rate and stroke volume. There was little indication of a selective inotropic action, a feature that confirmed the results obtained in isolated atrial preparations. The increase in cardiac output appeared to involve both alpha- and beta-receptor-mediated actions, because phentolamine reduced the rise in cardiac output by reducing stroke volume.

Adrenergic beta-Agonists↗