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Biomedical subjects

I Cavero

Publications and source records attributed to I Cavero.

At least 109 records · Page 6Linked to original sources
PubMed1980

Evidence against beta-adrenoceptor blocking activity of diltiazem, a drug with calcium antagonist properties.

1 The isolated spontaneously beating atria of the rat, diltiazem (0.01 to 0.1 microM) shifted the atrial rate concentration-response curves to isoprenaline to the right in a non-parallel manner and depressed their maxima. Under the same experimental conditions, (+/-)-propranolol (0.03 to 0.1 microM) behaved as a competitive beta-adrenoceptor antagonist. 2 Whereas (+/-)-propranolol (IC50 = 12 nM) and isoprenaline (IC50 = 0.9 microM) inhibited (-)-[3H]-dihydroalprenolol binding to rat brain membrane preparations, diltiazem failed to do so in concentrations up to 10 microM. 3 Diltiazem but not (+/-)-propranolol, antagonized the positive chronotropic responses to calcium in spontaneously beating rat atria. 4 It is proposed that diltiazem inhibited the tachycardia induced by isoprenaline through an effect on calcium which may be an essential modulator of the sequence of events linking the beta-adrenoceptor activation and heart rate response.

Adrenergic beta-Antagonists↗
PubMed1980

Effects of clonidine on canine cardiac neuroeffector structures controlling heart rate.

1 In intact dogs anaesthetized with pentobarbitone, clonidine (10 mug/kg, i.v.) produced a sustained decrease in heart rate. This effect was significantly smaller in vagotomized dogs in which the sympathetic drive to the heart was either left intact or experimentally created by continuous electrical stimulation of the decentralized cardioaccelerator nerve. In the latter preparation, the negative chronotropic action of clonidine was reversed by an intravenous injection of phentolamine, whereas in the former experimental situation it was antagonized only by an intravenous plus an intravertebral artery injection of phentolamine.2 In dogs with denervated hearts the tachycardia produced by electrical stimulation of the cardioaccelerator nerve was accompanied by a rise in noradrenaline overflowing into the coronary sinus plasma. Clonidine inhibited both these effects and phentolamine restored them to pre-clonidine levels.3 Clonidine decreased heart rate in dogs with an intact parasympathetically innervated heart and decentralized stellate ganglia. When the low basal heart rate of this preparation was elevated by electrical stimulation of the cardioaccelerator nerve, clonidine had a negative chronotropic effect, the degree of which was similar to that observed in intact dogs.4 Clonidine neither modified baseline heart rates of dogs with denervated hearts nor the levels of heart rate which in this preparation were reduced by a sustained electrical stimulation of the right vagus or increased by intravenous infusions of either isoprenaline or noradrenaline.5 These findings indicate that in the intact dog, bradycardia induced by clonidine resulted both from a reduction of sympathetic drive and from a concomitant increase in parasympathetic tone. The latter action did not occur at the level of cardiac neuroeffector structures since it was observed only in the presence of centrally connected vagal pathways. The inhibition of cardiac sympathetic tone was of both peripheral and central origin. Clonidine, in fact, diminished the quantity of noradrenaline overflowing into the coronary sinus plasma in cardiac denervated dogs with a tachycardia elicited by electrical stimulation of the decentralized cardioaccelerator nerve. This peripheral effect was probably due to an activation of alpha-adrenoceptors located on sympathetic nerve terminals since it was antagonized by phentolamine. However, in vagotomized dogs (intact sympathetic pathways) intravenous phentolamine failed to antagonize the heart rate effects of clonidine which were abolished by a subsequent injection of phentolamine into the vertebral artery. Thus, the clonidine-induced inhibition of both the peripheral and central sympathetic drive to the heart would appear to be mediated via alpha-adrenoceptors.

Animals↗
PubMed1980

Comparison of mianserin with desipramine, maprotiline and phentolamine on cardiac presynaptic and vascular postsynaptic alpha-adrenoceptors and noradrenaline reuptake in pithed normotensive rats.

1 The cardiovascular effects of intravenous desipramine (0.03 and 0.1 mg/kg), maprotiline (0.5 mg/kg), mianserin (1.0 and 3.0 mg/kg) and phentolamine (0.25 mg/kg) were examined and compared in pithed rats. Several experimental procedures were used in order to distinguish between the effects of the compounds on cardiac presynaptic alpha-adrenoceptors and on neuronal noradrenaline reuptake, as inhibition of either mechanism produces an increase of neurotransmitter concentration within the sympathetic synapse and therefore results in a greater end organ response.2 Pressor responses elicited by noradrenaline were potentiated by desipramine and maprotiline, reduced by phentolamine and not significantly modified by mianserin. However, all four compounds inhibited the pressor action of tyramine. Furthermore, mianserin reduced the pressor response to adrenaline.3 Desipramine, maprotiline and mianserin, but not phentolamine enhanced the positive chronotropic effects of noradrenaline, without affecting those of isoprenaline.4 All four compounds abolished the clonidine-induced inhibition of heart rate responses to short term electrical stimulation of the spinal cord. Moreover, in rats with a persistent tachycardia (induced by continuous stimulation of the thoracic spinal cord) desipramine, maprotiline and mianserin further increased heart rate. This effect was also observed in animals pretreated with phentolamine, administered in order to inhibit cardiac presynaptic alpha-adrenoceptors.5 In rats with a sustained tachycardia (100 beats/min produced by electrical stimulation of the spinal cord) both mianserin and phentolamine, in contrast to desipramine, shifted the clonidine heart rate dose-response curve to the right. Phentolamine was about 34 times more potent than mianserin in this respect.6 In pithed, reserpine-treated rats, the pressor responses to clonidine were not significantly modified by desipramine. The dose-response curves were shifted to the right by phentolamine (0.25 mg/kg) and mianserin (3.0 mg/kg).7 These results indicate that mianserin is an antagonist of both cardiac presynaptic and vascular postsynaptic alpha-adrenoceptors and also inhibits the neuronal reuptake of noradrenaline.

Animals↗
PubMed1979

Effects of clonidine, prazosin and phentolamine on heart rate and coronary sinus catecholamine concentration during cardioaccelerator nerve stimulation in spinal dogs.

1 In spinal dogs, continuous electrical stimulation of the cardioaccelerator nerve produced a transient rise in aortic blood pressure and a sustained increase in both heart rate and coronary sinus blood flow. The latter effects were accompanied by a significant elevation in the coronary sinus plasma noradrenaline concentration without significant changes in the levels of dopamine and adrenaline. The concentrations of the three catecholamines in thoracic aorta plasma were not significantly changed by cardioaccelerator nerve stimulation.2 Clonidine (20 mug/kg, i.v.), given during cardioaccelerator nerve stimulation, increased both mean aortic blood pressure and coronary sinus blood flow and decreased heart rate and coronary sinus venous plasma noradrenaline overflow.3 Phentolamine (0.3 mg/kg, i.v.) completely antagonized these effects of clonidine. Prazosin (0.3 mg/kg, i.v.) inhibited by only 43 and 38% the respective reductions in heart rate and noradrenaline overflow elicited by clonidine.4 On termination of cardioaccelerator stimulation (about 10 min after either prazosin or phentolamine), heart rate and coronary sinus noradrenaline overflow returned to control prestimulation levels.5 Phentolamine or prazosin, administered alone during stimulation of the cardioaccelerator nerve, increased heart rate and noradrenaline overflow into the coronary sinus plasma. However, intravenous phentolamine and prazosin, in contrast to desipramine (0.3 mg/kg, i.v.) or tyramine (1.0 mg, i.a.), failed to change the tachycardia resulting from the local administration of noradrenaline into the sinus node artery (i.a.).6 These results show that in spinal dogs the clonidine-induced reduction in heart rate (elevated by electrical stimulation of the cardioaccelerator nerve) is accompanied by a fall in the quantity of noradrenaline overflowing into the coronary sinus plasma. The latter effect is presumably the result of an action of clonidine on cardiac presynaptic alpha-adrenoceptors, the activation of which is followed by a reduction in the release of noradrenaline per nerve impulse. Phentolamine and prazosin are both antagonists of cardiac presynaptic alpha-adrenoceptors in spinal dogs, as suggested by their action against clonidine and by their positive chronotropic effect when administered during stimulation of the cardioaccelerator nerve.

Animals↗
PubMed1978

Studies on the mechanism of the vasodilator effects of prazosin in dogs and rabbits.

In pentobarbital (35.0 mg/kg) anaesthetised dogs, bolus injections of prazosin into the femoral artery (3.0--300.0 microgram) provoked a dose-related fall in the vascular resistance of the innervated hind limb. In contrast to papaverine, prazosin failed to produce the same effect in dogs under spinal anaesthesia even when the intrinsic femoral vascular tone was increased with vasopressin. However, vasodilator effects of prazosin were again observed when the tone of the limb was elevated by either stimulating the sympathetic lumbar chain or by infusing alpha-adrenoceptor agonists. A significant reduction of both aortic blood pressure and pressor response to bilateral carotid artery occlusion was noted in a group of normotensive dogs anaesthetised 12 h after the last dose of prazosin given twice daily at 0.5 mg/kg, p.o., for 3 day period. This short-term treatment modified neither the resting heart rate nor the positive chronotropic effect induced by either intravenous noradrenaline or electrical stimulation of pre- and post-ganglionic nerve fibres of the right stellate ganglion. However, it prevented the larger increase in heart rate in response to bilateral carotid occlusion in placebo-treated dogs after section of the vagi. A decrease in baseline sympathetic tone of the perfused hind limb as well as vasoconstrictor effects produced by i.a. injections of several alpha-adrenoceptor agonists and electrical stimulation of the lumbar sympathetic chain was observed in prazosin-treated animals. The dose--pressor response profiles to these alpha-adrenoceptor stimulants after prazosin were not parallel to those obtained in the control group. The vasoconstrictor response to angiotensin II was not changed by prazosin. In rabbit aortic strips, prazosin (0.1--3.0 micrometer) produced competitive antagonism of the contractile responses induced by cirazoline, noradrenaline and phenylephrine. In contrast to papaverine, prazosin in concentrations up to 100.0 micrometer neither relaxed the aortic strips contracted by potassium ions nor modified the concentration-response curve to calcium ions. These studies indicate that blood pressure lowering effects of prazosin given acutely or for three days can be accounted for by a clear-cut functional impairment of vascular postsynaptic alpha-adrenoceptors. No evidence for a direct myorelaxant property of prazosin could be obtained in these studies.

Adrenergic alpha-Agonists↗
PubMed1978

Effects of prazosin and phentolamine on cardiac presynaptic alpha-adrenoceptors in the cat, dog and rat.

In cats, dogs and rats, clonidine (20.0 microgram/Kg, i.v.) reduced the sustained tachycardia evoked by a continuous electrical stimulation of cardiac sympathetic nerve fibres. This effect of clonidine resulting from stimulation of cardiac presynaptic alpha-adrenoceptors could be completely antagonized by phentolamine and prazosin in the dog and the cat, whereas in the rat, prazosin, unlike phentolamine, failed to effectively inhibit the clonidine induced reduction in heart rate. The calculated doses of phentolamine and prazosin needed to produce a 50% antagonism were of similar magnitude in the dog, but in the cat prazosin was about three times less potent than phentolamine. As opposed to clonidine, LD 3098, a potent vascular postsynaptic alpha-adrenoceptor stimulating imidazoline, and phenylephrine (20.0 microgram/Kg, i.v.) did not significantly alter the sympathetic tachycardia in the pithed rat and the spinal dog. These results indicate that compounds stimulating postsynaptic alpha-adrenoceptors may be inactive as agonists of cardiac presynaptic alpha-adrenoceptors within the same animal species. Furthermore, a compound showing selective activity as an antagonist of vascular alpha-adrenoceptors in one species may not necessarily exert the same selective effects in other animals as demonstrated here for prazosin.

Animals↗
PubMed1978

The cardiovascular effects of the antihypertensive drug debrisoquin: a contribution to the pharmacology of chronic treatment. I. One-week administration to dogs.

Debrisoquin (5 mg/kg/day) was administered to mongrel dogs on 7 consecutive days either i.v. or p.o. Sixteen hours after the last dose, the animals were anesthetized with chloralose-urethane and subjected to several hemodynamic and biochemical measurements which serve for a comparison with the results of the chronic treatment in a subsequent paper. Aortic blood pressure, cardiac output, heart rate (after vagotomy) and pressor responses to bilateral carotid occlusion were decreased by debrisoquin; cardiac contractility and left ventricular end-diastolic pressure remained unaffected. The fall in vascular resistance of the perfused hind legs which occurred after cutting the lumbar sympathetic chain was smaller after debrisoquin than in controls. Increases in perfusion pressure elicited in the hind legs by electrical stimulation of the peripheral end of the sectioned lumbar sympathetic chain or by i.a. injection of tyramine were inhibited by treatment with debrisoquin. The vascular responses to i.a. injections of norepinephrine, angiotensin and acetylcholine remained unchanged. Isolated perfused mesenteric artery preparations obtained from dogs pretreated with debrisoquin showed reduced pressor responses to periarterial nerve stimulation. Dose-response curves for the pressor effect of norepinephrine were not altered by debrisoquin. Debrisoquin administered i.v. or p.o. depleted to a similar extent the stores of norepinephrine in the heart, spleen, mesenteric and femoral arteries.

Animals↗
PubMed1978

The cardiovascular effects of the antihypertensive drug debrisoquin: A contribution to the pharmacology of chronic treatment. II. Eight-week administration to dogs.

Debrisoquin was administered twice daily at the dose of 2.5 mg/kg p.o. to normotensive mongrel dogs for 8 weeks. Weekly measurements of systolic blood pressure in the conscious animals revealed a drug-induced fall by 10 to 12 mm Hg which was fully developed after 2 weeks and was maintained throughout the treatment period. Body weight, blood volume, hematocrit and plasma sodium and potassium did not change significantly under debrisoquin while there was a slight but just significant increase in plasma volume. No adverse effects were observed. Sixteen hours after the last dose, the animals were anesthetized with chloralose-urethane and subjected to several hemodynamic and biochemical measurements. The following results obtained after prolonged treatment with debrisoquin were not different from those after subacute administration (1-week treatment) reported in the preceding paper: decrease in blood pressure and cardiac output, reduction of the pressor response to bilateral carotid occlusion and of the vasoconstrictor effect of sympathetic nerve stimulation in the perfused hind legs and the isolated perfused mesenteric arteries, decrease in sympathetic tone to the vasculature of the hind leg and depletion of norepinephrine from adrenergic nerve endings. The sensitivity of arterial blood vessels to norepinephrine was not altered. However, the bradycardic effects of debrisoquin did fade in the course of the treatment. The results indicate the absence of the development of tolerance to nearly all cardiovascular effects of debrisoquin during a treatment of 8 weeks.

Anesthesia↗
PubMed1977

Vascular beta-adrenoceptor stimulating properties of phenylephrine.

In pithed rats pretreated with propranolol changes occurred in the slopes of dose--pressor response curves to i.v. phenylephrine and noradrenaline but not to LD 3098, a pure alpha-adrenoceptor stimulant. In dogs, cats, and spontaneously hypertensive rats pretreated with an alpha-adrenoceptor blocker, i.v. phenylephrine induced vasodilatory responses which were antagonised by propranolol. These results indicate that phenylephrine, in addition to its known beta1-agonistic properties, stimulates the vascular beta2-adrenoceptors.

Adrenergic beta-Agonists↗