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I Cavero

Publications and source records attributed to I Cavero.

At least 91 records · Page 5Linked to original sources
PubMed1983

"Calcium antagonists": a class of drugs with a bright future. Part I. Cellular calcium homeostasis and calcium as a coupling messenger.

The aim of this series of minireviews is to present material from multidisciplinary sources to facilitate the understanding of the pharmacology and the ample clinical potential of a class of drugs that were originally designated as "calcium antagonists" and more recently have been referred to as "calcium entry blockers", "calcium slow channel blockers" or "calcium modulators". In this first report our attention will be focussed on the pivotal role of Ca++ as a messenger linking stimuli of extracellular origin to the intracellular environment. Eucaryotic cells have a number of powerful means to control their cytosolic Ca++ concentration. Firstly, in a cell at rest the cellular membrane is relatively impermeable to passive Ca++ movements. This property of the plasmalemma prevents the high free Ca++ concentration (approximately 1 mM) of the extracellular compartment from invading the cytosol (approximately 0.1 microM). However, extracellular Ca++ can reach the cytosol through the Na+/Ca++ exchange mechanism and the plasmalemma possesses special Ca++ channels the conductance of which is controlled by gates that are opened by critical changes in cellular polarization (voltage-operated channels: VOC) or by receptor activation (receptor-operated channel: ROC). The Ca++ entering via VOC or ROC can subsequently trigger the liberation of Ca++ from the sarcoplasmic reticulum or from calcium stores located in the inner side of the plasmalemma. The intracellular message generated by external stimuli is transferred to the response mechanism by several cytosolic proteins that require Ca++ as activator. Finally, the termination of the response is the result of a reduction in the cytosolic Ca++ concentration that is accomplished by the Na+/Ca++ exchange mechanism or by energy-dependent pumps which extrude Ca++ from the cell or store it in subcellular organelles. Therefore, any of the numerous steps of the excitation-response coupling which employ Ca++ as a messenger or as a protein activator can be the site of action of a pharmacological agent. In the follow-up minireview, some methods to determine the basic pharmacological profile of compounds interfering with cellular Ca++-dependent functions will be described.

Action Potentials↗
PubMed1983

Differential inhibition of vascular smooth muscle responses to alpha 1- and alpha 2-adrenoceptor agonists by diltiazem and verapamil.

This work was undertaken to investigate whether diltiazem and verapamil, two blockers of the voltage-activated calcium channel, interfered with vascular smooth muscle responses mediated by stimulation of alpha 1- or alpha 2-adrenoceptors. In pithed rats (and in isolated canine saphenous vein strips) cirazoline behaved as a preferential alpha 1-adrenoceptor agonist, since its pressor (and contractile) effects were blocked selectively by the alpha 1-adrenoceptor antagonist prazosin and were relatively unaffected by the alpha 2-adrenoceptor antagonist yohimbine. In the same preparations, M-7 (2,N,N-dimethylamino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene) exhibited preferential alpha 2-adrenoceptor agonist properties. The pressor response to M-7 developed much more slowly than that to cirazoline, M-7 requiring approximately twice as long as cirazoline to reach the same peak effect. Pithed rats received a 30-minute intravenous infusion of either diltiazem (12.5-25.0 micrograms/kg per min) or verapamil (6.2-12.5 micrograms/kg per min) that was continued while dose-response curves to M-7 and cirazoline were generated. These compounds depressed the maxima and the slopes of arterial pressure dose-response curves to M-7 but not cirazoline. In canine saphenous vein strips, diltiazem did not change the contractile response to cirazoline but inhibited those to M-7. Verapamil however did antagonize the responses to cirazoline although significantly less than those to M-7. These results indicate that diltiazem and verapamil preferentially inhibit alpha 2-adrenoceptor-mediated responses. The hypothesis is advanced that the pharmacomechanical coupling for alpha 2-adrenoceptors involves a receptor-operated calcium channel that is sensitive to diltiazem and verapamil and, thus, might become activated when the potential across the cellular membrane attains critical values.

Adrenergic alpha-Agonists↗
PubMed1983

Sleeping times evoked by alpha adrenoceptor agonists in two-day-old chicks: an experimental model to evaluate full and partial agonists at central alpha-2 adrenoceptors.

The ability of a series of alpha adrenoceptor agonists to induce a sleep-like state (as measured by the time interval between the loss and regaining of the righting reflex) has been assessed in 2-day-old chicks in order to understand their pharmacological profile better. Guanabenz, guanoxabenz, UK-14,304, guanfacine and xylazine produced dose-related increases in sleeping time, the highest dose of these agonists causing the chicks to sleep for over 120 min. In contrast, the dose-response curves to tiamenidine and clonidine were flatter and bell-shaped with maxima of 30 and 60 min, respectively. The effects of all these compounds were antagonized by idazoxan (RX781094) and yohimbine (two selective alpha-2 adrenoceptor antagonists) but were moderately enhanced or unaffected by prazosin (a selective alpha-1 adrenoceptor antagonist) confirming that the state of arousal in chicks can be depressed by stimulation of alpha-2 adrenoceptors. In particular, idazoxan displaced significantly the guanoxabenz dose-response curve to the right without affecting its slope and apparent maximum and blocked the sleep induced by clonidine. However, idazoxan failed to affect the sleep evoked by ethanol, etorphine or pentobarbital. Naloxone antagonized the effects of etorphine but not those of guanoxabenz, ethanol or pentobarbital. The relatively selective alpha-1 adrenoceptor agonist, cirazoline, given in doses up to 20 mg/kg i.m., produced in chicks behavioral manifestations suggestive of enhanced arousal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1982

Peripheral dopamine receptors, potential targets for a new class of antihypertensive agents. Part II: Sites and mechanisms of action of dopamine receptor agonists.

Relatively selective dopamine receptor agonists, like bromocriptine, lergotrile, pergolide and N,N-di-n-propyl-dopamine, lower arterial pressure in conscious spontaneously hypertensive rats and in several anesthetized animal preparations. This effect has been attributed to stimulation of dopamine receptors since it can be specifically antagonized by several dopamine receptor blocking agents (domperidone, haloperidol, pimozide, sulpiride). The two main mechanisms which can theoretically intervene in the antihypertensive effects of dopamine agonists are direct smooth muscle relaxation mediated by stimulation of post junctional DA1-dopamine receptors and the reduction of the neural release of norepinephrine resulting from activation of of DA2-dopamine receptors on ganglionic bodies or sympathetic nerve terminals. Other accessory mechanisms of undoubted interest might be a natriuretic effect or a decrease of aldosterone release. On the basis of the presently available pharmacological results in experimental animals, it is not unreasonable to advance the hypothesis that agonists of DA1- and DA2-dopamine receptors produce cardiovascular changes most compatible with an antihypertensive activity being due to a fall in peripheral resistance. However, before any of these compounds can become of therapeutic interest further research in this field is necessary to explore whether it is possible to minimize or even entirely avoid certain unwanted effects (vomiting, nausea, endocrinological alterations) that appear to be intimately associated particularly with those agents stimulating the DA2-dopamine receptors subtype. A more thorough pharmacological characterization of human dopamine receptors would be useful to provide an insight into whether novel chemical approaches can solve some of these problems. Finally, the ideal profits of future dopamine receptor agonists aimed at the treatment of elevated arterial pressure is discussed.

Animals↗
PubMed1982

Peripheral dopamine receptors, potential targets for a new class of antihypertensive agents. Part I: Subclassification and functional description.

The dopamine receptors of the peripheral cardiovascular system are not a pharmacologically uniform population. A number of studies indicate that they belong to at least two distinct subtypes for which it is proposed to adopt the name DA1- and DA2-dopamine receptors in an attempt to follow the nomenclature presently in fashion for several vascular receptors. Typical DA1-dopamine receptors are those occurring postjunctionally in the renal and mesenteric arterial beds where their stimulation mediates direct smooth muscle relaxation. Typical DA2-dopamine receptors are those present on postganglionic sympathetic neurons (axonal varicosities and perhaps ganglionic cell bodies) where their excitation leads, under appropriate physiological conditions, to a reduction of the neural release of norepinephrine. The latter effect can manifest itself by a passive fall in vascular resistance and heart rate. Other populations of dopamine receptors not yet well characterized pharmacologically but of theoretical interest as additional potential target sites for cardiovascular drugs might be present on nephrons and in the adrenal cortex. Their stimulation can mediate a natriuretic effect and a reduction of aldosterone release, respectively. The pharmacological evidence favoring the subclassification of cardiovascular dopamine receptors into two distinct subtypes is reviewed. Furthermore, the main agonists and antagonists of these receptors and the complexity of their pharmacological profile are mentioned. Part II of this minireview will be dedicated to the description of the sites and mechanisms of the antihypertensive action of dopamine receptor agonists.

Animals↗
PubMed1982

Effects of prazosin on reflex changes in heart rate evoked by vasopressor and vasodepressor stimuli in conscious rabbits.

In conscious rabbits prepared for continuous arterial pressure measurements by means of a catheter placed into the main ear artery, intravenous administration of prazosin (5.0 micrograms/kg, i.v. over 20 min) produced a significant decrease in arterial pressure and cardioacceleration. This dose of prazosin inhibited by approximately 70% the pressor effects of phenylephrine. However, prazosin failed to produce significant functional modifications of either the bradycardia or the tachycardia which accompanied the changes in arterial pressure evoked, respectively, by intravenous bolus injections of angiotensin II or acetylcholine. It is concluded that prazosin in the dose studied does not appear to interfere with reflex heart rate responses to vasodepressor or vasopressor stimuli in conscious rabbits.

Acetylcholine↗
PubMed1982

Effects of pergolide, a dopamine receptor agonist, and clonidine on cardiovascular responses evoked by activation of peripheral sympathetic outflow in rats.

In pentobarbital anesthetized rats, pergolide (10.0 micrograms/kg, i.v.) and clonidine (3.0 micrograms/kg, i.v.) produced similar significant decreases in heart rate and carotid artery pressure. Sulpiride (0.3 mg/kg, i.v.) did not change the effects of clonidine but inhibited entirely the hypotension and partly the bradycardia produced by pergolide. However, yohimbine (0.4 mg/kg) antagonized the cardiovascular effects of clonidine and reduced the bradycardia produced by pergolide. In pithed rats with an experimental, submaximal tachycardia evoked by sustained electrical stimulation of the thoracic sympathetic outflow pergolide and clonidine decreased heart rate. This effect was antagonized by yohimbine (0.1 mg/kg, i.v.) but by not sulpiride (0.3 mg/kg, i.v.). In adrenalectomized, propranolol pretreated pithed rats the pressor responses to 15 sec periods of electrical stimulation of the entire spinal cord were depressed only by pergolide. This effect was blocked by sulpiride. These findings indicate that in the pithed rat the inhibition of neural sympathetic tachycardia by clonidine and pergolide is mediated by stimulation of cardiac presynaptic alpha 2-adrenoceptors. However, only pergolide decreased significantly the pressor responses evoked by electrical stimulation of the peripheral sympathetic outflow and this effect resulted from activation of dopamine receptors located on postganglionic sympathetic neurons innervating resistance blood vessels. Thus, vascular presynaptic alpha 2-adrenoceptors do not appear to contribute to the significant hypotensive effect exerted by 3.0 micrograms/kg, i.v. clonidine in intact rats. Finally, it is suggested that neuronal dopamine receptors might be considered potential target sites for novel peripherally acting antihypertensive agents.

Animals↗
PubMed1982

Functional and biochemical evidence for the lack of cardiac presynaptic alpha-2 adrenoceptor stimulant properties of cirazoline (LD 3098), a potent alpha-1 adrenoceptor agonist in dogs and rats.

In pithed rats, i.v. injection of cirazoline produced pressure effects which were antagonized in a competitive manner by the relatively selective alpha-1 adrenoceptor blocker, prazosin (0.01--0.1 mg/kg i.v.) but not by the relatively selective alpha-2 adrenoceptor blocker, yohimbine (0.3 mg/kg i.v.). The latter agent, however, inhibited the increases in arterial pressure produced by UK-14,304, a preferential alpha-2 adrenoceptor agonist. In contrast, both yohimbine and prazosin reduced the pressor effects of clonidine. In intact anesthetized, vagotomized rats or in pithed rats with a submaximal tachycardia evoked by electrical stimulation of the spinal cord, clonidine and oxymetazoline, in contrast to cirazoline (5.0 micrograms/kg i.v.), decreased heart rate through excitation of alpha-2 adrenoceptors. This lack of effect of cirazoline was not due to a concomitant pre- or postjunctional action of cirazoline leading to an enhanced chronotropic response to released norepinephrine because in phentolamine-pretreated rats cirazoline did not modify the neural sympathetic tachycardia. Although cirazoline potentiated the heart rate elevated by an i.v. infusion of either norepinephrine, isoproterenol, or aminophylline, this effect was probably of hemodynamic origin. In pithed rats with a submaximal neural tachycardia, cirazoline, like phentolamine (10.0--30.0 micrograms/kg i.v.), inhibited the decrease in heart rate produced by clonidine, suggesting that it possesses alpha-2 adrenoceptor blocking properties. In spinal dogs, cirazoline (10.0 micrograms/kg i.v.) modified neither base-line heart rate nor the tachycardia evoked by an intracoronary artery infusion of norepinephrine. In the same preparation, continuous electrical stimulation of cardioaccelerator sympathetic nerve fibers produced a sustained positive chronotropic effect accompanied by an increase in the coronary sinus venous plasma norepinephrine content. Neither parameter was significantly changed by cirazoline; however, clonidine at the same dose as used for cirazoline produced approximately 50% inhibition of the experimental neural tachycardia. Finally, cirazoline, like phentolamine at 10.0 micrograms/kg i.v., failed to block, cardiac presynaptic alpha-2 adrenoceptors in the spinal dog. These results indicate that cirazoline is a potent alpha-1 adrenoceptor agonist that lacks cardiac presynaptic alpha-2 adrenoceptor stimulant properties in either dogs or rats. In the latter species, cirazoline was found also to block cardiac presynaptic alpha-2 adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1982

Urethane inhibits cardiovascular responses mediated by the stimulation of alpha-2 adrenoceptors in the rat.

Clonidine and oxymetazoline (4.0 microgram/kg i.v. or i.a.) evoked a marked bradycardia in either methylatropine-pretreated conscious or pentobarbital-anesthetized (55 mg/kg i.p.), vagotomized rats. Urethane (1.2 g/kg i.p.) inhibited by more than 50% this effect which is mediated through the stimulation of peripheral and/or central neuronal alpha-2 adrenoceptors. However, in adrenalectomized rats only the inhibition of oxymetazoline by urethane was significantly less pronounced. In pithed rats in which the adrenal glands were either left untouched or surgically removed, urethane significantly attenuated the clonidine or oxymetazoline-induced decreases in experimental neural sympathetic tachycardia although it neither changed the base-line nor the experimentally elevated heart rate. Urethane, in contrast to pentobarbital, increased plasma epinephrine concentrations in intact but not in adrenalectomized or in pithed rats. Elevation of plasma epinephrine did not result from the low arterial pressure level associated with urethane anesthesia since the increase of this parameter with vasopressin did not abolish the effect of urethane. Furthermore, guanethidine-pretreated rats, when anesthetized with urethane, exhibited a higher heart rate and plasma adrenaline value than those anesthetized with pentobarbital. The elevated heart rate was decreased by either propranolol or adrenalectomy. The bradycardia produced by injecting clonidine into the lateral cerebral ventricles of either intact or adrenalectomized rats was markedly less in urethane- than in pentobarbital-anesthetized animals. Whereas in pentobarbital-anesthetized rats the peak heart rate effects of i.v. or i.c.v. clonidine were similar, in urethane-anesthetized animals the effects of clonidine were more inhibited when it was given centrally than when it was given peripherally. In pithed rats, the cumulative dose-pressor response curves elicited by the relatively selective alpha-2 adrenoceptor agonists, B-HT 930 and M-7, were depressed by urethane significantly more than those produced by the relatively selective alpha-1 adrenoceptor agonists, phenylephrine and cirazoline, or by angiotensin II. Urethane also decreased the pressor responses evoked by clonidine, oxymetazoline and norepinephrine which stimulate both alpha-1 and alpha-2 adrenoceptors. However, the extent of this inhibition was less than that of B-HT 920 and M-7 but greater than that of cirazoline and phenylephrine. These results show that urethane inhibits cardiovascular responses that are mediated by peripheral and central alpha-2 adrenoceptors. Furthermore, urethane increases the central drive to the adrenal medulla and this leads to the secretion of epinephrine. This may be partly responsible for the inhibitory activity of urethane on oxymetazoline-induced bradycardia. Although the basic mechanism by which urethane impairs responses mediated by alpha-2 adrenoceptors remains to be determined, it is advised that urethane anesthesia should be avoided, particularly for cardiovascular studies.

Adrenalectomy↗
PubMed1981

Effects of mianserin, desipramine and maprotiline on blood pressure responses evoked by acetylcholine, histamine and 5-hydroxytryptamine in rats.

1 In rats anaesthetized with pentobarbitone, intravenous administration of desipramine (0.1 mg/kg), maprotiline (0.5 mg/kg) or mianserin (0.3-3.0 mg/kg) did not modify the blood pressure lowering effects of acetylcholine (0.25-1.0 micrograms/kg, i.v.) which were significantly reduced by atropine (3.0 micrograms/kg, i.v.). 2 Maprotiline and mianserin, like promethazine (0.1 mg/kg, i.v.), inhibited the vasodepressor responses evoked by histamine (2.5-10.0 micrograms/kg,i.v.). however, desipramine was inactive against histamine. 3 In pithed rats, the pressor effects of intravenous 5-hydroxytryptamine (5-HT: 5.0-20.0 micrograms/kg) were antagonized by mianserin (0.01-0.3 mg/kg, i.v.) and cyproheptadine (0.01 mg/kg) but were unaffected by maprotiline and desipramine. 4 In syrosingopine pretreated rats given mianserin 0.1 mg/kg, intravenously, 5-HT (20.0 micrograms/kg, i.v.) produced a significant fall in blood pressure which could be reduced by a large dose of mianserin (10.0 mg/kg, i.v.). 5 In conclusion, desipramine, maptrotiline and mianserin, in doses previously found to inhibit noradrenaline neuronal reuptake in the rat cardiovascular system, lack muscarinic receptor antagonist properties. Whilst maprotiline and mianserin blocked vascular histamine receptors, only mianserin (10.0 mg/kg, i.v.). 5 In conclusion, desipramine, maptrotiline and mianserin, in doses previously found to inhibit noradrenaline neuronal reuptake in the rat cardiovascular system, lack muscarinic receptor antagonist properties. Whilst maprotiline and mianserin blocked vascular histamine receptors, only mianserin, like cyproheptadine, was a potent antagonist of the 5-HT receptors that mediate increases in blood pressure in rats. Finally, the vasodepressor effects of 5-HT in syrosingopine pretreated rats given a small dose of mianserin were antagonized by a large dose of mianserin, suggesting that 5-HT may activate two distinct types of receptors in the rat.

Acetylcholine↗
PubMed1981

Blood pressure lowering effects of N,N-di-n-propyl-dopamine in rats: evidence for stimulation of peripheral dopamine receptors leading to inhibition of sympathetic vascular tone.

In conscious or pentobarbital-anesthetized hypertensive or normotensive rats, N,N-di-n-propyl-dopamine (DPDA) produced sustained decreases in mean systemic arterial blood pressure. In anesthetized normotensive animals, these responses were not significantly changed by vagotomy, desipramine, indomethacin, methylatropine, promethazine or propranolol, were markedly reduced by phenoxybenzamine or phentolamine, were entirely blocked by domperidone, haloperidol or sulpiride and were reverted to an alpha adrenoceptor-mediated pressor response after removal of central sympathetic tone. In phenoxybenzamine-pretreated pithed rats in which the blood pressure was elevated to prepithing levels with vasopressin, DPDA, in contrast to dopamine, produced no hypotensive effect. In the pithed rat, DPDA reduced the pressor responses elicited by electrical stimulation of the spinal cord and this effect was inhibited by haloperidol or sulpiride. DPDA slightly enhanced the pressor effects of norepinephrine but modified neither the blood pressure increases produced by epinephrine, phenylephrine, 5-hydroxytryptamine or angiotension II nor the vasodepressor effects of acetylcholine, histamine or salbutamol. Intracerebroventricular administration of DPDA produced blood pressure decreases which were slightly smaller in magnitude but longer in duration than those elicited by i.v. DPDA. However, DPDA leaked from the cerebroventricular space into the peripheral circulation. These results indicate that in the rat DPDA lowers blood pressure via activation of peripheral dopamine receptors possibly located presynaptically on vascular sympathetic neurons. The stimulation of these receptors induces a decrease in norepinephrine release which in turn is followed by a passive relaxation of the vascular beds under active sympathetic constriction.

Anesthesia↗
PubMed1980

Stimulation of peripheral dopamine receptors in rats: a mechanism for novel antihypertensive agents.

1. The aim of this investigation was to provide support for the hypothesis that stimulation of peripheral dopamine receptors reduces sympathetic vasomotor tone and thus may be a mechanism for novel antihypertensive agents. 2. NN-Di-n-propyldopamine (DPDA: 0.03-0.1 mg min-1 kg-1 intra-arterially) produced sustained decreases in blood pressure measured from the cannulated tail artery in conscious spontaneously hypertensive rats. 3. This antihypertensive action of DPDA was antagonized by sulpiride but not by atropine, promethazine, propranolol or indomethacin. 4. DPDA failed to lower blood pressure in spontaneously hypertensive rats in which peripheral stores of catecholamines had been previously depleted with syrosingopine. 5. In the pithed atropine-pretreated spontaneously hypertensive rats in which the low blood pressure was elevated by electrical stimulation of the spinal cord, DPDA produced hypotensive effects which were antagonized by sulpiride. However, DPDA, in contrast to phentolamine, did not modify the blood pressure raised by an infusion of adrenaline. 6. In conclusion, the blood pressure-lowering action of DPDA is due to stimulation of dopamine receptors which decreases noradrenaline release and consequently sympathetic vasomotor tone. These receptors may be located on sympathetic ganglia or sympathetic endings innervating resistance vessels.

Animals↗