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Biomedical subjects

I Cavero

Publications and source records attributed to I Cavero.

137 records · Page 8Linked to original sources
PubMedDate not supplied

Regional distribution and pharmacological characterization of [125I]endothelin-1 binding sites in human fetal placental vessels.

High-affinity binding sites for [125I]endothelin(ET)-1 have been detected in purified membrane preparations of the fetal arteries and veins of the chorionic plate and the stem villi vessels of the human term placenta. Regardless of the vessel type, the apparent dissociation constant was found to be in the picomolar range (26----45 pM), and the Bmax value close to 600 fmol/mg protein. In stem villi vessels, ET-1, ET-2, sarafotoxin S6b and vasocontractor intestinal peptide (VIC) were approximately equipotent in their competitive displacement of [125I]ET-1 binding. The endothelin precursors, human and porcine big-endothelin, recognized ET-1 sites with low affinity (nM range), a finding which reflects their low potency as recognized vasocontractant agents. Interestingly, [125I]ET-1 binding parameters and pharmacological profiles were identical in fetal veins and arteries of the chorionic plate. Similarly, a study carried out in rat aortic membranes, revealed the presence of high affinity [125I]ET-1 binding sites with pharmacological characteristics close to those of the human stem villi vessels. In all vessels investigated, the binding pattern of ET-3 against [125I]ET-1 was of a non-competitive nature. Thus, these results demonstrate the presence of specific [125I]ET-1 binding sites along the vascular tree of the fetal side of the placenta and would support evidence currently available, favouring the existence of distinct ET-1 and ET-3 receptors. Finally, ET-1 in the human placenta may play an important physiological role as regulator of vascular resistance and/or be implicated as a pathological factor in certain pregnancy-related diseases.

Animals↗
PubMedDate not supplied

Mechanism of antihypertensive activity of orally administered prazosin in spontaneously hypertensive rats.

In conscious, spontaneously hypertensive rats (SHR) oral prazosin (0.03-3.0 mg/kg) resulted in dose-related reductions of systolic blood pressure measured with a tail cuff. In SHR whose tail artery blood pressure was continuously monitored the antihypertensive effect of prazosin (1.0 mg/kg, p.o.) was accompanied by a significant increase in heart rate. Several groups of SHR were pithed 2 hr after oral prazosin (1.0 mg/kg) or placebo. In this preparation the mean carotid blood pressure increases following i.v. injections of angiotensin II or 5-hydroxytryptamine and the positive chronotropic responses to i.v. norepinephrine or electrical stimulation of the spinal cord were similar in control and prazosin-pretreated animals. However, the dose-pressor response curves to i.v. norepinephrine or electrical stimulation of the spinal cord from prazosin-pretreated SHR lay to the right of the control curves. In addition, the slopes of the linear portion of these curves were flatter after prazosin and remained so even after i.v. propranolol was given alone or with cocaine. Prazosin-pretreated SHR responded to phenylephrine with a fall followed by a rise in carotid blood pressure. The depressor effect was abolished and the pressor phase enhanced by i.v. propranolol. The pressor responses to i.v. cirazoline or clonidine were significantly inhibited by prazosin. Finally, prazosin failed to significantly modify the negative chronotropic effects of clonidine observed in pithed SHR whose heart rate was raised by continuous electrical stimulation of the thoracic spinal cord. These results indicate that oral prazosin exerts pronounced antihypertensive effects in the SHR. This action apparently results from impairment of the sympathetic nervous system at the level of vascular postsynaptic alpha-adrenoceptors.

Administration, Oral↗
PubMedDate not supplied

Frequency-independent blockade of cardiac Na+ channels by riluzole: comparison with established anticonvulsants and class I anti-arrhythmics.

The Na+ channel blocking activity and the antiarrhythmic effects of riluzole, and established anticonvulsants (lamotrigine and lifarizine) and class I antiarrhythmics (lidocaine, flecainide and disopyramide) were studied under in vitro and in vivo conditions. Guinea-pig cardiac Purkinje fibres were superfused with Tyrode solution and electrically driven for recording action potentials with intracellular microelectrodes. In these preparations paced at 1 Hz, all compounds tested produced concentration-dependent (0.3-100 microM) reductions in the maximum rate of depolarization of the action potential (Vmax). For riluzole, phenytoin and carbamazepine this effect was frequency-independent (0.5-6 Hz) but for lamotrigine, lifarizine, lidocaine, flecainide and disopyramide it was frequency-dependent. In anaesthetized rats, riluzole, in contrast to flecainide, did not delay the appearance of aconitine-induced arrhythmias. Riluzole (0.3-3.9 mg/kg, i.v.) also lacked notable cardiac electrophysiological effects in anaesthetized dogs. At an i.v. dose of 3.0 mg/kg riluzole failed to restore a normal sinus rhythm in conscious dogs with polymorphic arrhythmias produced by ligation of the left anterior descending coronary artery 24 h earlier. These results indicate that riluzole, phenytoin and carbamazepine, unlike lamotrigine, lifarizine and flecainide, block cardiac Na+ channels in a frequency-independent manner. This property may account for the lack of antiarrhythmic activity of riluzole, phenytoin and carbamazepine in animal models of arrhythmias that respond to class I antiarrhythmic drugs. It may also account for the clinical observation that riluzole does not seem to cause the unfavourable electrocardiographic changes characteristic of drugs that block cardiac Na+ channels in a frequency-dependent manner.

Aconitine↗
PubMedDate not supplied

Recent developments in noradrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents.

This report reviews a number of significant developments in the fields of noradrenergic transmission and adrenergic receptors which suggest that, in addition to the classical postsynaptic adrenoceptors, there are also presynaptic adrenoceptors that help modulate the release of norepinephrine (NE) from peripheral as well as central noradrenergic nerve endings during nerve stimulation. In particular, stimulation of presynaptic alpha-adrenoceptors reduces this release of transmitter and the reverse is observed after blockade of these receptors. Clearcut pharmacological differences exist between the postsynaptic alpha 1-adrenoceptors that mediate the responses of certain organs and the presynaptic alpha 2-adrenoceptors that modulate the NE release during nerve stimulation. Therefore, subclassification of alpha-adrenoceptors into alpha 1 and alpha 2 subtypes is warranted but must be considered to be independent of the anatomical location of these receptors. Some noradrenergic nerve endings have also been shown to possess beta-adrenergic receptors, the stimulation of which increases the quantity of transmitter released by nerve impulses. Physiologically, these receptors could be activated by circulating epinephrine (E) and be involved in essential hypertension. A third type of catecholamine receptor found at the noradrenergic nerve ending is the inhibitory dopamine (DA) receptor, which might be of significance in the development of new antihypertensive agents. Application of these new concepts of noradrenergic neurotransmission and the subclassification of alpha-adrenoceptors to the treatment of hypertension is presented. Clonidine, for example, appears to be a potent alpha 2-adrenoceptor agonist; the central receptor involved in its antihypertensive action is pharmacologically an alpha 2-type but located postsynaptically. Clonidine also induces activation of peripheral presynaptic alpha 2-adrenoceptors, which might contribute to its cardiovascular action. The antihypertensive effects of alpha-methyldopa are related to the formation of alpha-methylnorepinephrine, a preferential alpha 2-adrenoceptor agonist, which can stimulate peripheral presynaptic alpha 2-adrenoceptors leading to a decrease of NE release and a reduction in sympathetic tone. Prazosin is a new antihypertensive agent the mechanism of action of which involves a selective blockade of postsynaptic alpha 1-adrenoceptors. This drug does not antagonize several effects of clonidine that are mediated via alpha 2-adrenoceptors. The mechanisms presently considered to account for the antihypertensive activity of beta-adrenoceptor blocking agents are numerous. It is proposed that blockade of peripheral presynaptic facilitatory beta-adrenoceptors could be of significance in the antihypertensive action of these drugs.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

RP 55778, a PAF receptor antagonist, prevents and reverses LPS-induced hemoconcentration and TNF release.

Platelet-activating factor (PAF) and tumor necrosis factor (TNF) are present in the plasma of animals injected with endotoxin (LPS). Furthermore, when exogenously administered to animals, PAF and TNF induce similar pathological effects. Thus, in order to explore a possible link between these two factors, the effects of a PAF receptor antagonist, RP 55778, and a glucocorticoid, dexamethasone, were studied on LPS-induced hemoconcentration in rats and on the release of TNF induced by exposing isolated murine macrophages to LPS. RP55778 administered either before or after LPS inhibited these endotoxin effects whereas dexamethasone was effective only when given prior to the LPS challenge. Additionally, in murine macrophages the strong TNF mRNA signal induced by LPS was abolished by RP 55778 and dexamethasone treatment. These results indicate that PAF and TNF can mediate the functional manifestations associated with endotoxemia and only RP 55778 appears to show potential for activity against an already established LPS response.

Animals↗
PubMedDate not supplied

[Nicardipine: experimental antihypertensive action and interactions with the alpha-adrenergic sympathetic system].

The antihypertensive properties of nicardipine have been studied in various experimental models of hypertension. Furthermore, the possible contribution of the nicardipine-alpha-adrenergic system interaction to the drug's antihypertensive effect has been investigated. In the conscious normotensive rat, nicardipine (10 and 30 mg/kg, orally) reduces arterial blood pressure (by about 25%) and increases heart rate; these effects are maximal one hour after drug administration and disappear within 4 to 6 hours. In the renovascular hypertensive rat and in the Grollman hypertensive dog, nicardipine (3 mg/kg, orally) significantly decreases blood pressure. Simultaneously, heart rate is increased in the dog but is not significantly modified in the rat. In the conscious adult spontaneously hypertensive rat (SHR), nicardipine administered either as a bolus, or by intra arterial perfusion (1, 5, 12.5 micrograms/kg/min during 30 min), or orally (10, 30 mg/kg) dose-dependently decreases blood pressure and increases heart rate. In the pithed SHR, nicardipine decreases systemic pressor and regional (kidney, mesentery, hindlimb) vasopressor responses to M7, an alpha 2-adrenoceptor specific agonist, but does not affect those to cirazoline, an alpha 1-adrenoceptor specific agonist. However, there is no evidence for an involvement of this alpha 2-sympathoinhibitory effect in the blood pressure lowering action of nicardipine. In conclusion, in the different investigated experimental models of hypertension, nicardipine exerts a potent but short-lasting antihypertensive effect generally accompanied by a reflex tachycardia and a systemic and regional vascular alpha 2-sympathoinhibitory action.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

[Arterial wall: a new pharmacological and therapeutic target?].

In recent years, endothelial dysfunction and arterial remodelling in various cardiovascular diseases have emerged as two key concepts, with numerous interrelationships. Both endothelial dysfunction and arterial remodelling occur in various pathologies including heart failure, atherosclerosis, restenosis after angioplasty, and pulmonary hypertension, and have modified the therapeutic approach by offering new pharmacological targets: specific receptors not only at the site of the vascular smooth muscle cells but also on the endothelial cells, growth factors that stimulate proliferation of smooth muscle, and receptors and enzymes of the extracellular matrix. Among the various substances under research, the present review will discuss angiotensin II receptor antagonists, endothelin receptor antagonists, nitrates-NO donors, potassium channel activators, and substances interfering with proteoglycans and other components of the extracellular matrix.

Animals↗