[Changes in the sensitivity of cardiovascular beta adrenergic receptors after sinoaortic denervation in rats].
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Animals↗
Biomedical subjects
M A Enero
Publications and source records attributed to M A Enero.
Serotonergic hypotensive mechanism in rats: involvement of bulbospinal fibres.
The present study concerns the involvement of descending bulbospinal serotonergic pathways in blood pressure regulation in both normotensive and neurogenically hypertensive rats. We found that direct stimulation of serotonergic receptors of the spinal cord induced a depressor response which was prevented by prior catecholaminergic denervation in anaesthetized normotensive rats. Twenty-four hours after neurogenic hypertension, depletion of the serotonergic system provoked a further increase in blood pressure in conscious rats. We suggest that stimulation of pre-synaptic serotonergic receptors localized on spinal catecholaminergic neurons decreases blood pressure. This hypotensive mechanism could be activated after baroreflex deafferentation to prevent a further increase in blood pressure.
Animals↗
Participation of cholinergic pathways in sinoaortic denervated rats.
Seven days after sinoaortic denervation (SAD), mean blood pressure (MBP) and heart rate measured in conscious rats were not significantly different from sham-operated animals. A high dose of atropine, 8 mg kg-1, reduced MBP only in SAD rats. Atropine, 0.08-0.8 mg kg-1, or methylatropine, 0.8 mg kg-1, induced tachycardia in sham rats. This effect was reduced after sinoaortic denervation and it involves peripheral muscarinic receptors. The hypertension and tachycardia provoked by physostigmine were more marked in SAD than in sham rats. The cardiovascular responses induced by physostigmine were abolished by atropine and were not affected by methylatropine. The hypertension caused by physostigmine in SAD animals was more sensitive to the antagonism of atropine than in sham rats. Our results show that baroreceptor deafferentation affects peripheral parasympathetic tone to the heart and changes the cholinergic pathways involved in the modulation of cardiovascular response.
Animals↗
alpha 1-Antagonist activity of the alpha 2-adrenoceptor agonist guanabenz in perfused mesenteric artery of the rat.
In the perfused mesenteric artery of the rat phenylephrine produced a concentration-dependent increase in perfusion pressure which was competitively antagonized by low concentrations of prazosin (pA2 9.56). Guanfacine, clonidine and guanabenz, three alpha 2-selective agonists, produced no response. However, guanabenz antagonized the phenylephrine-induced effect competitively (pA2 6.92) though guanfacine and clonidine did not affect it. These results suggest that the alpha 2-adrenergic agonist guanabenz possesses alpha 1-antagonist activity as well.
Animals↗
Decreased brain serotonergic activity after acute propranolol.
Acute propranolol reduced the synthesis rate of serotonin in several rat brain structures (hypothalamus, midbrain, pons, frontal cortex and medulla oblongata). Both optical isomers of propranolol were tested. From our results it may be concluded that both the beta-blocking property and the local anaesthetic action of the drug could be involved in its inhibitory effect, except in hypothalamus where only the levorotating isomer was effective. Our results suggest the possibility of a noradrenergic influence on brain serotonergic neurons.
5-Hydroxytryptophan↗
Influence of neuronal uptake on the presynaptic alpha-adrenergic modulation of noradrenaline release.
Conditions required for the inhibitory feedback modulation of noradrenergic neurotransmission were studied in isolated atria of the rat. The alpha adrenergic antagonist, yohimbine, 0.8 microM, or phentolamine, 1 microM, did not affect the chronotropic response to 4 or 8 shocks at 0.8 Hz but increased it when a higher number of shocks was applied. When neuronal uptake was inhibited by cocaine, 2.9 microM, or desipramine, 0.1 microM, the enhancement of neurotransmission by yohimbine or phentolamine was higher than that observed in the presence of alpha-adrenergic antagonists alone. In atria preincubated with 3H-noradrenaline, the effect of the drugs on the 3H-overflow evoked by 240 shocks at 2.0 Hz was studied. Cocaine 2.9 microM, did not increase the evoked overflow but yohimbine, 0.8 microM, did. The 3H-overflow obtained in the group of yohimbine plus cocaine was significantly higher than was expected from the effects of both drugs alone. It is concluded that yohimbine or phentolamine enhance the chronotropic response in rat atria only when the concentration of noradrenaline in the biophase is sufficiently high to activate presynaptic receptors. In this tissue, the efficiency of the neuronal uptake influences the degree of alpha-adrenergic autoinhibition.
Animals↗
Treatment with clorgyline and pargyline differentially decreases clonidine-induced hypotension and bradycardia.
A study was made of the effects of acute and chronic treatment with monoamine-oxidase (MAO) inhibitors on the peripheral and central cardiovascular response induced by clonidine in anaesthetized normotensive rats. Clonidine (30 nmoles X kg-1 i.v.) produced a biphasic change in mean blood pressure; an initial transient increase was followed by a prolonged hypotensive effect, coinciding with the maximal bradycardia. Twenty-four hours after acute (single) or chronic (daily for 7 days) administration of MAO inhibitors (pargyline 10 mg X kg-1 SC or clorgyline 0.3 mg X kg-1 SC) there was no effect either on the basal cardiovascular parameters or on the initial pressor response induced by clonidine. Chronic but not acute treatment with clorgyline, an inhibitor of type A MAO, greatly decreased the hypotension and bradycardia induced by clonidine for as long as 5 days after its discontinuation. On the other hand, after chronic administration of pargyline (10 mg X kg-1), a preferential type B MAO inhibitor, the hypotension and bradycardia caused by clonidine were differently affected. There was a reduction in the bradycardia up to the third day following the discontinuation of pargyline, whereas the hypotensive response induced by clonidine was only attenuated for 24 h and unaffected with a lower dose of pargyline (0.3 mg X kg-1). It is concluded that chronic administration of the type A MAO inhibitor, clorgyline, attenuates the central responses to clonidine through the reduction in sensitivity of brain alpha-adrenoceptors. Pargyline, that preferentially inhibits type B MAO, reduces only the bradycardia induced by clonidine. This result may indicate a different modulation of the receptors involved in this response to clonidine.
Animals↗
Central serotonergic activity after neurogenic hypertension.
Sinoaortic denervated rats, 24 h after operation, showed a 25% increase in the central (hypothalamus, frontal cortex, midbrain, pons and medulla oblongata) tryptophan content and about a 70% rise in plasma free fatty acid (NEFA) concentration. The synaptosomal serotonin (5-HT) uptake and tryptophan hydroxylase activity of slices from these central areas were not significantly different when compared to those from sham-operated rats. There was also an increase in tryptophan and NEFA concentration at 24 h in fasted sham-operated rats. Seven days after neurogenic hypertension, the central tryptophan content had returned to control values. However, a 50% increase in the tryptophan hydroxylase activity of slices from the midbrain area together with a higher turnover rate of serotonin was found in the denervated group of rats. The synaptosomal 5-HT uptake remained unchanged. These results suggest that sinoaortic denervation could induce changes in the serotonergic neurons localized in central nervous system areas during the first week after operation.
Animals↗
Effects of acute and short-term treatment with antihypertensive drugs in sinoaortic denervated rats.
Sinoaortic denervation (SAD) produced a marked increase of the systolic blood pressure (SBP). Clonidine (50 micrograms kg-1, i.p.) reduced SBP in SAD but not in sham rats. L-alpha-methyldopa (alpha-MD) (50 mg kg-1, i.p.) also induced a more effective hypotensive action in SAD than sham rats. The withdrawal of alpha-MD in SAD rats after the first treatment was not abrupt and the hypotension persisted for several days, but after the second treatment the withdrawal induced a rapid rebound hypertension. Our results suggest that SAD increases the response to the hypotensive agents. An alteration in the availability of alpha-MD to accumulate or synthesize the active metabolites was also observed after second treatment.
Animals↗
Mechanisms involved in the blocking effects of pimozide on smooth muscle contraction.
Pimozide, a dopamine-receptor antagonist, shifted to the right the concentration-response curves (CRC) induced by (-)-noradrenaline in the isolated posterior mesenteric artery of the cat. Since this antagonism could be related to a blockade of vascular alpha-adrenoceptors, we compared the effects of pimozide (0.20 microM) with those of phentolamine (0.31 microM). The onset of the blockade by pimozide on the (-)-noradrenaline-induced contractions was slower when compared with that of phentolamine. In addition, the effects of pimozide did not reverse by washing while those of phentolamine did. Pimozide but not phentolamine inhibited the contractions elicited by potassium and it decreased the maximum responses of the curves. This effect was partially reversed by CaCl2 10.2 mM. Pimozide displaced the CRC induced by CaCl2 to a greater extent than phentolamine. Even if a blocking effect on alpha-adrenoceptors cannot be discarded, our results suggest that pimozide may interfere with calcium in the arterial smooth muscle. Furthermore, vascular smooth muscle seems to be more sensitive than non-vascular tissue to the action of pimozide.
Animals↗
Norepinephrine release and vascular response elicited by nerve stimulation in rats with chronic neurogenic hypertension.
In rats with chronic neurogenic hypertension induced by sinoaortic baroreceptors denervation (SAD), dl-[3H]norepinephrine (dl-[3H]NE) release, metabolism and vascular response to nerve stimulation were studied in isolated perfused mesenteric arteries. Thirty weeks after SAD, systolic arterial pressure was increased and, in isolated mesenteric arteries, vascular resistance, vascular response to nerve stimulation and responses to exogenous NE were higher in hypertensive than in sham-operated normotensive rats. However, in the isolated mesenteric arteries labeled with dl-[3H]NE, the total increase in radioactivity elicited by nerve stimulation was similar in both SAD and sham-operated groups. Unmetabolized [3H]NE released in mesenteric arteries was higher than that observed in other peripheral noradrenergic tissues (such as cat nictitating membrane, cat spleen, guinea-pig atria) and deaminated glycol 3,4-dihydroxyphenylglycol was the main metabolite of [3H]NE released by nerve stimulation from the mesenteric arteries of both groups. Blockade of prejunctional alpha adrenoceptors with phentolamine increased [3H]NE overflow to the same extent in controls and hypertensive rats. These findings indicate that the negative feedback regulatory mechanism for [3H]NE release mediated by prejunctional alpha adrenoceptors is not affected in chronic neurogenic hypertension. Blockade of postsynaptic alpha receptors by phentolamine reduced the vascular response equally in both groups. In hypertensive rats, a higher fraction of [3H]NE released by nerve stimulation was collected as the extraneuronally formed metabolite 3H-normetanephrine. The results suggest that, in rats with chronic neurogenic hypertension, sympathetic neurotransmission is not altered in the mesenteric arteries. Increased vasoconstrictor response to a given level of sympathetic nerve stimulation and higher resting vascular resistance could, in part, maintain the high blood pressure after 30 weeks of SAD.
Animals↗
Central serotonergic participation on blood pressure regulation.
1. The changes on blood pressure induced by pharmacological handling of serotonergic systems were studied in normotensive anesthetized rats. Administration of 5-hydroxytryptophan (5-HTP) (5, 10 and 30 mg/kg i.v.) produced a dose-dependent decrease in mean blood pressure without significative effect on heart rate. 2. Inhibition of either peripheral L-aminoacid DOPA decarboxylase or monoamine oxydase enzymes increased this hypotensive effect. 3. Methysergide, a serotonergic antagonist, prevented the hypotension induced by 5 OH-TP in animals whose peripheral decarboxylase was inhibited. 4. Fenfluramine, a serotonergic releasing drug, produced a decrease in both blood pressure and heart rate. These effects were prevented by inhibiting fenfluramine uptake or by serotonin (5-HT) receptor blockade. 5. The hypotensive action induced by 5-HTP was not affected when opioid, dopaminergic or histaminergic receptors were blocked. 6. In animals injected intracisternally with a serotonergic neurotoxine a selective destruction of serotonergic terminals of spinal cord was obtained. 7. In these animals the dose-response curve relating hypotensive effect induced by a direct serotonergic agonist showed a significative shift to the left when compared with control group, suggesting the existence of supersensitivity. 8. Our results show that increases in central serotonergic activity produce a hypotensive effect in normotensive anesthetized rats. The receptor involved in this action could be localized in spinal cord.
5,7-Dihydroxytryptamine↗
Cocaine facilitates the effects of alpha-agonists and antagonists on adrenergic neurotransmission.
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Adrenergic alpha-Agonists↗
Further evidence for the purinergic inhibition of adrenergic neurotransmission in the rat portal vein.
The inhibition of 3H-noradrenaline (3H-NA) release by adenosine, and the possible involvement of purine receptors in the regulation of transmitter release in the portal vein were studied. The inhibitory effect of different concentrations of adenosine (10, 30, 100 and 300 microM) decreased with frequency of stimulation, but there was no marked concentration-dependence. Tetraethylammonium (TEA) enhanced the 3H-NA overflow induced by transmural stimulation. The adenosine-induced inhibition of 3H-NA overflow was antagonized by TEA. Transmural stimulation induced release of tritium from tissues prelabelled with either 3H-NA or 3H-adenine had a similar pattern of distribution. In contrast, when the rat portal vein was stimulated with (-) NA, the overflow of purine derivates was delayed and the maximum release was achieved 5 min later than the maximum induced by transmural stimulation. Phenoxybenzamine (PBA) increased 3H-NA overflow two-fold, but had no effect on the 3H-purine release induced by transmural stimulation. PBA reduced the 3H-purine release by exogenous (-) NA. These results indicate that in rat portal vein, the purine compounds have pre- and postjunctional origins and that the purine that modulates adrenergic neurotransmission might be of neuronal origin, possibly independent of adrenergic innervation.
Adenine↗
Sinoaortic denervation-induced changes in central serotonergic neurons.
Sinoaortic denervation in rats induced changes in endogenous levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in brain areas. The midbrain showed a sustained increase for 7 days after the operation, while in pons and medulla oblongata a marked rise was only observed during the first 24 h. No changes were obtained in spinal cord. It is thought that the changes in serotonergic activity described could be related to the neurogenic hypertension induced by sinoaortic denervation.
Animals↗
Pre- and postjunctional potentiation of the adrenergic neurotransmission by angiotensin II in the perfused rabbit kidney.
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Angiotensin II↗
Blood pressure and heart rate response to apomorphine in urethane anesthetized rats.
The mechanisms involved in the hypotensive effect of apomorphine were studied in urethane anesthetized rats. The intravenous injection of apomorphine (0.01-0.75 mg/kg) produced a dose dependent fall in mean blood pressure. At the higher doses used (0.5-0.75 mg/kg) a marked bradycardia accompanied the hypotensive effect. These cardiovascular effects were prevented by pretreating the animals with pimozide (0.01-0.1 mg/kg). Low doses of haloperidol (0.03-0.3 mg/kg) did not antagonize the hypotensive action of apomorphine. Higher doses of haloperidol (1-3 mg/kg) reduced markedly the mean blood pressure. Atropine (1 mg/kg) partially antagonized the decrease in mean blood pressure induced by apomorphine and prevented completely the bradycardia. Hexamethonium (10 mg/kg) reduced the mean blood pressure and when apomorphine was administered, a residual hypotensive effect and no bradycardia was observed. It is concluded that the cardiovascular actions of apomorphine are central in origin and mainly due to the stimulation of a dopamine receptor. A probable peripheral effect could not be discarded.
Animals↗
Effect of drugs on the force of spontaneous mechanical activity in rat portal vein.
A study was made on the force of spontaneous mechanical activity in the rat portal vein. Prostaglandin inhibitor, sodium meclofenamate, phosphodiesterase inhibitors, aminophylline and dipyridamole, adenosine and blockade of calcium entry by isoptin all reduced the force of spontaneous activity in a concentration-dependent manner, while imidazole enhanced it. Low concentration of aminophylline (10 microM), dipyridamole (6 microM) and meclofenamate (10 microM) depressed the spontaneous contraction of the vein by about 50% without modifying the response to noradrenaline. At higher concentration of these drugs, spontaneous mechanical contraction was reduced further and the response to noradrenaline antagonized. Low concentration of isoptin also reduced the mechanical activity without affecting maximum response to noradrenaline. A common mechanism of action for the drugs tested, namely the limiting of Ca2+ availability for muscular contraction, is discussed. Adenosine markedly reduced the spontaneous mechanical activity of the rat portal vein. Its relaxation effect could be due to the activation of a specific adenosine receptor.
Adenosine↗