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N Duval

Publications and source records attributed to N Duval.

48 records · Page 3Linked to original sources
PubMed1987

Presynaptic dopamine receptors in the cardiovascular system.

Stimulation by agonists of presynaptic dopamine receptors on nerve terminals of peripheral sympathetic neurons results in inhibition of norepinephrine release and a concomitant reduction of end organ responses to sympathetic nerve stimulation. These presynaptic dopamine receptors are of the DA-2 subtype and can be blocked selectively by the antagonist S-sulpiride. Presynaptic DA-2 receptors are the target of action of agonists with potential antihypertensive and bradycardic effects. Under control conditions exposure to S-sulpiride on its own does not enhance norepinephrine release. Following chronic treatment of cats with pargyline, S-sulpiride produced a small but significant increase in the electrically-evoked release of 3H-norepinephrine from perfused atrial slices. The possible involvement of peripheral presynaptic DA-2 receptors in the antihypertensive effects of monoamine oxidase inhibitors is discussed.

Animals↗
PubMed1986

Reserpine-resistant responses to nerve stimulation in the cat nictitating membrane involve the release of newly synthesized noradrenaline.

Preganglionic sympathetic nerve stimulation in cats pretreated with reserpine resulted in significant frequency-dependent contractions of the nictitating membrane, despite a severe depletion of tissue noradrenaline content. These residual responses to sympathetic nerve stimulation were potentiated by cocaine or pargyline, and were antagonised by the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine. In contrast to the residual responses to sympathetic stimulation in the nictitating membrane, the tachycardia evoked by postganglionic cardiac nerve stimulation was totally abolished by pretreatment with reserpine, even after the administration of cocaine. The alpha-adrenoceptor antagonists phentolamine or prazosin reduced, but did not abolish the reserpine-resistant responses of the nictitating membrane, suggesting the nerve-mediated release of a co-transmitter. In addition to this co-transmitter, a neuronal pool of neurotransmitter which is reserpine-resistant and involves newly synthesised noradrenaline, contributes to the residual responses of the nictitating membrane, following depletion of the neurotransmitter stores by the administration of reserpine. administration of reserpine.

Adrenergic alpha-Antagonists↗
PubMed1985

Inhibitory effects of alpha, beta-methylene ATP on nerve-mediated contractions of the nictitating membrane in reserpinised cats.

Residual responses of the cat nictitating membrane to nerve stimulation were obtained after reserpine pretreatment (40% of controls), in spite of a pronounced reduction in noradrenaline content. The putative ATP-receptor desensitising agent alpha, beta-methylene ATP (alpha, beta-MATP), administered intraarterially through the lingual artery produced a contraction of the nictitating membrane and subsequently inhibited the residual responses evoked by sympathetic nerve stimulation in reserpinised cats. These doses of alpha, beta-MATP did not modify the contractions evoked by exogenous noradrenaline (i.a.) but antagonized the contractions of the nictitating membrane elicited by beta, gamma-methylene ATP, which is an agonist at P2 receptors. These results are compatible with a co-transmitter role for ATP in the neurally mediated contractile responses of the nictitating membrane following depletion of endogenous noradrenaline stores by pretreatment with reserpine.

Adenosine Triphosphate↗
PubMed1985

Dopamine preferentially stimulates postsynaptic alpha 2-adrenoceptors in the femoral vascular bed, but alpha 1-adrenoceptors in the renal vascular bed of the anaesthetised dog.

The decrease in blood flow in response to dopamine (DA) injected intraarterially (i.a.) into the femoral or renal vascular beds was examined in the anaesthetised dog. DA or noradrenaline (NA) were 10 times more potent as vasoconstrictor agents in the femoral than in the renal vasculature. In the femoral bed, the DA induced vasoconstriction was completely resistant to antagonism by prazosin (30-300 micrograms/kg i.v.), but was dose-dependently blocked by the alpha 2-receptor antagonist idazoxan (30-300 micrograms/kg i.v.). In the renal bed the vasoconstrictor effects of DA were resistant to blockade by idazoxan, but were prazosin sensitive indicating that alpha 1-adrenoceptors were involved in this response. The alpha-receptor agonist profile for DA was not modified in the femoral bed after blockade of dilatory D1-receptors with SCH 23390 (0.5 mg/kg i.v. and 0.1 mg/kg per h i.v.). However, this antagonist significantly increased the vasoconstrictor potency for DA in the renal bed. The decrease in femoral blood flow induced by an injection of DA, appears to be mediated by alpha 2-adrenoceptors. In the renal vascular bed where the predominant alpha-adrenoceptor corresponds to the alpha 1-subtype and there are few postsynaptic alpha 2-receptors subserving vasoconstriction, DA can stimulate alpha 1-receptors but this action requires higher doses of agonist than those needed for alpha 2-adrenoceptor stimulation.

Adrenergic alpha-Antagonists↗
PubMed1985

Pharmacologic and therapeutic significance of alpha-adrenoceptor subtypes.

The concept that neurotransmitters can modulate their own release through presynaptic inhibitory autoreceptors is well established. The presynaptic inhibitory autoreceptors involved in a negative feedback mechanism that modulates the release of norepinephrine are of the alpha 2-subtype. Stimulation of central alpha 2-adrenoceptors by drugs like clonidine, guanfacine, and guanabenz produces an antihypertensive and bradycardiac effect through a decrease in sympathetic tone. In vascular smooth muscle, the alpha 1-adrenoceptor subtype predominates and mediates vasoconstriction although alpha 2-adrenoceptors mediating vasoconstriction are also present in some vascular beds. Phenylephrine preferentially stimulates alpha 1-adrenoceptors and guanabenz preferentially stimulates alpha 2-adrenoceptors in vascular smooth muscle, whereas norepinephrine is an agonist at both alpha 1- and alpha 2-subtypes. The pressor response to phenylephrine was markedly reduced by prazosin. In contrast, the response to norepinephrine was relatively resistant to blockade, and that to guanabenz, totally resistant to blockade by prazosin. Inhibition of neuronal uptake by cocaine or desipramine and pretreatment of cats with 6-hydroxydopamine increased the effectiveness of prazosin in blocking the pressor responses to norepinephrine, but not to guanabenz or phenylephrine. These results support the proposal that postsynaptic alpha 1-adrenoceptors are preferentially innervated (i.e., within the neuroeffector junction), while the postsynaptic alpha 2-adrenoceptors are in extrasynaptic locations. The subclassification of alpha-adrenoceptors into alpha 1- and alpha 2-subtypes opens the possibility of designing selective drugs to act as agonists or antagonists on these receptor subtypes. These compounds have useful therapeutic applications, and in the case of selective alpha 2-adrenoceptor antagonists, novel potential uses may exist, both at the level of the central nervous system and in the periphery.

Adrenergic alpha-Agonists↗
PubMed1982

Dopamine decreases mesenteric blood flow in the anaesthetised dog through the stimulation of postsynaptic alpha 2-adrenoceptors.

The decrease in mesenteric blood flow produced by dopamine administered intra-arterially in the anaesthetised dog was investigated by means of drugs selective for alpha 1- and alpha 2-adrenoceptors. The selective alpha 1-adrenoceptor agonist phenylephrine (0.3-100 microgram) given by intra-arterial injection (i.a.) into the superior mesenteric artery of the anaesthetized dog produced a decrease in mesenteric blood flow which was preferentially blocked by the alpha 1-adrenoceptor antagonist prazosin (30-300 microgram/kg i.v.). On the other hand, i.a. injections of the selective alpha 2-adrenoceptor agonist M7 (1-100 microgram) or of dopamine (1-300 microgram) produced a decrease in mesenteric blood flow which was blocked by the alpha 2-adrenoceptor antagonist yohimbine (100-300 microgram/kg i.v.) but was not significantly reduced by prazosin (300 microgram/kg i.v.). These results demonstrate that the mesenteric vascular bed of the dog contains both alpha 1- and alpha 2-adrenoceptors located postsynaptically and mediating vasoconstriction. The decrease in mesenteric blood flow produced by i.a. injections of dopamine is mediated predominantly via postsynaptic alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1981

Pre- and postsynaptic alpha adrenoceptor selectivity studies with yohimbine and its two diastereoisomers rauwolscine and corynanthine in the anesthetized dog.

The selectivity of yohimbine and its two diastereoisomers rauwolscine and corynanthine for pre- and postsynaptic alpha adrenoceptors has been investigated in the anesthetized dog. Antagonism of the inhibitory effect of clonidine on the tachycardia produced by electrical stimulation of the ansa subclavia was used as a measure of presynaptic alpha-2 adrenoceptor blockade. Inhibition of the diastolic pressor response to phenylephrine in ganglion and beta blocked dogs was used as a measure of postsynaptic alpha-1 adrenoceptor blockade. All three of the isomers reduced, and at higher doses reversed, the inhibitory effect of clonidine Yohimbine and rauwolscine were equipotent in this respect and were approximately 100-fold more potent than corynanthine. However, all the isomers were equipotent as antagonists of the diastolic pressure response to phenylephrine. Yohimbine and rauwolscine were approximately 30 times more potent as alpha-2 adrenoceptor than alpha-1 adrenoceptor antagonists, whereas corynanthine was 10-fold more potent at alpha-1 adrenoceptors than at alpha-2 adrenoceptors. These results are in broad agreement with those previously reported from in vitro experiments showing yohimbine and rauwolscine to be preferential alpha-2 adrenoceptor antagonists and corynanthine to be a preferential alpha-1 adrenoceptor antagonist. It is concluded that the high affinity of the antagonists yohimbine and rauwolscine for alpha-2 adrenoceptors is responsible for their selectivity because at the level of blockade of postsynaptic alpha-1 adrenoceptors both isomers were equipotent with corynanthine.

Animals↗