Dataset Information

Activation of ?_1A -adrenoceptors desensitizes the rat aorta response to phenylephrine through a neuronal NOS pathway, a mechanism lost with ageing.

ABSTRACT:

Background and purpose

A NO-mediated desensitization of vasoconstrictor responses evoked by stimulation of ?₁ -adrenoceptors has been reported in different vessels. We investigated the involvement of each ?₁ -adrenoceptor subtype and constitutive NOS isoforms and the influence of ageing and hypertension on this process.

Experimental approach

Wistar and spontaneously hypertensive rats (SHR), 16, 32, 52 and 72 weeks-old, were used to evaluate the desensitization process. Expression of ?₁ -adrenoceptor subtypes, endothelial NOS (eNOS) and neuronal NOS (nNOS) were determined in rat aorta and left ventricle (LV). Expression levels were also evaluated in LV of a group of heart failure patients with a wide age range.

Key results

Repeated application of phenylephrine decreased subsequent ?₁ -adrenoceptor-mediated vasoconstriction by increasing nNOS protein expression in aorta, but not in tail or mesenteric resistance arteries, where mRNA levels of nNOS were undetectable. This desensitization process disappeared in the absence of endothelium or in the presence of L-NAME (100 ?M), nNOS inhibitors, SMTC (1 ?M) and TRIM (100 ?M), and 5-methylurapidil (100 nM, ?_1A -antagonist), but not BMY7378 (10 nM, ?_1D -antagonist). The ?_1A /nNOS-mediated desensitization was absent in aged SHR and Wistar animals, where the expression of ?_1A -adrenoceptors was reduced in aorta and LV. In human LV, a negative correlation was found between age and ?_1A -adrenoceptor expression.

Conclusions and implications

The ?_1A -adrenoceptor subtype, through endothelial nNOS-derived NO, may act as a physiological 'brake' against the detrimental effects of excessive ?₁ -adrenoceptor-mediated vasoconstriction. Reduced ?_1A -adrenoceptor- and nNOS-mediated desensitization in aged patients could be involved in the age-dependent elevation of adrenergic activity.

SUBMITTER: Arce C

PROVIDER: S-EPMC5466529 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

Activation of α<sub>1A</sub> -adrenoceptors desensitizes the rat aorta response to phenylephrine through a neuronal NOS pathway, a mechanism lost with ageing.

Arce Cristina C Vicente Diana D Segura Vanessa V Flacco Nicla N Montó Fermi F Almenar Luis L Agüero Jaime J Rueda Joaquín J Jiménez-Altayó Francesc F Vila Elisabet E Noguera Maria Antonia MA D'Ocon Pilar P Ivorra Maria Dolores MD

British journal of pharmacology 20170510 13

<h4>Background and purpose</h4>A NO-mediated desensitization of vasoconstrictor responses evoked by stimulation of α<sub>1</sub> -adrenoceptors has been reported in different vessels. We investigated the involvement of each α<sub>1</sub> -adrenoceptor subtype and constitutive NOS isoforms and the influence of ageing and hypertension on this process.<h4>Experimental approach</h4>Wistar and spontaneously hypertensive rats (SHR), 16, 32, 52 and 72 weeks-old, were used to evaluate the desensitizatio ...[more]

PMID: 28369791

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Project description:Background and purposealpha(1)-Adrenoceptor agonists induce Ca(2+)-transients in endothelial cells (ECs) of arterioles. However, the presence of alpha(1)-adrenoceptors on arteriolar ECs has not been excluded, and the identity of alpha(1)-adrenoceptor subtypes in arterioles only has been inferred from pharmacology. Therefore, we determined which subtypes were expressed by vascular smooth muscle cells (VSMCs) and ECs, and which subtype mediated alpha(1)-adrenoceptor-induced constriction.Experimental approachEC Ca(2+)-transients in isolated, cannulated hamster cremasteric arterioles or freshly isolated ECs were studied using Fura 2. Arteriolar diameter was measured by video microscopy. alpha(1)-Adrenoceptor expression was assessed by western blot of whole-arteriolar homogenates and real-time RT-PCR on enzymatically isolated VSMCs and ECs.Key resultsPhenylephrine-induced constriction and EC Ca(2+)-transients were abolished by the alpha(1)-adrenoceptor antagonist prazosin (30 nM) in arterioles. Phenylephrine-induced constriction was inhibited by the alpha(1D)-adrenoceptor antagonist BMY 7378 (K(B)=2.96 nM) and the alpha(1A)-adrenoceptor antagonist 5-methylurapidil (K(B)=4.08 nM), suggesting a significant role for alpha(1D)-adrenoceptors. Western blots confirmed alpha(1D)-adrenoceptor expression, but did not detect alpha(1A)-adrenoceptors. VSMCs expressed alpha(1D)- and alpha(1A)-, but not alpha(1B)-, adrenoceptor transcripts. No alpha(1)-adrenoceptor transcripts were detected in ECs. Neither phenylephrine (10 microM) nor noradrenaline (0.1-1 microM) elicited Ca(2+)-transients in freshly isolated ECs, whereas the endothelium-dependent vasodilators methacholine (1 microM) and substance P (100 nM) consistently increased Ca(2+).Conclusions and implicationsWe reject the hypothesis that hamster cremasteric arteriolar ECs express alpha(1)-adrenoceptors and conclude that alpha(1)-adrenoceptor agonists predominantly act on VSMC alpha(1D)-adrenoceptors to cause vasoconstriction and a subsequent rise in EC Ca(2+).

Dataset Information

Activation of ?_1A -adrenoceptors desensitizes the rat aorta response to phenylephrine through a neuronal NOS pathway, a mechanism lost with ageing.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Activation of α<sub>1A</sub> -adrenoceptors desensitizes the rat aorta response to phenylephrine through a neuronal NOS pathway, a mechanism lost with ageing.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Activation of ?1A -adrenoceptors desensitizes the rat aorta response to phenylephrine through a neuronal NOS pathway, a mechanism lost with ageing.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Activation of α<sub>1A</sub> -adrenoceptors desensitizes the rat aorta response to phenylephrine through a neuronal NOS pathway, a mechanism lost with ageing.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Activation of ?_1A -adrenoceptors desensitizes the rat aorta response to phenylephrine through a neuronal NOS pathway, a mechanism lost with ageing.