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Carotid body function in aged rats: responses to hypoxia, ischemia, dopamine, and adenosine.

ABSTRACT: The carotid body (CB) is the main arterial chemoreceptor with a low threshold to hypoxia. CB activity is augmented by A(2)-adenosine receptors stimulation and attenuated by D(2)-dopamine receptors. The effect of aging on ventilatory responses mediated by the CB to hypoxia, ischemia, and to adenosine and dopamine administration is almost unknown. This study aims to investigate the ventilatory response to ischemia and to adenosine, dopamine, and their antagonists in old rats, as well as the effect of hypoxia on adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in the aged CB. In vivo experiments were performed on young and aged rats anesthetized with pentobarbitone and breathing spontaneously. CB ischemia was induced by bilateral common carotid occlusions. cAMP content was measured in CB incubated with different oxygen concentrations. Hyperoxia caused a decrease in cAMP in the CB at all ages, but no differences were found between normoxia and hypoxia or between young and old animals. The endogenous dopaminergic inhibitory tonus is slightly reduced. However, both the ventilation decrease caused by exogenous dopamine and the increase mediated by A(2A)-adenosine receptors are not impaired in aged animals. The bradycardia induced by adenosine is attenuated in old rats. The CB's peripheral control of ventilation is preserved during aging. Concerns have also arisen regarding the clinical usage of adenosine to revert supraventricular tachycardia and the use of dopamine in critical care situations involving elderly people.

SUBMITTER: Monteiro TC

PROVIDER: S-EPMC3168591 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Carotid body function in aged rats: responses to hypoxia, ischemia, dopamine, and adenosine.

Monteiro Teresa Castro TC Batuca Joana Rita JR Obeso Ana A González Constancio C Monteiro Emília Carreira EC

Age (Dordrecht, Netherlands) 20101005 3

The carotid body (CB) is the main arterial chemoreceptor with a low threshold to hypoxia. CB activity is augmented by A(2)-adenosine receptors stimulation and attenuated by D(2)-dopamine receptors. The effect of aging on ventilatory responses mediated by the CB to hypoxia, ischemia, and to adenosine and dopamine administration is almost unknown. This study aims to investigate the ventilatory response to ischemia and to adenosine, dopamine, and their antagonists in old rats, as well as the effect ...[more]

PMID: 20922488

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Project description:Key pointsWe have previously shown that carotid body stimulation by lysophosphatidic acid elicits a reflex stimulation of vagal efferent activity sufficient to cause bronchoconstriction in asthmatic rats. Here, we show that pathophysiological concentrations of asthma-associated prototypical Th2 cytokines also stimulate the carotid bodies. Stimulation of the carotid bodies by these asthmakines involves a PKC?-transient receptor potential vanilloid 1 (TRPV1) signalling mechanism likely dependent on TRPV1 S502 and T704 phosphorylation sites. As the carotid bodies' oxygen sensitivity is independent of PKC?-TRPV1 signalling, systemic blockade of PKC? may provide a novel therapeutic target to reduce allergen-induced asthmatic bronchoconstriction. Consistent with the therapeutic potential of blocking the PKC?-TRPV1 pathway, systemic delivery of a PKC?-blocking peptide suppresses asthmatic respiratory distress in response to allergen and reduces airway hyperresponsiveness to bradykinin.AbstractThe autonomic nervous system orchestrates organ-specific, systemic and behavioural responses to inflammation. Recently, we demonstrated a vital role for lysophosphatidic acid in stimulating the primary autonomic oxygen chemoreceptors, the carotid bodies, in parasympathetic-mediated asthmatic airway hyperresponsiveness. However, the cacophony of stimulatory factors and cellular mechanisms of carotid body activation are unknown. Therefore, we set out to determine the intracellular signalling involved in carotid body-mediated sensing of asthmatic blood-borne inflammatory mediators. We employed a range of in vitro and rat in situ preparations, site-directed mutagenesis, patch-clamp, nerve recordings and pharmacological inhibition to assess cellular signalling. We show that the carotid bodies are also sensitive to asthma-associated prototypical Th2 cytokines which elicit sensory nerve excitation. This provides additional asthmatic ligands contributing to the previously established reflex arc resulting in efferent vagal activity and asthmatic bronchoconstriction. This novel sensing role for the carotid body is mediated by a PKC?-dependent stimulation of transient receptor potential vanilloid 1 (TRPV1), likely via TRPV1 phosphorylation at sites T704 and S502. Importantly, carotid body oxygen sensing was unaffected by blocking either PKC? or TRPV1. Further, we demonstrate that systemic PKC? blockade reduces asthmatic respiratory distress in response to allergen and airway hyperresponsiveness. These discoveries support an inflammation-dependent, oxygen-independent function for the carotid body and suggest that targeting PKC? provides a novel therapeutic option to abate allergic airway disease without altering life-saving autonomic hypoxic reflexes.

Dataset Information

Carotid body function in aged rats: responses to hypoxia, ischemia, dopamine, and adenosine.

Publications

Carotid body function in aged rats: responses to hypoxia, ischemia, dopamine, and adenosine.

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