Adenosine receptor subtypes in the brainstem mediate distinct cardiovascular response patterns

Abstract

A limited occipital craniotomy was conducted on urethane-chloralose anesthetized, spontaneously breathing rats to expose the caudal medulla in the region of the obex. Microinjections of highly selective agonists for adenosine receptor subtypes were made into the medial region of the caudal nucleus tractus solitarius (NTS) at the level of the posterior portion of the area postrema. Cardiorespiratory parameters were subsequently recorded for a 60-min test period following microinjection of drug or vehicle solutions. The following selective adenosine receptor agonists were used: the A, agonist, N 6-cyclopentyladenosine (CPA), which is 480-fold selective for A 1 receptors in rat brain binding assays, and the A 2 agonist, 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine (COS 21680), which is 170-fold selective for A 2 receptors in rat brain binding studies and over 1500-fold selective in functional assays. The results showed that distinct and converse cardiovascular response patterns were elicited by these selective agonists for adenosine receptor subtypes following micro-injections into the caudal NTS. Specifically, COS 21680 selectively elicited potent dose-related decreases in mean arterial blood pressure (ED 50 = 0.064 nmol/kg) and dose-related decreases in pulse pressure (ED 50= 0.058 nmol/kg). Conversely, CPA selectively elicited potent dose-related increases in mean arterial blood pressure (ED 50 = 0.62 nmol/kg) and dose-related increases in pulse pressure (ED 50 = 0.70 nmol/kg). Additionally, the overall agonist-mediated response patterns were dramatically different wherein the COS agonist exhibited a considerably more rapid time course in eliciting its hypotensive responses whereas CPA exhibited a more delayed and substantially longer time course to exert its hypertensive responses. Additionally, these distinct and converse cardiovascular response patterns were further shown to be receptor-selective since the depressor responses elicited by the A 2 receptor agonist, COS 21680, and the pressor responses elicited by the A 1 receptor agonist, CPA, were completely and selectively blocked, respectively, by the selective A 2 receptor antagonist, COS 15943A, and the selective A, receptor antagonist, DPCPX. Taken together, these findings provide persuasive in vivo evidence showing that pharmacologic activation of adenosine receptor subtypes in the caudal NTS of rats elicits specific response patterns with selective and opposite actions on cardiorespiratory behavior. These data also indicate that separate physiologic responses are specifically mediated by A 2 receptors in the intact nervous system and thereby lend additional support to the case for using in vivo models to assess the functional role of adenosine A 2 receptors in brain function.