2-(4-(2-carboxyethyl)phenethylamino)-5--n-ethylcarboxamidoadenosine and Apnea

Activation of the laryngeal mucosa results in apnea that is mediated through, and can be elicited via electrical stimulation of, the superior laryngeal nerve (SLN). This potent inhibitory reflex has been suggested to play a role in the pathogenesis of apnea of prematurity and sudden infant death syndrome, and it is attenuated by theophylline and blockade of GABA(A) receptors. However, the interaction between GABA and adenosine in the production of SLN stimulation-induced apnea has not been previously examined. We hypothesized that activation of adenosine A(2A) receptors will enhance apnea induced by SLN stimulation while subsequent blockade of GABA(A) receptors will reverse the effect of A(2A) receptor activation. The phrenic nerve responses to increasing levels of SLN stimulation were measured before and after sequential intracisternal administration of the adenosine A(2A) receptor agonist CGS (n = 10) and GABA(A) receptor blocker bicuculline (n = 7) in ventilated, vagotomized, decerebrate, and paralyzed newborn piglets. Increasing levels of SLN stimulation caused progressive inhibition of phrenic activity and lead to apnea during higher levels of stimulation. CGS caused inhibition of baseline phrenic activity, hypotension, and enhancement of apnea induced by SLN stimulation. Subsequent bicuculline administration reversed the effects of CGS and prevented the production of apnea compared with control at higher SLN stimulation levels. We conclude that activation of adenosine A(2A) receptors enhances SLN stimulation-induced apnea probably via a GABAergic pathway. We speculate that SLN stimulation causes endogenous release of adenosine that activates A(2A) receptors on GABAergic neurons, resulting in the release of GABA at inspiratory neurons and subsequent respiratory inhibition.

Topics: Adenosine; Animals; Animals, Newborn; Apnea; Bicuculline; Blood Pressure; Cisterna Magna; Disease Models, Animal; Drug Antagonism; Electric Stimulation; GABA Antagonists; gamma-Aminobutyric Acid; Heart Rate; Injections, Intraventricular; Laryngeal Nerves; Phenethylamines; Phrenic Nerve; Receptor, Adenosine A2A; Swine

Dexamethasone increases the expression of adenosine A(3) receptors and augments degranulation in response to their activation in the rat basophilic leukemia cell line, RBL-2H3. We have studied the effects of dexamethasone on mast cell activation induced by A(3) receptor stimulation in vivo. Administration of the A(3) receptor agonist APNEA [N(6)-2-(4 aminophenyl)ethyladenosine; 10-30 microg kg(-1) i.v.] to anesthetized Sprague-Dawley rats induced falls in blood pressure. Pretreatment with dexamethasone (1 mg kg(-1), i.p., -24 h) blocked the hypotensive response to APNEA but not those induced by the A(1) receptor agonist N(6)-cyclopentyladenosine, the A(2A) receptor agonist 2-[p-(2-carboxyethyl)phenylamino]-5'-N-ethylcarboxamidoadenosine, or the mast cell degranulating agent compound 48/80 (100-300 microg kg(-1), i.v.). APNEA (10 and 30 microg kg(-1), i.v.) and compound 48/80 (100 and 300 microg kg(-1), i.v.) increased plasma histamine concentrations dose dependently. Pretreatment with dexamethasone significantly inhibited the increases induced by the lower doses of each compound. APNEA induced degranulation of mast cells in thymus but not in skin or skeletal muscle, whereas compound 48/80 induced degranulation in each tissue. Pretreatment with dexamethasone inhibited APNEA-induced degranulation of mast cells in the thymus and slightly, yet significantly, reduced degranulation induced by compound 48/80. Thus, in contrast to the findings in RBL-2H3 cells in vitro, in the whole animal, dexamethasone down-regulates the response of the mast cell to A(3) receptor activation. The qualitatively similar effects on compound 48/80 suggest that dexamethasone suppresses mast cell responsiveness by modulating site(s) downstream from the adenosine A(3) receptor, possibly at the level of the G(i) family of trimeric GTP-binding proteins.

Topics: Adenosine; Animals; Apnea; Blood Pressure; Cell Degranulation; Dexamethasone; Heart Rate; Histamine; Hypotension; Male; Mast Cells; Phenethylamines; Purinergic P1 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A3; Receptors, Purinergic P1

1. The adenosine A3 receptor agonist, N6-2-(4-aminophenyl)ethyladenosine (APNEA) induces hypotension in the anaesthetized rat. The present experiments were carried out to explore the role of mast cells in the response. 2. Intravenous injection of APNEA (1-30 micrograms kg-1 to rats in which the A3 receptor-mediated response had been isolated by pretreatment with 8-(p-sulphophenyl) theophylline (8-SPT)), induced dose-related falls in blood pressure accompanied at higher doses by small falls in heart rate. Responses to the mast cell degranulating agent, compound 48/80 (10-300 micrograms kg-1, i.v.) were qualitatively similar to those to APNEA. 3. Pretreatment with sodium cromoglycate (0.25-20 mg kg-1, i.v.) induced dose-related, although incomplete, blockade of the hypotensive responses to APNEA. At 20 mg kg-1, sodium cromoglycate also inhibited the cardiovascular response to compound 48/80 but had no effects on those to the selective A1 receptor agonist, N6-cyclopentyladenosine (CPA) or the selective A2A receptor agonist, 2-[p-(2-carboxyethyl)phenylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680). Lodoxamide (0.01-20 mg kg-1) also blocked selectively but incompletely the response to APNEA. 4. The cardiovascular responses to compound 48/80 (10-300 micrograms kg-1, i.v.) were markedly suppressed in animals which had received repeated doses of the compound by the intraperitoneal route. Similarly APNEA was essentially devoid of cardiovascular activity in such preparations. In contrast, responses to CPA were similar in animals treated repeatedly with compound 48/80 to those obtained in control animals. 5. Plasma and serum histamine concentrations were markedly increased associated with the pronounced hypotensive responses induced by intravenous injections of APNEA (30 or 100 microg kg-1) in the presence of 8-SPT, or compound 48/80 (300 microg kg-1).6. Taken together the data implicate the mast cell in a key role in adenosine A3 receptor-mediated hypotension in the anaesthetized rat.

Topics: Adenosine; Animals; Antihypertensive Agents; Apnea; Cromolyn Sodium; Dose-Response Relationship, Drug; Hypotension; Injections, Intravenous; Male; Mast Cells; Phenethylamines; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P1; Serotonin; Theophylline