Role of adenosine receptor subtypes in neural stunning of sympathetic coronary innervation TOYOHIKO ABE, DONALD A. MORGAN, AND DAVID D. GUTTERMAN Cardiovascular Center, University of Iowa College of Medicine, and Veterans Affairs Medical Center, Iowa City, Iowa 52242 Abe, Toyohiko, Donald A. Morgan, and David D. Gutterman. Role of adenosine receptor subtypes in neural stunning of sympathetic coronary innervation. Am. J. Physiol. 272 (Heart Circ. PhysioZ. 41): H25-H34, 1997.-Adenosine plays an important role in postischemic dysfunction of car- diac sympathetic nerves because exogenously infused adeno- sine produces and adenosine deaminase prevents “neural stunning.” We examined whether adenosine acts via a specific receptor mechanism to produce neural stunning. Anesthe- tized dogs were treated with propranolol to attenuate in- creases in coronary flow due to adrenergic stimulation of myocardial metabolism. A 15min occlusion of the left ante- rior descending coronary artery (LAD) attenuated subse- quent LAD coronary vasoconstriction to bilateral sympa- thetic stimulation during reperfusion by 75% (P < 0.05). Coronary infusion of the adenosine-receptor antagonist 8-p- sulfophenyltheophylline (nonspecific), 8-cyclopentyl-1,3-dipro- pylxanthine (A1 specific), or 3,7-dimethyl-1-propagylxanthine (A2 specific) d uring LAD occlusion prevented the attenuation of sympathetic coronary constriction. In separate experi- ments, either the specific adenosine agonist NG-cyclopentyl- adenosine (A, specific) or CGS-21680 (Aa specific) or a combi- nation of both agonists was infused into the LAD for 15 min. Neither agonist alone attenuated subsequent sympathetic coronary constriction. In contrast, 15 min after the combined administration of both agonists, sympathetic vasoconstric- tion was reduced. We conclude that adenosine is capable of attenuating neurogenic coronary constriction through a recep- tor-mediated mechanism. Activation of more than one recep- tor subtype is necessary to produce neural stunning. ischemia; reperfusion; vasoconstriction; heart; blood flow BRIEF PERIODS OF MYOCARDIAL ISCHEMIA lasting <20 min cause transient dysfunction of myocardial contraction extending long into the reperfusion period (7, 20, 33). This prolonged but reversible impairment of myocar- dial contraction after the recovery of brief ischemia (“myocardial stunning”) has been investigated in- tensely. In addition to the reversible attenuation of contrac- tile function, cardiac sympathetic and vagal neurotrans- mission is attenuated after brief myocardial ischemia (10, 15, 16, 23). This “neural stunning” is a phenom- enon with serious clinical implications because it may contribute to the genesis of ventricular tachyarrhyth- mias or impair the favorable transmural redistribution of myocardial perfusion produced by sympathetic neu- ral activation (4, 9, 24). However, the mechanism of neural stunning is not well understood. A recent study by Miyazaki and Zipes (28) suggested that the function of nerves running through ischemic myocardium could be affected by ischemic metabolites such as adenosine, potassium, or hydrogen ions. Pettersen et al. (30) recently reported an important role for adenosine in neural stunning. Exogenously infused adenosine pro- duced a sustained reduction in cardiac sympathetic neurotransmission, whereas elimination of endogenous adenosine with adenosine deaminase during myocar- dial ischemia prevented this attenuation. However, the mechanism by which adenosine contributes to neural stunning is not known. It may act directly through a receptor-mediated action on the nerves or indirectly via active purine metabolites. In this study, we examined the hypothesis that activation of specific adenosine receptors is responsible for neural stunning. METHODS General Preparation Thirty-two mongrel dogs of either sex weighing 21-30 kg were anesthetized with intravenous thiopental sodium (25 mg/kg). Anesthesia was maintained with ar-chloralose (60 mg/kg). Supplemental injections of cx-chloralose (20 mg/kg) were given as needed to suppress pressor responses to skin pinch and cornea1 reflex. All dogs were intubated and mechani- cally ventilated with continuous positive airway pressure at 4 cmH20. Arterial blood gases were sampled to measure PO,, Pco~, and pH. These parameters were maintained within physiological ranges by adjusting supplemental oxygen, ven- tilation rate, and tidal volume and by intravenous administra- tion of bicarbonate (2 meq/kg iv). With a heating pad, rectal temperature was maintained at 36-37°C slightly less than the core temperature of unanesthetized dogs. A polyethylene catheter was inserted into the left carotid artery and connected to a transducer (Viggo-Spectramed model P23XL) to measure phasic and mean arterial blood pressures. The right femoral vein was cannulated for the administration of fluids and pharmacological agents. Proxi- mal and distal aortic catheters were also placed via the femoral arteries for microsphere withdrawal. Through a ventral neck incision, both cervical vagi were isolated and transected. A left thoracotomy was performed by removing the second through fifth left ribs. The stellate ganglia were isolated bilaterally, and each was secured within a bipolar microstimulation electrode and covered with gauze soaked in mineral oil. Stimulation parameters were 10-V 5-ms pulses delivered at 15 Hz (10-s duration). After a pericardial cradle was formed, a micromanometer- tipped catheter was placed into the left ventricle via the left appendage for the continuous recording of left ventricular rate of pressure development (dPldt). This signal was also directed to a cardiotachometer for recording heart rate. A 14-gauge Teflon catheter was positioned in the left atrium for the injection of microspheres. A 26-gauge Teflon catheter was secured retrogradely into each of the left anterior descending coronary artery (LAD) and left circumflex coronary artery (LCX) for the administration of pharmacological agents. These catheters, which do not blunt reactive hyperemic responses to 10 s of coronary occlusion, were flushed with warmed saline and heparin. H25