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Adenosine Strongly Potentiates Pressor Responses to Nicotine in Rats (Caffeine/Blood Pressure/Sympathetic Nervous System) REID W

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Adenosine Strongly Potentiates Pressor Responses to Nicotine in Rats (Caffeine/Blood Pressure/Sympathetic Nervous System) REID W Proc. Nadl. Acad. Sci. USA Vol. 81, pp. 5599-5603, September 1984 Neurobiology Adenosine strongly potentiates pressor responses to nicotine in rats (caffeine/blood pressure/sympathetic nervous system) REID W. VON BORSTEL, ANDREW A. RENSHAW, AND RICHARD J. WURTMAN Laboratory of Neuroendocrine Regulation, Department of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge, MA 02139 Communicated by Walle J. H. Nauta, May 14, 1984 ABSTRACT Intravenous infusion of subhypotensive doses epinephrine output during nerve stimulation is decreased (6). of adenosine strongly potentiates the pressor response of anes- Adenosine can be produced ubiquitously and is present in thetized rats to nicotine. A dose of nicotine (40 jpg/kg, i.v.), plasma and cerebrospinal fluid (7, 8); the nucleoside can which, given alone, elicits a peak increase in diastolic pressure therefore potentially act at a number of different loci, both of -15 mm Hg, increases pressure by -70 mm Hg when arte- central and peripheral, within the complex neural circuitry rial plasma adenosine levels have been increased to 2 puM from involved in the regulation of a single physiological function, a basal concentration of =1 puM. The pressor response to ciga- such as maintenance of blood pressure or heart rate. Neither rette smoke applied to the lungs is also strongly potentiated normal plasma adenosine levels nor the relative and absolute during infusion of adenosine. Slightly higher adenosine con- sensitivities of neural and cellular processes to adenosine centrations (-4 jaM) attenuate pressor responses to electrical have been well characterized in intact animals. The studies stimulation of preganglionic sympathetic nerves, or to injec- described below explore the effects of controlled measured tions of the a-adrenergic agonist phenylephrine, but continue alterations in arterial plasma adenosine concentrations on to potentiate pressor responses to nicotine. Low doses (0.25-5 the responses of blood pressure to several pharmacological pg/kg) of the synthetic adenosine receptor agonists 5'-N-cyclo- and physiological treatments that modify sympathetic neuro- propylcarboxamidoadenosine, 2-chloroadenosine, and N6-L- transmission. phenylisopropyladenosine also potentiate pressor responses to nicotine. Caffeine and theophylline (10 mg/kg) block the po- METHODS tentiating effect of adenosine, and also decrease basal respons- Male Sprague-Dawley rats (Charles River Breeding Labora- es to nicotine, suggesting that endogenous adenosine might tories) weighing 250-350 g were used in all experiments. normally potentiate some nicotine responses. The synergism In animals anesthetized with Nembutal (50-60 mg/kg, between nicotine and adenosine appears to take place within i.p.), a silastic catheter (Dow-Corning 602-135) was intro- sympathetic ganglia. duced into the aorta via the left carotid artery for blood pres- sure measurement, periodic withdrawal of blood samples for In addition to serving as a constituent of biologically impor- assay of adenosine content, and, in some experiments, for tant molecules such as adenosine 3',5'-cyclic monophos- intra-arterial drug administration. For intravenous adminis- phate, adenosine triphosphate, S-adenosylmethionine, and tration of adenosine and other compounds, a multiple cathe- coenzyme A, the purine nucleoside adenosine can also modi- ter, consisting of three lengths of PE-10 polyethylene tubing fy neurotransmission and affect other physiological process- encased in a sheath of silastic tubing (Dow-Corning 602- es via interaction with specific adenosine receptors on the 155), was implanted in the right atrium via the right external outer surface of various excitable cells (1). The methylxan- jugular vein; bolus injections of drugs could thereby be given thines caffeine and theophylline are potent antagonists at without interrupting a concurrent steady intravenous infu- these receptors (2). sion of adenosine. Administration of adenosine to animals can elicit many re- For electrical stimulation of preganglionic sympathetic sponses, including sedation, hypotension, bradycardia, pro- nerves, the arterial and venous catheters were implanted in tection against experimentally induced seizures, suppression ether-anesthetized animals. The rat was then pithed by in- of the evoked release of several neurotransmitters, and sup- serting a stainless steel tube (13 gauge) through the orbit and pression of lipolysis (3-5). Adenosine can influence physio- the foramen magnum, into the spinal column to the level of logical processes by modifying the release of neurotransmit- the sixth cervical vertebra; this destroys the brainstem and ters or hormones; the responses of tissues to neurotransmit- effectively severs the spinal cord from the brain altogether ters, drugs, or hormones; or the rates of cellular processes (9). Through this trocar, a steel rod (1-mm diameter) was operating independently of particular neurotransmitters or inserted down the length of the spinal column, terminating in hormones. In assessing the response of a physiological sys- the sacral vertebrae. The portion of the rod that remained tem to adenosine, it is important to differentiate between inside the trocar was insulated with a silastic sheath. The these three modes of action, because the net direction (in- animal was respired artificially with room air (1 ml per 100 g hibitory versus facilitatory) of the influence of adenosine on of body weight, 50 strokes per min) via a tracheal cannula for neurotransmission can be different, even within a single pop- the duration of the experiment. Skeletal muscle was para- ulation of synapses or neuroeffector junctions, at presynap- lyzed with pancuronium bromide (0.02 mg/kg, i.v.) and an tic versus postsynaptic sites. For example, in the isolated indifferent electrode was inserted under the skin of the right rabbit kidney, adenosine acts both to inhibit the evoked re- hindlimb. Monophasic pulses (0.1 msec duration, 0.1-20 lease of norepinephrine from vascular sympathetic terminals pulses per sec, 10-80 V) were applied with a Grass S11 stim- and postsynaptically to enhance vascular responsiveness to ulator. norepinephrine; the net effect is to enhance vasoconstrictor In the isolated hindlimb preparation, both carotid arteries responses to stimulation of the renal nerve, even though nor- were cannulated, and blood from the right carotid artery was The publication costs of this article were defrayed in part by page charge Abbreviations: L-PIA, N -(L-phenylisopropyl)adenosine; D-PIA, payment. This article must therefore be hereby marked "advertisement" N6-(D-phenylisopropyl)adenosine; CPCA, N-cyclopropylcarbox- in accordance with 18 U.S.C. §1734 solely to indicate this fact. amidoadenosine; 2-CIA, 2-chloroadenosine. 5599 Downloaded by guest on September 30, 2021 5600 Neurobiology: von Borstel et al. Proc. Natl. Acad Sci. USA 81 (1984) perfused directly into the cannulated right femoral artery via a constant-flow infusion pump. The flow rate was adjusted 80 pressure, E to maintain basal hindlimb perfusion recorded dis- I'E tally to the pump, at 100 mm Hg. The 2- to 3-min circulation time delay through the pump and tubing of the perfusion cir- cuit allowed us to discriminate between drug effects at the C-en neuroeffector junction (vascular smooth muscle and sympa- .2 thetic nerve terminals) and effects mediated through modifi- a) + cation of the firing rate of postganglionic sympathetic nerves, which remain intact and functional in this system. Systemic ._c drug injections could be given into the descending aorta via 20 the, left carotid artery catheter (through which blood pres- a) sure was continuously monitored); drugs could also be in- Ca_ jected directly into the hindlimb perfusion circuit proximal to n the pump. 0 1 2 3 4 5 6 7 8 Arterial blood pressure and hindlimb perfusion pressure Arterial Plasma Adenosine (/LM) were monitored with Statham (Hato Rey, PR) 23PD pressure transducers interfaced with a Grass 7C polygraph. FIG. 1. Relationship between arterial plasma adenosine concen- Blood samples (0.3 ml) were rapidly withdrawn via the ar- tration and pressor response to nicotine in rats. Nicotine (40 ,ug/kg, terial catheter into syringes previously loaded with 0.3 ml of i.v.) was administered to anesthetized rats before (L*) and during (L) ice-cold heparinized (200 units/ml) saline containing 0.5 mM intravenous infusion of adenosine at controlled rates ranging from Ingelheim, Ridgefield, CT), which 0.15 to 0.9 mg/kg per min. Arterial blood samples were withdrawn dipyridamole (Boehringer (for assay of adenosine) immediately before nicotine injection. Each was inhibits the uptake of adenosine into cells. Each sample animal (n = 5) provided data for each plasma adenosine concentra- immediately centrifuged and 0.45 ml of the supernatant was tion; data represent mean ± SEM for both peak pressure increase deproteinized by mixing with 0.15 ml of 15% trichloroacetic and arterial adenosine concentration. acid followed by centrifugation. The final supernatant was neutralized with excess calcium carbonate. Pressor responses to nicotine, both before and during po- Adenosine in plasma extracts was assayed by high-pres- tentiation by adenosine, were almost completely abolished sure liquid chromatography, using a Waters gBondapak C- by pretreatment with hexamethonium bromide (10 mg/kg), 18 reversed-phase column with isocratic elution (10% metha- reserpine (3 mg/kg given 24 and 48 hr before testing), and nol in 10 mM potassium phosphate, pH
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