Role of Adenosine in Postischemic Dysfunction of Coronary Innervation
Abstract We sought to determine the role of adenosine in the sustained but reversible decrease in cardiac neurotransmission that occurs after brief ischemia. Adult mongrel dogs were anesthetized and instrumented for measurements of heart rate, arterial pressure, and left anterior descending coronary artery (LAD) and left circumflex coronary artery (LCX) flow velocities. Changes in coronary vascular resistance were measured during bilateral stimulation of the stellate ganglia. After β-adrenergic blockade and bilateral vagotomy, stellate stimulation increased coronary vascular resistance in the LAD and LCX beds 28±2% and 30±3%, respectively. After a 15-minute infusion of adenosine into the LAD, the peak increase in LAD resistance was significantly reduced (18±2%) compared with LCX (34±5%) and control (P<.05, n=6) resistance. The LAD response after infusion of the vasodilator papaverine was unchanged (n=6). Intracoronary infusion of adenosine deaminase (n=10) but not vehicle (n=5) into the LAD during a 15-minute LAD occlusion prevented the attenuation in constriction to stellate stimulation. We conclude that adenosine, exogenously infused or endogenously produced, is capable of reducing cardiac neurotransmission.
- sympathetic coronary vasoconstriction
- myocardial ischemia
- left anterior descending coronary artery
- left circumflex coronary artery
Brief periods of coronary occlusion, lasting <20 minutes, are not associated with necrosis of the myocardium1 2 but are capable of producing changes in cardiac function. During reperfusion, a marked and long-lasting reduction in myocardial contractility occurs.1 3 4 5 This temporary and reversible reduction in myocardial function has been termed “myocardial stunning” and has been the subject of recent intense investigation.
In addition to its effect on the myocardium, evidence has been emerging that neurotransmission is also impaired in the postischemic heart (“neural stunning”). Brief periods of ischemia have been shown to reduce inotropic6 7 and coronary vasoconstrictor8 responses to sympathetic stimulation and to reduce sympathetic and vagal reflex responses to bradykinin and nicotine.9 In all of these studies, reduced neural responsiveness begins during ischemia and lasts for up to several hours into the reperfusion period.
The mechanism of ischemic impairment of cardiac neurotransmission is unknown. Nervous tissue is typically quite resistant to anoxic or ischemic damage.10 However, in the heart, nerves exist among other metabolically active tissues that tolerate ischemia poorly and release metabolites, such as adenosine, potassium, and hydrogen ions, that could adversely affect neurotransmission. Indeed, epicardial superfusion of adenosine alone or in combination with other metabolic products from ischemic myocardium is capable of reducing efferent sympathetic and vagal neurotransmission during and after washout of the superfusate.11
Although these experiments provide indirect evidence that adenosine is involved in neural stunning, its role has not been directly examined. Therefore, we tested two hypotheses: (1) Intracoronary infusion of exogenous adenosine is capable of producing sustained impairment of sympathetic coronary vasoconstriction. (2) The postischemic attenuation in neurogenic coronary vasoconstriction is reduced by modulation of endogenous adenosine produced during the ischemic period.
Materials and Methods
In adult mongrel dogs (18 to 25 kg) of either sex, anesthesia was induced by sodium thiopental (25 mg/kg) and maintained with α-chloralose (45 mg/kg IV). Supplemental α-chloralose (20 mg/kg) was administered to prevent reflex pressor responses to skin pinch and to suppress corneal reflexes. Arterial blood gases were sampled for measurement of Po2, Pco2, and pH. Parameters were maintained within normal limits by adjusting ventilatory rate and supplemental oxygen delivery and by intravenous administration of sodium bicarbonate (2 mEq/kg). All procedures and protocols were approved in advance by the University of Iowa animal care and use committee and conform with Public Health Service guidelines for use of animals in research.
Arterial blood pressure was measured with a transducer connected to a polyethylene catheter inserted into the right femoral artery. The phasic pressure signal was directed to two couplers for measurements of phasic and mean arterial pressure and to a cardiotachometer for recording heart rate. Another polyethylene cannula was inserted into the right femoral vein for administration of fluids and pharmacological agents.
Through a ventral neck incision, both cervical vagi were isolated and transected. The heart was exposed by removing the second through fifth left ribs. The stellate ganglia were isolated, secured within a pair of bipolar microstimulating electrodes, and covered with gauze soaked in mineral oil. Stimulation parameters were 10-V 1.0-millisecond pulses at 10 Hz (10-second duration). A 24-gauge Teflon angiocatheter was secured retrogradely into the proximal left anterior descending coronary artery (LAD) and left circumflex coronary artery (LCX) for intracoronary administration of pharmacological agents. These catheters, which do not impair reactive hyperemic responses to 15 seconds of coronary occlusion, were flushed with heparinized warmed saline.
Coronary blood flow velocities were measured in both the LAD and LCX with suction-applied epicardial Doppler flow probes designed at the University of Iowa.12 13 Briefly, a 20-MHz piezoelectric crystal was mounted at a 45° angle in a silastic cupped housing and held to the epicardial surface by use of suction (4 mm Hg). This probe minimizes the risk of coronary denervation from surgical isolation of the vessels required for circumferential probes. Reproducible zero-flow velocities and reactive hyperemic responses >3:1 are regularly achieved with this probe.12 Changes in flow velocity correlate well with absolute changes in flow when measured with timed venous collections, radiolabeled microspheres, and electromagnetic flow probes.12 13 The probes were attached distal to the sites of cannulation on the LAD and LCX.
Phasic arterial pressure, mean arterial pressure, heart rate, and LAD and LCX blood flow velocities were continuously recorded on an eight-channel chart recorder. Data were tabulated from the recorded output and were analyzed by computer.
In seven dogs, 15-μm-diameter microspheres labeled with 46Sc, 85Sr, 141Ce, or 95Nb were used to determine baseline myocardial perfusion and to measure the reduction in flow during coronary occlusion. The methods used have been described previously.14 Briefly, more than 106 microspheres were agitated for 5 minutes before injection into the left atrium. Reference blood samples were drawn from the proximal and distal aorta at 4.94 mL/min for 90 seconds beginning 10 seconds before the injection of microspheres.
After instrumentation, propranolol was administered to minimize changes in myocardial metabolism during sympathetic stimulation. The dose of propranolol used (2 mg/kg IV) was sufficient to block the tachycardia to isoproterenol (3.5 μg IV).8 Supplemental bolus injections were given periodically throughout the experiment.
In six dogs, the effect of exogenously administered adenosine on sympathetic coronary vasoconstriction was tested (Fig 1⇓). Baseline arterial pressure, heart rate, and coronary flow velocities in the LAD and LCX beds were determined. Next, a series of two or three separate stellate stimulations was made. A maximally vasodilating dose of adenosine (0.75 mg/min) was then infused into the LAD, while saline was infused into the LCX control bed, for 15 minutes. Baseline coronary flow was reestablished ≈3 minutes after stopping the infusion. A repeat series of stellate stimulations was then performed at time periods of 15, 30, 45, and 60 minutes after cessation of the adenosine infusion.
In separate control experiments, 10 dogs underwent a similar protocol with infusion of the vasodilator papaverine (7.5 mg/min) instead of adenosine. In these dogs, the LAD response to stellate stimulation was measured before and 15, 30, and 60 minutes after the 15-minute infusion period. Not all time periods following ischemia were tested in each experiment. Therefore, the number of dogs at each time point varies.
In 16 dogs, the enzyme adenosine deaminase (ADA) was administered to determine if modulation of endogenous adenosine could affect the postischemic changes in neurogenic coronary vasoconstriction (Fig 1⇑). In these dogs, baseline measurements of arterial pressure, heart rate, and LAD coronary flow velocity were made. Two or three stellate stimulations and three bolus intracoronary injections of adenosine (1 μg in 0.05 cm3 saline) were given, and the resultant changes in coronary flow velocity were measured. ADA (5 U/kg per minute), dissolved in a vehicle of 0.2 mmol/L Na2HPO4 and 120 mmol/L NaCl, was infused into the LAD for 10 minutes. Three intracoronary injections of adenosine were then given to test the effects of the dose of ADA. The ADA infusion was then resumed for a period of 25 minutes, beginning 5 minutes before and ending 5 minutes after a 15-minute LAD occlusion. The LAD was occluded just proximal to the site of cannulation with a cotton-tipped swab by applying the minimum amount of pressure that reduces the coronary flow velocity to zero.8 Lidocaine (2%, 2 mL IV) and heparin (1000 U/mL, 4 mL IV) were given 1 minute before the occlusion. An additional 1 mL of lidocaine was administered before releasing the occlusion. Fifteen minutes later, when hemodynamics had reached baseline, the response to stellate stimulation and intracoronary adenosine was again measured. These measurements were repeated 60 minutes after the release of the occlusion.
In five dogs, a similar protocol used vehicle rather that ADA. Responses to stellate stimulation and intracoronary adenosine were measured before the occlusion and at 15 minutes and 1 hour after release.
Criteria for Acceptable Study
Animals included for data analysis met the following criteria: mean arterial pressure of >65 mm2 Hg, arterial pH of 7.35 to 7.45, Pco2 of 30 to 40 mm Hg, Po2 of >70 mm Hg, LAD and LCX flow signals with a signal to noise ratio of >20, reactive hyperemia to a 15-second coronary occlusion of >3.0:1, and reproducible hemodynamic and coronary responses to pharmacological agents and stellate stimulations.
All analyses (except baseline measurements) were made by using changes in coronary flow velocity and changes in calculated coronary vascular resistance index (CVRI) rather than absolute numerical values. Percent changes in CVRI were calculated by using the following formula: where P1 is baseline arterial pressure, P2 is arterial pressure at the time of the maximum decrease in coronary flow, F1 is baseline blood flow velocity, and F2 is blood flow velocity measured simultaneously with P2. Values from two or three stimulations were averaged for analysis.
Differences between baseline hemodynamics during control conditions and after interventions were detected by Student’s two-tailed t test. In cases where multiple measurements were made over time, a repeated-measures ANOVA was used so that each animal served as its own control. Post hoc determination of significant differences was tested by the Student-Newman-Keuls multiple comparison test. Statistical significance is defined as P<.05. Data are presented as mean±SEM.
Effect of Infused Adenosine
After β-adrenergic blockade, electrical stimulation produced no change in heart rate, a variable but minimal change in arterial pressure, and an early and transient peak increase in coronary vascular resistance in both the LAD (peak increase, 28±2%) and LCX (peak increase, 30±3%) beds (Fig 2⇓, Table 1⇓).
Fifteen minutes after cessation of a 15-minute infusion of adenosine into the LAD, baseline heart rate and arterial pressure returned to normal (Table 1⇑). Coronary vasoconstriction in the LCX control bed remained unchanged. However, when compared with the value before the infusion of adenosine, constriction in the LAD bed was markedly reduced (18±2% peak increase in resistance 15 minutes after terminating the infusion; P<.05 versus before infusion and versus LCX bed). The response to stellate stimulation in the LAD bed was also significantly depressed compared with the control value and with response in the LCX bed 30, 45, and 60 minutes after the infusion (Fig 3⇓).
To determine if the impaired neurogenic coronary constriction was due to the preceding sustained coronary vasodilation, papaverine, a vasodilator with a mechanism of action different from that of adenosine, was infused into the LAD in five dogs by using a similar protocol. Baseline hemodynamics were unchanged before and after infusion (Table 1⇑). The increase in coronary vascular resistance before and 15 minutes after infusion (27±2% and 27±6%, respectively) did not differ (Figs 1⇑ and 3⇑; Table 1⇑). The neural constriction was maintained. These data show that adenosine, but not papaverine, is capable of attenuating coronary vasoconstriction to stellate stimulation.
Effect of Lowering Endogenous Levels of Adenosine During Coronary Occlusion
In 10 dogs, ADA was infused into the LAD before and during a 15-minute LAD occlusion. Before the occlusion, baseline myocardial perfusion was 107±11 mL/min per 100 g in the LAD region and 124±11 mL/min per 100 g in the LCX region. Stellate stimulation produced an increase in LAD resistance of 31±5%. After the start of ADA but before LAD occlusion, repeat stellate stimulation decreased coronary flow in LAD and LCX beds in a similar fashion, indicating no direct effect of ADA on the stellate response (Table 2⇓). During the LAD occlusion, coronary flow in the LAD territory was reduced to 16±6 mL/min per 100 g, whereas flow to the LCX region was unchanged (118±15 mL/min per 100 g). After 15 minutes of occlusion and reperfusion, baseline heart rate and arterial pressure were unchanged (Table 2⇓). Coronary vasoconstriction in the LAD bed was also unchanged (34±6% increase after occlusion) (Fig 4⇓). The constriction after 60 minutes of reperfusion was also unchanged compared with the control value (Table 2⇓, Fig 5⇓).
Since ADA was infused into the LAD bed during coronary occlusion, it is possible that the infused volume rather than a direct effect of ADA was responsible for attenuating the neural stunning. Therefore, infusing vehicle rather than ADA, we studied five dogs in a similar protocol. Before occlusion, stellate stimulation increased LAD resistance by 37±6% compared with baseline. Fifteen minutes into reperfusion, baseline hemodynamics were unchanged (Table 2⇑). However, the response to stellate stimulation was significantly reduced (12±2% increase in resistance) compared with the control value and with ADA infusion (Table 2⇑, Fig 5⇑). The response to sympathetic stimulation at 60 minutes was also reduced compared with the control value and with the response after ADA infusion. These data show that ADA, but not vehicle alone, is capable of preserving neurogenic coronary vasoconstriction after coronary occlusion.
To determine if the dose of ADA used was sufficient to reduce the effects of exogenous adenosine, intracoronary bolus doses of adenosine (1 μg) were given, and the resulting vasodilation was measured. Before ADA, adenosine caused a transient but marked decrease in LAD resistance (−43±3% compared with baseline). After ADA, the vasodilator response was significantly reduced (−5±3%) compared with the control value and compared with the response after the administration of vehicle. The response to adenosine remained impaired at 15 and 60 minutes after release of the LAD occlusion (Fig 6⇓). These data demonstrate the effectiveness of the administered dose of ADA and indicate that its effect was present throughout the experimental protocol.
The major findings in the present study are as follows: (1) Intracoronary infusion of exogenous adenosine is capable of producing a sustained reduction in sympathetic coronary vasoconstriction. (2) Reducing the levels of endogenous adenosine, generated during coronary occlusion, prevents the attenuation of sympathetic constriction normally seen after brief ischemia. These findings are significant in that this is the first study to directly implicate adenosine as a mediator of neural stunning.
In the case of exogenously administered adenosine, the reduced neurotransmission was not due to the preceding episode of vasodilation. Papaverine was used to produce a similar state of vasodilation. However, sympathetic coronary vasoconstriction was unchanged after papaverine. In both cases, the dose of the drug was the minimal dose needed to produce maximal vasodilation and abolish reactive hyperemia.
A dose of ADA similar to that used in the present study has previously been shown to reduce myocardial interstitial adenosine levels to near zero.15 In the present study, ADA was shown to impair the coronary dilation to exogenously applied adenosine. This effect was of long duration, lasting for at least an hour after the infusion. The ability of ADA to preserve neural function was not due simply to the washout of metabolites produced during the occlusion. Vehicle, infused at an identical rate, did not prevent attenuation of efferent sympathetic function in the heart.
Regional myocardial function was not directly measured in the present study. However, the magnitude of the reduction in myocardial perfusion to the LAD territory was markedly reduced to ischemic levels (16±6 mL/min per 100 g). We have previously demonstrated myocardial stunning in a similar canine preparation after a 15-minute LAD occlusion.
We measured coronary flow velocity rather than absolute coronary flow in the present study for several reasons. First, with the epicardially attached probe, we avoid the potential for denervation that accompanies circumferentially attached probes. Second, changes in coronary flow velocity have been extensively validated as providing accurate estimates of changes in absolute flow.12 13 Third, in the anesthetized model, neural activation produces a characteristic transient vasoconstriction, which is readily seen when using the Doppler technique but which might not be detected when using methods with given time constraints, such as techniques involving microspheres. We limit our measurements to the initial few seconds of neural activation (when maximal changes in coronary resistance occur) before the appearance of marked increases in arterial pressure, which may independently alter coronary vascular resistance.
In calculating changes in coronary vascular resistance, we incorporated changes in perfusion pressure and flow but did not account for changes in back pressure to coronary flow. The true back pressure is not directly measurable and depends on left atrial pressure, intramural myocardial pressure, coronary capacitance, degree of ambient vasomotor tone, and left ventricular end-diastolic pressure.16 17 We assume that changes in back pressure are similar among interventions; thus, changes in calculated coronary resistance primarily reflect changes in vasomotor tone rather than changes in transmural pressure gradient due to increases or decreases in back pressure.
The present study provides intriguing data regarding the potentially divergent mechanisms of myocardial and neural stunning. Brief ischemia impairs both neural and myocardial function.3 6 8 9 18 19 Interventions such as preconditioning ischemia have demonstrated protection to both the myocardium20 21 and the cardiac nerves.22 However, unlike the depressant effect on the cardiac nerves seen in the present study, adenosine acts to protect myocardial function during reperfusion.1 23 24 The significance of these different effects of adenosine on the myocardium and cardiac nerves remains unclear.
The mechanism by which adenosine is able to suppress neural function is unknown. However, several possibilities exist. It is possible that postjunctional responses are altered. However, in experiments showing reduced inotropic and vasoconstrictor responses to sympathetic stimulation, exogenous norepinephrine produced normal responses.6 8 Thus, end-organ function is normal, excluding this mechanism.
Depletion of prejunctional stores of catecholamines is also not likely responsible. There is only a small depletion of norepinephrine after a 30-minute period of ischemia.25 Tyramine displaces normal amounts of norepinephrine from nerve terminals that have been exposed to adenosine.26 Finally, cardiac effects of bretylium and tyramine are not altered by this model of ischemia and reperfusion.8
Adenosine has been shown to markedly inhibit the release of norepinephrine evoked by nerve depolarization during electrical stimulation and administration of potassium.26 However, this inhibitory effect disappears quickly with removal of the adenosine. Since adenosine levels rapidly fall to normal during reperfusion,27 28 this mechanism is most likely effective only during ischemia and is not responsible for the prolonged state of denervation seen during reperfusion. In addition, afferent nerves are also susceptible to stunning,29 demonstrating that a mechanism of action other than inhibition of prejunctional release of neurotransmitter must be involved.
Impaired axonal conduction is a likely mechanism of impaired neurotransmission during reperfusion. Ischemia, but not anoxia, has been shown to increase threshold potentials and delay conduction in nerve axons.10 Other evidence is provided by the fact that ischemia or perfusion of solutions containing a high concentration of adenosine, along with other metabolic products, into a diagonal branch of the LAD is capable of reducing the sympathetic induced shortening of the effective refractory period at sites in the myocardium apical to the ischemic or perfused regions.11
Our data, together with data from Miyazaki and Zipes,11 implicate adenosine as a mediator of sustained neural dysfunction following brief ischemia. Thus, neural responsiveness is impaired during reperfusion, when adenosine levels have presumably returned to normal. This prolonged effect on neural conduction may involve one or more of several mechanisms, including initial stimulation of a second-messenger system that remains activated long after removal of the adenosine agonist. Alternatively, secondary products of adenosine metabolism, such as inosine or hypoxanthine, may be retained in the tissue or induce long-lasting effects. Finally, adenosine may act directly to alter the gating of potassium channels, producing sustained changes in ionic constituents of the axonal membrane that impair neurotransmission.30 The present investigation does not address these potential secondary mechanisms.
The present study has implications regarding the pathogenesis and treatment of the complications of coronary artery disease, including ventricular arrhythmias and abnormal coronary perfusion. After periods of ischemia, an imbalance could occur between the neurally stunned regions of the heart and the remaining areas. Preliminary studies suggest that vagal fibers are more sensitive to the effects of ischemia than are sympathetic fibers.31 These heterogeneous patterns of innervation enhance the propensity for ventricular arrhythmias. Thus, affected regions of myocardium may have a relative imbalance of autonomic innervation with a preponderance of sympathetic influence.
In terms of coronary flow, neural stunning may have the beneficial effect of preventing sympathetic vasoconstriction, which in the setting of an upstream coronary stenosis is capable of overpowering metabolic vasodilator mechanisms.32 Thus, stunning would prevent further reductions in flow to regions of the myocardium distal to the stenosis by temporarily inhibiting distal coronary constriction.
On the other hand, sympathetic coronary vasoconstriction has been shown to provide the beneficial effect of redistributing blood flow to the subendocardium during conditions of hypoperfusion.24 Stunning would be expected to reduce this effect and increase the amount of transmural steal. Compensatory redistribution of blood flow during exercise might also be impaired in stunned myocardium.33
In conclusion, adenosine applied exogenously or produced during coronary artery occlusion is capable of attenuating neurogenic coronary vasoconstriction. This is a sustained effect lasting well into the reperfusion period.
This study was supported by Grants-in-Aid from the Iowa Affiliate, Inc, and the National Center of the American Heart Association and by a VA Merit Review Award. The authors wish to acknowledge the expert technical assistance of Joann Leibold and Angie Goodson and the secretarial help provided by Marlene Blakley.
- Received June 8, 1994.
- Accepted September 14, 1994.
- © 1995 American Heart Association, Inc.
Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wavefront phenomenon of ischemic cell death, I: myocardial infarct size vs duration of coronary occlusion in dogs. Circulation. 1977;56:786-794.
Heyndrickx GR, Baig H, Nellens P, Leusen I, Fishbein MC, Vatner SF. Depression of regional blood flow and wall thickening after brief coronary occlusions. Am J Physiol. 1978;234:H653-H659.
Heyndrickx GR, Millard RW, McRitchie RJ, Maroko PR, Vatner SF. Regional myocardial functional and electrophysiological alterations after brief coronary artery occlusion in conscious dogs. J Clin Invest. 1975;56:978-985.
Ciuffo AA, Ouyang P, Becker LC, Levin L, Weisfeldt ML. Reduction of sympathetic inotropic response after ischemia in dogs. J Clin Invest. 1985;75:1504-1509.
Gutterman DD, Morgan DA, Miller FJ. Effect of brief myocardial ischemia on sympathetic coronary vasoconstriction. Circ Res. 1992;71:960-969.
Inoue H, Skale BT, Zipes DP. Effects of ischemia on cardiac afferent sympathetic and vagal reflexes in dog. Am J Physiol. 1988;255:H26-H35.
Miyazaki T, Zipes DP. Presynaptic modulation of efferent sympathetic and vagal neurotransmission in the canine heart by hypoxia, high K+, low pH, and adenosine. Circ Res. 1990;66:289-301.
Marcus ML, Wright CB, Doty DB, Eastham CL, Laughlin DE, Krumm P, Fastenow CF, Brody MJ. Measurements of coronary velocity and reactive hyperemia in the coronary circulation of humans. Circ Res. 1981;49:877-891.
Wangler RD, Peters KG, Laughlin DE, Tomanek RJ, Marcus ML. A method for continuously assessing coronary blood flow velocity in the rat. Am J Physiol. 1981;241:H816-H820.
Gutterman DD, Chilian WM, Eastham CL, Inou T, White CW, Marcus ML. Failure of pyruvate to salvage myocardium after prolonged ischemia. Am J Physiol. 1986;250:H114-H120.
Hanley FL, Grattan MT, Stevens MB, Hoffman JIE. Role of adenosine in coronary autoregulation. Am J Physiol. 1986;250:H558-H566.
Marcus ML. Autoregulation in the coronary circulation. In: Brehm JJ, Schwartz M, eds. The Coronary Circulation in Health and Disease. New York, NY: McGraw-Hill Publishing Co; 1983:93-112.
Feigl EO. Coronary physiology. Physiol Rev. 1983;63:1-205.
Aksnes G, Kirkeboen KA, Christensen G, Ilebekk A. Characteristics and development of myocardial stunning in the pig. Am J Physiol. 1992;263:H544-H551.
Zipes DP. Influence of myocardial ischemia and infarction on autonomic innervation of heart. Circulation. 1990;82:1097-1105.
Schott RJ, Rohmann S, Braun ER, Schaper W. Ischemic preconditioning reduces infarct size in swine myocardium. Circ Res. 1990;66:1133-1142.
Murray CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124-1136.
Gutterman DD, Bonham AC, Arthur JM, Gebhart GF, Marcus ML, Brody MJ. Central neural regulation of coronary blood flow. In: Buckley JP, Ferrario CM, eds. Brain Peptides and Catecholamines in Cardiovascular Regulation. New York, NY: Raven Press Publishers; 1987:125-135.
Grover GJ, Sleph PG, Dzwonczyk S. Role of myocardial ATP-sensitive potassium channels in mediating preconditioning in the dog heart and their possible interaction with adenosine A1-receptors. Circulation. 1992;86:1310-1316.
Nathan HJ, Feigl EO. Adrenergic vasoconstriction lessens transmural steal during coronary hypoperfusion. Am J Physiol. 1986;250:H645-H653.
Verhaeghe RH, Vanhoutte PM, Shepherd JT. Inhibition of sympathetic neurotransmission in canine blood vessels by adenosine and adenine nucleotides. Circ Res. 1977;40:208-215. Abstract.
Fenton RA, Dobson JG Jr. Measurement by fluorescence of interstitial adenosine levels in normoxic, hypoxic, and ischemic perfused rat hearts. Circ Res. 1987;60:177-184.
Headrick JP, Willis RJ. Adenosine formation and energy metabolism: a P-NMR study in isolated rat heart. Am J Physiol. 1990;258:H617-H624.
Cohen RA. Adenine nucleotides and 5-hydroxytryptamine released by aggregating platelets inhibit adrenergic neurotransmission in canine coronary artery. J Clin Invest. 1986;77:369-375.
Nichols CG, Lederer WJ. Adenosine triphosphate-sensitive potassium channels in the cardiovascular system. Am J Physiol. 1991;261:H1675-H1686.
Gutterman DD, Ben-Haim S, Simon M, Morgan DA. Brief myocardial ischemia alters the coronary vascular response to vagal stimulation. FASEB J. 1990;4:A402. Abstract.
Heusch G, Deussen A. The effects of cardiac sympathetic nerve stimulation on perfusion of stenotic coronary arteries in the dog. Circ Res. 1983;53:8-15.
Huang AH, Feigl EO. Adrenergic coronary vasoconstriction helps maintain uniform transmural blood flow distribution during exercise. Circ Res. 1988;62:286-298.