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Am J Physiol Heart Circ Physiol 291: H467-H472, 2006. First published March 3, 2006; doi:10.1152/ajpheart.01319.2005
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Role of A1 adenosine receptor in the regulation of coronary flow

Huda E. Tawfik, Bunyen Teng, R. Ray Morrison, J. Schnermann, and S. Jamal Mustafa

Department of Pharmacology, Brody School of Medicine, East Carolina University, Greenville, North Carolina

Submitted 14 December 2005 ; accepted in final form 27 February 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
To determine whether A1 adenosine receptors (AR) participate in adenosine-induced changes of coronary flow, isolated hearts from A1AR–/– and A1AR+/+ mice were perfused under constant pressure, and the effects of nonselective and selective agonists were examined. Adenosine, 5'-N-ethylcarboxamidoadenosine (NECA, nonselective), and the selective A2AAR agonist 2–2-carboxyethylphenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680) augmented maximal coronary vasodilation in A1AR–/– hearts compared with A1AR+/+ hearts. Basal coronary flow was increased (P < 0.05) in A1AR–/– hearts compared with A1AR+/+ hearts: 2.548 ± 0.1 vs. 2.059 ± 0.17 ml/min. In addition, selective activation of A1AR with 2-chloro-N6-cyclopentyladenosine (CCPA) at nanomolar concentrations (1–100 nM) did not significantly change coronary flow; at higher concentrations, CCPA increased coronary flow in A1AR–/– and A1AR+/+ hearts. Because deletion of A1AR increased basal coronary flow, it is speculated that this effect is due to removal of an inhibitory influence associated with A1AR. Adenosine and NECA at approximately EC50 (100 and 50 nM, respectively) increased coronary flow in A1AR+/+ hearts to 177.86 ± 8.75 and 172.72 ± 17% of baseline, respectively. In the presence of the selective A1AR antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 50 nM), the adenosine- and NECA-induced increase in coronary flow in A1AR+/+ hearts was significantly augmented to 216.106 ± 8.35 and 201.61 ± 21.89% of normalized baseline values, respectively. The adenosine- and NECA-induced increase in coronary flow in A1AR–/– hearts was not altered by DPCPX. These data indicate that A1AR may inhibit or negatively modulate coronary flow mediated by other AR subtypes (A2A and A2B).

isolated mouse heart; A1 adenosine receptor knockout; adenosine receptor agonists; adenosine receptor antagonists

ADENOSINE IS A POTENT VASODILATOR that acts through four subtypes of surface adenosine receptors (AR): A1, A2A, A2B, and A3. It is well established that adenosine-induced coronary vasodilation is mainly mediated by activation of AR subtype A2A (A2AAR) (1, 8, 9). Recent findings also support the involvement of AR subtype A2B (A2BAR) in adenosine-mediated vasodilation in the coronary vascular bed (10, 24). There is also evidence for the existence of a functional AR subtype A3 (A3AR) in the coronary circulation (33). The expression of AR subtype A1 (A1AR) with the other AR subtypes in the coronary vessels suggests a coregulatory role. However, the relative contribution of A1AR to modulation of coronary circulation remains to be elucidated.

A1AR have been known to protect against the injury caused by myocardial ischemia and reperfusion by inhibiting adenylyl cyclase and activating ATP-dependent potassium channels (15, 16, 23, 36). With increasing interest in the clinical use of adenosine or A1AR agonists to protect ischemic myocardium (13, 14, 18–20), it will be important to determine whether and to what extent selective manipulation (activation/antagonism) of A1AR might affect coronary flow.

The demonstration that A1AR activation induces contraction and reduces A2AAR- and A2BAR-mediated relaxation in mouse aorta (34) suggests that A1AR may indeed modify coronary circulation in a negative manner. Some indirect evidence supports a possible role for A1AR in the coronary circulation. For example, the isolated porcine coronary artery was contracted by the selective A1AR agonist 2-chloro-N6-cyclopentyladenosine (CCPA) (21, 22); this contraction was abolished by the nonselective AR antagonist CGS-15943 and the highly selective A1AR antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (21, 22). More recent evidence supporting a negative coregulatory role of A1AR includes the observation that cyclopentylxanthine, an A1AR-selective antagonist, enhanced adenosine-mediated dilation of human coronary arterioles (27). In the same study, coronary dilation by 2,2-carboxyethylphenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680), a highly selective A2AAR agonist, was attenuated by 2S-N6-(2-endo-norbonyl)adenosine, a selective A1AR agonist.

Most attempts to characterize the function of AR in coronary vessels rely heavily on traditional physiological and pharmacological techniques; however, these approaches are hampered by a general paucity of potent and selective ligands (6, 12). In this study, we combined receptor knockout technology with traditional pharmacological techniques. Thus, to determine whether A1AR activation participates in the regulation of coronary flow, coronary vascular responses to nonselective and selective AR agonists were examined in hearts from A1AR+/+ and A1AR–/– mice. We hypothesized that targeted deletion of A1AR would modulate coronary flow mediated by other AR subtypes.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Langendorff-perfused mouse heart preparation. Hearts were isolated from age-matched (12- to 14-wk-old) A1AR–/– and A1AR+/+ mice as described for A2AAR+/+ and A2AAR–/– mice by Morrison et al. (24). A1AR–/– mice of a mixed C57BL6/129J genetic background were bred at the East Carolina University animal facility as a subcolony of the original A1AR strain maintained at the National Institutes of Health. The generation and initial characterization of the A1AR+/+ and A1AR–/– mice have been described previously (31). Heterozygous (A2AAR+/–) mice were bred to obtain A1AR+/+ and A1AR–/– mice. For PCR genotyping, genomic DNA was isolated from tail snips. DNA fragments of predicted lengths were detected by 1.5% agarose gel electrophoresis and ethidium bromide staining. The mice were kept in community cages with 12:12-h light-dark cycles and maintained on a standard laboratory mouse diet with access to water ad libitum. All animal care and experimentation were approved and carried out in accordance with the East Carolina University Institutional Animal Care and Use Committee and in accordance with the principles and guidelines of the National Institutes of Health "Guide for the Care and Use of Laboratory Animals."

Mice were anesthetized with pentobarbital sodium (100 mg/kg ip). A thoracotomy was performed, and the heart was removed. The hearts were retrogradely perfused at a constant pressure of 80 mmHg with oxygenated Krebs-Henseleit buffer at 37°C in a standard Langendorff fashion and allowed to beat spontaneously. The left ventricle was vented with a small polyethylene apical drain, and a water-filled balloon made of plastic wrap was inserted into the left ventricle across the mitral valve through a left atriotomy. The balloon was connected to a fluid-filled pressure transducer by polyethylene tubing for continuous measurement of left ventricular developed pressure (LVDP).

Coronary flow was continuously measured using an ultrasonic flow probe placed in the aortic perfusion line. Functional data were recorded on an Apple G4 Power Mac computer using Power Lab Chart 3.5.6 software. Baseline coronary flow, LVDP, and heart rate (derived from the ventricular pressure trace) were monitored for an initial 30-min equilibration period. Hearts with persistent arrhythmias or poor LVDP (<80 mmHg) during the equilibration period were excluded from the study (30).

Protocol of agonist dose-response curve. Hearts from A1AR–/– and A1AR+/+ mice of both sexes were equilibrated for 30 min before the experiment. Coronary flow, heart rate, and developed pressure (systolic – diastolic pressure) were recorded from A1AR–/– and A1AR+/+ mouse hearts, and baseline data for these parameters were sampled at the end of the equilibration period. For evaluation of concentration-response relations for adenosine, 5'-N-ethylcarboxamidoadenosine (NECA), CGS-21680, and CCPA (0.1 nM–10 µM), these agonists were infused into the coronary perfusate through an injection port directly proximal to the aortic cannula. The infusion rate was controlled to a maximum of 1% of the total coronary flow by a microinjection infusion pump (7, 24, 33, 34).

After baseline data were acquired, each heart was exposed to progressively increasing concentrations of a single agonist to achieve a concentration-response relation. Each concentration of agonist was infused for 5 min, with plateau effects being achieved uniformly between 3 and 5 min. Data were sampled at the end of the 5-min infusion period. After infusion of each concentration of agonist, a ≥5-min perfusion period was allowed for complete drug washout, with recovery to baseline parameters. Drug infusion and washout periods of 5 min were chosen on the basis of previous studies done in this laboratory (24, 32, 33).

Data were collected at the end of each washout period and used as a reference for normalization of the response to each subsequent agonist concentration. The washout period was sufficient to fully replace the volume of superfusate in the water-jacketed bath (6-ml capacity), ensuring complete clearance of each preceding dose before infusion of a subsequent concentration of agonist (24, 32, 33).

Antagonist experiments. Because preliminary experiments with A1AR–/– hearts demonstrated an increase in baseline coronary flow and developed pressure compared with A1AR+/+ hearts, a subset of experiments were performed in A1AR+/+ hearts to identify the role of A1AR in wild-type animals at unaltered coronary flow and developed pressure. DPCPX, a selective A1AR antagonist, was used for these experiments. A1AR+/+ hearts were dissected, cannulated, and equilibrated as described above. After baseline data for each heart were sampled at the end of the 30-min equilibration period, a nonselective agonist (adenosine or NECA) was infused at 1% of coronary flow for 5 min at an approximate EC50 of 100 nM for adenosine and 50 nM for NECA, and the plateau effects on coronary flow, heart rate, and LVDP were recorded. After 10 min of washout of this initial agonist infusion, 50 nM DPCPX was infused (also at 1% of coronary flow) for 15 min. At 10 min into the DPCPX infusion, data were sampled and normalized as a new "baseline," and 100 nM adenosine or 50 nM NECA was again added to the coronary perfusate for the remaining 5 min of the DPCPX infusion. Data were sampled at the end of these two drug infusions for comparison with data resulting from infusion of the agonists alone.

Data analysis. Values are means ± SE. Baseline functional data and differences in dose responses between A1AR–/– and A1AR+/+ groups at individual agonist concentrations were analyzed by t-test. EC50 values were derived using GraphPad Prism, with EC50 describing the effective concentration mediating 50% of the maximal response and the slope factor indicating the steepness of the dose-response curve. EC50 values from each A1AR–/– and A1AR+/+ group were derived from each group curve fit. Student's t-test and one-way ANOVA were used to analyze coronary flow data. The results were considered significant when P < 0.05.

Chemicals. A stock solution of adenosine (Sigma, St. Louis, MO) was prepared using distilled water. Stock solutions of NECA, CGS-21680, CCPA, and DPCPX (all from Sigma) were prepared in DMSO (Sigma), and serial dilutions to desired concentrations were made in distilled water. It has been shown that DMSO at 1% of coronary flow for 5 min elicited a <5% increase in baseline coronary flow (24).


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Baseline functional parameters in isolated mouse hearts. Baseline functional parameters for A1AR–/– and A1AR+/+ mice (n = 23 in each group) were recorded at the end of the 30-min equilibration period for each heart before initiation of the experimental protocol. Coronary flow (normalized to wet weight of each heart), LVDP, and rate of pressure development (+dP/dt) were significantly higher for A1AR–/– hearts at equilibrium than for A1AR+/+ hearts, whereas heart rate did not differ between A1AR–/– and A1AR+/+ mice (Table 1).


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  		Table 1. Baseline functional data

 
Effects of adenosine and its analogs on coronary flow in A1AR–/– and A1AR+/+ mouse hearts. Adenosine and its analogs NECA and CGS-21680 caused concentration-dependent increases in coronary flow (vasodilation) in isolated A1AR–/– and A1AR+/+ hearts perfused at constant pressure (Figs. 1A, 2A, and 3A). The maximal response to each agonist was higher for A1AR–/– than for A1AR+/+ hearts (P < 0.05). However, the A1AR–/– hearts demonstrated an increase in baseline coronary flow (Table 1).


Figure 1
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  		Fig. 1. Concentration-response curves for adenosine on coronary flow (A) and heart rate (B) in isolated perfused mouse hearts with (A1AR+/+) and without (A1AR–/–) adenosine receptor subtype A1. Values are means ± SE (n = 4). *P < 0.05.

 

Figure 2
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  		Fig. 2. Concentration-response curves for 5'-N-ethylcarboxamidoadenosine (NECA) on coronary flow (A) and heart rate (B) in isolated perfused hearts from A1AR+/+ and A1AR–/– mice. Values are means ± SE (n = 7). *P < 0.05.

 

Figure 3
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  		Fig. 3. Concentration-response curves for 2–2-carboxyethylphenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680) on coronary flow (A) and heart rate (B) in isolated perfused hearts from A1AR+/+ and A1AR–/– mice. Values are means ± SE (n = 6). *P < 0.05.

 
The maximal increase in coronary flow caused by 10 µM adenosine was 37.29 ± 1.4 and 32.31 ± 1.3 ml·min–1·g–1 in A1AR–/– and A1AR+/+ hearts, respectively (P < 0.05; Fig. 1A). However, the coronary vasodilation induced by 10 µM NECA was 31.84 ± 1.3 and 20.37 ± 0.8 ml·min–1·g–1 in A1AR–/– and A1AR+/+ hearts, respectively (P < 0.05; Fig. 2A). Similarly, 10 µM CGS-21680 resulted in a maximal increase in coronary flow of 33.39 ± 0.6 and 27.50 ± 0.6 ml·min–1·g–1 in A1AR–/– and A1AR+/+ hearts, respectively (P < 0.05; Fig. 3A).

The relative order of potency for increases in coronary flow in A1AR+/+ and A1AR–/– hearts based on the EC50 values for each agonist was as follows: CGS-21680 > NECA > adenosine.

On the other hand, 1–100 nM CCPA (a selective A1AR agonist) tended to decrease coronary flow in A1AR+/+ hearts (Fig. 4A). At low doses (1–100 nM), CCPA did not alter coronary flow in A1AR–/– hearts but increased coronary flow at higher doses (1–10 µM; Fig. 4A). The apparent decrease in coronary flow in A1AR+/+ hearts at 10 µM CCPA was likely secondary to profound bradycardia (Fig. 4).


Figure 4
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  		Fig. 4. Concentration-response curves for 2-chloro-N6-cyclopentyladenosine (CCPA) on coronary flow (A) and heart rate (B) in isolated perfused hearts from A1AR+/+ and A1AR–/– mice. Values are means ± SE (n = 6). *P < 0.05.

 
Effects of adenosine and its analogs on heart rate in A1AR–/– and A1AR+/+ mouse hearts. Neither adenosine nor CGS-21680 significantly affected heart rate in A1AR–/– and A1AR+/+ mice, whereas NECA at ≥10 nM significantly decreased heart rate in A1AR+/+ mice (Figs. 1B, 2B, and 3B; P < 0.05). CCPA at ≥10 nM significantly reduced heart rate in A1AR+/+ mice, with prohibitive accompanying dysrhythmias at 1 and 10 µM (Fig. 4B; P < 0.05). Heart rate was not altered by NECA and CCPA in A1AR–/– hearts because of the absence of A1AR (Figs. 2B and 4B).

Effects of A1AR blockade on adenosine- and NECA-induced coronary flow in A1AR+/+ mouse hearts. The influence of DPCPX on coronary flow responses induced by adenosine and NECA was investigated in A1AR+/+ hearts. The approximate EC50 for adenosine (100 nM) and NECA (50 nM) was used for the antagonist experiments. Adenosine at 100 nM increased coronary flow in A1AR+/+ and A1AR–/– hearts to 177.86 ± 8.75 and 156.25 ± 3.5% of baseline, respectively (Fig. 5). NECA (50 nM) increased coronary flow in A1AR+/+ and A1AR–/– hearts to 172.72 ± 17 and 154.4 ± 13.6% of baseline, respectively.


Figure 5
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  		Fig. 5. Effect of 50 nM 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) on adenosine (Ado)-induced (100 nM) increase in coronary flow in hearts from A1AR+/+ (A, n = 7) and A1AR–/– (B, n = 4) mice. Values are means ± SE. *P < 0.05.

 
In the presence of 50 nM DPCPX, adenosine- and NECA-induced coronary flow in A1AR+/+ hearts significantly increased to 216.106 ± 8.35 and 201.61 ± 21.89% of baseline, respectively (Figs. 5A and 6A). In contrast, the adenosine- and NECA-induced increase in coronary flow in A1AR–/– hearts was not altered by DPCPX (Figs. 5B and 6B).


Figure 6
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  		Fig. 6. Effect of DPCPX (50 nM) on NECA-induced (100 nM) increase in coronary flow in hearts from A1AR+/+ (A, n = 9) and A1AR–/– (B, n = 7) mice. Values are means ± SE. *P < 0.05.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
There is little information regarding the role of A1AR in adenosine-mediated changes of coronary flow. The physiological significance of A1AR in the coronary vasculature remains controversial. Studies using selective A1AR antagonists such as DPCPX have questioned the presence of "functional" A1AR in the coronary vasculature (3, 35). Furthermore, Hinschen et al. (10) reported that DPCPX failed to modify the potency of NECA at the high- and low-affinity sites and the magnitude of the response in young rat hearts. In contrast, Dart and Standen (4) showed that A1AR might cause vasodilation via activation of potassium channels in porcine coronary arteries. In other studies, functional A1AR are more likely to mediate vasoconstriction as shown by Stogall and Shaw (29) in guinea pig aorta, Merkel et al. (21) in porcine coronary arteries, and Prentice et al. (26) in mouse aorta and, more recently, in A1AR+/+ compared with A1AR–/– mouse aorta (34). One explanation for these varied findings with antagonists involves mixed selectivity and potency of the agents that were used. In the present study, we provide the first evidence that genetic deletion of A1AR significantly limits the vasodilator potency of A2AAR and A2BAR agonists in the coronary circulation. We tested the effect of the nonselective agonists adenosine and NECA in A1AR–/– and A1AR+/+ hearts. Both agonists increased coronary flow to a greater maximum level in A1AR–/– than in A1AR+/+ hearts.

In view of the predominant expression of A2AAR in the coronary circulation, we tested the vasodilator potency of CGS-21680 in A1AR–/– and A1AR+/+ hearts. In earlier studies, A1AR activation attenuated adenosine- and CGS-21680-induced coronary vasodilation in isolated human coronary arterioles (27), whereas CCPA reduced coronary flow in guinea pig isolated working hearts in the absence of endothelium (17). Also, cyclopentylxanthine (an A1AR antagonist) blocked adenosine-induced decreases in coronary flow in goat hyperemic hearts (25). Our results showed that NECA and CGS-21680 increased maximum coronary flow in A1AR–/– compared with A1AR+/+ mice. These data suggest a negative modulatory role for A1AR in A2A and A2B-mediated coronary flow in isolated mouse hearts.

It is well documented that A1AR activation elicits negative inotropic and antiadrenergic effects in the heart (5, 11, 28). In this study, a highly selective A1AR agonist, CCPA, was used to study the effect of A1AR activation in A1AR+/+ and A1AR–/– hearts. At low concentrations (10 and 100 nM), CCPA tended to reduce coronary flow in A1AR+/+, but not in A1AR–/–, hearts. The apparent reduction in coronary flow in A1AR+/+ hearts was accompanied by bradycardia. Thus it is possible that the effect of A1AR on coronary flow was masked by more profound effects on heart rate and developed pressure.

Although we found that baseline coronary flow was greater in A1AR–/– than in A1AR+/+ hearts (Table 1), the baseline flow rates for both groups were within the range of those observed in this well-characterized model of constant-pressure-perfused, isovolumically contracting isolated mouse hearts (2, 7). Hearts from A1AR–/– and A1AR+/+ mice demonstrated submaximal coronary dilation at baseline (see starting agonist concentrations in Figs. 1A, 2A, and 3A). Because concentration-response experiments in A1AR–/– hearts were begun at a higher coronary flow baseline, in A1AR–/– hearts were also nearer to maximal agonist-induced coronary dilation. That is, by virtue of a higher baseline coronary flow, the coronary reserve for adenosine-induced vasodilation may be limited in A1AR–/– hearts (2).

Because we observed an increase in baseline coronary flow in A1AR–/– hearts, we examined blockade of A1AR in genetically unmodified hearts to determine whether A1AR has an impact on mouse coronary flow. At concentrations of adenosine and NECA near EC50 for coronary dilation (100 and 50 nM, respectively), 50 nM DPCPX (a selective A1AR antagonist) significantly increased adenosine- and NECA-mediated coronary flow in A1AR+/+ hearts, whereas it had no effect in A1AR–/– hearts (Figs. 5B and 6B). The most likely explanation for this observation is the removal of the negative modulatory effect of A1AR in A1AR–/– hearts.

The most remarkable finding in the present study was that targeted deletion of A1AR resulted in an increase in CGS-21680-mediated coronary flow. Also, deletion of A1AR resulted in an increase in basal coronary flow in isolated mouse heart. This finding is further supported by the observation that, in A1AR+/+ hearts, blockade of A1AR with DPCPX increased adenosine- and NECA-mediated coronary flow. The mechanism by which deletion of A1AR increases basal coronary flow may be removal of an inhibitory influence at the level of intracellular signaling pathways in coronary vascular smooth muscle or endothelial cells, resulting in increases in coronary flow. These data suggest that A1AR activation negatively modulates coronary vasodilation produced by stimulation of A2AR in isolated mouse hearts.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported in part by National Heart, Lung, and Blood Institute Grant HL-027339.


   ACKNOWLEDGMENTS
 
Present addresses: H. E. Tawfik, Dept. of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912; B. Teng and S. J. Mustafa, Dept. of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, WV 26505; R. R. Morrison, Div. of Critical Care Medicine, St. Jude Children's Research Hospital, Memphis, TN 38105; and J. Schnermann, NIDDK/NIH, Bldg. 10, Rm. 4D51, Bethesda, MD 20892.


   FOOTNOTES
 

Address for reprint requests and other correspondence: S. J. Mustafa, WVU Health Sciences Center, 2267 Health Sciences South, PO Box 9104, Morgantown WV 26506-9104 (e-mail: smustafa{at}hsc.wvu.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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