PubMed · 1754287
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E Farrington. Adenosine.. https://pubmed.ncbi.nlm.nih.gov/1754287/
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OBJECTIVES: This study examined whether stimulation of adenosine receptors before ischemia enhances myocardial resistance to stunning in vivo. BACKGROUND: We previously demonstrated the attenuation of myocardial stunning by ischemic preconditioning through adenosine receptor activation in rabbits. METHODS: 1) To confirm the efficacy of an intravenous infusion of adenosine to stimulate adenosine receptors in the heart, we assessed the effect of an adenosine infusion on the inotropic response to an isoproterenol challenge. 2) Myocardial stunning was induced by 10 min of coronary occlusion and reperfusion. The regional thickening fraction was monitored by an epicardial Doppler sensor. Rabbits were pretreated with either no drug (control group), adenosine, 8-phenyltheophylline or a combination of 8-phenyltheophylline plus adenosine. RESULTS: An intravenous infusion of adenosine at 0.15 mg/kg body weight per min attenuated by 50% the elevation of left ventricular dP/dtmax by isoproterenol (0.075 microgram/kg per min). The same dose of adenosine infused for 15 min before ischemia significantly improved the postischemic recovery of the thickening fraction, and the thickening fraction at 30 min reperfusion was 76.8 +/- 3.3% (mean +/- SE) of the baseline value, which was significantly higher than the control value (42.9 +/- 4.5%). The relation between thickening fraction and systolic left ventricular pressure after reperfusion was shifted toward higher thickening fraction by adenosine. This beneficial effect of adenosine was not detected in rabbits given 8-phenyltheophylline before adenosine, and 8-phenyltheophylline-treated rabbits showed a time course of thickening fraction similar to that in the control group. CONCLUSIONS: An intravenous infusion of adenosine is capable of protecting rabbit hearts against stunning through adenosine receptor activation.
A3 adenosine receptor (A3AR) activation contributes to both the cardioprotective and antihypertensive effects of adenosine. To date, no studies have examined the mechanisms by which this receptor undergoes rapid homologous desensitization. Therefore, a functional hemagglutinin epitope-tagged A3AR has been stably expressed in Chinese hamster ovary cells, and its regulation by the AR agonist 5'-N-ethylcarboxamidoadenosine (NECA) has been studied. Cellular exposure to NECA induces rapid (t1/2 = approximately 1 min) A3AR phosphorylation on serine and threonine residues. This is associated with a functional desensitization and a 30-40% reduction in the number of high affinity agonist binding sites as determined by radioligand binding assays. Activation of second messenger-regulated kinases could not mimic the effect of NECA, suggesting a role for G-protein-coupled receptor kinases (GRKs). In vitro phosphorylation assays demonstrate that phosphorylation of agonist-occupied A3ARs is enhanced by GRK2 and that cellular pretreatment with NECA dramatically inhibits subsequent GRK2-mediated phosphorylation in vitro. Therefore, the A3AR is phosphorylated in situ by a kinase similar or identical to GRK2, and this may be involved in rapid functional desensitization of the A3AR.
BACKGROUND: Fractional flow reserve (FFR), defined as the ratio of maximum flow in the presence of a stenosis to normal maximum flow, is a lesion-specific index of stenosis severity that can be calculated by simultaneous measurement of mean arterial, distal coronary, and central venous pressure (Pa, Pd, and Pv, respectively), during pharmacological vasodilation. The aims of this study were to define ranges of FFR values, whether associated with inducible ischemia or not, and to investigate FFR in normal coronary arteries. METHODS AND RESULTS: In 60 patients accepted for percutaneous transluminal coronary angioplasty (PTCA) of single-vessel disease, with a positive exercise test (ET) < 24 hours before PTCA, FFR was determined during adenosine-induced hyperemia just before and 15 minutes after angioplasty. Pa was measured by the guiding catheter, Pd by an 0.018-in fiber-optic pressure-monitoring wire, and Pv, by a multipurpose catheter. The ET was repeated after 5 to 7 days, and only if this second ET had reverted to normal was the pre-PTCA value of FFR definitely considered to be associated with inducible ischemia and the post-PTCA value not. Myocardial FFR (FFRmyo) increased from 0.53 +/- 0.15 before PTCA to 0.88 +/- 0.07 after PTCA. Coronary FFR increased from 0.38 +/- 0.19 to 0.83 +/- 0.12. In all patients, values of FFRmyo definitely associated with ischemia were < or = 0.74, whereas all except two values not associated with inducible ischemia exceeded 0.74. Moreover, FFRmyo in 18 coronary arteries in 5 normal patients equaled 0.98 +/- 0.03. CONCLUSIONS: A value of FFRmyo of 0.74 reliably discriminates coronary stenosis, whether associated with inducible ischemia or not. Therefore, FFRmyo is a useful index to determine the functional significance of an epicardial coronary stenosis and may facilitate clinical decision making in patients with an equivocal coronary stenosis.