thioinosine and Ventricular-Fibrillation

To determine the role of the p-nitrobenzylthioinosine-sensitive equilibrative nucleoside transporter 1 (es-ENT1) in postmyocardial infarction reperfusion injury-mediated ventricular fibrillation and regional dysfunction. We used erythro-9 (2-hydroxy-3-nonyl)-adenine and p-nitrobenzylthioinosine to inhibit both adenosine deamination and transport in a canine model of off pump acute myocardial infarction.. Anesthetized adult dogs (n = 37), instrumented to monitor the percentage of systolic segmental shortening and wall thickening using sonomicrometry, underwent 90 minutes of left anterior descending coronary artery occlusion and 120 minutes of reperfusion. Myocardial coronary blood flow, adenosine triphosphate pool, infarct size, and the incident of ventricular fibrillation and cardioversion were also measured. The dogs received an intravenous infusion of the vehicle (control) or 100 μM of erythro-9 (2-hydroxy-3-nonyl)-adenine and 25 μM p-nitrobenzylthioinosine before ischemia (preconditioning group) or just before reperfusion (postconditioning group).. In the control group, adenosine triphosphate depletion was associated with the accumulation of more inosine than adenosine during ischemia and washed out during reperfusion. Myocardial adenosine and inosine were the major nucleosides in the pre- and postconditioning groups during ischemia and remained detectable during reperfusion. In both groups, recovery of systolic segmental shortening and wall thickening and a reduction in the incidence of ventricular fibrillation (P < .05 vs the control group) coincided with retention of myocardial nucleosides. The infarct size in the 3 groups was not significantly different, independent of myocardial blood flow during ischemia.. Preconditioning or postconditioning with erythro-9 (2-hydroxy-3-nonyl)-adenine/p-nitrobenzylthioinosine significantly reduced the incidence of ventricular fibrillation and cardioversion and attenuated regional contractile dysfunction mediated by postmyocardial infarction reperfusion injury. It is concluded that p-nitrobenzylthioinosine-sensitive equilibrative nucleoside transporter 1 played a major role in these events.

Topics: Adenosine Deaminase Inhibitors; Adenosine Triphosphate; Analysis of Variance; Animals; Coronary Circulation; Dogs; Equilibrative Nucleoside Transporter 1; Ischemic Preconditioning; Least-Squares Analysis; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardial Stunning; Thioinosine; Ventricular Fibrillation

The aim of this study was to determine whether endogenous adenosine has antiarrhythmic effects on ischemia-induced ventricular tachyarrhythmias. We therefore modulated the effect of endogenous adenosine in isolated rat hearts using four different approaches. First, interstitial adenosine was elevated by metabolic inhibition with either EHNA (erythro-9-(2-hydroxy-3-nonly)adenine) or acadesine [5-amino-1-beta-D-imidazole-4-carboxamide). Second, cardiac effects of A1 adenosine receptors were allosterically enhanced with PD81,723 (2-amino-4,5-dimethyl-3-thienyl)[3-(trifluoromethyl)phenyl]-methanone . Third, endogenous adenosine release was suppressed with NBMPR (S-(4-nitrobenzyl)-6-thioinosine), and fourth, adenosine receptor subtypes were blocked with antagonists of different selectivity. Regional ischemia, induced by coronary artery ligation, caused ventricular fibrillation of a reproducible kind in about 20% of untreated hearts with a low calcium concentration in the perfusion medium (0.80 mmol/l CaCl2) and in about 75% with high calcium (1.85 mmol/l) within an observation period of 30 min. At high calcium, EHNA (1 and 10 micromol/l) and acadesine (500 micromol/l) suppressed the occurrence of ventricular fibrillation from 68% (controls) to 47%, 33% and 38%, respectively. Conversely, PD81,723 (10 micromol/l) did not influence the occurrence of ventricular fibrillation. At low calcium, NBMPR (0.1 and 1 micromol/l) resulted in a concentration-dependent rise of ventricular fibrillation from 13% (controls) to 40% and 57%, respectively. The adenosine receptor antagonists theophylline (100 micromol/l), XAC (Xanthine Amine Congener; 1 micromol/l) and 8-PT (8-phenyltheophylline; 1 micromol/l) caused a rise in the occurrence of ventricular fibrillation from 25%, 15% and 18% (controls) to 57%, 39% and 44%, respectively, and the selective A2a receptors antagonist CSC (8-(3-chlorostyryl)caffeine; 5 micromol/l) from 20% to 56%. Conversely, the selective A1 receptor blocker DPCPX (8-cyclopentyl-1,3-dipropyl-xanthine; 1 micromol/l) was ineffective. NBMPR or EHNA concentration-dependent suppressed or increased ischemia-induced adenosine overflow, respectively, in a concentration-dependent manner, whereas the adenosine receptor antagonists did not influence adenosine overflow. We conclude that endogenous adenosine is an antiarrhythmic mediator accumulating in acute ischemic myocardium to a level which effectively decreases the occurrence of ventricular fibrillation by an A2

Topics: Adenine; Adenosine; Aminoimidazole Carboxamide; Animals; Caffeine; Creatine Kinase; Electrocardiography; Enzyme Inhibitors; Hypoxanthine; Inosine; Male; Myocardial Ischemia; Myocardium; Perfusion; Rats; Rats, Wistar; Reperfusion Injury; Ribonucleosides; Theophylline; Thioinosine; Thiophenes; Time Factors; Ventricular Fibrillation; Xanthines

Adenosine is an antiarrhythmic substance particularly effective in catecholamine-dependent tachycardias. Although endogenous adenosine substantially accumulates in catecholamine-stimulated hearts, little is known about the antiarrhythmic potency of endogenous adenosine in this condition. Therefore, we sought to demonstrate a potential antifibrillatory effect of endogenous adenosine either by blockade of adenosine receptors with 8-phenyltheophylline (8-PT) or by suppression of endogenous adenosine release with nitrobenzyl-6-thioinosine (NBTI). The study was performed in spontaneously beating Langendorff-perfused rat hearts. Adenosine release into the effluent was determined by HPLC methods. Catecholamine stimulation was induced by perfusing the hearts with norepinephrine (1 mumol/l) for 30 min, which caused ventricular tachycardia (VT) in 31% and ventricular fibrillation (VF) in 25% of control hearts (n = 35). When 8-PT (10 mumol/l) was added to the perfusion buffer prior to norepinephrine, the incidence of VT and VF increased to 79 and 68%, respectively. The addition of 8-PT did not affect the catecholamine-dependent formation of adenosine. Perfusion of the hearts with NBTI (10 mumol/l) prior to norepinephrine reduced adenosine release and increased the occurrence of both VT (65%) and VF (40%). In summary, the results indicate that adenosine is an endogenous antiarrhythmic substance, which accumulates in catecholamine-stimulated myocardium to a level, which effectively suppresses the occurrence of ventricular arrhythmias.

Topics: Adenosine; Animals; Electrocardiography; Heart; In Vitro Techniques; Male; Myocardium; Norepinephrine; Purinergic P1 Receptor Antagonists; Rats; Rats, Wistar; Theophylline; Thioinosine; Vasoconstrictor Agents; Ventricular Fibrillation

This study was designed to determine whether intermittent warm aortic crossclamping induces cumulative myocardial stunning or if the myocardium becomes preconditioned after the first episode of ischemia in canine models in vivo. The role of adenosine triphosphate catabolism and subsequent release of purines on reperfusion-mediated postischemic ventricular dysfunction and arrhythmias was assessed with the use of selective inhibitors of nucleoside transport, p-nitrobenzylthioinosine (NBMPR), and a specific adenosine deaminase inhibitor, erythro-9-[2-hydroxy-3-nonyl] adenine (EHNA). Thirty-two anesthetized dogs were instrumented to monitor left ventricular contractility, off bypass, by sonomicrometry. During cardiopulmonary bypass dogs were treated before ischemia with either saline solution (control group, n = 8) or EHNA (100 mumol/L) and NBMPR (25 mumol/L) (EHNA/NBMPR group, n = 8). Hearts were subjected to either 60 minutes of global ischemia and 120 minutes of reperfusion (n = 16) or 6 episodes of 10 minutes of global ischemia and 10 minutes of reperfusion, followed by 60 minutes of reperfusion (n = 16). Sixty minutes of sustained ischemia resulted in 80% loss of adenosine triphosphate and induced reperfusion-mediated ventricular fibrillation and severe left ventricular dysfunction in the control group. EHNA/NBMPR treatment augmented myocardial adenosine trapping during ischemia, attenuated ventricular fibrillation, and enhanced left ventricular functional recovery, despite similar depletion of adenosine triphosphate (80% loss). In the intermittent ischemia experiment, the first episode of 10 minutes of ischemia and reperfusion caused significant adenosine triphosphate depletion, ventricular fibrillation, and left ventricular stunning in both control and drug-treated groups. The prevalence of ventricular fibrillation was greater in the control group than in the drug-treated group after the first episode of ischemia (p < 0.05). Adenosine was the major nucleoside accumulated in the myocardium at the end of 10 minutes of ischemia in the EHNA/NBMPR-treated group (p < 0.05 versus control). Subsequent episodes of ischemia prevented ventricular fibrillation and did not cause cumulative left ventricular stunning in either group. Left ventricular function fully recovered in the EHNA/NBMPR-treated group after intermittent ischemia, but remained stunned in the control group. Unlike sustained ischemia, intermittent ischemia and reperfusion preserved myocardial adeno

Topics: Adenine; Adenosine; Adenosine Deaminase Inhibitors; Adenosine Triphosphate; Animals; Aorta; Constriction; Dogs; Inosine; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocardial Stunning; Myocardium; Thioinosine; Ventricular Dysfunction, Left; Ventricular Fibrillation; Ventricular Function, Left