n(6)-cyclopentyladenosine and Arrhythmias--Cardiac

Atrial fibrillation (AF) is the most commonly encountered sustained clinical arrhythmia with an estimated 2.3 million cases in the US (2001). A(1) adenosine receptor agonists can slow the electrical impulse propagation through the atrioventricular (AV) node (i.e., negative dromotropic effect) resulting in prolongation of the stimulus-to-His bundle (S-H) interval to potentially reduce ventricular rate. Compounds that are full agonists of the A(1) adenosine receptor can cause high grade AV block. Therefore, it is envisioned that a compound that is a partial agonist of the A(1) adenosine receptor could avoid this deleterious effect. 5(') Phenyl sulfides (e.g., 17, EC(50)=1.26 microM) and phenyl ethers (e.g., 28, EC(50)=0.2 microM) are partial agonists with respect to their AV nodal effects in guinea pig isolated hearts. Additional affinity, GTPgammaS binding data suggesting partial activity of the A(1) adenosine receptor, and PK results for 5(') modified adenosine derivatives are shown.

Topics: Adenosine; Adenosine A1 Receptor Agonists; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrioventricular Node; Binding Sites; Bundle of His; Dose-Response Relationship, Drug; Ethers; Guinea Pigs; Heart Rate; Hydrocarbons, Aromatic; Receptor, Adenosine A1; Structure-Activity Relationship; Sulfides

The relationship between atrial stretching and changes in cell excitability is well documented. Once stretched, human atrial myocytes (HuAM) release atrial natriuretic peptide (hANP). Receptors for hANP (NPR) are coupled to a guanylyl cyclase (GC) activity, and are present on HuAM, but the electrophysiological effects of hANP are largely unknown. We investigated the effect of hANP on If, the hyperpolarization-activated current present in HuAM, and the underlying intracellular pathway.. HuAM were isolated from atrial appendages and utilized for patch-clamp recording.. hANP caused a significant and concentration dependent shift of the midpoint activation potential (DeltaVh) toward less negative potentials of 6.9 +/- 1.0 mV at 0.1 nM; 13.0 +/- 2.6 mV at 1 nM and 15.3 +/- 2.2 mV at 10 nM (p < 0.001 for all); a parallel increase of If rate of activation occurred. The effect of hANP was completely blocked by isatin, a potent antagonist of NPR (p < 0.01 vs. hANP). In the presence of the inhibitors of guanylyl cyclase (ODQ and LY83583), hANP caused a significantly smaller DeltaVh (p < 0.01 vs. hANP for both). 8Br-cGMP mimicked the effect of hANP, both in the presence and absence of KT5823, a selective inhibitor of Protein kinase G. Pretreatment with pertussis toxin (PTX) did not change the effect of hANP, thus excluding a major role for the coupling of NPR with the Gi-Proteins system. Pretreating cells with cyclopentyladenosine (CPA), an A1-adenosine receptor agonist, completely blocked hANP effect. Adding hANP to maximal serotonin concentration produced an additive response.. Our data demonstrate for the first time that ANP is able to increase If, likely through a modulation of intracellular cGMP and cAMP levels. This effect could have implications in the relationship between stretch and arrhythmogenesis in the human atrium.

Topics: Adenosine; Adult; Aged; Aged, 80 and over; Aminoquinolines; Arrhythmias, Cardiac; Atrial Natriuretic Factor; Calcium Channels; Carbazoles; Cyclic GMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Female; Guanylate Cyclase; Heart Atria; Humans; Indoles; Isatin; Male; Middle Aged; Myocytes, Cardiac; Patch-Clamp Techniques; Purinergic P1 Receptor Agonists; Receptors, Atrial Natriuretic Factor; Serotonin; Signal Transduction

1. The goal of this study was to investigate the effects of the delayed pharmacological preconditioning produced by an adenosine A(1)-receptor agonist (A(1)-DPC) against ventricular arrhythmias induced by ischaemia and reperfusion, compared to those of ischaemia-induced delayed preconditioning (I-DPC). 2. Eighty-nine instrumented conscious rabbits underwent a 2 consecutive days protocol. On day 1, rabbits were randomly divided into four groups: 'Control' (saline, i.v.), 'I-DPC' (six 4-min coronary artery occlusion/4-min reperfusion cycles), 'A(1)-DPC(100)' (N(6)-cyclopentyladenosine, 100 microg kg(-1), i.v.), and 'A(1)-DPC(400)' (N(6)-cyclopentyladenosine, 400 microg kg(-1), i.v.). On day 2, i.e., 24 h later, the incidence and severity of ventricular arrhythmias during a 30-min coronary artery occlusion and subsequent reperfusion were analysed in all animals, using an arrhythmia score. 3. I-DPC, A(1)-DPC(100) and A(1)-DPC(400) significantly reduced the infarct size (34+/-5, 42+/-3 and 43+/-7% of the area at risk, respectively) as compared to Control (55+/-3% of the area at risk). 4. During both ischaemia and reperfusion, neither the incidence nor the severity of ventricular arrhythmias were altered by A(1)-DPC(100), A(1)-DPC(400) or I-DPC as compared to Control. 5. Thus, despite reduction of infarct size induced by delayed preconditioning, A(1)-DPC as well as I-DPC failed to exert any anti-arrhythmic effect in the conscious rabbit model of ischaemia-reperfusion.

Topics: Adenosine; Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Disease; Dose-Response Relationship, Drug; Electrocardiography; Heart Rate; Heart Ventricles; Hemodynamics; Ischemic Preconditioning, Myocardial; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Purinergic P1 Receptor Agonists; Rabbits