guanosine-triphosphate and Tetralogy-of-Fallot

In adult human heart, both beta(1)- and beta(2)-adrenergic receptors mediate hastening of relaxation; however, it is unknown whether this also occurs in infant heart. We compared the effects of stimulation of beta(1)- and beta(2)-adrenergic receptors on relaxation and phosphorylation of phospholamban and troponin I in ventricle obtained from infants with tetralogy of Fallot.. Myocardium dissected from the right ventricular outflow tract of 27 infants (age range 21/2 to 35 months) with tetralogy of Fallot was set up to contract 60 times per minute. Selective stimulation of beta(1)-adrenergic receptors with (-)-norepinephrine (NE) and beta(2)-adrenergic receptors with (-)-epinephrine (EPI) evoked phosphorylation of phospholamban (at serine-16 and threonine-17) and troponin I and caused concentration-dependent increases in contractile force (-log EC(50) [mol/L] NE 5.5+/-0.1, n=12; EPI 5.6+/-0.1, n=13 patients), hastening of the time to reach peak force (-log EC(50) [mol/L] NE 5.8+/-0.2; EPI 5.8+/-0.2) and 50% relaxation (-log EC(50) [mol/L] NE 5.7+/-0.2; EPI 5.8+/-0.1). Ventricular membranes from Fallot infants, labeled with (-)-[(125)I]-cyanopindolol, revealed a greater percentage of beta(1)- (71%) than beta(2)-adrenergic receptors (29%). Binding of (-)-epinephrine to beta(2)-receptors underwent greater GTP shifts than binding of (-)-norepinephrine to beta(1)-receptors.. Despite their low density, beta(2)-adrenergic receptors are nearly as effective as beta(1)-adrenergic receptors of infant Fallot ventricle in enhancing contraction, relaxation, and phosphorylation of phospholamban and troponin I, consistent with selective coupling to G(s)-protein.

Topics: Calcium-Binding Proteins; Child, Preschool; Cyclic AMP-Dependent Protein Kinases; Epinephrine; Female; GTP-Binding Protein alpha Subunits, Gs; Guanosine Triphosphate; Heart Ventricles; Humans; Infant; Male; Myocardial Contraction; Myocardium; Phosphorylation; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2; Serine; Tetralogy of Fallot; Threonine; Troponin I

Patients with tetralogy of Fallot may have episodes of paroxysmal hypoxic spells ("tet spells") or could be asymptomatic. In patients who have these episodes, treatment with a beta-adrenoceptor (betaAR) blocking agent can often ameliorate or attenuate the severity of the symptoms. Additionally, excitement, crying, and situations associated with increased sympathetic activity could provoke the occurrence of these hypoxic spells. We hypothesized that altered myocardial betaAR function may contribute to the development of paroxysmal hypoxic spells in the symptomatic tetralogy patient. Surgically excised right ventricular infundibular myocardial specimens from symptomatic (patients with spells) and asymptomatic patients were used to determine total beta1 and beta2 betaAR density and betaAR adenylyl cyclase activity. Symptomatic patients had a significantly greater number of total betaAR. The relative proportion of beta1 and beta2 receptors was comparable in both patient groups. betaAR-stimulated adenylyl cyclase activity was found to be more enhanced in the symptomatic patient group. Our results indicate that infundibular betaARs may play a role in the development of paroxysmal hypoxic spells.

Topics: Adenylyl Cyclases; Adrenergic beta-Antagonists; Child; Child, Preschool; Colforsin; Female; Guanosine Triphosphate; Heart Ventricles; Humans; Hypoxia; Imidazoles; In Vitro Techniques; Infant; Isoproterenol; Male; Myocardium; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2; Sodium Fluoride; Tetralogy of Fallot