propylthiouracil and Myocardial-Ischemia

During ischemia intracellular concentrations of P(i) and H+ increase. Also, changes in myosin heavy chain (MHC) isoform toward beta-MHC have been reported after ischemia and infarction associated with coronary artery disease. The purpose of this study was to investigate the effects of myoplasmic changes of P(i) and H+ on the loaded shortening velocity and power output of cardiac myocytes expressing either alpha- or beta-MHC. Skinned cardiac myocyte preparations were obtained from adult male Sprague-Dawley rats (control or treated with 5-n-propyl-2-thiouracil to induce beta-MHC) and mounted between a force transducer and servomotor system. Myocyte preparations were subjected to a series of isotonic force clamps to determine shortening velocity and power output during Ca2+ activations in each of the following solutions: 1) pCa 4.5 and pH 7.0; 2) pCa 4.5, pH 7.0, and 5 mM P(i); 3) pCa 4.5 and pH 6.6; and 4) pCa 4.5, pH 6.6, and 5 mM P(i). Added P(i) and lowered pH each caused isometric force to decline to the same extent in alpha-MHC and beta-MHC myocytes; however, beta-MHC myocytes were more resistant to changes in absolute power output. For example, peak absolute power output fell 53% in alpha-MHC myocytes, whereas power fell only 38% in beta-MHC myocytes in response to elevated P(i) and lowered pH (i.e., solution 4). The reduced effect on power output was the result of a greater increase in loaded shortening velocity induced by P(i) in beta-MHC myocytes and an increase in loaded shortening velocity at pH 6.6 that occurred only in beta-MHC myocytes. We conclude that the functional response to elevated P(i) and lowered pH during ischemia is MHC isoform-dependent with beta-MHC myocytes being more resistant to declines in power output.

Topics: Animals; Antimetabolites; Energy Metabolism; Hydrogen-Ion Concentration; Male; Muscle Contraction; Myocardial Ischemia; Myocytes, Cardiac; Myosin Heavy Chains; Phosphates; Propylthiouracil; Rats; Rats, Sprague-Dawley; Ventricular Myosins

1. It has been postulated that stimulation of myocardial alpha-adrenoceptors is one of the primary mediators of the dysrhythmias which occur during periods of myocardial ischaemia and reperfusion. This study examines arrhythmogenesis during coronary artery occlusion and reperfusion in isolated perfused rat hearts from control animals and from rats with enhanced myocardial alpha-adrenoceptor responsiveness. 2. Rats were administered propylthiouracil (PTU) in their drinking water for 8 weeks. This treatment resulted in an enhanced responsiveness of isolated left atria to the alpha-adrenoceptor agonist phenylephrine compared with atria from control animals. 3. In Langendorff-perfused isolated hearts, the spontaneous rate of contraction was significantly lower in the PTU-pretreated group than in either age-matched or weight-matched controls. Occlusion of the left anterior descending artery (LAD) for 25 min resulted in ventricular tachycardia (VT) of similar incidence and duration in all groups and ventricular fibrillation (VF) in both control groups but not the PTU-pretreated group. 4. Following the 25-min ischaemic period the myocardium was reperfused for 10 min. The incidence and duration of VT and VF during this period was similar in all groups except that the duration of VF in the PTU-pretreated group was significantly lower than in controls. 5. In perfused hearts paced at 4 Hz, the incidence and duration of dysrhythmias during ischaemia and reperfusion was again similar in all groups, only the duration of VF being affected (reduced) by PTU-pretreatment. 6. In conclusion, this study does not lend support to the hypothesis that myocardial alpha-adrenoceptors have a primary role in arrhythmogenesis, but the data would support a role for these receptors in myocardial protection.

Topics: Adrenergic alpha-Agonists; Animals; Arrhythmias, Cardiac; Atrial Function, Left; Male; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Phenylephrine; Propylthiouracil; Rats; Rats, Wistar; Receptors, Adrenergic, alpha