Michael G. Worthington

The effect of alpha- and beta-adrenoceptor antagonist agents on reperfusion ventricular fibrillation and metabolic status in the isolated perfused rat heart

This study was designed to assess the effect of alpha-and beta-adrenoceptor antagonist agents on reperfusion ventricular fibrillation and myocardial metabolic status preceding the onset of reperfusion ventricular fibrillation in the isolated Langendorff perfused rat heart. Prazosin (alpha1antagonist), yohimbine (alpha2-antagonist) and phentolamine (alpha1- and alpha2-antagonist) protected against reperfusion ventricular fibrillation, the median effective dose (ED50) values being 2.0, 0.7 and 2.5 μmol/liter, respectively, when given before coronary artery ligation. The ability of alpha-antagonist agents to prevent reperfusion ventricular fibrillation appeared to be the consequence of alpha-adrenoceptor antagonism or the consequence of “membrane-stabilizing activity,” or both. Reserpinization before reperfusion reduced but did not eliminate reperfusion ventricular fibrillation. Relative to the reported dissociation constants of myocardial alpha-adrenoceptors, yohimbine (alphas-antagonist) appeared more active; such antiarrhythmic potential apparently has not been reported previously. The beta-adrenoceptor antagonist agents dl-propranolol (ED50value, 3 μmol/liter) and metoprolol in high concentrations (ED50value, 50 μmol/liter) prevented reperfusion ventricular fibrillation, whereas atenolol was virtually without effect. d-Propranolol (ED50value, 2.5 μmol/liter), the propranolol isomer with modest beta-antagonist activity but with marked membrane-stabilizing activity, evoked protection equivalent to that of racemic propranolol. Beta-adrenoceptor antagonists did not appear to prevent reperfusion ventricular fibrillation as a consequence of receptor antagonism but rather by membrane-stabilizing activity. Some circumstantial association was evident between improved metabolic status on reperfusion, in preservation of tissue levels of adenosine triphosphate and phosphocreatine, reduction of tissue levels of lactate and cyclic adenosine monophosphate and protection against reperfusion ventricular fibrillation. However, agents affording a similar degree of metabolic preservation were associated with different degrees of protection against reperfusion ventricular fibrillation. Of the four possible protective procedures: alpha-receptor antagonism, beta-adrenoceptor antagonism, membrane-stabilizing activity and metabolic preservation, alpha-receptor antagonism and membrane-stabilizing activity most warrant further evaluation, especially in other species.

Protective action of amiodarone against ventricular fibrillation in the isolated perfused rat heart

The pretreatment of rats with amiodarone for 2 minutes to 3 weeks before the excision of their hearts caused a dose-related decrease in heart rate and an increase in the ventricular fibrillation threshold both before and after coronary arterial ligation. Similarly, amiodarone decreased the incidence of ventricular premature extrasystoles, ventricular tachycardia and fibrillation during the period of regional ischemia after coronary arterial ligation and also after reperfusion of the ischemic myocardium. There was no evidence of a metabolic protective effect on ischemic myocardium because tissue high energy phosphate content decreased to a similar extent in ischemic myocardium from control and amiodarone-treated rats. Instead, the protective effect of amiodarone against fibrillation was accompanied by attenuation of the increase in tissue cyclic adenosine monophosphate in ischemic myocardium after coronary arterial ligation. It is proposed that amiodarone exerts a potent antifibrillatory effect by decreasing tissue cyclic adenosine monophosphate in ischemic myocardium.

Isolated thoracic duct injury after penetrating chest trauma.

BACKGROUND Isolated thoracic duct injuries as a result of penetrating chest trauma without any major vascular or tracheoesophageal injury seldom are seen. METHODS A retrospective 13-year review identified 8 patients with this injury. RESULTS Seven had supraclavicular or suprascapular knife stabs, and the eighth had a low-velocity gunshot injury entering the mid-lateral right chest wall. All 7 stab victims presented with left-sided chylothoraces, and the site of injury of the thoracic duct was within Poiriers triangle, the borders of which are the arch of aorta, the left subclavian artery, and the vertebral column as seen from a lateral approach. Five patients initially were treated conservatively for 13.4 +/- 4.4 days without success. Surgical intervention thus was necessary and was successful in all 8 patients. The thoracic duct injury was controlled successfully through a left posterolateral thoracotomy in 6 patients. A supraclavicular repair was attempted in 1 patient but failed to control the leak and required reexploration via the supraclavicular approach. The right chylothorax from the gunshot injury was explored via a right posterolateral thoracotomy; the leak into the pleura was identified and obliterated. CONCLUSIONS As conservative management was uniformly unsuccessful, we advocate early operative management through a thoracotomy on the side of the chylothorax for this relatively rare injury.

Surgical relief of acute airway obstruction due to primary tuberculosis

Primary pulmonary tuberculosis in children remains a leading cause of mortality and morbidity in developing countries. Thirteen children requiring urgent thoracotomy for relief of acute respiratory distress resulting from critical major airway narrowing caused by enlarged tuberculous mediastinal lymph nodes were admitted to two hospitals over a 4-year period. Ages ranged from 2 months to 10 years. The condition of each patient had deteriorated despite appropriate antituberculosis therapy and an oral corticosteroid. At operation, the enlarged tuberculous subcarinal or paratracheal lymph nodes or both were decompressed. Surgical complications included a bronchial tear and a pulmonary artery laceration. Additional procedures included a right upper lobectomy, two pneumonectomies, plication of a hemidiaphragm, and mobilization of two muscle flaps. Postoperatively all children showed dramatic improvement. The trachea to main bronchi diameter ratio improved by 49.1% on the left and 44.9% on the right in the immediate postoperative period. In children with respiratory distress produced by compression of the main bronchi between enlarged subcarinal and paratracheal lymph nodes, surgical decompression of the lymph nodes is indicated if there is no marked initial response to appropriate medical therapy. At operation, lymph nodes should be decompressed only by incision and curettage. Attempts at lymph node excision are associated with increased complications.

Arrhythmogenic action of α1-adrenoceptor stimulation in normoxic rat ventricular myocardium: Influence of nisoldipine, reduced extracellular Ca2+ and ryanodine

This study examines the arrhythmogenic action of alpha 1 and alpha 2-adrenoceptor stimulation in the isolated perfused rat heart. The alpha 1-agonist methoxamine in the presence of the beta 1-antagonist atenolol 10(-6) M decreased the ventricular fibrillation threshold in the normoxic rat ventricular myocardium: VFT values (mA): Control 11.2 +/- 0.5; methoxamine 10(-6) M 4.9 +/- 0.9 (P less than 0.01 vs control); methoxamine 10(-5) M 3.5 +/- 0.5 (P less than 0.01 vs control). The alpha 1-antagonist prazosin 10(-8) M prevented the methoxamine-induced fall in ventricular fibrillation threshold. The alpha 2-agonist BHT 933 (azepexole) in the presence of atenolol 10(-6) M produced no alteration in the ventricular fibrillation threshold. Methoxamine 10(-6) M to 10(-5) M had a positive inotropic effect with increased left ventricular pressure development, myocardial oxygen consumption and QT-interval; however, tissue levels of cyclic AMP remained unchanged. Methoxamine 10(-6) M did not alter heart rate, coronary flow rate or deplete tissue levels of adenosine triphosphate, phosphocreatine or glycogen. The enhanced vulnerability to ventricular fibrillation induced by methoxamine could be demonstrated only at supraphysiological extracellular calcium concentrations (2.5 mM) but not at physiological calcium concentrations (1.25 mM). The arrhythmogenic and inotropic effect of methoxamine 10(-6) M was prevented by inhibition of transsarcolemmal Ca2+ ion influx by nisoldipine 10(-8) M or by inhibition of release of Ca2+ from sarcoplasmic reticulum by ryanodine 10(-9) M to 10(-8) M. Thus in isolated normoxic rat heart preparations, activity of the alpha 1-receptor appears to mediate ventricular arrhythmogenesis but only in the setting of myocardial calcium overload. The arrhythmogenic effect of alpha 1-stimulation may be due to increased transsarcolemmal calcium influx and enhanced release of calcium from the sarcoplasmic reticulum; increased myocardial oxygen consumption secondary to greater left ventricular pressure development may contribute in part.

Antiarrhythmic and metabolic effects of indoramin during acute regional ischemia and reperfusion in isolated rat heart.

The antiarrhythmic effect of α1-adrenbceptor antagonists during myocardial ischemia and reperfusion remains controversial. The potential antiarrhythmic properties of indoramin, an α1-antagonist, were assessed in the isolated perfused rat heart during regional ischemia and during sustained reperfusion. Coronary artery ligation (CAL) decreased the ventricular fibrillation threshold (VFT) of control hearts from 9.1 ± 1.3 (pre-CAL, mean ± SEM) to 2.1 ± 0.5 mA 15 min post-CAL (p < 0.0001). Perfusion with indoramin 10−8 M (α1-receptor antagonistic concentration) started 5 min prior to CAL did not prevent the fall in VFT after CAL. Indoramin 10−6 M prevented the fall in VFT after CAL relative to the control group. Indoramin 10−5 M markedly increased the VFT before CAL from 9.9 ± 1.0 to 28.6 ± 2.9 mA (p < 0.0001) and prevented the fall in VFT after CAL. During reperfusion, indoramin 10−5 M decreased the incidence of spontaneous ventricular fibrillation (VF) to 1 of 6 vs. 6 of 6 in the control group (p < 0.02). Indoramin 10−5 M preserved adenosine triphosphate in the reperfused myocardium: 2.82 ± 0.06 vs. 2.16 ± 0.21 μmol/g in the control group (p < 0.05). Specific α1-antagonist properties of indoramin did not appear to be involved in the antiarrhythmic effects.