Ischemic and peroxynitrite preconditioning effects in chronic hypoxic rat lung.

Chronic hypoxic pulmonary hypertension is characterized by vasoconstriction and vascular remodeling and impaired endothelial nitric oxide (NO) production. Although ischemic preconditioning of the lung leads to protective effect against ischemic reperfusion injury, the mechanisms of this protection are not well documented in the lung. The aim of this study was to investigate the effects of chronic hypoxia on preconditioning induced by ischemia or peroxynitrite in isolated rat lungs. The isolated rat lung, from exposed to hypobaric hypoxia for 21 days, was mounted on a modified Langendorff perfusion apparatus. Lungs were preconditioned by either 5 minutes' ischemia and 5 minutes' reperfusion or 10 microM peroxynitrite prior to 2 hours of normothermic ischemia. Although ischemia-reperfusion or peroxynitrite preconditioning markedly reduced KCl responses on perfusion pressure, phenylephrine-induced responses were not significantly modified. Pretreatment of the hypoxic lungs with peroxynitrite scavenger, uric acid, or poly (ADP-ribose) synthase inhibitors (PARS), 3-aminobenzamide (3-AB) or nicotinamide, did not modify the KCl- and phenylephrine-induced responses in chronic hypoxic lungs. There were also no marked differences either in wet to dry weight ratio or malondialdehyde levels of chronic hypoxic lungs. These results imply that preconditioning does not occur in the chronic hypoxic rat lungs.

Ischemic preconditioning modulates ischemia-reperfusion injury in the rat lung: role of adenosine receptors.

Recent studies have been focused on the protective role of ischemic preconditioning against ischemia-reperfusion injury of the lung occurring following cardiopulmonary by-pass surgery and lung or heart transplantation. The present study was undertaken to investigate the role of adenosine in ischemic preconditioning in the isolated buffer-perfused rat lung. Since the pulmonary perfusion flow rate and left atrial pressure were constant, changes in pulmonary arterial pressure directly reflect changes in pulmonary vascular resistance. When compared to control values, ischemia-reperfusion injury in the form of 2 h of normothermic ischemia significantly reduced the pulmonary vasoconstrictor response to phenylephrine and KCl, increased wet-to-dry lung weight ratios and increased malondialdehyde content of rat lungs. Ischemic preconditioning in the form of one cycle of 5 min of ischemia and reperfusion applied prior to ischemia-reperfusion, as well as, adenosine preconditioning in the form of adenosine infusion prior to ischemia-reperfusion independently prevented the reduction in pulmonary vasoconstrictor responses and the increases in pulmonary edema and malondialdehyde formation in response to ischemia-reperfusion injury. Pretreatment with adenosine receptor antagonists, theophylline or 8-cyclopentyl-1,3-dipropyl xanthine (DPCPX) prior to ischemic preconditioning or adenosine preconditioning abolished the protective effects of preconditioning by ischemic preconditioning and adenosine preconditioning. The present data demonstrate that ischemic preconditioning and adenosine preconditioning prevent the vascular and biochemical alterations studied in response to ischemia-reperfusion injury in the pulmonary vascular bed of the rat. Results of the present study suggest activation of adenosine A(1) receptors mediates the protective properties of ischemic preconditioning and adenosine preconditioning on ischemia-reperfusion injury in the lung. Moreover, the present data further suggest selective adenosine receptor agonists may be useful as pharmacologic preconditioning agents in preventing ischemia-reperfusion injury in lung transplantation and other forms of pulmonary vascular ischemia.

Protective effects of poly (ADP-ribose) synthase inhibitors on digoxin-induced cardiotoxicity in guinea-pig isolated hearts.

Reactive oxygen species, generated and released during digoxin-induced cardiotoxicity, can produce an activation of poly (ADP-ribose) synthase (PARS). Our objective was to examine the effects of PARS inhibitors, 3-aminobenzamide (3-AB ) and nicotinamide, on digoxin-induced arrhythmias in guinea-pig isolated hearts. 3-AB (0.1-0.3 mM) and nicotinamide (0.3 mM) were added to the perfusion solution starting 10 min before digoxin infusion (8 microg x ml (-1)min (-1)reaching the heart) and maintained throughout the experiments. Electrocardiograms and coronary perfusion pressure were recorded continuously, and digoxin-induced arrhythmias were determined. Nicotinamide markedly inhibited ventricular tachycardia (VT) incidence (from 100%, n= 7, to 29%, n= 7), and abolished ventricular fibrillation (VF) incidence. 3-AB (0.1 mM, n= 9) significantly decreased VT incidence from 100% ( n= 7) to 22% ( n= 9) and VF incidence from 86% ( n= 7) to 11% ( n= 9). Both nicotinamide and 3-AB (0.1 mM) markedly decreased number of ventricular ectopic beats (VEBs) and arrhythmia score. 3-AB at 0.3 mM ( n= 8) appeared to decrease the VT (to 63%) and VF incidence (to 38%), but these reductions did not reach statistically significance levels. Moreover, 3-AB at high concentration (0.3 mM) did not significantly modify the number of VEBs and arrhythmia score. There were no significant changes in coronary perfusion pressure, heart rate or pressure rate index measured at certain time points throughout the experiment in all groups. Our results suggest that PARS activation plays a role in the digitalis-induced cardiotoxicity in guinea-pig isolated hearts.