nitrophenols and Heart-Failure

Congestive heart failure has been shown to affect oxidative drug metabolism, however, there has been little study of its effects on drug conjugation. Using the isolated perfused livers from rats with right ventricular failure (RVF) due to pulmonary artery constriction, we studied the effects of RVF on hepatic elimination of p-nitrophenol (PNP) under controlled flow and oxygen delivery conditions. Hepatic clearance of the drug was found to be significantly impaired in RVF as compared with the sham group (0.80 +/- 0.23 versus 1.28 +/- 0.26 ml/min/g of liver). The impairment of PNP clearance in RVF occurred in parallel with significant reduction in metabolic formation clearance of p-nitrophenyl-beta-D-glucuronide; the major metabolite of PNP (0.51 +/- 0.12 versus 1.03 +/- 0.26 ml/min/g of liver). The intrinsic drug-glucuronidation capacity of livers was evaluated by measuring the microsomal content and activity of the UDP-glucuronosyltransferase(s) (UDP-GT) toward p-nitrophenol. There was no significant difference between sham and the RVF groups in either the content or the activity of the UDP-GT. The latency of the UDP-GT enzymes in microsomes was measured and was found to be similar between the two groups. The results of this study show that RVF impairs hepatic elimination of PNP and that this appears to be independent of changes in hepatic perfusion and oxygenation or alterations in hepatic content, activity, and latency of the UDP-GT.

Topics: Animals; Enzyme Activation; Glucuronates; Glucuronosyltransferase; Heart Failure; Liver; Male; Microsomes, Liver; Nitrophenols; Rats; Rats, Sprague-Dawley; Ventricular Dysfunction, Right

The results reported in this paper indicate that dinitrophenol acts directly on the isolated heart, increasing its metabolic rate. It also produces heart failure associated with a low phosphocreatine content of the muscle but with no change in adenosine triphosphate, which may or may not be due to a relative hypoxia of the cardiac tissue. Experimental arterial hypoxaemia, if severe, produces a similar picture of heart failure with a decrease in phosphocreatine and no change in adenosine triphosphate. Ligation of the coronary arteries results in disappearance of the major part of the phosphocreatine within a few minutes regardless of whether or not ventricular fibrillation ensues; the adenosine triphosphate remains unchanged.

Topics: Adenosine Triphosphate; Animals; Blood Circulation; Coronary Vessels; Dinitrophenols; Dogs; Heart; Heart Failure; Humans; Hypoxia; Ischemia; Myocardium; Nitrophenols; Phosphocreatine; Phosphorus; Phosphorus Compounds

Hypoxaemia, resulting from increased tissue metabolism, is an important factor in dinitrophenol failure in the conventional heart-lung preparation. Improved oxygenation of the blood by a technique described in this paper prolongs the life of dinitrophenol-treated hearts. Dinitrophenol acts very rapidly; oxygen consumption and coronary flow increase in a few minutes and the increase is proportional to the dose. The increase in oxygen consumption diminishes with time. Dinitrophenol decreases the phosphocreatine content of the heart, even when there is no failure or hypoxia. There is no evidence that dinitrophenol failure can be due to a decrease of phosphocreatine or adenosine triphosphate content of the heart, although this is to be expected in view of the observed "uncoupling" action of dinitrophenol.

Topics: Adenosine Triphosphate; Dinitrophenols; Heart; Heart Arrest; Heart Failure; Humans; Nitrophenols; Oxygen Consumption; Phosphocreatine