Displacement of bilirubin from albumin by ibuprofen in vitro.

Ibuprofen binds to plasma albumin and could interfere with the binding of bilirubin in jaundiced newborn infants. Most clinical studies have not shown increased concentrations of unbound bilirubin (UB) in plasma from infants treated with ibuprofen for a patent ductus arteriosus. However, studies in vitro have not been equally conclusive. Plasma were obtained from routine samples from jaundiced newborn infants and pooled. Total and UB were measured with the peroxidase method after addition of ibuprofen or sulfisoxazole as a known bilirubin displacer. Final ibuprofen concentrations varied from 0.43 to 2.6 mM. Bilirubin concentrations were varied from 176 to 708 microM by adding bilirubin to plasma samples. Ibuprofen caused a linear increase in UB up to +54% at a concentration of 1.8 mM, compared with an increase of 87% by sulfisoxazole (1.32 mM). A double reciprocal plot of molar concentrations of bound versus UB at bilirubin concentrations ranging from 176 to 708 microM showed a competitive displacement of bilirubin by ibuprofen. The data indicate that ibuprofen is a competitive displacer of bilirubin in vitro. Ibuprofen should be used with caution in premature infants with a significant hyperbilirubinemia.

Carbon monoxide levels experienced by heavy smokers impair aerobic capacity and cardiac contractility and induce pathological hypertrophy.

Cigarette smoke contains hundreds of potentially toxic compounds and is an important risk factor for cardiovascular disease. However, the key components responsible for endothelial and myocardial dysfunction have not been fully identified. The objective of the present study was to determine the cardiovascular effects of long-term inhalation of carbon monoxide (CO) administrated to give concentrations in the blood similar to those observed in heavy smokers. Female rats were exposed to either CO or air (control group) (n = 12). The CO group was exposed to 200 ppm CO (100 h/wk) for 18 mo. Rats exposed to CO had 24% lower maximal oxygen uptake, longer (145 vs. 123 microm) and wider (47 vs. 25 microm) cardiomyocytes, reduced cardiomyocyte fractional shortening (12 vs. 7%), and 26% longer time to 50% re-lengthening than controls. In addition, cardiomyocytes from CO-exposed rats had 48% lower intracellular calcium (Ca2 +) amplitude, 22% longer time to Ca2 + decay, 34% lower capacity of sarcoplasmic reticulum Ca2 +-ATPase (SERCA2a), and 37% less t-tubule area compared to controls. Phosphorylation levels of phospholamban at Ser16 and Thr17 were significantly reduced in the CO group, whereas total concentration of phospholamban and SERCA2a were unchanged. Cardiac atrial natriuretic peptide, vascular endothelial growth factor, cyclic guanosine monophosphate, calcineurin, calmodulin, pERK, and pS6 increased, whereas pAkt and pCaMKII delta remained unchanged by CO. Endothelial function and systemic blood pressure were not affected by CO exposure. Long-term CO exposure reduces aerobe capacity and contractile function and leads to pathological hypertrophy. Impaired Ca2 + handling and increased growth factor signaling seem to be responsible for these pathological changes.

Chronic inhalation of carbon monoxide: effects on the respiratory and cardiovascular system at doses corresponding to tobacco smoking.

Carbon monoxide (CO) is a dangerous poison in high concentrations, but the long-term effects of low doses of CO, as in the gaseous component of tobacco smoke, are not well known. The aims of our study were to evaluate the long-term effects of inhaled CO on the respiratory and cardiovascular system at doses corresponding to tobacco smoking and its effect on tumourigenesis and pulmonary neuroendocrine (NE) cells. Female Wistar rats were exposed to either CO (200 ppm) for 20 h/day (n=51) or air (n=26) for 72 weeks. Carboxyhaemoglobin was 14.7+/-0.3% in CO exposed animals and 0.3+/-0.1% in controls. In the lungs, no signs of pathology similar to that associated with cigarette smoking were observed, and no differences in number of pulmonary NE cells were observed between the groups. Chronic CO inhalation induced a 20% weight increase of the right ventricle (p=0.001) and a 14% weight increase of the left ventricle and interventricular septum (p<0.001). Histological examination of the myocardium did not reveal any signs of scarring. In the aorta and femoral artery, no signs of atherosclerosis were observed in CO exposed rats. No exposure related carcinogenic effects were observed. Spontaneous tumours were identified in 29% of CO exposed animals and in 28% of the controls. Our results suggest that low dose CO exposure is probably not responsible for the respiratory pathology associated with tobacco smoking. The effects on the cardiovascular system seem to involve myocardial hypertrophy, but not atherogenesis.

Chronic exposure to carbon monoxide and nicotine: endothelin ET(A) receptor antagonism attenuates carbon monoxide-induced myocardial hypertrophy in rat.

The aims of the present study were to determine the effects of endothelin ET(A) receptor antagonism on carbon monoxide (CO)-induced cardiac hypertrophy and endothelin-1 (ET-1) expression and to compare myocardial effects of chronic nicotine with CO exposure. Female Sprague-Dawley rats (n = 84) were randomized to three groups exposed 20 h/day to CO (200 ppm), nicotine (500 microg/m3), or air for 14 consecutive days. In each exposure group, animals were randomized to ET(A) receptor antagonist LU 135252 in drinking water (0.5 mg/ml) or placebo. Myocardial ET-1 and atrial natriuretic peptide (ANP) expression was measured by competitive RT-PCR and plasma ET-1 by immunoassay. Carboxyhemoglobin was 22.1 +/- 0.3% in CO-exposed animals and 2.8 +/- 0.3% in controls. Plasma nicotine was 57 +/- 7 ng/ml and plasma cotinine was 590 +/- 23 ng/ml in nicotine-exposed animals and below detection levels in controls. CO exposure induced a 21% increase in right ventricular hypertrophy (p < 0.01), a 7% increase in left ventricular hypertrophy (p < 0.01), a 25% increase in right ventricular ET-1 expression (p < 0.05), and an eightfold increase in ANP expression (p = 0.08). ET(A) receptor antagonism reduced right ventricular hypertrophy by 60% (p < 0.05) with no significant effect on left ventricular hypertrophy or myocardial ET-1 expression. Chronic nicotine exposure did not significantly affect cardiac weights or ANP and ET-1 expression. We conclude that ET(A) receptor antagonism reduces right ventricular hypertrophy induced by chronic CO exposure, whereas CO-induced myocardial ET-1 expression remains unchanged.