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It has been reported that the transport function for organic anions on the kidney is maintained in multidrug resistance-associated protein 2 (Mrp2)-deficient rats. Different from Mrp2-deficient rats, Long–Evans Cinnamon (LEC) rats have impaired urinary excretion of Mrp2-substrate, phenolsulfonphthalein (PSP). PSP is transported by the potential-sensitive urate transport system in rat brush-border membranes. We analyzed the function of PSP transport system in LEC rats. Unlike Long–Evans Agouti (LEA) rats, the initial uptake of PSP and urate into the renal brush-border membrane vesicles of LEC rats were not significantly enhanced in the presence of positive intravesicular potential, suggesting that the potential-sensitive urate transport system is impaired in LEC rats. LEC rats should be useful for elucidating the potential-sensitive urate transport system in rats at the molecular level.

Wilson's disease is an inherited, autosomal recessive disorder of copper accumulation and toxicity. Lifelong chelation therapy is essential in all Wilson's disease patients. Intestinal absorption of some compounds is limited partly because they are preferentially transported in the secretory direction. Several ATP-binding cassette (ABC) transporters are expressed in the apical membrane of the small intestine and secrete various drugs into the lumen. In this study, we investigated the characteristics of the intestinal efflux ABC transporters in LEC rats. We found that the expression of multidrug resistance-associated protein 2 (Mrp2) in the jejunum of Long-Evans Cinnamon (LEC) rats, an animal model for Wilson's disease, is decreased.

Purpose: It has been reported that a significant portion of the lactone form of 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin (CPT-11) is excreted into the gastrointestinal lumen via the intestinal membrane and that carboxylesterase activity, which converts CPT-11 to SN-38, was detected in the intestine. It is possible that a reduction in the excretion of CPT-11 lactone into the gastrointestinal lumen induces the gastrointestinal toxicity. The purpose of this study was to investigate the characteristics of transporter(s) that contribute to the jejunal efflux of the lactone form of CPT-11. Methods: The serosal-to-mucosal permeation rate of CPT-11 lactone was investigated in everted sac studies. Results: The secretory transport required metabolic energy and was diminished by sulfobromophthalein (BSP) and 1-naphthol, inhibitors of the ME3277 transport system. However, inhibitors of breast cancer resistance protein (Bcrp), multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein (P-gp) did not affect the secretion of CPT-11 lactone. Conclusions: The results suggest that a specific transport system, which is identical to the ME3277 transport system, plays a major role in the secretion of CPT-11 lactone.

It is known that secretory transport limits the oral bioavailability of certain drugs. However, there is little information on the secretion of anionic compounds in the intestine. Phenolsulfonphthalein (PSP) and p-aminohippuric acid (PAH) have been used widely as substrates for organic anion transport systems. PAH is transported in the secretory direction in the intestine. It is possible that PSP and PAH share the same transport system at the mucosal membrane. The purpose of this study was to characterize the transport system for PSP in the intestine. In the jejunum, the serosal-to-mucosal permeation rate of PSP was significantly reduced in an ATP-depleted condition, whereas a significant difference was not observed in the ileum. Some multidrug resistance-associated protein 2 (Mrp2) inhibitors inhibited PSP permeation in the jejunum. However, pravastatin, a substrate of Mrp2, did not inhibit the PSP permeation. The jejunal secretory transport of pravastatin was significantly reduced in an ATP-depleted condition and by addition of probenecid, but PSP did not affect the jejunal permeation of pravastatin. These results suggest that PSP is secreted into the intestinal lumen by Mrp2-like transporter and that two Mrp2 substrates, PSP and pravastatin, are likely to be transported by different transport systems at the mucosal membrane.

We studied plasma levels of atrial and brain natriuretic peptides at rest and after exercise before and after intracardiac surgery with and without the maze procedure in patients with chronic heart failure secondary to valvular heart disease. The present study found that an increased response of both cardiac natriuretic peptides is attenuated with resulting water retention after the maze procedure.

This study examined the peripheral endothelium-dependent vasodilatory response to acetylcholine and the endothelium-independent vasodilatory response to nitroprusside in 19 patients with chronic heart failure and eight controls. These peripheral blood flow responses were compared with hyperemic calf blood flow changes after maximum leg exercise and 5-min femoral occlusion. The peripheral blood flow response to forearm intra-arterial infusion of acetylcholine and sodium nitroprusside, and reactive hyperemic calf blood flow changes were measured by plethysmography. All peripheral blood flow responses were significantly reduced in patients with chronic heart failure (P0.05). Reduction of acetylcholine-mediated changes in peripheral blood flow was correlated with exercise-induced calf blood flow response (r = 0.51, P0.05), but not with occlusion-induced calf blood flow response (r = 0.02, NS). Sodium nitroprusside-mediated changes were not correlated with any reactive hyperemic blood flow responses (exercise: r = 0.27, NS; occlusion: r = 0.11, NS). When the patients were divided into two subgroups based on the median exercise-induced calf blood flow change, the subgroup with the lower calf blood flow response showed a reduction in exercise capacity (anaerobic threshold: 11.8 +/- 0.6 vs. 14.6 +/- 1.0 ml/kg/min; P0.05). These findings suggest that endothelial dysfunction is related to a decrease in exercise-induced skeletal muscle blood flow and exercise capacity in patients with chronic heart failure.

Several neurohormonal factors have been proposed as markers of the severity of acute myocardial infarction (MI). To determine whether plasma concentrations of atrial natriuretic factor (ANF) might predict post-MI prognosis, we studied 130 patients with acute MI (97 males and 33 females, mean age 62 years). Within one-half to one day after admission, a blood sample was taken for estimation of circulating ANF. The mean follow-up period was 37 months, and the follow-up rate was 97%. Of the 130 patients, 28 died from cardiac causes during the follow-up period. Patients were classified into three groups according to plasma ANF levels (group 1,99 pg/ml; group 2, 100-199 pg/ml; group 3;200 pg/ml). The survival curves were constructed by the Kaplan-Meier method. There were significant differences in the cumulative survival rate among the three groups (group 1group 2group 3; p0.001). The baseline characteristics (age, atrial pressure, and cardiac index) were different among the groups, therefore these variables were analyzed by a Cox multiple regression model. Significant predictors of cardiac mortality were plasma ANF class (p0.002) and pulmonary capillary wedge pressure (p0.007). In conclusion, these observations demonstrated that stratification of acute MI patients by plasma ANF level is a useful non-invasive method for predicting prognosis and for identifying individuals at high risk of cardiac death.

To examine whether atrial natriuretic factor (ANF) is secreted adequately in the early phase of myocardial infarction, plasma ANF concentration and clinical parameters, including hemodynamic variables, were studied in 118 patients with acute myocardial infarction (AMI). The patients were divided into 2 subgroups according to the absence (group A, n = 41) or presence (group B, n = 77) of a history of valvular heart disease, previous myocardial infarction, hypertension, or renal failure. Although no significant difference in atrial pressure after the infarction was found between the 2 groups, the plasma ANF level was significantly lower in group A than in group B (76 +/- 6 vs. 185 +/- 26 pg/ml; mean +/- SEM, p0.01). Plasma ANF was correlated with pulmonary capillary wedge pressure in group B (r = 0.54, p0.001), whereas no relationship with hemodynamic parameters was observed in group A. In 56 of the 118 patients (group A, n = 18; group B, n = 38), the pulmonary arterial plasma level was significantly higher in group A (p0.05), whereas the difference was not significant in group B. Seven of the 8 expired cases among these 56 patients had peripheral plasma ANF levels of more than 150 pg/ml, which were higher than those in pulmonary arterial plasma. These observations suggest firstly that the plasma level of ANF is lower in patients with a new onset of myocardial infarction compared to those with a history of cardiac or renal diseases, and secondly that stimulated ANF release originates not only from the right side of the heart, but also from additional site(s), particularly in patients with chronic ventricle overload and a poor prognosis.

Various mechanisms can influence the intestinal absorption and oral bioavailability of drugs. The barrier effects of efflux transporters may be one of the critical factors limiting the bioavailability of certain drugs. It has been reported that multidrug resistance-associated protein 2 (Mrp2) is expressed in the mucosal membrane of the epithelium of the small intestine and secretes various drugs into the jejunum lumen. However, it is possible that total intestinal secretion of Mrp2 substrates is accounted for the contribution of Mrp2 and other transporter(s) to the intestinal secretion of Mrp2 substrates. In this study, we found that phenolsulfonphthalein and pravastatin, both Mrp2 substrates, are transported by different transport systems in the intestine. These results suggest that contribution of transporters to the drug transport may be a critical factor affecting drug disposition and drug-drug interaction. In addition to evaluating the substrate specificity of a transporter, it is important to be aware of the contribution of a transporter to drug disposition.

The liver plays important roles in the detoxification of xenobiotics. Hepatobiliary transporters contribute to hepatic uptake and efflux processes of xenobiotecs. Expressions of these transporters may be modulated under the condition of hepatic failure. Long-Evans Cinnamon (LEC) rats provide a pertinent model for basic and clinical studies on hepatitis. However, only a few reports describing the properties of hepatobiliary transporters in LEC rats have appeared in the literature. We investigated the expression levels of hepatobiliary transporters in LEC rats by real-time RT-PCR. We found that hepatic expressions of three sinusoidal organic anion transporters, Ntcp, Oatp1a1 and Oatp1a4, were decreased in LEC rats. However, no significant difference of the expressions of Mrp2 and Bsep, organic anion transporters located on canalicular membrane, were found between Wistar rats and LEC rats.

In conclusion, we observed that the reduced peripheral endothelium-dependent response is restored after recovery from chronic heart failure, and that improvement in this type of vascular dysfunction is related to an increase in exercise capacity.

Impairment of endothelium-dependent vasodilation has recently been reported in the peripheral vascular bed in patients with chronic heart failure. However, the clinical implications of this type of vascular dysfunction have yet to be elucidated. We have determined the degree of impairment of endothelium-dependent vasodilation as evaluated by acetylcholine-induced changes in forearm blood flow and compared this to various clinical parameters in 23 patients with chronic heart failure. Cumulative changes in forearm blood flow induced by acetylcholine (3.0 and 4.5 micrograms/min/dl tissue volume) were significantly lower in patients with chronic heart failure than in normal controls (10.1 +/- 8.0 ml/min/100 ml vs 20.4 +/- 11.7 ml/min/100 ml tissue volume; p0.01). In patients with heart failure, no significant relation was found between acetylcholine-induced changes in forearm blood flow and age, sex, duration of symptoms, duration of hospital stay, or resting hemodynamic parameters, although a significant positive correlation was observed with peak oxygen uptake (r = 0.53, p0.05) and ventilatory threshold (r = 0.42, p0.05). These observations suggest that the impairment of endothelium-dependent peripheral vasodilation may be one of the factors contributing to exercise intolerance in patients with chronic heart failure, probably resulting from its limiting effect on nutritive skeletal muscle blood flow during exercise.

We have investigated the relationship between plasma endothelin (ET) concentrations and several clinical characteristics in 31 patients with acute myocardial infarction (MI). ET levels were also measured in 10 age-matched healthy subjects, 9 patients with unstable angina, and 20 patients with chronic heart disease. In patients with MI, although no significant relationship was observed between plasma ET concentrations and measured hemodynamic parameters, plasma levels were higher in patients with pulmonary congestion than in those without this complication (1.61 +/- 0.29 vs 1.21 +/- 0.33 fmol/ml; p < 0.01). No significant difference in plasma ET levels was found between cardiac and peripheral sampling sites (pulmonary artery; 1.07 +/- 0.28, right atrium; 1.02 +/- 0.28, peripheral artery; 1.12 +/- 0.23, peripheral vein; 1.14 +/- 0.38 fmol/ml: N.S.), or among patients with uncomplicated MI, unstable angina (1.00 +/- 0.32 fmol/ml), and healthy subjects (1.01 +/- 0.29 fmol/ml). Increased level were observed in patients with decompensated heart failure due to chronic heart disease, but were not found in patients without pulmonary congestion (1.62 +/- 0.60 vs 1.11 +/- fmol/ml; p < 0.01). These observations suggest that plasma ET concentrations are elevated in the presence of congestive heart failure or severe ventricular depression, but are not persistently increased by myocardial ischemia per se.

The maze procedure, a new surgical treatment for lone atrial fibrillation, was initially described by Cox and associates. 1 Recently, combined treatment for organic heart disease and atrial fibrillation has been reported, hut there have been few studies on atrial activity after combined treatment with surgical repair for organic heart disease and the maze procedure for atrial fibrillation. It is important to know how well atrial function recovers after combined surgical methods. Therefore we investigated the recovery of atrial funetion after the combined surgical treatment of organic heart disease and atrial fibrillation. Methods. Twelve patients who received cardiac operation with a successful maze procedure were enrolled in this study. The patients consisted of four men and eight women, with a mean age of 60 _+ 11 years. Organic heart diseases were mitral stenosis in two patients, mitral regurgitation in eight, and atrial septal defect in two. All patients underwent symptom-limited cardiopulmonary exercise testing with use of an upright bicycle ergometer with measurements of atrial natriuretic peptide (ANP) before and after exercise testing and Doppler echocardiography 1 week before the operation (control phase), 1 month after the operation (early phase), and 3 months after the operation (late phase). Ventilatory threshold was determined in a standard manner by the V-slope method. Peak velocities of the early filling (E) wave, atrial filling (A) wave, and A/E ratio were determined by Doppler echocardiography. The timevelocity integrals of the E (Ea) and A (Aa) waves were then obtained by planimetry of the flow velocity profile. Left atrial active contractile fraction (LAACF) was expressed as the ratio of the atrial component during active atrial contraction (Aa) to the total diastolic time velocity integral (Ea + Aa) and calculated as LAACF = Aa/(Ea + Aa).