Prevalence of hypoxemia in 102 Japanese patients with alcoholic and nonalcoholic cirrhosis.

OBJECTIVE: Liver cirrhosis is often accompanied by arterial hypoxemia in the absence of cardiopulmonary disease. The aim of this study was to investigate the relationship between various clinicopathological conditions and the hypoxemia seen in Japanese patients with liver cirrhosis. METHODS: In 102 consecutive patients with alcoholic (N = 45) and nonalcoholic (N = 57) cirrhosis not associated with cardiopulmonary disease, we performed lung perfusion scintigraphy, contrast echocardiography, and arterial blood gas analysis and measured oxygen consumption. RESULTS: No abnormality was seen in pulmonary blood flow in cirrhotic patients, but 38 (38%) of them had a decreased partial pressure of oxygen (PaO2). The hypoxemic patients did not show any pulmonary signs or symptoms. The hypoxemia was not associated with the Child-Pugh grade, and was observed in 32 (71%) of the 45 alcoholic patients but in only six (11%) of the 57 nonalcoholic patients (p < 0.001). Oxygen consumption was significantly higher in the alcoholic group than in the nonalcoholic group (p < 0.0001), and a high incidence of oxygen consumption was seen in all 45 (100%) of the alcoholic patients and in 34 (60%) of the nonalcoholic subjects, the difference being significant (p < 0.01). The relationship between oxygen consumption and PaO2 in the 102 cirrhotic patients showed an inverse correlation (r = -0.85, p < 0.0001). Among the alcoholic patients, the incidence of hypoxemia did not differ between the 33 smokers and the 12 nonsmokers. After 1 wk of abstinence from alcohol a significant increase (p < 0.0001) in the PaO2 was seen in 14 of 19 patients with alcoholic cirrhosis. CONCLUSIONS: We conclude that the hypoxemia in Japanese patients with liver cirrhosis occurs mainly in drinking alcoholic patients, presumably due to an increased oxygen consumption by alcohol.

Direct effects of angiotensin I, angiotensin II, an ACE inhibitor and a serine proteinase inhibitor on cultured heart cells from spontaneously hypertensive rats.

1. The purpose of the present study was to investigate how angiotensin I (AI), angiotensin II (AII), an angiotensin converting enzyme inhibitor (ACE inhibitor; ACE-I) and a serine proteinase inhibitor contribute to the protein metabolism of cultured newborn spontaneously hypertensive rats (SHR) heart cells. We examined the uptake of [3H]-uridine and [3H]-proline into cultured cardiac myocytes and fibroblasts, respectively. 2. Both AI and AII increased the uptake of [3H]-uridine into myocytes in a concentration-dependent manner. However, the effect of AI was denied in the presence of the ACE-I with the concentration of 10(-6) g/mL. Both AI and AII increased the uptake of [3H]-proline into cardiac fibroblasts in a concentration-dependent manner. However, this effect was only partially abolished in the presence of 10(-6) g/mL of the ACE-I, which was the maximal concentration that did not exert any effect on the [3H]-proline uptake. In the presence of AII receptor antagonist, [Sar1, Leu8]-AII, the uptake of [3H]-proline into cardiac fibroblasts was completely inhibited. Moreover, the stimulatory effects of AI on the uptake of [3H]-proline into cardiac fibroblasts were completely inhibited in the presence of a serine proteinase inhibitor in addition to the ACE-I. 3. These results suggest that an ACE-I has different effects on protein metabolism in the heart and also suggest the presence of serine proteinase in cultured cardiac fibroblasts from SHR.

Contrasting effects of isoproterenol and phosphodiesterase III inhibitor on intracellular calcium transients in cardiac myocytes from failing hearts.

1. Effects of a newly developed phosphodiesterase (PDE) III inhibitor, E-1020, on intracellular calcium transients were compared with those of isoproterenol (ISO) in isolated single myocytes from failing hearts secondary to pulmonary hypertension induced by monocrotaline injection. Myocytes were isolated by enzyme digestion using a Langendorff apparatus. Changes in intracellular calcium concentrations ([Ca2+]i) were recorded using a fura-2 fluorescence microscopic technique. Cyclic AMP contents of the hearts were measured by radio-immunoassay. 2. Myocytes from failing hearts showed Ca2+ transients with a low peak (low amplitude) and delayed decline of Ca2+ transients. Both ISO and E-1020 increased peak [Ca2+]i, max + d[Ca2+]i/dt, and max - d[Ca2+]i/dt in a concentration-dependent manner while both agents decreased T80L (time to 80% decline of amplitude from peak light). The concentrations which increased peak [Ca2+]i by 50% were 1.6 x 10(-9) mol/L of ISO and 2 x 10(-6) mol/L of E-1020. These concentrations increased cAMP in the heart to the same levels. Analysis of the effects of both agents on peak [Ca2+]i versus max - d[Ca2+]i/dt showed that ISO is much more effective on peak [Ca2+]i while E-1020 is more effective on max - d[Ca2+]i/dt. 3. These results showed that the effects of ISO and E-1020 on the parameters of intracellular Ca2+ transients of single myocytes from failing hearts are slightly different, and suggest that E-1020 may improve diastolic function as well as systolic function in failing hearts.

Biochemical remodeling of collagen in the heart of spontaneously hypertensive rats--prominent increase in type V collagen.

To determine how collagen is remodeled in the heart during the development of cardiac hypertrophy, the collagen concentration and the proportions of types I, III, and V collagen were analyzed in the hearts of 10-, 20-, 32-, and 40-week-old spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. The collagen concentration was calculated after the hydroxyproline content was measured and the proportions of types I, III, and V collagen were determined by non-interrupted SDS-polyacrylamide gel electrophoresis (SDS-PAGE). There was no significant difference between the collagen concentrations in 10-week-old SHR and WKY. At 20 weeks, the collagen concentration in the hearts of the SHR had decreased significantly (p < 0.01) when compared to that in the WKY, at 40 weeks, this concentration in SHR had increased significantly (p < 0.05) when compared to that in the WKY. Type V collagen in WKY increased with age and type I collagen in the 20- and 40-week-old WKY decreased significantly (p < 0.05) when compared to that in the 10-week-old WKY. However, the proportion of type I collagen in the 20-week-old WKY did not differ from that of the 40-week-old WKY. There was no significant difference between the proportions of the various types of collagen in 10-week-old SHR and those in age- and sex-matched WKY. However, the proportion of type V collagen in the 20- and 40-week-old SHR was significantly (p < 0.01) higher than that in age- and sex-matched WKY.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin converting enzyme inhibitor, captopril, inhibits cardiac hypertrophy without changing collagen types and concentration in spontaneously hypertensive rats.

1. The effects of the ACE inhibitor, captopril, on collagen metabolism in spontaneously hypertensive rats (SHR) with cardiac hypertrophy was examined. Captopril (100 mg/kg per day) was administered in drinking water to 20 week old male SHR for 12 weeks. Collagen concentration was calculated from hydroxyproline content, and relative proportions of types I, III and V collagen were determined by non-interrupted SDS-polyacrylamide gel electrophoresis (SDS-PAGE). These parameters were examined in age and sex matched Wistar-Kyoto (WKY) rats, as well as in non-treated SHR, and compared with those of captopril-treated SHR. 2. Captopril significantly reduced both blood pressure (191 +/- 12.1 vs 146 +/- 11.2 mmHg, P < 0.01), and the ratio of left ventricular (LV) weight to bodyweight (BW; 2.38 +/- 0.17 vs 2.05 +/- 0.12 mg/g, P < 0.01). There were no significant differences in collagen concentration among WKY rats, captopril-treated SHR and non-treated 32 week old SHR. However, total collagen content in captopril-treated SHR reduced significantly compared with non-treated 32 week old SHR (16.8 +/- 2.0 vs 21.3 +/- 0.8 mg, P < 0.01). The relative proportion of type V collagen was significantly higher in both captopril-treated (58.6 +/- 3.4 vs 46.8 +/- 1.3%, P < 0.01) and non-treated 32 week old SHR (59.9 +/- 3.1 vs 46.8 +/- 1.3%, P < 0.01) compared with WKY rats. However, there were no significant differences between captopril-treated SHR and non-treated 32 week old SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Biochemical and structural remodeling of collagen in the right ventricular hypertrophy induced by monocrotaline.

We investigated biochemical and structural changes in collagen in ventricles in right ventricular hypertrophy (RVH) induced by monocrotaline injection in Sprague-Dawley rats. Rats injected with monocrotaline showed significant RVH after 2 weeks compared with the vehicle-treated rats (controls). After 4 weeks, the monocrotaline-treated rats showed severe RVH with heart failure. After 2 weeks, the proportion of type III collagen in the right ventricles (RV) of the monocrotaline-treated rats increased significantly compared with controls, with a concomitant decrease in type I collagen. After 4 weeks, there was a significant increase in the proportion of type III and type V collagens in the RV. In the left ventricles (LV), the proportion of collagen types was similar in the monocrotaline-treated and control rats at 2 and 4 weeks. There was no significant difference in collagen concentration (% collagen in dry defatted tissue) between the monocrotaline-treated rats and controls at either 2 or 4 weeks in the LV and RV. Scanning electron microscopy revealed that the collagen fibrillar sheaths around the myocytes in the endomysium of the RV had thickened and formed a dense network in the monocrotaline-treated rats. In the perimysium, tendon-like collagen fibers increased and became thicker than those in the RV of controls. Giant coiled perimysial fibers were also observed in the monocrotaline-treated RV. These structural changes were more pronounced after 4 weeks of monocrotaline-treatment: Loss of myocytes was evident and was accompanied by replacement fibrosis, where dense collagen fibers aggregated parallel to the long axes of the myocytes. Our results show that biochemical and structural remodeling of collagen occurred in the RV but not in the LV during the development of RVH and heart failure, providing important clues to the pathogenesis and pathophysiology of RVH and cardiac failure in response to pressure overload.

Changes in contractile and noncontractile protein metabolisms in both ventricles in monocrotaline-treated rats.

To clarify the metabolism of contractile and noncontractile proteins of both ventricles (BVs) during the development of right ventricular hypertrophy (RVH) induced by pressure overload, monocrotaline (M) was injected subcutaneously into Sprague-Dawley (SD) rats. Myosin isoenzymes (MIEs) were analyzed by pyrophosphate gel electrophoresis. Acid-soluble collagens were analyzed using improved noninterrupted sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Tissue collagen concentrations were also measured. M induced RVH, but not left ventricular hypertrophy, at 2 weeks, and severe RVH at 4 weeks. In right ventricles (RVs) of M-treated rats, MIE significantly shifted from V1 to V3, and the proportions of type III and V collagens increased compared to control at 2 and 4 weeks. In the left ventricles (LVs) of M-treated rats, similar but less remarkable MIE shifts were found without remodeling of collagen types at 2 and 4 weeks. Collagen concentrations of BVs treated with M did not show any significant changes compared to control at 2 and 4 weeks. Our results show remodelings of contractile and noncontractile proteins in RVs during the development of RVH, and also provide evidence for the changes in protein metabolism of the counterpart of RVs (i.e., LVs) during the development of cardiac hypertrophy.