Myocardial oxygenation during high work states in hearts with postinfarction remodeling.

BACKGROUND: Postinfarction left ventricular remodeling (LVR) is associated with reductions in myocardial high-energy phosphate (HEP) levels, which are more severe in animals that develop overt congestive heart failure (CHF). During high work states, further HEP loss occurs, which suggests demand-induced ischemia. This study tested the hypothesis that inadequate myocyte oxygen availability is the basis for these HEP abnormalities. METHODS AND RESULTS: Myocardial infarction was produced by left circumflex coronary artery ligation in swine. Studies were performed in 20 normal animals, 14 animals with compensated LVR, and 9 animals with CHF. Phosphocreatine (PCr)/ATP was determined with 31P NMR and deoxymyoglobin (Mb-delta) with 1H NMR in myocardium remote from the infarct. Basal PCr/ATP tended to be decreased in postinfarct hearts, and this was significant in animals with CHF. Infusion of dobutamine (20 microg x kg-1 x min-1 IV) caused doubling of the rate-pressure product in both normal and LVR hearts and resulted in comparable significant decreases of PCr/ATP in both groups. This decrease in PCr/ATP was not associated with detectable Mb-delta. In CHF hearts, rate-pressure product increased only 40% in response to dobutamine; this attenuated response also was not associated with detectable Mb-delta. CONCLUSIONS: Thus, the decrease of PCr/ATP during dobutamine infusion is not the result of insufficient myocardial oxygen availability. Furthermore, in CHF hearts, the low basal PCr/ATP and the attenuated response to dobutamine occurred in the absence of myocardial hypoxia, indicating that the HEP and contractile abnormalities were not the result of insufficient oxygen availability.

Direct comparison of an intravascular and an extracellular contrast agent for quantification of myocardial perfusion. Cardiac MRI Group.

A direct comparison of extracellular and intravascular contrast agents for the assessment of myocardial perfusion was carried out in a porcine model (N = 5) with a flow-limiting occluder on the left anterior descending coronary artery. Rapid imaging during the first pass of an extracellular or intravascular contrast agent with a saturation-recovery-prepared TurboFLASH sequence showed comparable peak contrast-to-noise enhancements in myocardial tissue regions with flows averaging 1.1 +/- 0.2 at baseline to 4.8 +/- 0.6 ml/min/g during hyperemia. The coefficient of variation between the MR estimates of blood flow with Gadomer-17 and the microsphere blood flow measurements was 11 +/- 11%, while the corresponding co-efficient of variation for blood flow estimates with the extracellular CA was 23 +/- 11%. Blood volume differences between rest and hyperemia observed with the intravascular tracer were significant (Vvasc(rest) = 0.078 +/- 0.013 ml/g, versus Vvasc(hyperemia) = 0.102 +/- 0.019 ml/g; p < 0.05). The effects of water exchange were minimized through the choice of pulse sequence parameters to provide blood volume estimates consistent with the changes expected between rest and hyperemia. This study represents the first application of multiple indicators in first pass imaging studies for the assessment of myocardial perfusion. The use of an intravascular instead of an extracellular contrast agent allows a reduction of the degrees of freedom for modeling tissue residue curves and results in improved accuracy of blood flow estimates.

Effects of ACE inhibition and beta-blockade on collagen remodelling in the heart of Bio 14.6 hamsters.

1. The effects of angiotensin converting enzyme (ACE) inhibition and beta-blockade on collagen in the heart and on plasma catecholamines and tissue angiotensin (Ang) I and II were examined in Bio 14.6 Syrian hamsters. Male hamsters (76-79 days old) were given low-dose enalapril (3 mg/kg per day), high-dose enalapril (30 mg/kg per day), atenolol (50 mg/kg per day) or vehicle for 65 days. Age and sex matched healthy F1b hamsters were used as controls. Collagen concentration was determined by measuring hydroxyproline content and the relative proportion of type I, III, and V collagens was obtained by non-interrupted sodium dodecyl polyacrylamide gel electrophoresis (SDS-PAGE). Per cent collagen area (PCA) was measured by pixel counting in myocardial tissue by a personal computer. 2. Although heartweight (HW) and bodyweight (BW) in F1b controls were significantly higher compared with drug-treated groups and vehicles, the HW/BW ratio in cardiomyopathic Bio 14.6 hamsters tended to be high compared with F1b controls and was decreased by each drug treatment. 3. Collagen concentration, total collagen content and PCA in the heart of Bio 14.6 hamsters were significantly higher than F1b controls. Collagen concentration and total collagen content were significantly decreased in all drug-treated groups compared with vehicles. 4. The proportion of type I collagen tended to decrease while that of type III collagen tended to increase in all drug-treated groups compared with vehicles. Type V collagen in vehicle-treated group was significantly higher than in F1b controls, while it tended to decrease in all drug-treated groups compared with vehicles. 5. Plasma concentrations of catecholamines (adrenaline and noradrenaline) were decreased significantly by atenolol and high-dose enalapril, but not by low-dose enalapril. Tissue AngI remained unaltered in any of the drug-treated hamsters. Tissue AngII was decreased by the high-dose enalapril and beta-blockade, and tended to be decreased by low-dose enalapril treatment. 6. These results reveal that enalapril and atenolol produced similar beneficial effects on collagen remodelling in Bio 14.6 hamsters by decreasing the total amount of collagen, and also by changing collagen phenotypes through the inhibition of the renin-angiotensin system. Both drugs also improved myocardial morphological integrity.

Endothelin induced collagen remodeling in experimental pulmonary hypertension.

To investigate pathophysiological roles of endothelin-1 (ET-1) in collagen remodeling in pulmonary hypertension, we measured: (a) mRNA expression, concentration, localization of ET-1; (b) changes in types and content of collagen in the lung; (c) and confirmed direct effects of ET-1 on type V collagen metabolism in vascular smooth muscle cells. Monocrotaline-treated rats showed pulmonary hypertension with medial hypertrophy and perivascular fibrosis of pulmonary arteries. At the progressive stage of pulmonary hypertension, both ET-1 levels and its mRNA expression in the lung increased. Total collagen in the lung rose markedly with a higher rate of increase in type V collagen. ET-1, which exists in vascular smooth muscle cells, other perivascular cells and endothelium, stimulated type V collagen production. Our results suggest that local production of ET-1 in the lung contributes to progression of pulmonary hypertension through changes in phenotypes and content of collagen.

Different effects of an angiotensin converting enzyme inhibitor and a calcium antagonist on protein metabolism in rats with right ventricular hypertrophy.

OBJECTIVE: We examined the effects of a calcium antagonist and an angiotensin converting enzyme (ACE) inhibitor on contractile and non-contractile protein metabolism and cardiac function in a monocrotaline-induced right ventricular hypertrophy model, in order to define the effects of these drugs on cardiac hypertrophy. METHODS: One week after monocrotaline injection, male Sprague-Dawley rats were given either a calcium antagonist (nilvadipine; 3 mg/kg per day) or an ACE inhibitor (delapril-HCl; 30 mg/kg per day) for 2 weeks. Right ventricular pressure, the right ventricle: (left ventricle + interventricular septum) ratio, myosin isoenzymes, collagen concentration, collagen types and contractility of right ventricular free wall were examined. RESULTS: In untreated rats significant monocrotaline-induced right ventricular hypertrophy with an increase in the proportion of collagen types III and V was observed. There were no significant changes in collagen concentration. Both drugs reduced right ventricular pressure to the same degree and decreased right ventricular hypertrophy. However, the inhibitory effect of delapril on right ventricular hypertrophy was stronger than that of nilvadipine. Nilvadipine reduced the collagen concentration and reversed changes in collagen types, whereas delapril did not have any significant effect on collagen concentration or collagen types. Cardiac contractility was improved by delapril, but not by nilvadipine. CONCLUSIONS: The results show that a calcium antagonist disproportionately inhibited contractile and non-contractile protein metabolism, whereas an ACE inhibitor proportionally inhibited them and improved cardiac function in a model of right ventricular hypertrophy. The improvement in cardiac function may be due partly to the proportional inhibition of contractile and non-contractile proteins elicited by an ACE inhibitor.

Contrasting effects of an angiotensin converting enzyme inhibitor and a calcium antagonist on calcium transients in isolated rat cardiac myocytes.

OBJECTIVE: The aim was to examine the effects of an angiotensin converting enzyme (ACE) inhibitor and a calcium antagonist on intracellular calcium transients in isolated cardiac myocytes from a monocrotaline induced right ventricular hypertrophy model. METHODS: One week after monocrotaline injection, Sprague-Dawley rats were given either an ACE inhibitor (delapril-HCl) or a calcium antagonist (nilvadipine) for two weeks. Using fura-2/AM, calcium transients were measured in single myocytes separated from the right ventricle. RESULTS: The severe right ventricular hypertrophy observed in untreated rats was significantly reduced in drug treated animals. The inhibitory effects of delapril were more prominent than those of nilvadipine, although both drugs reduced right ventricular pressure to the same extent. Calcium transients in delapril treated rats were similar to those in control rats. On the other hand, the calcium transient in nilvadipine treated rats was decreased and its time course was prolonged. The changes were similar to those found in monocrotaline treated rats. The responsiveness of calcium transients to isoprenaline in delapril treated rats was similar to that in control rats. The responsiveness in nilvadipine treated rats was decreased, and was similar to that in monocrotaline treated rats. Delapril improved developed tension and the beta adrenoreceptor responsiveness of developed tension to isoprenaline. CONCLUSIONS: Although delapril and nilvadipine inhibited cardiac hypertrophy in monocrotaline treated rats, significant improvement of contractile function and beta adrenoreceptor responsiveness was observed only in the delapril treated rats. This improvement was partially due to the improvement in calcium transients and the restoration of the beta adrenoreceptor responsiveness of the calcium transient to beta adrenergic stimulation.

Kinetics of plasma homocysteine in healthy subjects after peroral homocysteine loading.

The kinetics of plasma homocysteine were determined in 13 healthy subjects after peroral administration and in one person after intravenous injection. Various forms of homocysteine completely dissolved in an aqueous solution were rapidly absorbed after peroral administration, and the bioavailability was estimated to be 0.53. The volume of distribution was 0.66 L/kg. The area under the plasma concentration curve (AUC0-48 h) was proportional to the administered dose (33.5-134 mumol/kg body wt), and showed small interindividual variations. Plasma homocysteine showed first-order elimination kinetics for at least 6 h. The half-life (t1/2) was 223 +/- 45 min, and there was a significant correlation between t1/2 values determined on two different occasions in the same individual. The transient hyperhomocysteinemia was associated with an increase in plasma methionine, which probably reflects intracellular remethylation of homocysteine. Less than 2% of the administered homocysteine dose was recovered in the urine. These findings may form the basis for future studies on the regulation of plasma homocysteine in health and disease, and should motivate the evaluation of a homocysteine loading test as a diagnostic tool.

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)

Analysis of karyotype, SCE, and point mutation of RAS oncogene in Indian MDS patients.

Thirty Indian patients diagnosed as having primary myelodysplastic syndrome as per the French-American-British classification were investigated, on admission, for the frequencies of nonrandom karyotype abnormalities, sister chromatid exchange, and point mutations of the RAS oncogene. Successful karyotype analysis was possible in 24 patients, of whom 9 (37.5%) showed nonrandom karyotypic changes. Anomalies of chromosomes 5, 7, and 8 were detected in their bone marrow (BM). In addition, two new anomalies, del(8)(q22) and +19, were observed for the first time in our series. Six MDS patients were studied for SCE in either BM or peripheral blood. These data revealed a normal SCE incidence. Of the 10 MDS patients studied for point mutations of NRAS 12 and 61 and KRAS 12 and 61, one patient exhibited a base substitution at position 1 of the 12th codon of the KRAS gene. These data, gathered for the first time on the Indian patients, throw some light on the nature of genetic changes in MDS of our country.

Loss of heterozygosity at D3S2 locus of short arm of chromosome 3 in chronic myelogenous leukemia.

Loss of heterozygosity (LOH) on the short arm of chromosome 3 was studied in four patients with chronic myelogenous leukemia (CML). The bcr gene rearrangement-negative spleen cells and a B-cell line were used as normal tissue controls. Five probes showing restriction fragment length polymorphisms (RFLP) and a variable number of tandem repeats on chromosome 3 were used. DNA patterns in Southern blotting were compared between normal cells and leukemic cells. One of the four patients had LOH at the D3S2 locus mapped to 3p14.3-3p21.3. The LOH was detected in the blastic phase, but not in the chronic phase. This patient showed normal chromosomes 3 in the blastic phase. These data suggest the possibility of the existence of LOH in CML, occurring as a secondary event in the blastic phase, and which might have been induced by submicroscopic deletion or somatic recombination.