trandolapril and Cardiac-Output--Low

The long-term prognostic importance of hyperkinesia is unknown following an acute myocardial infarction (AMI). The American Society of Echocardiography recommends that hyperkinesia should not be included in calculation of wall motion index (WMI). The objective of the present study was to determine if hyperkinesia should be included in WMI when it is estimated for prognostic purposes following an AMI. Six thousand, six hundred seventy-six consecutive patients were screened 1 to 6 days after AMI in 27 Danish hospitals. WMI was measured in 6,232 patients applying the 9-segment model and the following scoring system: 3 for hyperkinesia, 2 for normokinesia, 1 for hypokinesia, 0 for akinesia, and -1 for dyskinesia. All patients were followed with respect to mortality for at least 3 years. WMI was calculated in 2 different ways: 1 including hyperkinetic segments (hyperkinetic-WMI) and the other excluding nonhyperkinetic segments (nonhyperkinetic-WMI) by converting the hyperkinetic segments to normokinetic segments. Hyperkinesia occurred in 736 patients (11.8%). WMI was an important prognostic factor (relative risk 2.49; p = 0.0001) for long-term mortality together with heart failure, history of hypertension, angina, or diabetes, previous AMI, age, thrombolytic therapy, arrhythmias, and bundle branch block. In a multivariate analysis including nonhyperkinetic-WMI, hyperkinesia was associated with a relative risk of 0.84, which was statistically significant (confidence intervals 0.74 to 0.96; p = 0.01). When hyperkinesia was included, both in WMI (hyperkinetic-WMI) and as an independent variable, no additional prognostic information (relative risk 0.93; p = 0.26) was obtained. An echocardiographic evaluation shortly after an AMI gave important prognostic information, especially if the information concerning hyperkinesia was included. If WMI is used for prognostic purposes, hyperkinesia should be included in calculation of the index.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Angina Pectoris; Angiotensin-Converting Enzyme Inhibitors; Arrhythmias, Cardiac; Bundle-Branch Block; Cardiac Output, Low; Confidence Intervals; Diabetes Complications; Echocardiography; Female; Follow-Up Studies; Humans; Hypertension; Indoles; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Myocardial Contraction; Myocardial Infarction; Prognosis; Risk Factors; Survival Rate; Thrombolytic Therapy; Ventricular Dysfunction, Left

Angiotensin II blockade and spironolactone effectively reduces proteinuria in humans. To clarify the mechanisms of the beneficial effect of blockade of both aldosterone and angiotensin II, we associated the aldosterone antagonist eplerenone to an angiotensin-converting enzyme inhibitor (ACEI) and examined the effect on renal transforming growth factor (TGF)-beta expression and oxidative stress by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the Dahl salt-sensitive rat with heart failure (DSHF).. Dahl salt-resistant control rats and DSHF rats were fed with 8% NaCl diet and at 11 weeks the DSHF rats were treated with vehicle, eplerenone (Epl), trandolapril or a combination of both drugs for 7 weeks.. DSHF rats showed increased NADPH oxidase and decreased superoxide dismutase (SOD) resulting in increased oxidative stress. ACEI and Epl reduced NADPH oxidase showing an additive effect in their combination; ACEI increased manganese SOD (MnSOD) and Epl increased MnSOD, copper-zinc SOD and catalase, resulting in the lowest levels of oxidative stress with the combination therapy. Glomerulosclerosis and proteinuria were increased in the DSHF rats, and Epl suppressed them more effectively than ACEI to levels not different from the combination of both, showing a positive correlation with NADPH oxidase expression and TGF-beta. Renal TGF-beta was specifically suppressed with Epl. The association of Epl to ACEI is beneficial due to further reduction of NADPH oxidase and specific inhibition of TGF-beta resulting in improvement of renal damage.

Topics: Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiac Output, Low; Drug Synergism; Eplerenone; Hypertension; Indoles; Kidney; Male; Mineralocorticoid Receptor Antagonists; NADPH Oxidases; Oxidative Stress; Rats; Rats, Inbred Dahl; Reactive Oxygen Species; Sodium-Potassium-Exchanging ATPase; Spironolactone; Superoxide Dismutase; Transforming Growth Factor beta

1. The effects of long-term treatment with trandolapril, an angiotensin I-converting enzyme inhibitor, on exercise capacity of rats with chronic heart failure (CHF) following coronary artery ligation were examined. CHF was developed by 8 weeks after the coronary artery ligation. 2. The running time of rats with CHF in the treadmill test was shortened to approximately 65% of that of sham-operated rats (16.3+/-1.2 vs. 25.1+/-1.6 min, n = 7; P<0.05). ATP, creatine phosphate (CP), and lactate contents of the gracilis muscle of rats with CHF were similar to those of sham-operated rats before running. After running, ATP and CP were decreased and lactate was increased in both rats with CHF and sham-operated rats. There were no significant differences in the levels of energy metabolites between rats with CHF and sham-operated rats. The rates of decrease in ATP and CP and rate of increase in lactate in the gracilis muscle of rats with CHF during exercise were greater than those of sham operated rats (2.5, 2.0 and 1.5 fold high, respectively), suggesting wastage of energy during exercise in the animals with CHF. 3. Myofibrillar Ca2+ -stimulated ATPase (Ca-ATPase) activity of skeletal muscle of rats with CHF was increased over that of the sham-operated control (62.03+/-1.88 vs. 52.34+/-1.19 micromol Pi mg(-1) protein h(-1) n = 7; P<0.05). The compositions of myosin heavy chain (MHC) isoforms of gracilis muscle were altered by CHF; decreases in MHC types I and IIb and an increase in MHC type IIa were found (P<0.05). 4. Rats with CHF were treated with 1 mg kg(-1) day(-1) trandolapril from the 2nd to 8th week after surgery. Treatment with trandolapril prolonged the running time, reversed the rates of decrease in ATP and CP and the rate of increase in lactate, and restored the Ca-ATPase activity (51.11+/-0.56 micromol Pi mg(-1) protein h(-1), n = 7; P<0.05) and composition ratio of MHC isoforms in the gracilis muscle. 5. The results suggest that long-term trandolapril treatment of rats with CHF may restore their ability to utilize energy without wastage and thus improve exercise capacity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium-Transporting ATPases; Cardiac Output, Low; Energy Metabolism; Hemodynamics; Indoles; Male; Myosin Heavy Chains; Physical Conditioning, Animal; Protein Isoforms; Rats; Rats, Wistar; RNA, Messenger

1 Calcium transport activity of isolated cardiac sarcoplasmic reticulum (SR) including Ca2+ uptake and release is decreased in animals with chronic heart failure (CHF) following myocardial infarction. The present study was undertaken to determine whether an angiotensin converting enzyme (ACE) inhibitor, trandolapril, improves cardiac sarcoplasmic reticular function in animals with CHF following myocardial infarction. 2 CHF was induced by left coronary artery ligation in rats, which resulted in an infarction of approximately 45% of the left ventricle. Aortic flow and cardiac output index were decreased, and left ventricular end-diastolic pressure was increased 8 weeks after the operation, suggesting the development of CHF. 3 The developed force transients of cardiac skinned fibres of the rats with CHF were decreased when the skinned fibre was preloaded for 0.25-1 min with 10(-5) M Ca2+ (48-88%) and when preloaded with 10(-6) M Ca2+ and then exposed to 0.1-1 mM caffeine (45-93%). 4 The [3H]-ryanodine-binding activity in SR-enriched fractions was reduced by 23% in the CHF group. These results suggest that the amount of Ca2+ released from SR is decreased due to a reduced rate of SR Ca2+ uptake and a downregulation of the SR Ca2+-release channel. 5 Rats were treated orally with 3 mg kg(-1) day(-1) trandolapril from the 2nd to the 8th week after the coronary artery ligation. Treatment with trandolapril attenuated the reduction in aortic flow and cardiac output index and the increase in left ventricular end-diastolic pressure, and improved the developed force transients of the skinned fibre of the animal with CHF without causing a reduction of infarct size. Treatment with trandolapril also attenuated the reduction in ryanodine receptor density in the viable left ventricle of the rat with CHF. 6 It is concluded that long-term treatment with trandolapril attenuates cardiac SR dysfunction in rats with CHF and that the mechanism underlying this effect is, at least in part, attributed to prevention of downregulation of Ca2+ release channel.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium; Cardiac Output, Low; Chronic Disease; Heart; Hemodynamics; Indoles; Male; Myocardial Infarction; Myocardium; Rats; Rats, Wistar; Ryanodine; Sarcoplasmic Reticulum

1 Characteristics of cyclic GMP- and cyclic AMP-mediated relaxation in aortic segments of rats with chronic heart failure (CHF) and the effects of chronic treatment with an angiotensin I converting enzyme (ACE) inhibitor, trandolapril, were examined 8 weeks after coronary artery ligation. 2 Cardiac output indices of coronary artery-ligated and sham-operated rats were 125+/-8 and 189+/-10 ml min(-1) kg(-1), respectively (P<0.05), indicating the development of CHF at this period. 3 The maximal relaxant response of aortic segments to 10 microM acetylcholine in rats with CHF and sham-operated rats was 64.0+/-5.7 and 86.9+/-1.9%, respectively (P<0.05), whereas the relaxant response to sodium nitroprusside (SNP) remained unchanged. Tissue cyclic GMP content in rats with CHF was lower than that of sham-operated rats. 4 In endothelium-intact segments of rats with CHF, the maximal relaxant response to 10 microM isoprenaline (44.5+/-6.7%) was lower that sham-operated rats (81.3+/-2.5%, P<0.05) and the concentration-response curve for NKH477, a water-soluble forskolin, was shifted to the right without a reduction in the maximal response. Isoprenaline-induced relaxation of aortic segments was attenuated by NG-nitro-L-arginine methyl ester (L-NAME) in sham-operated rats, but not in rats with CHF. Relaxation to 30 microM dibutyryl cyclic AMP in rats with CHF (26.8+/-2.7%) was lower than that in sham-operated rats (63.4+/-11.8%, P<0.05). 5 Trandolapril (3 mg kg(-1) day(-1)) was orally administered from the 2nd to 8th week after the operation. Aortic blood flow of rats with CHF (38.5+/-3.6 ml min(-1)) was lower than that of sham-operated rats (55.0+/-3.0 ml min(-1)), and this reduction was reversed (54.1+/-3.4 ml min(-1)) by treatment with trandolapril. The diminished responsiveness described above was normalized in the trandolapril-treated rat with CHF (i.e., the maximal relaxation to acetylcholine, 94.7+/-1.0%; that to isoprenaline, 80.5+/-2.8%; that to dibutyryl cyclic AMP, 54.7+/-6.2%). However, aortic segments of trandolapril-treated rats with CHF, L-NAME did not attenuate isoprenaline-induced relaxation and the tissue cyclic GMP level was not fully restored, suggesting that the ability of the endothelium to produce NO was still partially damaged. 6 The results suggest that vasorelaxation in CHF, diminished mainly due to dysfunction in endothelial nitric oxide (NO) production and cyclic AMP-mediated signal transduction, was partially restored by long-term treatment

Topics: Acetylcholine; Adrenergic beta-Agonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta; Cardiac Output, Low; Colforsin; Cyclic AMP; Cyclic GMP; Hemodynamics; Indoles; Isoproterenol; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroprusside; Rats; Rats, Wistar; Vasodilator Agents

The effects of long-term treatment with a novel angiotensin I converting enzyme (ACE) inhibitor, trandolapril, on ACE activity and cardiac function in rats with chronic heart failure (CHF) were examined and compared with those of captopril and enalapril. Left coronary artery ligation of rats resulted in decreases in mean arterial pressure, left ventricular systolic pressure, dP/dt, cardiac output and stroke volume indices, and increases in left ventricular end-diastolic pressure and systemic vascular resistance 12 weeks after the operation. A significant increase in ACE activity of the myocardium, but not that of serum or other tissues, was detected in the CHF rat 12 weeks after the operation. Oral treatment with ACE inhibitors (10 mg/kg/day captopril, 10 mg/kg/day enalapril or 3 mg/kg/day trandolapril) from the 2nd to 12th week, attenuated the changes in cardiac output and stroke volume indices, left ventricular end-diastolic pressure and systemic vascular resistance of the CHF rat. Treatment also attenuated the increase in the cardiac. ACE activity of CHF rats. A close relationship between the decrease in cardiac output index and the increase in cardiac ACE activity was detected. The results suggest that trandolapril, like other ACE inhibitors, exerts a beneficial effect on cardiac function in the CHF rat and that one of the mechanisms for this effect is attenuation of elevated cardiac ACE activity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiac Output; Cardiac Output, Low; Hemodynamics; Indoles; Male; Myocardial Infarction; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Wistar