Search

The effect of glucocorticoid on the prostaglandin E1 (PGE1)-mediated cyclic AMP (cAMP) formation by vascular smooth muscle cells (VSMC) from renal arteries (RA) was studied in rats. Dexamethasone (DEX) at concentrations ranging from 10 -10to ~10-8mol/l dosedependently potentiates the PGE1-mediated response. This facilitation began at 6h and reached its maximum after 24 h of DEX administration. Aldosterone (10-6mol/l) did not affect the dose-response curve of PGE1. Inhibitors of protein and RNA synthesis blocked this glucocorticoid effect. The basal activity of adenylate cyclase in DEX-treated cells was twice as high as in control cells. Treatment of VSMC with DEX increased cholera toxinand pertussis toxin-stimulated adenylate cyclase activity. DEX treatment also augments foskolin-stimulated adenylate cyclase activity. These results suggest that DEX increases PGE1-mediated cAMP formation of VSMC from RA through a mechanism that involves the induction of protein synthesis, and that the activation of the catalytic unit may play some role in this facilitating process

There is evidence that protein kinase C activity in platelets from adult SHR is significantly higher than this activity in age-matched WKY. In the present study, protein kinase C activity in the SHR was measured following antihypertensive drug treatment. Chronic administration of enalapril to SHR for 2 weeks decreased both systolic blood pressure and protein kinase C activity to the levels seen in the WKY. Similar results were obtained in case of chronic treatment of SHR with hydralazine or nifedipine. These results suggest that enhanced protein kinase C activity of SHR can be suppressed by lowering blood pressure by antihypertensive drugs.

The effect of once daily low-dose carvedilol on circadian variations of blood pressure (BP) was studied in Japanese patients with mild or moderate essential hypertension. Thirty-one patients were admitted to hospital whose BP was 150/90 mm Hg/day or greater and they participated in the study. After a placebo period of 1 week, 5 or 10 mg carvedilol was given once daily in the morning for 3 to 7 days, and if BP reduction was not sufficient, the dose was increased to 20 mg daily. The blood pressure variation was monitored before and 1, 2, 4, 6, 8, 10, 12, and 24 h after administration of the drug on the last day of placebo and final dose of carvedilol. Of the 31 cases receiving carvedilol once daily, cumulative effectiveness (13 mm Hg reduction in mean BP) was 48.4 at 10 mg/day and 54.8 at 20 mg/day. Both systolic and diastolic pressures decreased significantly and heart rate decreased slightly. There was no significant difference between the standard deviations of BP on the last days of the control period and the carvedilol treatment. The difference between maximum and minimum BP during the day was not significant between the two periods. Circadian variations of heart rate were also not significantly different for the two periods. This indicates that carvedilol did not have any effect on circadian variations of BP and heart rate. The present study also suggests that low-dose carvedilol once daily may be effective in the treatment of hypertension.

In order to evaluate the usefulness of urapidil in the treatment of severe hypertension and in the long-term treatment of essential hypertension, two open multicentre studies were performed.

We have recently shown that circulating atrial natriuretic polypeptide (ANP) in adult spontaneously hypertensive rats (SHR) is higher than that in age-matched Wistar-Kyoto rats (WKY). The present experiment was designed to examine the possible effects of chronic treatment with angiotensin I converting enzyme inhibitors (ACEI) on plasma ANP levels in SHR. Captopril and enalapril lowered blood pressure and reduced relative ventricular weight in SHR but not to the level of WKY. Plasma ANP levels were decreased by captopril and enalapril compared with untreated SHR. These results suggest that the ANP release may be suppressed in ACEI-treated SHR compared with untreated SHR. We speculate that a reduction of cardiac overload by ACEI may in part explain the decline of circulating ANP.

To examine the relationship between the urinary levels of alanine aminopeptidase (AAP) or N-acetyl-β-D-glucosaminidase (NAG) and the advance of essential hypertension, we measured the urinary levels of these enzymes in 20 normotensive controls, 8 subjects with borderline hypertension and 40 subjects with WHO stage I and stage II essential hypertension. The urinary level of NAG in stage II hypertensives was higher than that in the normotensives, and borderline or stage I hypertensives (p < 0.01). Systolic blood pressure and the urinary level of NAG was positively correlated in hypertensives (rs=0.43, p < 0.01). The urinary level of NAG was correlated inversely with renal blood flow (rs=-0.61, p < 0.01). The urinary level of AAP in stage II hypertensives was also higher than that in the normotensives (p < 0.01) or stage I hypertension (p < 0.01), but the urinary AAP level was not significantly correlated with systolic blood pressure or renal blood flow in hypertension.

• The relationship between the renal pathologic activity of systemic lupus erythematosus (SLE) and serum lactate dehydrogenase (LDH) was examined in 28 patients with active SLE involving only the kidney. Serum levels of total LDH, LDH1, and LDH2 were significantly higher in the patients with diffuse proliferative lupus nephritis (World Health Organization class IV) than in those with milder renal disease (classes I through III and V). Total LDH levels showed good correlations with the activity index and the total pathologic score of the renal pathologic scoring system, and with the glomerular hypercellularity and overall deposits. The elevated level of LDH was mainly due to elevated levels of its isozymes LDH1 and LDH2. These results suggest that the elevation of serum LDH levels in patients with SLE reflects the renal pathologic changes due to lupus nephritis.(Arch Intern Med 1986;146:548-552)

The effects of endothelin-1 on cytosolic Ca2and inositol 1,4,5-triphosphate (IP3) levels were investigated in cultured, untreated human endothelial cells and in endothelial cells pretreated with anti-endothelin-1 serum for 24 h to exclude the effect of endogenous endothelin-1. Endothelin-1 was found to increase the intracellular Ca2level, either in the presence or absence of extracellular Ca2, in endothelial cells pretreated with antiserum by the fura-2 fluorescence technique. IP3levels immediately started to rise following endothelin-1 stimulation. Resting intracellular Ca2levels were significantly lower when the cells were pretreated with antiserum than without antiserum pretreatment. Following stimulation by endothelin-1, intracellular Ca2and IP3levels in endothelial cells pretreated with antiserum increased significantly compared to those in untreated endothelial cells. Endothelin-1 also increased 45Ca influx from the extracellular space. These results suggest that endothelin-1 increases intracellular Ca2in endothelial cells through extracellular Ca2-dependent mechanisms and by the release of Ca2from intracellular stores, this presumably being induced by IP3formation.

Objective The present study was designed to examine whether adrenomedullin affects fetal calf serum (FCS) stimulated proliferation in cultured rat vascular smooth muscle cells (VSMCs).

Neutrophils from asthmatic patients seem to be in an activated state. This study demonstrated that superoxide radical (O2–) production was enhanced in asthmatic patients compared with healthy control subjects. Production of (O2–) also increased with progression of disease and with disease duration. In addition, (O2–) release was inversely correlated with FEV1and midflows and was greater in neutrophils from patients with exacerbated disease than in those from patients with stable disease. These findings suggest that oxygen metabolites may play a direct or indirect role in the modulation of airway inflammation.

In a randomized study in 26 elderly patients with mild essential hypertension, acute effects of α- and β-adrenoceptor blockade on plasma ANP levels were examined at rest and during ergometric exercise. Plasma ANP level and LVEF were measured before and after administration of prazosin (an α1-adrenergic blocker), atenolol (a cardioselective β-adrenergic blocker), or carteolol (a nonselective β-adrenergic blocker). Plasma ANP level was increased by exercise. Carteolol and atenolol increased plasma ANP levels at rest and during exercise, but the effect of atenolol was not statistically significant. Prazosin significantly suppressed the ANP values at rest and during exercise. The LVEF was increased by prazosin and decreased by β-blockers, especially by carteolol. Multivariate regression analysis showed that LVEF was the most significant predictor of the plasma ANP level at maximal exercise; the resting blood pressure and heart rate were not predictors of this value. The results showed that single administrations of an α-blocker and a nonselective β-blocker had opposite effects on the plasma ANP level both at rest and during exercise in elderly patients with mild essential hypertension. The observed difference in the ANP response seems to be related to changes in left ventricular function rather than changes in blood pressure or heart rate.

To investigate the contribution of the cardiac renin-angiotensin system to ventricular dilatation after myocardial infarction, we examined the effects of 3-week treatments with an angiotensin converting enzyme inhibitor, delapril, and a selective angiotensin II type 1 (AT₁) receptor antagonist, TCV-116, on haemodynamics and ventricular angiotensin II contents in myocardial-infarcted rats. TCV-116 reduced mean aortic pressure, and prevented the increase of right and left ventricular weight, left ventricular end-diastolic pressure and volume of myocardial-infarcted rats, to a similar extent to delapril. Thus, AT₁ receptor-mediated action of angiotensin II plays a central role in the development of ventricular dilatation. Angiotensin II contents in the right and non-infarcted left ventricles (6.0±1.0 and 5.9±0.7 pg/g tissue, respectively, mean±S.E.M.) of myocardial-infarcted rats were not different from those of sham-operated rats. However, angiotensin II contents in the infarcted scar (21.7±3.5 pg/g) of myocardial-infarcted rats were 4.2-fold higher than those in the left ventricle of sham-operated rats. Delapril reduced angiotensin II contents in the right and non-infarcted left ventricles, and the scar by 48, 81 and 60%, respectively, but did not reduce plasma angiotensin II in myocardial-infarcted rats. TCV-116 also decreased angiotensin II in the right and non-infarcted left ventricles by 57 and 56%, respectively, while increased plasma angiotensin II by 4.3-fold. Thus, the prevention of ventricular dilatation by these two agents was associated with the decrease in ventricular angiotensin II contents. These observations suggest that the cardiac renin-angiotensin system rather than the circulating system may play an important role in ventricular dilatation after myocardial infarction. Copyright 1993, 1999 Academic Press

Carvedilol, a new β-blocker with vasodilating activity, was given orally to 9 hypertensive inpatients with impaired renal function in a dosage regimen of 5 to 20mg once daily to evaluate its clinical efficacy and safety. Treatment with carvedilol produced a significant decrease in blood pressure from 172/ 101 to 150/87 mm Hg (p < 0.01), but it did not cause orthostatic hypotension. Heart rate was decreased from 74.3 to 72.8 beats/min, but the decrease was not statistically significant. Serum creatinine and BUN levels were unchanged and other laboratory parameters were within normal limits. There were no side effects in any of the patients during the trial. These results suggest that carvedilol is a useful and safe drug for the treatment of renal hypertension.

This study was performed to find the optimal dose of carvedilol, in terms of efficacy and safety, in Japanese patients with mild to moderate essential hypertension. 134 patients with blood pressure > 160/95mm Hg after a 4-week placebo run-in period were initially given carvedilol 5mg once daily. The dose was increased to 10 and 20mg at 4-weekly intervals if the target blood pressure was not achieved. The duration of treatment was 12 weeks. After 12 weeks’ administration, the average blood pressure was significantly (p < 0.001) reduced from 170/101 to 150/91mm Hg. The hypotensive activity of carvedilol 5mg was mild, but sufficient hypotensive effect was observed in 65% of patients receiving up to 20 mg/day. No significant postural changes in blood pressure were observed. Although heart rate was significantly decreased (77 to 66 beats/min, p < 0.001), no patient was judged to have bradycardia. Side effects occurred in 5.2% of patients. Carvedilol 10 to 20mg once daily is considered to be an effective and safe treatment for essential hypertension.

To clarify the difference between alcoholic cardiomyopathy and dilated cardiomyopathy and to investigate the characteristics of alcoholic cardiomyopathy, right ventricular endomyocardial biopsy was performed, and the two diseases were compared clinically and histologically. Changes in the cardiothoracic ratio, cardiac index, and systolic blood pressure/end-systolic volume index were greater after treatment in patients with alcoholic cardiomyopathy than in patients with dilated cardiomyopathy. Histologically, myocytic hypertrophy, fibrosis, and nuclear change were less significant in the former than in the latter. Among patients with alcoholic cardiomyopathy, the cardiac index in those with less fibrosis was greater than in those with more fibrosis. Thus patients with alcoholic cardiomyopathy had more preserved and reversible cardiac function and fewer histologic changes than the patients with dilated cardiomyopathy. Reversibility of cardiac function in patients with alcoholic cardiomyopathy correlated inversely with the severity of histologic changes.

We studied the possibility of predicting PaO2during exercise of a given oxygen uptake ( V˙o2) from resting pulmonary function tests (PFTs) in patients with chronic obstructive pulmonary disease (COPD). The three-minute incremental treadmill exercise was performed with serial measurements of PaO2via intra-arterial catheter in 46 patients (mean FEV1= 1.09±0.49L, mean FEV1/FVC = 44±15 percent). In most of the patients, the changes of PaO2were quite linear in relation to the oxygen uptake, so a slope (PaO2/ V˙o2) could be obtained from the regression equation in each patient. The mean value of the slope (SL) was –23.0±16.6 mm Hg/L V˙o2/min. Correlation between SL and all parameters of resting PFTs were computed. Because of the high correlation coefficient between SL and %Dco(SL = –59.3 + 0.501· %Dco, r = 0.851, p<0.001), it was possible to predict PaO2at a given V˙o2using the following equation: PaO2predicted = PaO2rest + SL·( V˙o2–0.25), where SL was derived from measured %Dcoand resting V˙o2was assumed 0.25 L/min. There was a high correlation between the predicted PaO2at V˙o2of 1.0 L/min and the estimated PaO2obtained from individual PaO2regression with an r value=0.898 and SEE = ± 5.8 mm Hg. A prospective study in 12 patients with COPD was then carried out. There was a high correlation (r=0.857) between the predicted PaO2obtained from the present equation and the estimated PaO2at V˙o2= 1.0 L/min. It was concluded that PaO2during treadmill walking with a given oxygen uptake is predictable from a resting PaO2and a diffusing capacity. This predicted value may be useful in the management of patients with COPD.

A 47-year-old man was admitted for follow-up of an abnormal chest x-ray. He had a history of epistaxis and a brain abscess and a family history of pulmonary arteriovenous fistulas. Physical examination showed clubbed fingers and telangiectasia of the tongue. Laboratory data revealed evidence of polycythemia and hypoxia. Contrast echocardiography and pulmonary perfusion scintigraphy were suggestive of a right-to-left shunt. From the oxygen tension and content of blood taken at cardiac catheterization, the shunt ratio was calculated to be 57.8%. Multiple bilateral pulmonary arteriovenous fistulas were confirmed by angiography, and the patient was diagnosed as having hereditary hemorrhagic telangiectasia. A review of x-ray films taken over a 24-year period demonstrated that the fistulas in both lungs had been increasing gradually in size at different rates. A right lower lobectomy relieved the hypoxia, but the patient died unexpectedly on the twelfth postoperative day. There was no evidence of fistula rupture on chest film, but no autopsy was performed.

1. The cytoplasmic free calcium concentration ([Ca2+]i) in the platelets of spontaneously hypertensive rats (SHR), Wistar–Kyoto rats (WKY), deoxycorticosterone–salt hypertensive rats (DOC) and normotensive Sprague–Dawley rats (SD) was measured with the fluorescent dye, quin-2-tetra-acetoxymethyl ester. 2. No significant difference in platelet [Ca2+]i was found between SHR and WKY or between DOC and SD rats. 3. No correlations were found between systolic blood pressure and [Ca2+]i. 4. These results suggest that the elevation of platelet [Ca2+]i does not necessarily accompany hypertension in rats.

Intracellular pH in platelets from spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY) was measured using a pH-sensitive fluorescent dye, 2‘,7’-bis(carboxyethyl)carboxyfluorescein tetraacetoxy methyl ester (BCECF). Intracellular pH in platelets was significantly higher in SHR than in WKY (7.12 ± 0.04 versus 7.06 ± 0.02, P< 0.01; n = 10). There was a close correlation between intracellular pH and systolic blood pressure (r = 0.66, P< 0.01). Addition to platelets of 1-(5-isoquinolinesulphonyl)-2-methylpiperazine (H-7), a specific inhibitor of protein kinase C, produced a significantly larger decrease in intracellular pH in SHR than in WKY (0.06 ± 0.02 versus 0.03 ± 0.00, P< 0.01, n = 5). These results suggest that protein kinase C may play an important role in the increased intracellular pH in SHR.

Calcium-activated phospholipid-dependent protein kinase (protein kinase C) and cyclic AMP-dependent protein kinase (protein kinase A) were measured in tissue extracts of aortas from 7-, 14− and 20-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Protein kinase C and protein kinase A activity was significantly higher in 14− and 20-week-old SHR. Furthermore, protein kinase C and protein kinase A activity in the aorta was positively correlated with systolic blood pressure. Since protein kinase A is known to relax vascular smooth muscle, the observed increase in its activity may represent a compensatory mechanism to offset further elevation of blood pressure in SHR. These results suggest that protein kinase C in the aorta may play a role in the maintenance of hypertension in SHR.

We studied the expression of c-myc proto-oncogene in hearts and cultured aortic smooth muscle cells of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY), in order to investigate the association of the c-myc gene with cardiac hypertrophy and atherosclerosis in SHR. Transcription of the c-myc gene in hearts of SHR was higher than that of WKY at 10 weeks of age, when cardiac hypertrophy had developed in SHR. The c-myc gene expression in cultured aortic smooth muscle cells of SHR, after the addition of serum to the serum-deprived cultures, was higher than that of WKY. These results suggest that the enhanced expression of the c-myc gene in the hearts and cultured aortic smooth muscle cells of SHR may be associated with the growth control of these cells, and may play a role in the development of cardiac hypertrophy and atherosclerotic lesions in SHR.

TO THE EDITOR. —Mammalian cardiac atria contain biologically active peptides that are capable of producing diuresis, natriuresis, and vasodilation.1,2 Recently, we have shown that plasma levels of atrial natriuretic polypeptide (ANP) is significantly higher in spontaneously hypertensive rats at 20 weeks of age (blood pressure, 184 ±7 mm Hg) than values observed in age-matched normotensive Kyoto-Wistar strain rats3 (blood pressure, 114 ±5 mm Hg).A recently developed radioimmunoassay4 has permitted us to measureplasma ANP concentration in two patients with severe essential hypertension. The plasma ANP values were measured before therapy and after two weeks and four weeks of antihypertensive therapy with nifedipine.Report of Cases.—Case 1.—A 60-year-old man was admitted to our hospital as a hypertensive emergency, with visual disturbance. His pulse rate was 84 beats per minute and his blood pressure was 262/150 mm Hg. Severe hypertensive retinopathy, including massive retinal hemorrhage, was observed. Renal

• Cough productive of sputum, exertional dyspnea, and hypoxemia developed in two patients with Graves' disease after six months (patient 1) or three weeks (patient 2) of treatment with propylthiouracil, 300 mg/day. Chest roentgenograms and transbronchial lung biopsy specimens revealed diffuse interstitial pneumonitis. Lymphocyte transformation by phytohemagglutinin was highly stimulated by propylthiouracil. Symptoms and signs improved after cessation of the drug therapy and administration of prednisolone acetate. These cases represent the first report of a complication of diffuse interstitial pneumonitis induced by propylthiouracil.(Arch Intern Med 1984;144:1764-1765)

Arginine vasopressin may contribute to cardiovascular regulation by causing vasoconstriction and stimulating renal water absorption through V1 and V2 receptors, respectively. Arginine vasopressin may play an important role in congestive heart failure. Recently, oral vasopressin V1 and V2 receptor antagonists were synthesized, however, the effect of vasopressin V1 and V2 receptor antagonists on heart failure is still unclear. We examined the effect of vasopressin Vl receptor antagonist and vasopressin V2 receptor antagonist on heart failure after acute and chronic myocardial infarction. Myocardial infarction was made to the rats by ligation of left anterior descending coronary artery. On one day (acute) and two months (chronic) after the surgery, we orally administered V1 receptor antagonist at 60mg/kg/day or V2 receptor antagonist at 30 mg/kg/day to myocardial infarcted rats. After one week of treatment, we measured the hemodynamics and electrolytes in the blood. In the acute and chronic myocardial infarcted rats, the left ventricular endodiastolic pressure (LVEDP) increased to 16±3 and 20±4 mmHg, respectively, and V2-ant decreased LVEDP to 6±4(p&lt;0,01) and 5±3 mmHg (p&lt;0.011, respectively. V2-ant decreased significantly the left ventricular endodiastolic volume (LVEDV) in chronic myocardial infarction (non-treated rats; 2.31±0.18, V2-ant treated vats; 1,76±0.10 ml/kg)(p&lt;0,01). In the chronic myocardial infarcted rats, abdominal ascites appeared, and the weight of lung or liver increased. V2 receptor antagonist decreased them. V2 receptor antagonist improved hemodynamics and the signs of heart failure in myocardial infarcted rats. V1 receptor antagonist tended to decrease LVEDP in the acute and chronic myocardial infarcted rats. V1 and V2 receptor antagonists did not change the electrolytes in the blood, Vasopressin antagonist, especially V2 receptor antagonist, is a useful drug for heart failure after myocardial infarction.

Objective: The excessive release of adenosine has been reported to cause hyperaemia and to attenuate ischaemic injury in microembolised hearts. The direct effects of exogenous adenosine on cardiac performance were investigated in microembolised guinea pig hearts with the simultaneous measurement of phosphate compounds. Methods: 21 male guinea pig hearts were perfused according to the Langendorff technique and microembolism was induced by injecting microspheres. Hearts were then treated as follows: group A, adenosine 20 μM and theophylline 60 μM; group B, theophylline 60 μM; group C, saline (control). Cardiac performance was monitored and phosphate compunds were measured by 31P magnetic resonance spectroscopy. Results: Group A showed a significant increase in the left ventricular developed pressure and coronary flow, and a modest restoration of ATP content. Pi/(Pi+Pcr) remained virtually constant. There were no significant changes in left ventricular developed pressure or coronary flow in groups B and C. There was a gradual decrease in tissue ATP content and slight increase in Pi/(Pi+Pcr). Conclusions: Adenosine improved cardiac performance without adverse effect on energy metabolism in microembolised hearts. Adenosine also restored the ATP stores in microembolised hearts. (Pi=inorganic phosphate; Pcr=phosphocreatine.) Cardiovascular Research 1992;26:851–856

Objective: The aim was to evaluate regional coronary blood flow, contractile function, and concentration of phosphate compounds with inotropic stimulation in moderately ischaemic canine hearts. Methods: Dogs were prepared with instrumentation for the determination of regional coronary blood flow (non-radioactive microsphere method), contractile function (sonomicrometry), and haemodynamics. Myocardial phosphate compounds were measured simultaneously by the phosphorus-31 magnetic resonance spectroscopic technique. Results: In the non-ischaemic condition, dobutamine increased regional coronary blood flow and enhanced contractile function with no significant changes in myocardial phosphate compounds. After constricting the left anterior descending coronary artery, dogs were divided into two groups according to their heart beat response to dobutamine, classified as no pronounced tachycardia with dobutamine (group NT), and pronounced tachycardia (group T). In group NT, dobutamine increased regional coronary blood flow and improved regional contractile function with no significant effect on myocardial phosphate compounds. In group T, dobutamine failed to increase regional coronary blood flow or to improve contractile function, but there was a significant increase in the inorganic phopshate to creatinine phosphate ratio. Conclusions: Dobutamine increased coronary blood flow and augmented contractile function without significant changes in phosphate compounds in the moderately ischaemic heart, when pronounced tachycardia was not induced. The augmentation of contractile function occurred without prominent improvement in energy metabolism. Cardiovascular Research 1993;27:1435-1443

Objective: The aims were (1) to investigate the effect of hypertension on left ventricular dilatation and haemodynamic alterations following acute myocardial infarction in spontaneously hypertensive rats (SHR) and normotensive rats (WKY); (2) to compare haemodynamic indices between the two groups; (3) to assess whether the angiotensin II type 1 receptor antagonist (AIIA), TCV-116, prevented left ventricular dilatation after myocardial infarction; and (4) to compare the effect of AHA with that of the angiotensin converting enzyme (ACE) inhibitor, delapril. Methods: Myocardial infarction was produced in SHR and WKY by coronary artery ligation. Haemodynamic measurements were obtained three weeks later in rats that had been treated from the next day after the operation for three weeks with TCV-116 (1 mg·kg−1·d−1) or delapril (1 g·litre−1 in drinking water), and in untreated controls. Results: After myocardial infarction, left ventricular systolic pressure, mean arterial pressure, left ventricular end diastolic volume index (LVEDVI), right ventricular weight, and left ventricular weight were greater in SHR than in normotensive rats. Right ventricular weight, left ventricular end diastolic pressure, and LVEDVI correlated positively with infarct size in both SHR and WKY and these slopes were steeper in SHR than in WKY (P < 0.05). TCV-116 and delapril each significantly attenuated the increases in left ventricular end diastolic pressure, left ventricular weight, right ventricular weight, and LVEDVI following myocardial infarction in both in WKY and SHR, and shifted pressure-volume curve significantly to the left. Conclusions: Hypertension accelerates left ventricular dilatation and haemodynamic alterations following myocardial infarction in rats. These effects are attenuated by an angiotensin II type 1 receptor antagonist as well as by an ACE inhibitor.

Point mutations of mitochondrial DNA (mtDNA) were reported in various diseases. We studied them in patients with alcoholic heart muscle disease (AHMD). In habitual heavy drinkers with heart failure (ten men, mean age 53.1±8.2 years, mean daily ethanol intake 119.5±40.0 ml, mean drinking duration 30.3±7.9 years), right ventricular endomyocardial biopsies were performed. MtDNA was extracted from the specimens and amplified using PCR. Then the total base-sequence was analysed and compared with the wild type. Eight point mutations which cause amino acid substitution were detected among five patients. These point mutations were the same as previously reported in mitochondrial diseases or cardiomyopathies. Thus, Point mutations of mtDNA may be related to the pathogenesis of AHMD.

Objective: The aim was to investigate changes in cardiac transforming growth factor β₁, (TGF-β₁), fibronectin, and collagen types I and III mRNA levels in isoprenaline induced cardiac hypertrophy, and the effects of delapril, an angiotensin converting enzyme inhibitor, and TCV-116, an angiotensin II type 1 receptor antagonist, on this hypertrophy. Methods: Rats were continuously infused with saline and low or high dose of isoprenaline (0.5 or 3 mg·kg–1·d–1) by an osmotic minipump for 24 h, 48 h or 7 d. Treatment with delapril (100 mg·kg–1·d–1) or TCV-116 (10 mg·kg–1·d–1) was started from 1 d before the implantation of minipump to the end of experiments. After the experimental periods, left ventricular weight was measured and the mRNA was extracted and measured by northern blot hybridisation. Results: Both low and high doses of isoprenaline infusion resulted in increased left ventricular weight. With low dose infusion, cardiac TGF-β₁, mRNA was not stimulated throughout the infusion, while fibronectin mRNA and collagen types I and III mRNAs began to increase at 24 h and 48 h, respectively, after the infusion. In high dose isoprenaline infusion, not only was extracellular matrix mRNA but also TGF-β₁, mRNA in the ventricle significantly increased. TCV-116 prevented isoprenaline induced left ventricular hypertrophy as much as delapril. However, with delapril or TCV-116, the time course of TGF-β₁ and ECM mRNA expression was almost similar to isoprenaline infusion only. Conclusions: The extracellular matrix mRNA expressions are enhanced in myocardial hypertrophy by a low dose of isoprenaline, which is probably not mediated by TGF-β₁. The preventive effects of TCV-116 on this hypertrophy indicate that the inhibitory effects of angiotensin converting enzyme inhibitor on cardiac hypertrophy are due to the inhibition of angiotensin II and that angiotensin II type I receptor plays an important role in isoprenaline induced left ventricular hypertrophy. However, the renin-angiotensin system may play a minor role in isoprenaline induced cardiac fibrosis. Cardiovascular Research 1994;28:1835-1842