Possible involvement of free radicals and antioxidants in the early stages of the development of cardiomyopathy in BIO 14.6 Syrian Hamster.

The BIO 14.6 cardiomyopathic Syrian hamster is a well-known animal model of congestive cardiomyopathy. To evaluate the role of free radicals and antioxidant protection in the pathogenesis of cardiomyopathy in this animal, we studied the concentration of heart mitochondrial free radicals, the activities of glutathione peroxidase (GSHPx) and superoxide dismutase (SOD), and the effect of alpha-tocopherol on the early stage of myocardial damage (up to 90 days). The GSHPx activity in BIO 14.6 hamsters was found to be twice that in the normal control hamsters at 30 days of age, while SOD activity was unchanged at 30 and 90 days of age. The concentrations of mitochondrial free radicals in BIO 14.6 hamsters at 40 and 90 days of age were significantly higher than those in the normal control hamsters. A protective effect of alpha-tocopherol therapy was shown in BIO 14.6 hamsters treated during the early stage of cardiomyopathy (up to 90 days). These results show the role of free radicals and antioxidant protection in the pathogenesis of hamster cardiomyopathy. We suspect that an increase in the GSHPx activity in BIO 14.6 hamsters may be due to a compensatory mechanism to counteract oxidative stress, but antioxidant reserve was not sufficient to protect the heart from the toxic effects of increased free radicals in the early stage of cardiomyopathy.     

Opposing effect of p38 MAP kinase and JNK inhibitors on the development of heart failure in the cardiomyopathic hamster

OBJECTIVE: p38 MAP kinase (p38 MAPK) and c-Jun NH2-terminal kinase (JNK) have been implicated in the pathophysiology of heart failure. We investigated the effects of chronic treatment with p38 MAPK and JNK inhibitors on the development of heart failure in dilated cardiomyopathy (DCM) hamster heart. METHODS AND RESULTS: BIO14.6 hamster hearts showed markedly increased p38 MAPK and JNK activities at 6 weeks of age when there was no significant increase in the area of fibrosis, heart weight/body weight, left ventricular (LV) chamber dilation and LV dysfunction. p38 MAPK and JNK activities were attenuated at 26 weeks of age and abolished at 40 weeks of age in BIO14.6 hamster hearts. BIO14.6 hamsters and the control BIOF1B hamsters were chronically treated (i.p.) with the p38 MAPK inhibitors, SB203580 (1 mg/kg/day) and FR167653 (3 mg/kg/day), or the JNK inhibitor, SP600125 (1 mg/kg/day) or vehicle for 20 weeks starting from 6 weeks of age. Treatment of BIO14.6 hamster hearts with SB203580 and FR167653 reduced the number of TUNEL-positive myocytes, the area of fibrosis and heart weight/body weight associated with a significant decrease of LV dimension and an increase in LV ejection fraction and LV contractility compared to the vehicle-treated counterpart. In contrast, treatment with SP600125 increased the number of TUNEL-positive myocytes and the area of interstitial fibrosis associated with aggravation of LV chamber dilation and LV dysfunction. CONCLUSIONS: These results suggest that chronic treatment with p38 MAPK and JNK inhibitors produces opposing effects on the development of heart failure in the DCM hamster heart.     

Effects of long term treatment with an alpha 1 adrenoceptor blocker on cardiac hypertrophy, contractility, and myosin isoenzymes in spontaneously hypertensive rats.

STUDY OBJECTIVE--The aim was to investigate the effects of long-term treatment with an alpha 1 blocker, bunazosin hydrochloride, on blood pressure, heart weight, myocardial contractility, and ventricular myosin isoenzyme pattern in spontaneously hypertensive rats (SHR). DESIGN--Bunazosin hydrochloride was given orally in a dose of 10 mg.kg-1.d-1 for 8-9 weeks. Isometric tension development was measured in isolated left ventricular papillary muscles. The left ventricular myosin isoenzyme pattern was determined by pyrophosphate gel electrophoresis. SUBJECTS--14 male SHR (seven treated and seven untreated rats) aged 23 to 24 weeks were studied. MEASUREMENTS AND MAIN RESULTS--The blood pressure of the bunazosin treated rats was approximately 14% lower than that of the untreated rats at the end of the treatment period. The ventricular weight of treated SHR was significantly lower (around 8%) than that of untreated rats, but there were no significant differences between the two groups in the mechanical data obtained from isolated left ventricular papillary muscles. The myosin isoenzyme pattern of the left ventricle was significantly shifted toward VM-1 in the bunazosin treated SHR, the VM-1 concentration in the treated group being 38% greater than in the untreated group. CONCLUSIONS--These results indicate that long term treatment with bunazosin hydrochloride reduces blood pressure and leads to the regression of cardiac hypertrophy in SHR. Myocardial energetics (as represented by the myosin isoenzyme pattern) were affected, but there was no influence on myocardial tension development.     

Diminished beta-adrenergic receptor responsiveness and cardiac dilation in hearts of myopathic Syrian hamsters (BIO 53.58) are associated with a functional abnormality of the G stimulatory protein

Previous studies have demonstrated a diminution in the bioactivity of the guanine nucleotide-binding regulatory protein that stimulates adenylyl cyclase (Gs) in hearts of the hypertrophic BIO 14.6 Syrian hamster. In this study, we measured functional activity and immunodetectable levels of Gs in a mutant strain of hamsters (BIO 53.58) that develop a dilated cardiomyopathy. Pathological studies demonstrated that 100-day-old BIO 53.58 hamsters had substantial ventricular dilation when compared with age-matched F1B controls. Additionally, these 100-day-old hamsters demonstrated diminished contractile response to beta-adrenergic receptor stimulation. The pathological and hemodynamic changes were associated with defective coupling of Gs to adenylyl cyclase as adenylyl cyclase activation was distinctly decreased in the presence of isoproterenol, fluoride ion, guanine nucleotides, and forskolin. Additionally, the ability of the alpha-subunit of Gs to reconstitute isoproterenol-stimulated adenylyl cyclase activity in S49 cyc- membranes was reduced approximately 65%. By contrast, cyc- complementation assays did not reveal a difference between the functional activity of Gs in hearts from 30-day-old BIO 53.58 hamsters and F1B controls. Furthermore, beta-adrenergic receptor stimulation of adenylyl cyclase in the membranes of the young BIO 53.58 hamsters was not significantly different from controls. The substantial alterations in Gs bioactivity in hearts of the 100-day-old BIO 53.58 hamsters was not associated with alterations in the immunodetectable levels of either alpha Gs or alpha Gi on Western Blots. These results suggest that G protein changes are associated with ventricular dilation in BIO 53.58 hamsters and that G protein levels are not always reflective of G protein bioactivity.     

Does an impaired adenosine mediated feedback control play a role in the development of hereditary dystrophic cardiomyopathy?

A study was carried out to investigate whether or not an impairment of the adenosine mediated negative inotropic effect in the presence of beta adrenoceptor stimulation plays a role in the pathogenesis of the hereditary cardiomyopathy of the Syrian hamster. In electrically driven papillary muscles isolated from the hearts of cardiomyopathic (strain BIO 8262) and age matched healthy control Syrian hamsters the effects of isoprenaline, adenosine, and adenosine in the presence of isoprenaline were studied within the first 30 days of life (the prenecrotic stage of the disorder). In both cardiomyopathic and control hamsters adenosine antagonised the positive inotropic effect of isoprenaline, whereas adenosine alone had no or, only a weak, inhibitory effect on the force of contraction. The effects in both groups were similar. The effect of isoprenaline on the force of contraction also did not differ in the two groups. The data show that in both cardiomyopathic and control hamsters adenosine reduces the force of contraction during beta adrenergic stimulation. The potency or efficacy of adenosine did not differ in the two groups. An impaired adenosine mediated feedback control of the heart does not therefore seem to play a role in the pathogenesis of the hereditary dystrophic cardiomyopathy of the Syrian hamster.     

Alterations in calcium antagonist receptors and sodium-calcium exchange in cardiomyopathic hamster tissues

The Syrian cardiomyopathic (CM) hamster (BIO 14.6) develops a progressive cardiomyopathy characterized by cellular necrosis, hypertrophy, and, eventually, cardiac dilatation and congestive heart failure. Several lines of evidence implicate cellular calcium overload as an important etiologic factor. We previously reported an increased number of receptors for calcium antagonist drugs, which block voltage-dependent calcium channels, in heart, skeletal muscle, and brain tissue of these hamsters in the early necrotic stage of the disease. To better characterize the pathophysiological significance of this abnormality we evaluated calcium antagonist receptor binding and Na+-Ca2+ exchange in CM and control hamsters at different stages of disease as documented by quantitative histopathologic assessment. In CM hamsters as young as 10 days, an age previously thought to be before the onset of disease, we identified cardiac myocyte hypertrophy, a twofold increase in calcium antagonist receptor binding in heart and brain, and a 50% increase in skeletal muscle. Overt histological lesions were present in skeletal muscle at 25 days and in heart between 28-30 days. The size of cardiac lesions increased over time and changed from necrotic foci with cellular infiltration to fibrotic or calcified lesions by 360 days. Myocardial cellular hypertrophy persisted through the late stages of the disease (360 days), but increased calcium antagonist binding was present in heart only to 6 months of age, in skeletal muscle to 90 days, and in brain to 30 days. Na+-Ca2+ exchange in heart was normal until 15 days and then increased by 400% at 30 days suggesting that this augmentation might be a secondary response to the earlier increase in calcium antagonist receptors. At 360 days cardiac Na+-Ca2+ exchange was decreased by 50%, likely reflecting progressive cardiac damage. The increase in calcium antagonist receptors in CM animals as young as 10 days supports the hypothesis that abnormalities in voltage-dependent calcium channels play a role in the pathophysiology of CM hamsters.     

Isoprenaline-evinced disturbances in action potentials from hearts of young cardiomyopathic hamsters

The electrophysiology of ventricular cells from prenecrotic stage 10 to 14 day old hamsters with hereditary cardiomyopathy (BIO 14.6 strain) was studied with the intent of learning more about the previously documented relationship of stimulation with beta-adrenergic agonist and the sarcolemmal defect contributing to the excessive uptake of calcium by diseased cells. Before catecholamine treatment only slight differences were observed in the configuration of action potentials of myopathics and control random bred hamsters (BIO RB strain). However, isoprenaline in varying concentrations, increased the action potential duration (APD) at 50% and 95% repolarisation levels to a significantly greater extent in myopathics than in controls. Repetition of the dose-response to isoprenaline in the presence of the beta-adrenergic antagonist propranolol (0.1 mumol X litre-1) permitted the calculation of the dissociation equilibrium constant for the antagonist. The similarity of dissociation constants between strains, 0.008 mumol X litre-1 for controls and 0.011 mumol X litre-1 for myopathics, suggests that a difference in interstrain receptor affinities is an unlikely cause of the isoprenaline effect. Rather, the data are more consistent with the hyper-sensitivity resulting from larger numbers of beta-adrenoceptors on sarcolemma of myopathic cells. Also, the increase in APD of myopathics indicates that isoproterenol elicits an imbalance of slow inward calcium and late outward potassium currents. The possible significance of the isoprenaline hyper-sensitivity, which is the earliest pathophysiology seen in this disease, to the etiology of cellular calcium overload and degeneration of diseased myocardium remains to be determined.     

Subtype-selective down-regulation of rat renal cortical alpha- and beta-adrenergic receptors by catecholamines

In the current studies, we have explored agonist-mediated down-regulation of adrenergic receptors in vivo. We infused catecholamines from sc implanted osmotic minipumps and examined the effects of the resultant increases in circulating levels of catecholamines on rat renal cortical alpha- and beta-adrenergic receptor subtypes, as assessed in radioligand binding studies. Infusion of epinephrine or norepinephrine (at 150 micrograms/kg X h) elevated plasma levels of each catecholamine 10- to 20-fold and decreased renal cortical alpha 1-receptor number about 50% without changing alpha 2-receptor number. Isoproterenol infusion (150 micrograms/kg X h) raised plasma levels of this catecholamine, but had no effect on the number of either alpha 1- or alpha 2-receptors. Renal cortical beta-adrenergic receptor number was decreased by infusion of all three catecholamines. However, the beta 1- and beta 2-adrenergic receptors were altered selectively by the different agonists. Infusion of norepinephrine decreased both beta 1- and beta 2-receptor number, but was more effective for the beta 1-receptors; this result was somewhat at variance with that we previously reported for rats bearing transplanted pheochromocytomas. The decrease in beta-receptor number due to epinephrine infusion was largely due to loss of the renal cortical beta 2-receptors. Infusion of isoproterenol decreased the number of both beta 1- and beta 2-receptors (69% and 75%, respectively). Infusion of norepinephrine maximally decreased the number of alpha 1-, beta 1-, and beta 2-receptors within 2 days, and the t 1/2 for receptor loss was about 12 h. beta-Receptors lost in response to isoproterenol infusion could not be recovered in a pellet prepared by high speed centrifugation of the supernatant derived from the preparation of renal cortical membranes. These results indicate that adrenergic receptor subtypes are differentially down-regulated by elevated levels of circulating catecholamines and that this differential loss of receptors depends on the nature of the receptor subtype, the agonist, and perhaps also whether catecholamines are infused rather than increased by pheochromocytoma.     

Heart failure and Ca++ activation of the cardiac contractile system: hereditary cardiomyopathy in hamsters (BIO 14.6), isoprenaline overload and the effect of APP 201-533

In the present paper, two experimental models of heart failure, namely hereditary cardiomyopathy in hamsters (BIO 14.6) and cardiac insufficiency due to mild (0.06 microM) isoprenaline overload of rabbit isolated perfused hearts, were compared in terms of resulting alterations at the level of the functionally isolated contractile system of detergent/glycerol treated skinned cardiac fibres. As the main features of Ca activation of tension in these models, the following were found: 1. Within the same species (RB hamsters, BIO 14.6 hamsters or rabbits), the Ca sensitivity, measured as pCa for half maximal Ca activation, was invariably higher in left than in right ventricular skinned fibres. 2. During the development of hereditary cardiomyopathy (BIO 14.6), maximum Ca-activated tension, measured per unit cross-sectional area, was reduced in an age-dependent manner, without any significant reduction in Ca sensitivity. This effect appeared to be more pronounced in left than in right ventricles. 3. In skinned fibres from right or left ventricular papillary muscles from in vitro isoprenaline pretreated rabbit hearts, no significant alteration in the maximum Ca-activated tension (per unit area) was observed in comparison to non-pretreated control hearts, whereas the Ca sensitivity was reduced. Treatment of control or failing heart skinned fibres with cAMP showed no additivity to the Ca desensitization induced by isoprenaline pretreatment. 4. Skinned fibres from isoprenaline pretreated left ventricular rabbit hearts showed a higher susceptibility to the Ca sensitizing effect of APP 201-533 than fibres from unpretreated control hearts. Mild isoprenaline overload and hereditary cardiomyopathy both are forms of heart failure which are presumably not associated with a lack of activator Ca. It is concluded that cardiotonic agents increasing the cardiac myofibrillar sensitivity to Ca ions would be beneficial in both cases, representing a phenomenologically causative treatment in hearts failing due to isoprenaline pretreatment. A main advantage over "classical" cardiotonic agents like cardiac glycosides, beta adrenergic stimulants or phosphodiesterase inhibitors would be the absence of the risk of drug-induced Ca overload.     

L-carnitine treatment for congestive heart failure--experimental and clinical study.

To evaluate the therapeutic efficacy of l-carnitine in heart failure, the myocardial carnitine levels and the therapeutic efficacy of l-carnitine were studied in cardiomyopathic BIO 14.6 hamsters and in patients with chronic congestive heart failure and ischemic heart disease. BIO 14.6 hamsters and patients with heart failure were found to have reduced myocardial free carnitine levels (BIO 14.6 vs FI, 287 +/- 26.0 vs 384.8 +/- 83.8 nmol/g wet weight, p less than 0.05; patients with heart failure vs without heart failure, 412 +/- 142 vs 769 +/- 267 nmol/g p less than 0.01). On the other hand, long-chain acylcarnitine level was significantly higher in the patients with heart failure (532 +/- 169 vs 317 +/- 72 nmol/g, p less than 0.01). Significant myocardial damage in BIO 14.6 hamsters was prevented by the intraperitoneal administration of l-carnitine in the early stage of cardiomyopathy. Similarly, oral administration of l-carnitine for 12 weeks significantly improved the exercise tolerance of patients with effort angina. In 9 patients with chronic congestive heart failure, 5 patients (55%) moved to a lower NYHA class and the overall condition was improved in 6 patients (66%) after treatment with l-carnitine. L-carnitine is capable of reversing the inhibition of adenine nucleotide translocase and thus can restore the fatty acid oxidation mechanism which constitutes the main energy source for the myocardium. Therefore, these results indicate that l-carnitine is a useful therapeutic agent for the treatment of congestive heart failure in combination with traditional pharmacological therapy.     

Effect of isoproterenol and taurine on heart calcium in normal and cardiomyopathic hamsters

Calcium accumulation has been implicated in the cardiac necrosis induced by isoproterenol and in the development of the cardiomyopathy in the BIO 14.6 hamster. Taurine, a natural constituent of the heart, has been shown to exert a modulating effect on calcium levels in the heart. Heart calcium and taurine levels were determined in BIO 14.6 and random bred (F₁B) hamsters treated with isoproterenol (80 mg/kg) following a 60 day drinking regimen of either taurine (100 mmol/l) or guanidinoethyl sulfonate (1%). Taurine supplementation provided some protection for the random bred hamster heart against isoproterenol induced calcium accumulation, but that protection was not demonstrable in the BIO 14.6 strain despite an elevated heart taurine content. The feeding of guanidinoethyl sulfonate decreased the taurine content of the heart in both strains, but guanidinoethyl sulfonate was unable to block taurine elevation following isoproterenol treatment in either strain. Since taurine feeding retards the usual calcium accumulation in the BIO 14.6, but is without statistically significant effect on the additional calcium accumulation induced by isoproterenol, the protecitive action of taurine seems insufficient to counteract the combined effect of isoproterenol and the myopathic process.     

Effects of cerulein on the normal pancreas and on experimental pancreatic carcinoma in the Syrian golden hamster

The effects of cerulein on normal pancreas and on N-nitrobis (2-hydroxypropyl) amine (BHP)-induced experimental pancreatic carcinoma in Syrian golden hamsters were studied. Twenty hamsters received a subcutaneous injection of cerulein (20 micrograms/kg). The results showed that when cerulein was injected subcutaneously for 10 days, pancreatic weight and amylase increased. DNA and the pancreatic weight/DNA ratio were also increased significantly in treated hamsters compared with controls (p less than 0.02 versus p less than 0.01). These results indicated that chronic cerulein injection had hypertrophic and hyperplastic effects. DNA synthesis, as measured by histoautoradiography of tritiated thymidine-labeled tissue, increased in pancreatic acinar cells (p less than 0.01) and increased slightly in islet cells and in ductal cells. Tritiated thymidine uptake in the pancreas of the treated group indicated a rather selective exocrine gland incorporation by acinar rather than ductal cells. Sixty hamsters received a subcutaneous injection of BHP (500 mg/kg) once a week, while 63 hamsters received BHP (500 mg/kg) plus cerulein (20 micrograms/kg). Twenty-seven hamsters received cerulein (20 micrograms/kg) alone. All animals were killed from 8 to 27 weeks later, and no cancer-bearing hamsters were observed during the eighth and ninth week following administration. From the 10th to 14th weeks after administration of BHP and cerulein, 87.9% (13 of 15) had tumors compared with 18.7% (3 of 16) after BHP alone (p less than 0.01). One of three and two of 13 tumors were adenoma.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of regression of left ventricular hypertrophy following atenolol or bunazosin therapy on ischemic cardiac function and myocardial metabolism in spontaneously hypertensive rats.

The effects of regression of left ventricular hypertrophy following atenolol and bunazosin therapy on ischemic cardiac function and myocardial metabolism in spontaneously hypertensive rats (SHR) were studied. Atenolol (50 mg/kg/day) and bunazosin (5 mg/kg/day) were administered to SHR from 19 to 26 weeks of age, whereas tap water was given to control SHR and normotensive Wistar-Kyoto rats (WKY). Both atenolol and bunazosin significantly decreased arterial blood pressure and significantly decelerated the increase in left ventricular weight in SHR. At the end of the long-term treatment, hearts were removed and perfused by the working heart technique for 15 min, and then global ischemia was induced for either 10 or 30 min. The ischemic heart was reperfused for 30 min. The pressure-rate product and the extent of recovery of the coronary flow after reperfusion following 30 min of ischemia in the bunazosin-treated SHR were significantly higher than those in the control SHR and the atenolol-treated SHR. The levels of adenosine triphosphate (ATP), creatine phosphate (CrP), and energy charge potential in the SHR heart reperfused after 30 min of ischemia were significantly lower than those in the reperfused WKY. Both atenolol and bunazosin improved the restoration of ATP and CrP in SHR after reperfusion following 30 min of ischemia. In conclusion, antihypertensive therapy with either atenolol or bunazosin was effective in preventing cardiac hypertrophy and ischemic damage caused by different mechanisms. Factors resulting from stimulation of the cardiac alpha 1 adrenoceptor may play an important role in the development of hypertensive cardiac hypertrophy, just as factors resulting from stimulation of the beta 1-adrenoceptor do.     

Carnitine derivatives in hereditary cardiomyopathic animals

BIO 14.6 Syrian hamsters and diabetic KK mice have been reported to develop hereditary cardiomyopathy spontaneously. In order to investigate the pathophysiological role of carnitine metabolism in hereditary cardiomyopathy, tissue levels of carnitine derivatives and the histology of the heart, liver and skeletal muscles from BIO 14.6 hamsters and KK mice were studied. Free carnitine levels in the heart of the BIO 14.6 hamsters (287.0 +/- 27.0 n mole/g wet tissue) were significantly lower than in the control group (348.8 +/- 83.8, p less than 0.05). Short chain acylcarnitine (197.0 +/- 56.0 n mole/g wet tissue) and total carnitine (667.6 +/- 136.4 n mole/g wet tissue) in the hearts of the BIO 14.6 hamsters were significantly lower than in the control group (short: 425.2 +/- 54.8, total: 1023.6 +/- 81.4, p less than 0.001). There was no significant difference in the levels of various carnitine derivatives of the liver and skeletal muscles from the BIO 14.6 hamsters and control hamsters. On the other hand, carnitine derivatives in KK mice did not change significantly compared with those in the heart, liver and skeletal muscles of the control mice. Histological findings showed that heart muscle degeneration and necrosis were found in both cardiomyopathic animals. Coagulative necrosis was found in both animals, whereas myocytolytic necrosis was found only in the BIO 14.6 hamsters. In KK mice, the right ventricle, especially tissue under the epicardium, was severely affected compared with the left ventricle. In the BIO 14.6 hamsters, however, lesions were scattered over both ventricles with a predilection for the left ventricle.     

Effect of Bunazosin and Atenolol on Glucose Metabolism in Obese, Nondiabetic Patients with Primary Hypertension

Antihypertensive drugs, recommended by the World Health Organization for use in monotherapy, exert different effects on glucose and lipid metabolism. In our study we compared the effects of the beta-blocker atenolol (AT) and the alpha1-blocker bunazosin (BU) on glucose metabolism. The doses administered were chosen to produce similar antihypertensive effects with both drugs. The study was conducted as a bicenter, parallel, controlled, and double-blind study. All patients suffered from mild to moderate primary hypertension, were obese (body mass index >26 kg/m2), but were nondiabetic. After a drug-free period of 4 weeks, patients were treated either with 6 and 12 mg of bunazosin (n = 15) or with 50 and 100 mg of atenolol (n = 17) once daily for 12 weeks. Glucose metabolism was measured by the iv glucose tolerance test (GTT) and the euglycemic hyperinsulinemic clamp test. The results show a similar blood pressure reduction with both drugs. However, their effects on glucose metabolism were significantly (p < 0.05) different: The area under the curve (AUC) of glucose in the iv GTT increased 26.8% during atenolol treatment but decreased 30% during bunazosin treatment. The same influence on the AUC of insulin was observed [AT +478.5 ± 441.8 (+22%) vs. BU, –588.5 ± 411.1 (–22%)]. Similar changes were found in the glucose clamp test. The metabolic clearance rate increased 11.4% during bunazosin use and decreased 8.4% during atenolol use to the same degree that the insulin sensitivity index changed (BU +13.2% vs. AT –21.9%). The differences between the two treatment regimes were statistically significant (p < 0.05). These results in obese hypertensives confirm the well-known negative effects of beta-blockers on glucose metabolism. Additionally, they demonstrate that an alpha1-blocker such as bunazosin develops the same blood pressure–lowering effect as beta-blockers, but with a significantly better profile with regard to glucose metabolism. Therefore, the use of alpha1-blockers can be recommended for obese hypertensives without any special care for glucose metabolism.     

Effect of chronic AT(1) receptor blockade on cardiac Smad overexpression in hereditary cardiomyopathic hamsters

OBJECTIVE: As the pharmacological suppression of angiotensin has been associated with cardioprotective effects in cardiomyopathy, our primary aim was to determine whether the expression of Smad protein components of the cardiac TGF-beta signaling cascade is modulated by chronic AT(1) receptor blockade. Furthermore, we examined the relationship between cardiac Smad protein expression and altered collagen turnover in the cardiomyopathic heart. METHODS: Male UM-X7. 1 cardiomyopathic (CMP) Syrian hamsters at early (65 days) and late (200 days) stages of cardiomyopathy were subjected to 4 week losartan (15 mg/kg/day) treatment. Expression of left ventricular (LV) receptor-activated (Smad 2) and common-mediator (Smad 4) Smads from control (F1-beta strain) hamsters, non-treated cardiomyopathic (CMP), and losartan-treated CMP animals was assessed. Collagen turnover, including fibrillar collagen synthesis/accretion and cardiac MMP activity was assessed. RESULTS: Elevated mRNA abundance of fibrillar collagens and ANF were present in cardiomyopathic hearts and these trends were normalized in the early stage losartan-treated group. 4-Hydroxyproline and zymographic assays confirmed fibrosis and elevated MMP-1 and -2 activities in CMP hearts. Losartan treatment was associated with a modest reduction of cardiac 4-hydroxyproline concentration, and a significant reduction of both MMP-1 and MMP-2 activities. While TGF-beta(1) mRNAs were elevated in both CMP groups vs. controls, total TGF-beta protein content was not different in CMP vs. controls. In LV preparations containing nuclear extract, elevated Smad 2 and Smad 4 protein expression was noted in cardiomyopathic hearts vs. controls. Losartan treatment of late-stage CMP hamsters was associated with a significant reduction in Smad 2 and a modest reduction of Smad 4 protein expression vs. untreated CMP samples. CONCLUSIONS: Altered cardiac Smad expression, present in both early and late stage cardiomyopathy, is positively correlated with the occurrence of cardiac fibrosis and elevated collagen turnover in failing CMP hearts. Four week AT(1) blockade is associated with normalized expression of cardiac Smad 2 proteins, and these changes occur in parallel with some aspects of collagen turnover in failing cardiomyopathic hearts.     

Decreased 1,2-diacylglycerol levels in myopathic hamster hearts during the development of heart failure

1,2-Diacylglycerol is believed to play an important role in cellular functions through protein kinase C activation, although its role in cardiac functions remains largely unexplored. We determined the level of 1,2-diacylglycerol and its fatty acid composition in heart tissues from Syrian hamsters with hereditary cardiomyopathy (BIO 14.6 strain) during the development of congestive heart failure from 90 days to 240 days of age. The myopathic hamsters had lower contents of triglyceride and of the major phospholipids, phosphatidylcholine, phosphatidylethanolamine and cardiolipin, in the myocardium when compared to normal hamsters, whereas there was no difference in the cholesterol content. No difference in the myocardial 1,2-diacylglycerol content was observed at 90 days of age. On the other hand, 1,2-diacylglycerol contents in myopathic hearts at 160 and 240 days of age were significantly lower by 21% and 52%, respectively, then in age-matched normal hamsters. The oldest hamsters (240-day-old) showed reduced 1,2-diacylglycerol levels in both groups despite an age-related increase in most lipids. The 1,2-diacylglycerol fatty acid composition profile was found to be different from that of other lipids, and there were several differences in the fatty acid composition of 1,2-diacylglycerol between the two groups at 240 days of age. These results indicate that decreased levels of 1,2-diacylglycerol occur concomitantly with congestive heart failure in the myopathic hamsters.     

Effect of early propranolol treatment in an animal model of congestive cardiomyopathy. II. beta-adrenergic receptors and left ventricular function

Young turkeys inbred for congestive cardiomyopathy (CCM) were treated with propranolol prior to the development of cardiac enlargement. One-day-old inbred CCM and commercial turkeys received 2 mg X kg-1 X day-1 of propranolol for 1 month and were compared with untreated age matched inbred CCM and commercial turkeys. Heart weight, body weight, and binding characteristics of cardiac beta-adrenergic receptors, using (-)3H-dihydroalprenolol as a ligand, were determined at 10 and 28 days. Left ventricular shortening fraction was determined at 28 days and at 32 days, 4 days after propranolol was discontinued, in treated and untreated inbred CCM and commercial turkeys. Propranolol did not prevent the development of cardiac hypertrophy in inbred CCM turkeys at 28 days of age and did not effect body weight or heart weight in either inbred CCM or commercial turkeys at 10 or 28 days of age. In the inbred CCM turkeys, the maximum number of binding sites (Bmax) and the binding affinity (Kd) of beta-adrenergic receptors were not changed by propranolol treatment. In the propranolol-treated commercial turkeys, Bmax the of beta-receptors was increased at 28 days of age compared with untreated age matched controls, 382 vs 194 fmol X mg-1 (p less than 0.05). Untreated inbred CCM turkeys when compared with untreated age matched commercial turkeys show a significant reduction of binding affinity of beta-receptors at both 10 and 28 days of age, Kd = 10.4 vs 6.2 nmol X litre-1 at 10 days and 11.3 vs 5.2 nmol X litre-1 at 28 days (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of quinapril, a new angiotensin converting enzyme inhibitor, on left ventricular failure and survival in the cardiomyopathic hamster. Hemodynamic, morphological, and biochemical correlates.

The effect of chronic therapy with quinapril on the temporal progression of left ventricular failure and survival was assessed in the CHF 146 cardiomyopathic (CM) hamster, which is an idiopathic model of congestive heart failure. Age-matched Golden Syrian (GS) hamsters served as normal controls. Quinapril was administered in the drinking water at average daily doses of 10.2, 112.4, and 222.4 mg/kg/day. In untreated CM hamsters, in vitro left ventricular performance progressively deteriorated with increasing age beginning at roughly 180 days. This decline in left ventricular performance was accompanied by a decrease in coronary flow and an increase in left ventricular volume. Administration of quinapril from 180 to 300 days of age prevented the decline of in vitro left ventricular contractile performance and coronary flow and also reduced the age-dependent increases in left ventricular volume. The cardioprotective effects of quinapril were observed at doses of 112.4 and 222.4 mg/kg/day but not at 10.2 mg/kg/day. Lung angiotensin converting enzyme activity was significantly inhibited by quinapril in GS and CM hamsters at 240 and 300 days of age at all dose levels. In contrast, significant inhibition of ventricular angiotensin converting enzyme activity was observed consistently at doses of 112.4 and 222.4 mg/kg/day quinapril but not at 10.2 mg/kg/day. In the survival protocol, CM and GS hamsters were treated with vehicle or quinapril (100 mg/kg/day) from 180 to 522 days of age. During the initial 210 days of treatment (from 180 to 390 days of age) 78.3% of the vehicle-treated CM hamsters died compared with 27.7% of quinapril-treated CM hamsters. Quinapril increased the median survival time of CM hamsters by 32.9% (112 days). It is concluded that chronic quinapril therapy exerts a significant cardioprotective effect and also increases survival.     

Growth hormone-releasing peptide can improve left ventricular dysfunction and attenuate dilation in dilated cardiomyopathic hamsters

OBJECTIVE: The mammalian heart contains specific growth hormone-releasing peptide (GHRP) binding sites whose physiological significance is unknown. We sought to compare the effects of GHRP and GH on progressive left ventricular (LV) dysfunction in the TO-2 hamster model of dilated cardiomyopathy. METHODS: TO-2 hamsters (8 weeks old) were injected with GHRP-6 (100 microg/kg day), GH (2 mg/kg day), or saline for 4 weeks; F1B hamsters served as controls. LV functional and structural changes were evaluated by echocardiography and pathology. RESULTS: The increase in body weight of GH-treated TO-2 hamsters was greater than that of animals in the other two groups. Plasma GH and insulin-like growth factor-1 (IGF-1) concentrations were not increased by GHRP-6. LV fractional shortening (LVFS) decreased from 42.0+/-2.6% to 25.4+/-1.8% and the LV end-diastolic dimension (LVDd) increased from 4.0+/-0.1 to 5.0+/-0.1 mm in untreated TO-2 hamsters between 8 and 12 weeks. LVFS was substantially improved by treatment with GHRP-6 (33.4+/-2.0%) or GH (32.0+/-2.1%). The LVDd was significantly smaller in animals treated with GHRP-6 than in those treated with GH. The cross-sectional LV myocyte area and the amount of atrial natriuretic peptide mRNA in the LV were increased by GH but not by GHRP-6. Treatment woth GH at a lower dose (0.2 mg/(kg day)) exerted minimal cardiac and systematic growth effects without improving LV function. CONCLUSION: GHRP can ameliorate the development of progressive LV dysfunction independently of the GH-IGF-1 axis, suggesting a potential new approach to the heart failure.