MCI-154, a Ca2+ sensitizer, increases survival in cardiomyopathic hamsters.

To assess the long-term efficacy of a Ca2+ sensitizer MCI-154, 6-[4-(4'-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride trihydrate, on chronic heart failure, we studied the effects of the agent on the life span of cardiomyopathic hamsters of the BIO-14.6 strain. At approximately 150 days of age, 210 male hamsters were randomly divided into three groups: MCI-154 0.1 mg kg(-1), day(-1)(MCI-154-low), MCI-154 1 mg kg(-1) day(-1) (MCI-154-high), and control group. The median survival time in control, MCI-154-low and MCI-154-high groups was 227, 243 and 260 days after the start of treatment, respectively. Final survival rate at 284 days in control, MCI-154-low and MCI-154-high groups was 0, 17.1 and 38.6%, respectively. The cumulative survival times in the two MCI-154 treated groups were significantly prolonged in comparison with that in the control group (P < 0.0001). Thus, the present study clearly showed that MCI-154 prolonged the life span of cardiomyopathic hamsters, suggesting that long-term therapy with MCI-154 would be promising in the treatment of congestive heart failure.     

Acute and chronic effects of T-1032, a novel selective phosphodiesterase type 5 inhibitor,on monocrotaline-induced pulmonary hypertension in rats

We examined the hemodynamic property of T-1032 (methyl 2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridylmethoxy)-4-(3,4,5-trimethoxy-phenyl)-3-isoquinoline carboxylate sulfate), a novel selective phosphodiesterase type 5 (PDE5) inhibitor, and evaluated the chronic effect of T-1032 on cardiac remodeling and its related death in monocrotaline (MCT)-induced pulmonary hypertensive rats. T-1032 (1, 10, 100 micro g/kg, i.v.) significantly reduced mean arterial pressure (MAP) and right ventricular systolic pressure (RVSP) without a change in heart rate. The change in RVSP was more potent than that in MAP with 1 micro g/kg T-1032 treatment (RVSP: -8.2+/-1.2%, mean arterial pressure: -5.7+/-1.2%), and reductions in RVSP and MAP reached a peak at doses of 1 and 10 micro g/kg, respectively. In contrast, nitroglycerin (0.1, 1, 10 micro g/kg, i.v.) and beraprost (0.1, 1 micro g/kg, i.v.) did not cause a selective reduction in RVSP at any dose. When T-1032 (300 ppm in diet) was chronically administered, it delayed the death, and significantly suppressed right ventricular remodeling (T-1032-treated: 0.318+/-0.021 g, control: 0.401+/-0.013 g, p<0.05). Our present results suggest that T-1032 selectively reduces RVSP, and resulting in the suppression of right ventricular remodeling with a delay of the death in MCT-induced pulmonary hypertensive rats.     

Cardiotonic agent SCH00013 prolongs survival of cardiomyopathic hamsters

The authors examined the effects of long-term treatment with SCH00013, a novel cardiotonic agent with calcium-sensitizing action, on survival of hereditary cardiomyopathic BIO 14.6 hamsters. Sixty-nine male hamsters at 223 days of age were divided into untreated, SCH00013-low (approximately 1 mg/kg/d), and SCH00013-high (approximately 10 mg/kg/d) groups. Survival curves were constructed in the three groups. The first deaths in the untreated, SCH00013-low, and SCH00013-high groups were found at 263, 290, and 314 days of age, respectively. A 50% mortality rate was observed at 392 days in the untreated group, 396 days in the SCH00013-low group, and 445 days in SCH00013-high group. The survival time distribution of the SCH00013-high group was significantly different from that of the untreated group (P < 0.005). However, histomorphometric examinations revealed that the degree of progression of calcification and fibrosis in the ventricular wall of the BIO 14.6 hamsters was not different between the untreated and SCH00013-treated groups. Plasma concentration of this agent was 2 microM at the end of the second week of continuous administration via drinking water in SCH00013-high group. Thus, SCH00013 was beneficial for the survival of cardiomyopathic hamsters, suggesting that this agent is a possible candidate for the treatment of chronic heart failure.     

Pimobendan increases survival of cardiomyopathic hamsters

We investigated the effect of the new cardiotonic drug pimobendan on survival of hereditary cardiomyopathic hamsters. Untreated cardiomyopathic hamsters served as controls. A 50% mortality was observed after 280 days for the control group and after 318 days for the pimobendan-treated animals. After 340 days, survival was 0% for the untreated cardiomyopathic hamsters and 27% in the pimobendan-treated group. We conclude that pimobendan slows the progression of heart failure in cardiomyopathic hamsters.     

Long-term treatment with a phosphodiesterase type 5 inhibitor improves pulmonary hypertension secondary to heart failure through enhancing the natriuretic peptides-cGMP pathway

In advanced heart failure (HF), the compensatory pulmonary vasodilation is attenuated due to the relative insufficiency of cGMP despite increased secretion of natriuretic peptides (NPs). Phosphodiesterase type 5 (PDE5) inhibitors prevent cGMP degradation, and thus may potentiate the effect of the NPs-cGMP pathway. We orally administered a specific PDE5 inhibitor, T-1032 (1 mg/kg; twice a day, n = 7) or placebo (n = 7) for 2 weeks in dogs with HF induced by rapid pacing (270 bpm, 3 weeks) and examined the plasma levels of atrial natriuretic peptide (ANP), cGMP, and hemodynamic parameters. We also examined the hemodynamic changes after injection of a specific NPs receptor antagonist, HS-142-1 (3 mg/kg), under treatment with T-1032. T-1032 significantly increased plasma cGMP levels compared with the vehicle group despite low plasma ANP levels associated with improvement in cardiopulmonary hemodynamics. HS-142-1 significantly decreased plasma cGMP levels in both groups, whereas it did not change all hemodynamic parameters in the vehicle group. In contrast, in the T-1032 group, HS-142-1 significantly increased pulmonary arterial pressure and pulmonary vascular resistance. These results indicated that long-term treatment with a PDE5 inhibitor improved pulmonary hypertension secondary to HF and the NPs-cGMP pathway contributed to this therapeutic effect.     

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 electro-phoresis (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 drugtreated 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 drugtreated 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 Angl remained unaltered in any of the drug-treated hamsters. Tissue Angll 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.

     

T-1032, a novel specific phosphodiesterase type 5 inhibitor, increases venous compliance in anesthetized rats.

Nitric oxide (NO) donors including organic nitrates dilate capacitance vessels. As inhibition of phosphodiesterase type 5 results in the accumulation of guanosine 3'5'-cyclic monophosphate (cGMP), specific phosphodiesterase type 5 inhibitors are expected to have a vasodilator property similar to that of NO donors. To test this hypothesis, we examined the effect of methyl2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate (T-1032), a novel specific phosphodiesterase type 5 inhibitor, on mean arterial pressure and mean circulatory filling pressure (an index of venodilation) compared with that of nitroglycerin and diltiazem in mecamylamine- and noradrenaline-treated anesthetized rats. Intravenous infusion of T-1032 (0.1, 1, 10 microg/kg/min) dose-dependently decreased mean arterial pressure (-3.8+/-0.3%, -9.1+/-0.8%, -16.8+/-1.5% at doses of 0.1, 1 and 10 microg/kg/min, respectively) and mean circulatory filling pressure (-6.1+/-0.9%, -12.5+/-0.7%, -18.6+/-3.0% at doses of 0.1, 1 and 10 microg/kg/min, respectively). The mean circulatory filling pressure-mean arterial pressure relationship revealed that T-1032 had a selective action on the mean circulatory filling pressure compared with diltiazem (10, 100 microg/kg/min) and a similar or more selective effect than nitroglycerin (0.3, 3 and 30 microg/kg/min). In the next study, we calculated venous compliance and unstressed volume from the mean circulatory filling pressure-volume relationship. Intravenous infusion of T-1032 (3 microg/kg/min) increased venous compliance (3.35+/-0.40 in T-1032 vs. 2.31+/-0.15 ml/kg/mm Hg in vehicle, P<0.05) without changing the unstressed volume (37.2+/-2.80 in T-1032 vs. 42.6+/-2.37 ml/kg in vehicle, P>0.05). It was concluded that T-1032 increased venous capacitance by increasing venous compliance, and that this selective phosphodiesterase type 5 inhibitor appeared to have a different vasodilator action from that of an NO donor and a Ca(2+) channel antagonist in that it had a selective action on the mean circulatory filling pressure.     

T-1032, a cyclic GMP phosphodiesterase-5 inhibitor, acutely blocks physiologic insulin-mediated muscle haemodynamic effects and glucose uptake in vivo

1. Cyclic GMP phosphodiesterase-5 inhibitors have been shown to alter blood flow in specific tissues by potentiating local NO-dependent vasodilatory mechanisms. Since the haemodynamic effects of physiologic insulin, particularly capillary recruitment, may be critical for muscle glucose uptake in vivo and are blocked by inhibitors of nitric oxide synthase, we have explored the acute effects of the specific cGMP phosphodiesterase-5 inhibitor T-1032 on physiologic insulin action in anaesthetized healthy rats in vivo. 2. Whole-body glucose infusion (GIR), femoral blood flow (FBF), hind leg vascular resistance (VR), hind leg glucose uptake (HGU), 2-deoxyglucose uptake into muscles of the lower leg (R'g), hind leg metabolism of infused 1-methylxanthine (1-MX), a measure of capillary recruitment, and muscle cGMP were determined. The experimental groups were T-1032 (10 microg min-1 kg-1) infused for 1 h before and during a euglycaemic insulin clamp (3 mU min-1 kg-1 x 2 h), T-1032 infused for 3 h with saline, T-1032 during a 2 h clamp, T-1032 with saline for 2 h, and a 2 h saline control. 3. Insulin increased GIR from zero to 13 mg min-1 kg-1, HGU from 0.1+/-0.01 to 0.43+/-0.05 micromol min-1, R'g and 1-MX, marginally increased FBF, and had no effect on blood pressure or heart rate. T-1032 alone had no effect on blood pressure, heart rate, FBF, VR, HGU, R'g or 1-MX, but increased muscle cGMP. T-1032 1 h before and during insulin completely blocked GIR (1 h), HGU (2 h), R'g (2 h), and 1-MX (2 h). T-1032 commenced with insulin had only partial blocking activity against insulin. 4. We conclude that T-1032 is a potent acutely acting inhibitor of the muscle effects of physiologic insulin on capillary recruitment and glucose uptake in vivo. These, together with inhibition of whole-body glucose infusion during insulin, may caution against the use of isoenzyme-5-specific cyclic GMP phosphodiesterase inhibitors as therapeutic agents.     

Correlation between changes in morphology, electrical properties, and angiotensin-converting enzyme activity in the failing heart.

Evidence is available that morphologic and electrophysiologic abnormalities are present in the failing heart. In the present work, the progressive changes in electrical properties and morphology of the failing heart of Syrian cardiomyopathic hamsters (TO2) were investigated at different stages of the pathological process, and the possible role of the renin-angiotensin system was studied. Cardiomyopathic hamsters 2 and 11 months of age were used. Age-matched normal hamsters (F1B) were utilized as controls. Measurements of membrane potential, conduction velocity and refractoriness were made with conventional intracellular electrodes connected to a high impedance DC amplifier. Serum and cardiac angiotensin-converting enzyme (ACE) activities were measured in controls and cardiomyopathic animals. The results indicated that interstitial fibrosis and calcification were present in the heart of 2-month old Syrian cardiomyopathic hamsters. Measurements of the resting potential performed in the isolated right ventricle of 2-month old Syrian cardiomyopathic hamsters indicated an average value of -66.7 +/- 0.96 mV (n = 25); in the controls of the same age was -78.5 +/- 1 mV (n = 25, P < 0.05); and in 11-month old cardiomyopathic hamsters was -67.8 +/- 0.83 mV (n = 10). The duration of the action potential measured at 50 and 90% of repolarization in 2-month old hamsters was well above the controls. The conduction velocity measured in the isolated right ventricle of 2-month old Syrian cardiomyopathic hamsters (44.2 +/- 1.6 cm/s, n = 12) was not different from the control (43.7 +/- 1.1 cm/s, n = 7, P > 0.05) but was significantly larger than that recorded from the ventricle of 11-month old animals (37.8 +/- 2.9 cm/s, n = 11, P < 0.05). ACE activity was 0.26 +/- 0.01 nmol/mg x min in the heart of controls at 2 months of age and did not change with age. Although in the 2-month old cardiomyopathic hamsters the enzyme activity (0.28 +/- 0.04 nmol/mg x min) was not different from the controls (P > 0.05), in myopathic animals at 11 months of age, the enzyme activity (0.56 +/- 0.027 nmol/mg x min) was greater than controls (P < 0.05). The ACE activity in plasma followed the same pattern. The conclusion from these experiments is, that some parameters like resting potential, action potential duration, and morphological abnormalities appeared quite early in the failing process. The decline in conduction velocity, however, appeared later on, concurrently with the activation of plasma and cardiac renin-angiotensin systems.     

Ethanol in cardiomyopathic hamsters: Na and water excretion and righting response

This study examined the effects of ethanol and hereditary cardiomyopathy on sodium and water excretion by golden Syrian hamsters of both sexes. Ethanol (4 g/kg) or the isotonic saline vehicle were injected IP into 60-70-day-old hamsters of normal and cardiomyopathic (BIO 14.6) strains. Urine and blood were collected after 90 or 350 min in different groups. Cardiomyopathic hamsters more quickly lost their righting responses, eliminated ethanol more slowly, and had lower urine volume and sodium excretion than normal hamsters after ethanol injections. Plasma creatine kinase levels were normal in all animals tested, indicating no active skeletal or cardiac lesioning in the cardiomyopathic hamsters at the time of the experiment. Some factors which could contribute to the increased CNS and renal sensitivity to ethanol in cardiomyopathic hamsters include impaired ethanol metabolism, enhanced myocardial depression, and reduced atrial content of natriuretic peptides. The results do not owe to decompensated heart failure. Thus, the genetic mutation which causes skeletal and cardiac myopathy in these hamsters may also affect the metabolism and sensitivity to ethanol.     

Increased sensitivity of vascular smooth muscle to nitric oxide in dilated cardiomyopathy of Syrian hamsters (Bio TO-2 strain)

We assessed the evolution with time of the responsiveness of three vascular beds in dilated cardiomyopathic hamsters of the Bio TO-2 strain. Eight cardiomyopathic hamsters and 8 control hamsters were investigated at 180 and 300 days of age. Thoracic aorta and mesenteric and renal artery rings were studied in isolated organ baths. Cumulative concentration-response relations to phenylephrine, acetylcholine, sodium nitroprusside, and angiotensin II were established for each ring. Maximum effect (Emax) and concentration inducing 50% of Emax (EC50) were determined from each concentration-response curve and pD2 was calculated as -log(EC50). Compared with control hamsters, in cardiomyopathic hamsters, Emax of phenylephrine was not modified in aorta, whereas it was significantly lower in mesenteric (-6% and -33% at 180 and 300 days, respectively) and renal (-17% and -24%) arteries. Emax of acetylcholine was significantly higher in aorta (+57% and +30%), mesenteric (+42% and +34%), and renal (+168% and +70%) arteries. Emax of sodium nitroprusside was significantly higher in aorta (+26% and +16%) and tended to be higher in mesenteric (+25% and +23%) and renal (+27% and +10%) arteries. Emax of angiotensin II was not modified in aorta and tended to be lower in mesenteric artery at 300 days. The pD2 of phenylephrine was significantly increased in aorta and the pD2 of sodium nitroprusside was significantly increased in aorta and renal artery. In conclusion, in dilated cardiomyopathic hamsters, endothelium-dependent and -independent vasodilations are enhanced early, demonstrating increased sensitivity of vascular smooth muscle to nitric oxide. This abnormality may be involved in the decreased responsiveness to phenylephrine and angiotensin II.     

Characterization and effects of methyl-2- (4-aminophenyl)-1, 2-dihydro-1-oxo-7- (2-pyridinylmethoxy)-4-(3,4, 5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate (T-1032), a novel potent inhibitor of cGMP-binding cGMP-specific phosphodiesterase (PDE5)

An isoquinolone derivative, methyl-2-(4-aminophenyl)-1, 2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4, 5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate (T-1032), was found to be a novel potent inhibitor of cyclic GMP (cGMP)-binding cGMP-specific phosphodiesterase (PDE5). We investigated the inhibitory effects of T-1032 on six PDE isozymes isolated from canine tissues. T-1032 specifically inhibited the hydrolysis of cGMP by PDE5 partially purified from canine lung, at a low concentration (IC(50) = 1.0 nM, K(i) = 1.2 nM), in a competitive manner. In contrast, the IC(50) values of T-1032 for PDE1, PDE2, PDE3, and PDE4 were more than 1 microM. T-1032 also inhibited PDE6 from canine retina with an IC(50) of 28 nM, which is of the same order of magnitude as the IC(50) of sildenafil. cGMP hydrolytic activities of two alternative splice variants of canine PDE5 expressed in COS-7 cells were inhibited by this compound to a similar extent. T-1032 increased the intracellular concentration of cGMP in cultured rat vascular smooth muscle cells in the presence and absence of C-type natriuretic peptide, an activator of membrane-bound guanylate cyclase, whereas the compound did not change cyclic AMP levels. These data indicated that T-1032, which belongs to a new structural class of PDE5 inhibitors, is a potent and selective PDE5 inhibitor. This compound may be useful in pharmacological studies to examine the role of a cGMP/PDE5 pathway in tissues.     

Radioligand binding and inotropic effects of ryanodine in the cardiomyopathic Syrian hamster.

We compared the radioligand-binding and inotropic effects of ryanodine [known specific regulator of sarcoplasmic reticulum (SR) calcium release channel] on BIO 14.6 cardiomyopathic Syrian hamsters with those on age-matched F1B controls. Scatchard analyses of [3H]ryanodine binding to cardiac membranes prepared from 1-2-month-old BIO 14.6 and F1B Syrian hamsters revealed the presence of a significant increase in binding capacity (Bmax = 942 +/- 49 vs. 567 +/- 33 fmol/mg protein) with no difference in affinity (KD = 3.9 +/- 0.4 vs. 3.5 +/- 0.5 nM, p less than 0.01). Ryanodine is a significantly less potent negative inotrope in isolated papillary muscles prepared from 1-2-month-old BIO 14.6 hamsters than in muscles from F1B controls (IC50 = 4.3 +/- 1 vs. 0.5 +/- 0.4 microM, p less than 0.05). Ryanodine was 200-fold less potent in the 4-6-month-old myopathic muscles than in controls (IC50 = 20 +/- 5 vs. 0.1 +/- 0.01 microM, p less than 0.01). A paradoxic positive inotropic effect of ryanodine observed in 4-6-month-old myopathic muscles at low concentrations was not seen in controls (ECmax = 126 +/- 5% at 1 +/- 0.1 x 10(-8) M). These data support the presence of a defect both biochemical and physiologic in the ryanodine-sensitive SR calcium release channel in the BIO 14.6 cardiomyopathic Syrian hamster. Purification, cloning, sequencing, and expression studies will be required to distinguish among primary, secondary, intrinsic, and regulatory defects in the ryanodine-sensitive SR calcium release channel in the cardiomyopathic Syrian hamster.     

A dopamine D(1/5) receptor antagonist, SCH23390, prevents stress-induced sudden death in cardiomyopathic hamsters

Stress is known to have an impact on the development of life-threatening cardiovascular dysfunction. We have previously demonstrated that repeated exposure to cold-immobilization stress had lethal effects on cardiomyopathic Syrian hamsters (BIO 14.6), and that stress-induced sudden death was prevented by daily treatment with propranolol, suggesting an important role of sympathetic nerves in the etiology of stress-induced cardiac sudden death. In an attempt to clarify further the mechanisms of the sudden death, in the present study we investigated the effects of D(1/5) receptor blockade by SCH23390 on the sudden death of cardiomyopathic hamsters. In accordance with our previous results, repeated exposure for 5 days to cold-immobilization stress induced a lethal effect in the cardiomyopathic hamsters but not in control healthy hamsters. SCH23390 (0.1-10 mg/kg, IP), administered just before the exposure for 5 consecutive days, dose-dependently and significantly prevented the lethal effects of the stress. Furthermore, it was demonstrated that the drug significantly reduced the increase in the weights of the adrenal and kidneys observed in the stressed-cardiomyopathic hamsters. On the other hand, specific D(2) antagonist haloperidol (0. 1-10 mg/kg) failed to prevent the stress-induced sudden death and minimally affected the increase in organ weights. Collectively, these results suggest that D(1/5) receptors had an important role in the etiology of stress-induced cardiac sudden death of the cardiomyopathic hamsters, and provide the first experimental evidence of the potential therapeutic values of D(1/5) antagonists against cardiac sudden death associated with stress.     

Acute hemodynamic effects of beta-blockers in patients with severe congestive heart failure: comparison of celiprolol and esmolol

The present study was designed to investigate, in patients with severe heart failure, the dose-dependent acute hemodynamic effects of celiprolol versus those of esmolol. Celiprolol is a beta 1 -receptor blocker with vasodilating properties, whereas esmolol is an ultra-short-acting beta 1 -blocker. Included were 14 patients with decompensated chronic heart failure (NYHA class IV) due to coronary heart disease (n = 8) or to dilated cardiomyopathy (n = 6). Each patient received both celiprolol and esmolol in random fashion. The beta-blockers were administered in four dose tiers, with an increase in dosage every 15 min. Hemodynamic measurements were obtained with a Swan-Ganz thermodilution catheter. Administration of celiprolol (5, 10, 20, and 50 microg/kg) took place intravenously. After intravenous administration of a loading dose of 500 microg/kg, we continuously infused esmolol at increasing doses, which were individually titrated for each patient. Mean infusion rates of esmolol were as follows: 40, 75, 140, and 230 micromol/kg per minute. Celiprolol and esmolol induced a comparable dose-dependent decrease in heart rate to a minimum of -10% below baseline. Esmolol caused a significant dose-dependent decrease (-25% below baseline at the highest dose level) in cardiac index (CI). After administration of celiprolol, CI decreased only transiently (-10% below baseline at the second and third dose level) and did not differ from the baseline at the highest dose level. For treatment of severe heart failure, initiation of intravenous beta-blocker therapy with low doses of a beta 1 -blocker with vasodilating effects may have hemodynamic advantages over conventional beta-blockade.     

Nebivolol increases survival in cardiomyopathic hamsters with congestive heart failure.

The genetically inbred cardiomyopathic Syrian hamster provides a valuable model of congestive cardiomyopathy: myocytolytic necrosis at 30-50 days of age is followed by cardiac hypertrophy at 150-250 days, and finally by congestive failure and death at 250-350 days. Successful drug treatment has been reported in the prenecrotic stage, but not when started during congestive failure. The present study evaluated survival of the cardiomyopathic hamster treated with the new beta-adrenoceptor blocker nebivolol, which was initiated during congestive failure. Fifty animals (BIO82.62, either sex, age 200 days) were acclimated to an environmentally controlled room for 20 days, receiving food and water ad libitum; seven hamsters died, indicating development of congestive failure. The remaining animals were then randomly assigned to one of three groups: 15 animals received control food; food for the others was supplemented with nebivolol, yielding a daily intake of either 0.1 mg/kg (n = 14) or 1 mg/kg (n = 14). At the lower nebivolol dose, death rate was unaltered in comparison with controls. However, at 1 mg/kg, survival was markedly improved (p = 0.042). Nebivolol treatment, started during congestive failure, thus significantly delays mortality in the cardiomyopathic hamster.     

Effect of tedisamil on cell communication, impulse propagation, and excitability of the failing heart.

In the present work, the effect of tedisamil on gap junctional conductance (gj) and conduction velocity was investigated in the failing heart of cardiomyopathic hamsters (TO-2 strain). It was found that tedisamil (10(-7) M) increased gj by 53.8+/-1% (n = 23) in cell pairs isolated from 2 months old cardiomyopathic hamsters. The effect of tedisamil was suppressed by intracellular dialysis of an inhibitor of protein kinase A and also by adenosine indicating that the drug increases gj through the activation of adenylcyclase. Tedisamil also increased the conduction velocity and cardiac refractoriness of ventricular muscle from young cardiomyopathic hamsters. At an advanced stage of the disease, however, when the beta-adrenoceptor, adenylcyclase signaling system is impaired, tedisamil was unable to increase gj. The present results indicate that the antiarrhythmic action of tedisamil is in part related to an increase in junctional conductance and conduction velocity.     

3H]PN200-110 and [3H]glibenclamide binding in normal and cardiomyopathic hamsters.

1. We examined the binding of the Ca2+ channel ligand [3H]PN200-110 and the ATP-sensitive K+ channel ligand [3H]glibenclamide to brain and heart from cardiomyopathic hamsters and compared them to controls. 2. We found that [3H]PN200-110 binding site density was elevated in the heart, but not in the brain, of 30- and 180-day old cardiomyopathic hamsters when compared to controls. 3. [3H]Glibenclamide binding site density was greatly reduced in the heart of 180-day old cardiomyopathic animals compared with all other groups. 4. Quantitative autoradiography revealed that [3H]glibenclamide binding was elevated in several brain areas of 30-day old cardiomyopathic hamsters relative to controls. 5. It is concluded that alterations in both Ca2+ and K+ channels exist in the cardiomyopathic hamster.     

Sildenafil and T-1032, phosphodiesterase type 5 inhibitors, showed a different vasorelaxant property in the isolated rat aorta

The vasorelaxant effects of sildenafil and T-1032 [methyl-2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate], two phosphodiesterase type 5 inhibitors, were examined in the isolated rat aorta. Sildenafil and T-1032, both of which have almost the same potency and selectivity regarding phosphodiesterase type 5 inhibitory activity, produced a similar, moderate, relaxation at 10(-10) to 10(-7) M (sildenafil: 66.8 +/- 13.7%; T-1032: 77.9 +/- 10.8% at 10(-7) M). However, sildenafil, but not T-1032, produced further relaxation at the higher concentrations (sildenafil: 102.0 +/- 0.6%; T-1032: 81.0 +/- 7.2% at 10(-4) M, P < 0.05). Sildenafil also produced a more potent relaxation than did T-1032 at the high concentrations (10(-5) and 10(-4) M) in endothelium-denuded aortic rings and in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor (3 x 10(-4) M). Moreover, the high concentrations of sildenafil, but not of T-1032, caused a rightward shift of the concentration-response curve for calcium chloride in K(+)-depolarized endothelium-denuded preparations. In the ligand binding assay for the L-type Ca(2+) channels, the affinities of sildenafil at 10(-5) M for binding sites of nitrendipine and (--)-desmethoxyverapamil [(--)- D888] (35.2 +/- 3.3% and 35.8 +/- 1.9%, respectively) were higher than those of T-1032 (11.8 +/- 4.0% and -13.1 +/- 1.3%, respectively, P < 0.05). Regarding cyclic nucleotide levels, both phosphodiesterase type 5 inhibitors increased cGMP levels at 10(-6) M. However, sildenafil, but not T-1032, further increased cGMP levels at the higher concentrations (sildenafil: 15.7 +/- 2.7 pmol/mg protein; T-1032: 5.6 +/- 0.6 pmol/mg protein at 10(-4) M, P < 0.05). These results suggested that high concentrations of sildenafil had additional vasorelaxant properties through mechanisms other than phosphodiesterase type 5 inhibition. Sildenafil-induced relaxation appears to be due to inhibition of the external Ca(2+)-dependent cascade for contraction and/or to an increase in cGMP levels. In contrast, T-1032 only showed a vasorelaxant property due to phosphodiesterase type 5 inhibition. In conclusion, T-1032 appears to be a specific phosphodiesterase type 5 inhibitor compared with sildenafil and a useful compound to examine the physiological function of phosphodiesterase type 5.     

Autonomic nervous system activity imbalance in cardiomyopathic hamster

There is strong evidence that autonomic imbalance plays an important role in progression of heart failure. Analysis of heart rate variability (HRV) has achieved substantial acceptance as a noninvasive method for the assessment of autonomic tone. The purpose of this investigation was to study HRV in an experimental model of heart failure using cardiomyopathic (BIO TO.2) hamsters. Animals showed an autonomic imbalance of cardiac control that seems due to attenuation of parasympathetic activity and an enhanced sympathetic tone. The reduction of parasympathetic activity in BIO TO.2 hamsters is suggested by (a) the reduction of the high-frequency (HF) spectrum, and (b) the lack of atropine to generate a response. The increased sympathetic activity is indicated by (a) the decreased time-domain indexes, (b) the increased LF/HF ratio of the power spectrum, and (c) the alteration of HRV indexes induced by propranolol. These results support the notion that in heart failure, there is a similar autonomic imbalance in both human and hamster and suggest that the cardiomyopathic hamster is a suitable experimental model for studying the involvement of the autonomic nervous system in the progression of heart failure.