Modulation of Vascular ACE by Oxidative Stress in Young Syrian Cardiomyopathic Hamsters: Therapeutic Implications.

Increased vascular angiotensin-converting enzyme (ACE) activity and oxidative stress are present in young Syrian cardiomyopathic hamsters (SCH) before the clinical manifestation of heart failure (HF). The developmental time-course of these alterations and their potential interactions, however, are still unknown. We evaluated mRNA and protein levels of ACE, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) in the vasculature of SCH from one to four months of age. Total RNA and proteins were quantified with real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot, respectively. The role of nitric oxide (NO) on vascular ACE activity was also assessed. ACE mRNA and protein levels were up-regulated in SCH at two months of age compared with controls (CT) (p < 0.05). At this two-month stage, eNOS protein levels were lower in SCH (87%) than in CT (100%) (p < 0.05), although iNOS protein levels increased significantly (482%) compared to CT (100%; p < 0.05). In addition, ACE mRNA expression and activity were modulated by NO at two months of age. Thus, the combination of low eNOS and high iNOS protein levels may underlie vascular renin-angiotensin system (RAS) over-activation. Altogether, these factors may contribute to the development of endothelial dysfunction and vascular hyper-reactivity in the early stages of heart failure, and eventually trigger cardiac deterioration in this animal model of HF.

Atorvastatin improves systolic function, but does not prevent the development of dilated cardiomyopathy in streptozotocin-induced diabetic rats.

BACKGROUND: Therapy with HMG-CoA reductase inhibitors (statins) has been associated with a significant reduction in the number of major cardiovascular (CV) events in diabetic patients. The mechanisms by which these drugs improve cardiac status remain unclear. We assessed the effects of atorvastatin (10 mg/kg/day) on CV function in streptozotocin (STZ)-induced diabetic rats. METHODS: Age-matched, nondiabetic rats were used as controls. Echocardiographic parameters, systolic blood pressure (SBP), endothelial-dependent relaxation, cardiac and vascular oxidative stress, perivascular fibrosis, and cholesterol levels were evaluated after a 4-week atorvastatin treatment period. RESULTS: In diabetic rats, SBP was higher than in controls. Atorvastatin decreased SBP in diabetic rats by 14% (n = 10, p < 0.05), and significantly increased stroke volume, ejection fraction, and cardiac output index. Whereas atorvastatin reduced left ventricular end systolic volume (LVESV) by 50% (p < 0.05), it failed to reduce left ventricular end diastolic volume (LVEDV). Total cholesterol was higher in diabetic rats than in controls and atorvastatin was ineffective in reducing cholesterol levels. The statin, however, decreased perivascular fibrosis and media thickness, and the markers of oxidative stress malondialdehyde (MDA) and 4-hidroxyalkenals (4-HAE) in aortic homogenates from diabetic rats. In addition, atorvastatin improved endothelial function by increasing the E MAX value of the acetylcholine-induced relaxation from 53.7 ± 4.1% in untreated diabetic to 82.1 ± 7.0% in treated diabetic rats (n = 10, p < 0.05). L-NAME fully abolished this improvement, suggesting that the increased vascular relaxation with atorvastatin is NO-dependent. CONCLUSIONS: Whereas atorvastatin does not reverse ventricular dilatation, it does have a positive hemodynamic effect on the CV system of diabetic rats. This hemodynamic benefit is independent of cholesterol levels, and is observed concomitantly with reduced oxidative stress, vascular remodeling, and improved endothelial function. Together, these results suggest that atorvastatin decreases the workload on the heart and improves systolic performance in type 1 diabetic rats by reducing oxidative stress, vascular tone, and systemic vascular resistance.

Daily administration of atorvastatin and simvastatin for one week improves cardiac function in type 1 diabetic rats.

Short-term administration of statins during the perioperative period has been suggested to improve cardiovascular (CV) outcomes in patients undergoing cardiac and vascular surgery. The effectiveness of this therapy, the optimal administration time and the statin best suited to improve cardiac performance under hyperglycemic conditions, however, are unknown. In this study, we compared the effects of 10 mg/kg/day simvastatin (SV), pravastatin (PV) and atorvastatin (AV), on the CV status of fully anesthetized streptozotocin-induced diabetic rats 4 weeks following diabetes induction. At this stage, cardiac function is compromised. The rats were anesthetized to mimic presurgical conditions. Cardiac status was evaluated twice by echocardiography, first 24 h after statin administration, and then after daily statin administration for 1 week. After 24 h of statin administration, CV parameters were not improved. Continued daily administration of SV and AV over a 1-week period, by contrast, significantly improved ejection fraction from 52.20 ± 2.33% before treatment to 64.89 ± 1.12% with AV and to 69.71 ± 2.30% with SV (n = 9, p < 0.05). The cardiac output index was also significantly improved from 51.13 ± 6.86 ml/min × 100 g body weight (BW) before treatment to 98.74 ± 13.78 ml/min × 100 g BW with AV and to 84.94 ± 8.64 ml/min × 100 g BW with SV. Only AV increased stroke volume from 0.50 ± 0.08 to 0.83 ± 0.13 ml (n = 9, p < 0.05). Unlike the other statins tested, PV provided no beneficial effects, regardless of the regimen of administration. Our results indicate that daily administration of AV and SV for 1 week enhances cardiac performance in fully anesthetized diabetic rats. This study of short-term statin administration may have strong clinical implications for improving perioperative outcomes in diabetic patients.

Diabetes alters cardiovascular responses to anaesthetic induction agents in STZ-diabetic rats.

BACKGROUND: People with diabetes are at increased risk of cardiovascular (CV) morbidity and mortality during surgery. The most appropriate anaesthetic induction agent for these patients is unknown. METHODS AND RESULTS: We assessed the CV effects of propofol, etomidate and ketamine in streptozotocin (65 mg/kg, IP) diabetic rats. In non-diabetic rats, none of these anaesthetics significantly modified cardiac output, heart rate or stroke volume, but ketamine increased systolic blood pressure (SBP) compared to etomidate and propofol (89.6 ± 2.4 mmHg, vs. 72.7 ± 3.0 and 75.4 ± 1.9; p < 0.05). In diabetic rats, by contrast, cardiac output was lower with ketamine (82.6 ± 14 ml/min) and etomidate (78.2 ± 15.8 ml/min) than with propofol (146 ± 21 ml/min, N = 8, p < 0.01). SBP, however, was higher in the propofol-treated group (93.3 ± 3.4 mmHg, p < 0.05). CONCLUSION: These results suggest that hyperglycaemia modifies CV responses to induction anaesthetics.

Chronic treatment with N-acetylcysteine improves cardiac function but does not prevent progression of cardiomyopathy in Syrian cardiomyopathic hamsters.

Oxidative stress has been postulated to contribute to the onset and development of heart failure (HF). The efficacy of antioxidant therapy in HF, however, remains controversial. This study evaluates the effect of the antioxidant N-acetylcysteine (NAC, 1 g/kg per day) on cardiovascular function in 2- and 6-month-old Bio-TO2 Syrian cardiomyopathic hamsters (SCH) after treatment for 1 month and 5 months with this drug. Endothelial function, systolic blood pressure (SBP), and echocardiographic parameters were evaluated. Age-matched F1-B golden hamsters were used as controls. One month of NAC administration significantly decreased SBP in 2-month-old SCH (n = 5, P < 0.001) without modifying echocardiographic values. Five-month treatment of cardiomyopathic animals with the antioxidant improved the acetylcholine-induced relaxation in aortic rings by 24% (E( Max) value from 45.8% ± 4% to 55.3% ± 2% n = 7, P < .05) but did not modify EC(50) values for the acetylcholine concentration-response curve. In addition, 5-month administration of NAC to SCH increased ejection fraction from 39% ± 4% to 57% ± 4% (n = 11, P < .001) and decreased left ventricular end-diastolic and end-systolic volumes (from 0.38 ± 0.04 mL/100 g body weight (BW) and 0.22 ± 0.03 mL/100 g BW, before, to 0.24 ± 0.04 mL/100 g BW and 0.12 ± 0.03 mL/100 g BW after treatment, P < .01). Cardiac output index also improved after 5 months of treatment, although it did not reach statistical significance. These results suggest that antioxidant therapy alone decreases ventricular dilatation and improves cardiovascular function in this animal model of dilated cardiomyopathy, but it does not prevent the appearance of HF.

Enalapril and losartan are more effective than carvedilol in preventing dilated cardiomyopathy in the Syrian cardiomyopathic hamster.

To assess the role of the renin-angiotensin (RAS) and adrenergic systems in the development and progression of dilated cardiomyopathy in the Syrian cardiomyopathic hamster (SCH), echocardiographic parameters were evaluated in 6-month-old animals after 5 months of treatment with enalapril (25 mg/kg/day) plus losartan (10 mg/kg/day), or with carvedilol (1 mg/kg/day). Cardiac output indexes (COI) increased by 53% after RAS blockade and by 20% after beta-blockade in SCH. Moreover, LVEDV and LVESV decreased 30% and 62%, respectively (P < .05) during RAS blockade, whereas ejection fraction (EF) increased by 48%. By contrast, carvedilol reduced LVESV by only 28% (P < .05) and increased EF by only 15% (P < .05). These results suggest that RAS activation plays a critical role in the development of cardiac dysfunction in SCH and that suppression of RAS may be more effective than beta-blockade in retarding the development of cardiomyopathy in SCH. Owing to timing (pre-heart failure stage) and to the single dose protocol, the implications of this study for human subjects remain to be clarified.

Cardiac oxidative stress is elevated at the onset of dilated cardiomyopathy in streptozotocin-diabetic rats.

The association between nitric oxide synthase (eNOS and iNOS) status, oxidative stress, and cardiac function was evaluated in streptozotocin (STZ)-diabetic rats to understand the etiology of diabetic cardiomyopathy. Cardiac function was determined by echocardiography. eNOS and iNOS status and superoxide production were assessed by immunohistochemistry and chemiluminescence, respectively. In STZ-diabetic rats, stroke volume, cardiac output, and left ventricular ejection fraction were significantly lower than in controls (CT, P < .05), whereas left ventricular end-systolic volume was higher. Cardiac NOS activity increased from 161 +/- 18 cpm/mg tissue in CT rats to 286 +/- 20 cpm/mg tissue (P < .001) in STZ-diabetic rats. Furthermore, superoxide production and cardiac eNOS and iNOS levels were higher in STZ-diabetic rats than in CT rats (P < .05). An increased activation of cardiac eNOS and iNOS is observed concomitantly with decreased cardiac function. Thus, increased oxidative stress in the heart may be implicated in the development of dilated cardiomyopathy in STZ-diabetic rats.

Chronic administration of carvedilol improves cardiac function in 6-month-old Syrian cardiomyopathic hamsters.

Heart failure (HF) is a multifactorial and progressive disease that has been linked to activation of the renin-angiotensin and sympathetic systems. In recent years, beta-blockers have been shown to improve the status of HF patients, although the precise mechanisms remain unclear. The present study evaluates the effect of beta-blockade with carvedilol (1 mg/kg/day) on cardiovascular function in 2- and 6-month-old cardiomyopathic hamsters (SCH) after 1-month and 5-month treatment periods with the drug, respectively. Age-matched golden hamsters were used as controls (CT). Systolic blood pressure (SBP) and echocardiographic studies were evaluated. The latter studies included left ventricular end-systolic (LVESV) and end-diastolic (LVEDV) volumes, ejection fraction (EF), cardiac output index (COI), heart rate (HR), and left ventricular posterior wall thickness (LVPWT). In 2-month-old SCH, carvedilol administration during a 1-month period reduced SBP from 107.59 +/- 3.49 to 77.26 +/- 3.49 mm Hg (n = 5, p < 0.05). At this stage, cardiac parameters in SCH were similar to those of controls and were not affected by carvedilol administration. In 6-month-old SCH, 5-month administration of carvedilol decreased SBP from 102.16 +/- 3.61 to 90.60 +/- 2.80 mm Hg (n = 5, p < 0.05), HR from 363 +/- 14 to 324 +/- 14 bpm (n = 5, p < 0.05), and LVESV from 0.18 +/- 0.01 to 0.13 +/- 0.01 ml/100 g BW (n = 5, p < 0.05), and increased EF and COI by 14 and 23%, respectively (n = 5, p < 0.05). The drug did not modify LVEDV or LVPWT. These results reveal that carvedilol significantly improves cardiac function in 6-month-old cardiomyopathic hamsters, but it does not prevent ventricular dilatation. Improved cardiac function appears to be secondary to decreased total peripheral resistance, due mainly to the vasodilator properties of the drug. Thus, overactivation of the sympathetic system is not likely to be a determining factor in the etiology of dilated cardiomyopathy in this animal model.