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.

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.

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.

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.

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, β-blockers have been shown to improve the status of HF patients, although the precise mechanisms remain unclear. The present study evaluates the effect of β-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.