Effects of aged garlic extract on left ventricular diastolic function and fibrosis in a rat hypertension model.

Daily consumption of garlic is known to lower the risk of hypertension and ischemic heart disease. In this study, we examined whether aged garlic extract (AGE) prevents hypertension and the progression of compensated left ventricular (LV) hypertrophy in Dahl salt-sensitive (DS) rats. DS rats were randomly divided into three groups: those fed an 8% NaCl diet until 18 weeks of age (8% NaCl group), those additionally treated with AGE (8% NaCl + AGE group), and control rats maintained on a diet containing 0.3% NaCl until 18 weeks of age (0.3% NaCl group). AGE was administered orally by gastric gavage once a day until 18 weeks of age. LV mass was significantly higher in the 8% NaCl + AGE group than in the 0.3% NaCl group at 18 weeks of age, but significantly lower in the 8% NaCl + AGE group than in the 8% NaCl group. No significant differences were observed in systolic blood pressure (SBP) between the 8% NaCl and 8% NaCl + AGE groups at 12 and 18 weeks of age. LV end-diastolic pressure and pressure half-time at 12 and 18 weeks of age were significantly lower in the 8% NaCl + AGE group compared with the 8% NaCl group. AGE significantly reduced LV interstitial fibrosis at 12 and 18 weeks of age. Chronic AGE intake attenuated LV diastolic dysfunction and fibrosis without significantly decreasing SBP in hypertensive DS rats.

Angiotensin-converting enzyme inhibition promotes coronary angiogenesis in the failing heart of Dahl salt-sensitive hypertensive rats.

BACKGROUND: The biologic response to angiotensin-converting enzyme (ACE) inhibitors may be influenced by the local environment. The effect of ACE inhibition on coronary angiogenesis was investigated in a rat model of hypertensive heart failure. METHODS AND RESULTS: Dahl salt-sensitive (DS) rats fed a high-salt diet from 6 weeks of age were treated with a nonantihypertensive dose of the ACE inhibitor perindopril or vehicle from 9 to 18 weeks. Treatment of rats with perindopril attenuated the heart failure as well as cardiac hypertrophy and fibrosis that were manifest in the vehicle-treated animals. Myocardial capillary density as well as the expression of the bradykinin B(2) receptor, endothelial nitric oxide synthase, and vascular endothelial growth factor were reduced in the heart of vehicle-treated rats compared with that of nonhypertensive control rats, and all of these changes were attenuated by treatment with perindopril. CONCLUSIONS: These results indicate that ACE inhibition by perindopril promotes myocardial capillary formation as well as attenuates cardiac remodeling and failure in a manner independent from the antihypertensive effect of the drug in DS hypertensive rats. The beneficial cardiac effects of perindopril were associated with activation of the bradykinin-nitric oxide pathway in the heart.

Mechanism underlying the efficacy of combination therapy with losartan and hydrochlorothiazide in rats with salt-sensitive hypertension.

Although thiazide diuretics are commonly used to supplement angiotensin receptor blockers for treatment of hypertension, the mechanism underlying the therapeutic effects of this drug combination remains unclear. We investigated the antihypertensive and cardioprotective effects of combination therapy with losartan (LOS) and hydrochlorothiazide (HCTZ), in comparison with those of either drug alone, in Dahl salt-sensitive hypertensive rats. Rats fed a high-salt diet from 6 weeks of age were treated with LOS, HCTZ, both drugs (COMB) and vehicle from 6 to 11 weeks. The salt-induced increase in systolic blood pressure was attenuated moderately by LOS and to a greater extent by HCTZ and COMB. Left ventricular (LV) hypertrophy and fibrosis, diastolic dysfunction, as well as angiotensin-converting enzyme and angiotensin II type 1A (AT(1A)) receptor gene expression were attenuated similarly by LOS and HCTZ and more so by COMB. LOS downregulated expression of the AT(1A) receptor gene, without affecting that of the AT(2) receptor gene, in the aorta. In contrast, neither HCTZ nor COMB affected aortic expression of the AT(1A) receptor gene, but both markedly upregulated that of the AT(2) receptor gene. The salt-induced decrease in the plasma concentration of nitric oxide metabolites was attenuated substantially by LOS and abolished by both HCTZ and COMB. In conclusion, the combination of LOS and HCTZ attenuated hypertension, as well as LV remodeling and diastolic dysfunction, more effectively than did LOS or HCTZ alone in rats with salt-sensitive hypertension. Modulation of the cardiac and vascular renin-angiotensin system may have contributed to these beneficial effects of the drug combination.

Evidence for the importance of adiponectin in the cardioprotective effects of pioglitazone.

The favorable effects of the peroxisome proliferator-activated receptor-gamma ligand pioglitazone on glucose metabolism are associated with an increase in the fat-derived hormone adiponectin in the bloodstream. A recent clinical trial, Prospective Pioglitazone Clinical Trial in Macrovascular Events, demonstrated that pioglitazone improved cardiovascular outcomes in patients with type 2 diabetes mellitus. However, the functional role of adiponectin in cardioprotection by pioglitazone has not been examined experimentally. Here we investigated the effect of pioglitazone on angiotensin II (Ang II)-induced cardiac hypertrophy and assessed the potential contribution of adiponectin to the action of pioglitazone on the heart. Wild-type or adiponectin-deficient mice were treated with pioglitazone as food admixture at a concentration of 0.01% for 1 week followed by 2 weeks of infusion with Ang II at 3.2 mg/kg per day. Ang II infusion in wild-type mice resulted in exacerbated myocyte hypertrophy and increased interstitial fibrosis, which were accompanied by elevated phosphorylation of extracellular signal-regulated kinase and expression of transforming growth factor-beta1 in the heart. Treatment of wild-type mice with pioglitazone attenuated cardiac hypertrophy and fibrosis, extracellular signal-regulated kinase phosphorylation, and transforming growth factor-beta1 expression in response to Ang II. Pioglitazone also increased the plasma adiponectin level and phosphorylation of cardiac AMP-activated protein kinase in wild-type mice in the presence of Ang II. The suppressive effects of pioglitazone on Ang II-induced cardiac hypertrophy and fibrosis were diminished in adiponectin-deficient mice. Furthermore, pioglitazone had no effects on the phosphorylation of extracellular signal-regulated kinase and AMP-activated protein kinase in the Ang II-infused heart of adiponectin-deficient mice. These data provide direct evidence that pioglitazone protects against Ang II-induced pathological cardiac remodeling via an adiponectin-dependent mechanism.

Exercise training alters left ventricular geometry and attenuates heart failure in dahl salt-sensitive hypertensive rats.

The clinical efficacy of exercise training in individuals with heart failure is well established, but the mechanism underlying such efficacy has remained unclear. An imbalance between cardiac hypertrophy and angiogenesis is implicated in the transition to heart failure. We investigated the effects of exercise training on cardiac pathophysiology in hypertensive rats. Dahl salt-sensitive rats fed a high-salt diet from 6 weeks of age were assigned to sedentary or exercise (swimming)-trained groups at 9 weeks. Exercise training attenuated the development of heart failure and increased survival, without affecting blood pressure, at 18 weeks. It also attenuated left ventricular concentricity without a reduction in left ventricular mass or impairment of cardiac function. Interstitial fibrosis was increased and myocardial capillary density was decreased in the heart of sedentary rats, and these effects were attenuated by exercise. Exercise potentiated increases in the phosphorylation of Akt and mammalian target of rapamycin observed in the heart of sedentary rats, whereas it inhibited the downregulation of proangiogenic gene expression apparent in these animals. The abundance of the p110alpha isoform of phosphatidylinositol 3-kinase was decreased, whereas those of the p110gamma isoform of phosphatidylinositol 3-kinase and the phosphorylation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase were increased, in the heart of sedentary rats, and all of these effects were prevented by exercise. Thus, exercise training had a beneficial effect on cardiac remodeling and attenuated heart failure in hypertensive rats, with these effects likely being attributable to the attenuation of left ventricular concentricity and restoration of coronary angiogenesis through activation of phosphatidylinositol 3-kinase(p110alpha)-Akt-mammalian target of rapamycin signaling.