Masafumi Ohtake

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 p110&agr; isoform of phosphatidylinositol 3-kinase was decreased, whereas those of the p110&ggr; 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(p110&agr;)-Akt-mammalian target of rapamycin signaling.

Cardiac remodeling and diastolic dysfunction in DahlS.Z- Lepr fa / Lepr fa rats: a new animal model of metabolic syndrome

We recently characterized male DahlS.Z-Leprfa/Leprfa (Dahl salt-sensitive (DS)/obese) rats, which were established from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of metabolic syndrome (MetS). We have now investigated cardiac pathophysiology and metabolic changes in female DS/obese rats in comparison with homozygous lean female littermates (DahlS.Z-Lepr+/Lepr+, or DS/lean, rats). Animals were maintained on a normal diet and were subjected to echocardiography followed by various pathological analyses at 15 weeks of age. Systolic blood pressure was significantly higher in female DS/obese rats than in DS/lean females at 12 weeks of age and thereafter. The survival rate of DS/obese rats was significantly lower than that of DS/lean rats at 15 weeks. Body weight, as well as visceral and subcutaneous fat mass were significantly increased in DS/obese rats, which also manifested left ventricular (LV) diastolic dysfunction and marked LV hypertrophy and fibrosis. In addition, myocardial oxidative stress and inflammation were increased in DS/obese rats compared with DS/lean rats. Serum insulin and triglyceride levels as well as the ratio of low-density lipoprotein- to high-density lipoprotein-cholesterol levels were markedly elevated in DS/obese rats, whereas fasting serum glucose concentrations were similar in the two rat strains. The phenotype of female DS/obese rats is similar to that of MetS in humans. These animals also develop salt-sensitive hypertension and LV diastolic dysfunction as well as LV hypertrophy and fibrosis, and these changes are associated with increased cardiac oxidative stress and inflammation.

Effects of Estrogen on Cardiovascular Injury in Ovariectomized Female DahlS.Z-Leprfa/Leprfa Rats as a New Animal Model of Metabolic Syndrome

Although recent clinical trials have found an increased incidence of cardiovascular disease in women on estrogen replacement therapy, the underlying mechanism remains unclear. We have recently characterized DahlS.Z-Leprfa/Leprfa (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of metabolic syndrome. We have now examined the effects of estrogen replacement on cardiac pathophysiology in ovariectomized female DS/obese (Ovx-DS/obese) rats. Animals subjected to ovariectomy at 7 weeks of age were implanted subcutaneously with a 60-day release pellet containing 0.5 mg of 17&bgr;-estradiol (E2) or placebo at 8 weeks. Age-matched female homozygous lean littermates (DahlS.Z-Lepr+/Lepr+ or DS/lean rats) of DS/obese rats served as controls. Animals were maintained on a normal diet and were subjected to echocardiography followed by various pathological analyses at 13 weeks of age. Ovx-DS/obese rats manifested hypertension at 7 weeks of age and thereafter and showed left ventricular (LV) fibrosis and diastolic dysfunction at 13 weeks. Treatment with E2 attenuated hypertension in Ovx-DS/obese rats but had no effect on blood pressure in ovariectomized female DS/lean (Ovx-DS/lean) rats. E2 treatment exacerbated LV fibrosis and diastolic dysfunction, as well as further increased cardiac oxidative stress and inflammation in Ovx-DS/obese rats, and it elicited similar effects in Ovx-DS/lean rats. E2 reduced food intake, body weight, and visceral fat content in both Ovx-DS/obese and Ovx-DS/lean rats. E2 treatment attenuated hypertension and obesity but exacerbated LV fibrosis and diastolic dysfunction in Ovx-DS/obese rats, with these latter effects being associated with increased cardiac oxidative stress and inflammation.

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.

Comparison of the effects of cilnidipine and amlodipine on cardiac remodeling and diastolic dysfunction in Dahl salt-sensitive rats.

Objective: The L/N-type calcium channel blocker (CCB) cilnidipine suppresses sympathetic nerve activity and has a superior renoprotective effect compared with L-type CCBs such as amlodipine. The cardioprotective action of cilnidipine has remained largely uncharacterized, however. We have now investigated the effects of cilnidipine, in comparison with amlodipine, on cardiac pathophysiology in rats with salt-sensitive hypertension. Methods: Dahl salt-sensitive rats fed a high-salt diet from 6 weeks of age were treated with vehicle (LVH group), amlodipine (3 mg/kg per day), or cilnidipine (3 mg/kg per day) from 7 to 11 weeks. Results: The salt-induced increase in SBP apparent in LVH rats was attenuated to a similar extent by treatment with amlodipine or cilnidipine. The two drugs also similarly inhibited the development of left ventricular (LV) hypertrophy. However, cilnidipine attenuated the increase in relative wall thickness as well as ameliorated LV perivascular and interstitial fibrosis and diastolic dysfunction to a greater extent than did amlodipine. In addition, cilnidipine treatment was associated with greater inhibition of cardiac oxidative stress, inflammation, and renin–angiotensin system (RAS) gene expression. The decrease in cardiac norepinephrine content apparent in LVH rats was similarly inhibited by both drugs. Conclusions: Cilnidipine attenuated LV fibrosis and diastolic dysfunction as well as LV concentricity to a greater extent than did amlodipine in Dahl salt-sensitive rats. The superior cardioprotective action of cilnidipine is likely attributable, at least in part, to the greater antioxidant and anti-inflammatory effects associated with inhibition of cardiac RAS gene expression observed with this drug.

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 (AT1A) receptor gene expression were attenuated similarly by LOS and HCTZ and more so by COMB. LOS downregulated expression of the AT1A receptor gene, without affecting that of the AT2 receptor gene, in the aorta. In contrast, neither HCTZ nor COMB affected aortic expression of the AT1A receptor gene, but both markedly upregulated that of the AT2 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.

Effects of salt status and blockade of mineralocorticoid receptors on aldosterone-induced cardiac injury

The mineralocorticoid aldosterone regulates sodium and water homeostasis in the human body. The combination of excess aldosterone and salt loading induces hypertension and cardiac damage. However, little is known of the effects of aldosterone on blood pressure and cardiac pathophysiology in the absence of salt loading. We have now investigated the effects of salt status and blockade of mineralocorticoid receptors (MRs) on cardiac pathophysiology in uninephrectomized Sprague-Dawley rats implanted with an osmotic minipump to maintain hyperaldosteronism. The rats were fed a low-salt (0.0466% NaCl in chow) or high-salt (0.36% NaCl in chow plus 1% NaCl in drinking water) diet in the absence or presence of treatment with a subdepressor dose of the MR antagonist spironolactone (SPL). Aldosterone excess in the setting of low salt intake induced substantial cardiac remodeling and diastolic dysfunction without increasing blood pressure. These effects were accompanied by increased levels of oxidative stress and inflammation as well as increased expression of genes related to the renin–angiotensin and endothelin systems in the heart. All of these cardiac changes were completely blocked by the administration of SPL. On the other hand, aldosterone excess in the setting of high salt intake induced hypertension and a greater extent of cardiac injury, with the cardiac changes being only partially attenuated by SPL in a manner independent of its antihypertensive effect. The combination of dietary salt restriction and MR antagonism is thus a promising therapeutic option for the management of hypertensive patients with hyperaldosteronism or relative aldosterone excess.