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Ca(2+) channel blocker benidipine promotes coronary angiogenesis and reduces both left-ventricular diastolic stiffness and mortality in hypertensive rats.

ABSTRACT: The beneficial cardiac effects of some Ca(2+) channel blockers have been attributed to blood pressure reduction, but these pleiotropic effects require further investigation. We compared the effects of benidipine, which has beneficial cardiac effects, and nitrendipine, which does not, in an animal model of hypertensive diastolic heart failure (DHF).Male Dahl salt-sensitive rats were fed a high-salt diet from age 7 weeks to induce hypertension and were either vehicle or orally administered benidipine (3 mg/kg daily) or nitrendipine (10 mg/kg daily) from age 10 to 18 weeks. Control rats were maintained on a low-salt diet. In vehicle-treated rats, left-ventricular (LV) fractional shortening was preserved but LV end-diastolic pressure was increased, indicative of DHF. Benidipine and nitrendipine had similar antihypertensive effects and reduced both LV weight and cardiomyocyte hypertrophy. Benidipine reduced LV diastolic stiffness and mortality to a greater extent than did nitrendipine. Benidipine, but not nitrendipine, also reduced lung weight. The extent of interstitial fibrosis and the abundance of mRNAs for prohypertrophic, profibrotic, or proinflammatory genes in the left ventricle were reduced by benidipine and nitrendipine. Benidipine, but not nitrendipine, increased capillary density and restored the expression of hypoxia-inducible factor 1alpha, vascular endothelial growth factor, and endothelial nitric oxide synthase in the left ventricle.Benidipine reduced LV diastolic stiffness and increased survival, effects likely attributable predominantly to promotion of coronary angiogenesis rather than to attenuation of interstitial fibrosis. Benidipine may thus be more effective than purely L-type Ca(2+) channel blockers in preventing hypertensive DHF.

SUBMITTER: Nishizawa T

PROVIDER: S-EPMC3070381 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Ca(2+) channel blocker benidipine promotes coronary angiogenesis and reduces both left-ventricular diastolic stiffness and mortality in hypertensive rats.

Nishizawa Takao T Cheng Xian Wu XW Jin Zhehu Z Obata Koji K Nagata Kohzo K Hirashiki Akihiro A Sasaki Takeshi T Noda Akiko A Takeshita Kyosuke K Izawa Hideo H Shi Guo-Ping GP Kuzuya Masafumi M Okumura Kenji K Murohara Toyoaki T

Journal of hypertension 20100701 7

<h4>Background</h4>The beneficial cardiac effects of some Ca(2+) channel blockers have been attributed to blood pressure reduction, but these pleiotropic effects require further investigation. We compared the effects of benidipine, which has beneficial cardiac effects, and nitrendipine, which does not, in an animal model of hypertensive diastolic heart failure (DHF).<h4>Methods and results</h4>Male Dahl salt-sensitive rats were fed a high-salt diet from age 7 weeks to induce hypertension and wer ...[more]

PMID: 20543715

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Project description:AimsConcentric hypertrophy following pressure-overload is linked to preserved systolic function but impaired diastolic function, and is an important substrate for heart failure with preserved ejection fraction. While increased passive stiffness of the myocardium is a suggested mechanism underlying diastolic dysfunction in these hearts, the contribution of active diastolic Ca2+ cycling in cardiomyocytes remains unclear. In this study, we sought to dissect contributions of passive and active mechanisms to diastolic dysfunction in the concentrically hypertrophied heart following pressure-overload.Methods and resultsRats were subjected to aortic banding (AB), and experiments were performed 6 weeks after surgery using sham-operated rats as controls. In vivo ejection fraction and fractional shortening were normal, confirming preservation of systolic function. Left ventricular concentric hypertrophy and diastolic dysfunction following AB were indicated by thickening of the ventricular wall, reduced peak early diastolic tissue velocity, and higher E/e' values. Slowed relaxation was also observed in left ventricular muscle strips isolated from AB hearts, during both isometric and isotonic stimulation, and accompanied by increases in passive tension, viscosity, and extracellular collagen. An altered titin phosphorylation profile was observed with hypophosphorylation of the phosphosites S4080 and S3991 sites within the N2Bus, and S12884 within the PEVK region. Increased titin-based stiffness was confirmed by salt-extraction experiments. In contrast, isolated, unloaded cardiomyocytes exhibited accelerated relaxation in AB compared to sham, and less contracture at high pacing frequencies. Parallel enhancement of diastolic Ca2+ handling was observed, with augmented NCX and SERCA2 activity and lowered resting cytosolic [Ca2+].ConclusionIn the hypertrophied heart with preserved systolic function, in vivo diastolic dysfunction develops as cardiac fibrosis and alterations in titin phosphorylation compromise left ventricular compliance, and despite compensatory changes in cardiomyocyte Ca2+ homeostasis.

Project description:PurposeThe study is aimed at identifying echocardiographic and circulating biomarkers as well as hemodynamic indices of embolic stroke of undetermined etiology (ESUS) in patients aged <65.MethodsWe prospectively investigated 520 patients with confirmed ischemic stroke and selected those 65 patients who were diagnosed with ESUS (age 54 (47-58) years, 42% male). An additional 36 without stroke but with a similar risk profile were included as a control group (age 53 (47-58) years, 61% male). All patients underwent echocardiography, noninvasive assessment of hemodynamic parameters using a SphygmoCor tonometer (AtCor Med., Australia), and measurements of selected biomarkers.ResultsESUS patients and controls were well matched for baseline characteristics including blood pressure and left ventricular ejection fraction (LVEF). Compared to controls, patients with ESUS had lower mean early diastolic (E') and systolic (S') mitral annular velocities and a higher ratio of the peak velocity of early diastolic transmitral flow to the peak velocity of early diastolic mitral annular motion (all p < 0.01). The peak velocity flow in the late diastole (A wave) value and LV mass indexed to the body surface area (LVMI) (g/m2) were higher in the ESUS group than in the control group (both p < 0.01). The isovolumetric relaxation time (IVRT) was longer and the mean left atrial volume index (LAVI) was higher in ESUS patients compared to the control group. Parameters of arterial stiffness such as augmentation pressure, augmentation index, and augmentation index adjusted to a heart rate of 75 bpm (AIx75) were higher in ESUS patients compared to controls (p < 0.05). Patients in the ESUS group had higher levels of asymmetric dimethylarginine, interleukin 6, and N-terminal probrain natriuretic peptide (NT-proBNP, all p < 0.05) than those in the control group. In multivariate analysis, the following factors were significantly associated with the presence of ESUS: AIx75 (odds ratio (OR) 1.095, 95% confidence interval (CI) 1.004-1.194; p = 0.04), IVRT (OR 1.045, 95% CI: 1.009-1.082; p = 0.014), LAVI (OR 1.3, 95% CI: 1.099-1.537; p = 0.002), and NT-proBNP (OR 1.003, 95% CI: 1.001-1.005; p = 0.005).ConclusionsIncreased arterial stiffness and indices of diastolic dysfunction as well as a higher NT-proBNP level are significantly associated with ESUS. These parameters require further scrutiny over time to understand their impact on the development of symptomatic heart failure. The ClinicalTrials.gov identifier is NCT03377465.

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Ca(2+) channel blocker benidipine promotes coronary angiogenesis and reduces both left-ventricular diastolic stiffness and mortality in hypertensive rats.

Publications

Ca(2+) channel blocker benidipine promotes coronary angiogenesis and reduces both left-ventricular diastolic stiffness and mortality in hypertensive rats.

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