Ca2+ channel blocker benidipine promotes coronary angiogenesis and reduces both left-ventricular diastolic stiffness and mortality in hypertensive rats

Takao Nishizawa, Xian Wu Cheng, Zhehu Jin, Koji Obata, Kohzo Nagata, Akihiro Hirashiki, Takeshi Sasaki, Akiko Noda, Kyosuke Takeshita, Hideo Izawa, Guo Ping Shi, Masafumi Kuzuya, Kenji Okumura, Toyoaki Murohara

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: The beneficial cardiac effects of some Ca2+ 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). Methods and results: 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 1α, vascular endothelial growth factor, and endothelial nitric oxide synthase in the left ventricle. Conclusions: 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 channel blockers in preventing hypertensive DHF.

Original languageEnglish
Pages (from-to)1515-1526
Number of pages12
JournalJournal of Hypertension
Volume28
Issue number7
DOIs
Publication statusPublished - 01-07-2010

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Nitrendipine
Mortality
Diastolic Heart Failure
Heart Ventricles
Fibrosis
Inbred Dahl Rats
Blood Pressure
Sodium-Restricted Diet
benidipine
Weights and Measures
Hypoxia-Inducible Factor 1
Nitric Oxide Synthase Type III
Cardiac Myocytes
Hypertrophy
Antihypertensive Agents
Vascular Endothelial Growth Factor A
Animal Models
Salts
Diet
Hypertension

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Nishizawa, Takao ; Cheng, Xian Wu ; Jin, Zhehu ; Obata, Koji ; Nagata, Kohzo ; Hirashiki, Akihiro ; Sasaki, Takeshi ; Noda, Akiko ; Takeshita, Kyosuke ; Izawa, Hideo ; Shi, Guo Ping ; Kuzuya, Masafumi ; Okumura, Kenji ; Murohara, Toyoaki. / Ca2+ channel blocker benidipine promotes coronary angiogenesis and reduces both left-ventricular diastolic stiffness and mortality in hypertensive rats. In: Journal of Hypertension. 2010 ; Vol. 28, No. 7. pp. 1515-1526.
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Nishizawa, T, Cheng, XW, Jin, Z, Obata, K, Nagata, K, Hirashiki, A, Sasaki, T, Noda, A, Takeshita, K, Izawa, H, Shi, GP, Kuzuya, M, Okumura, K & Murohara, T 2010, 'Ca2+ channel blocker benidipine promotes coronary angiogenesis and reduces both left-ventricular diastolic stiffness and mortality in hypertensive rats', Journal of Hypertension, vol. 28, no. 7, pp. 1515-1526. https://doi.org/10.1097/HJH.0b013e328339fd3a

Ca2+ channel blocker benidipine promotes coronary angiogenesis and reduces both left-ventricular diastolic stiffness and mortality in hypertensive rats. / Nishizawa, Takao; Cheng, Xian Wu; Jin, Zhehu; Obata, Koji; Nagata, Kohzo; Hirashiki, Akihiro; Sasaki, Takeshi; Noda, Akiko; Takeshita, Kyosuke; Izawa, Hideo; Shi, Guo Ping; Kuzuya, Masafumi; Okumura, Kenji; Murohara, Toyoaki.

In: Journal of Hypertension, Vol. 28, No. 7, 01.07.2010, p. 1515-1526.

Research output: Contribution to journalArticle

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T1 - Ca2+ channel blocker benidipine promotes coronary angiogenesis and reduces both left-ventricular diastolic stiffness and mortality in hypertensive rats

AU - Nishizawa, Takao

AU - Cheng, Xian Wu

AU - Jin, Zhehu

AU - Obata, Koji

AU - Nagata, Kohzo

AU - Hirashiki, Akihiro

AU - Sasaki, Takeshi

AU - Noda, Akiko

AU - Takeshita, Kyosuke

AU - Izawa, Hideo

AU - Shi, Guo Ping

AU - Kuzuya, Masafumi

AU - Okumura, Kenji

AU - Murohara, Toyoaki

PY - 2010/7/1

Y1 - 2010/7/1

N2 - Background: The beneficial cardiac effects of some Ca2+ 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). Methods and results: 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 1α, vascular endothelial growth factor, and endothelial nitric oxide synthase in the left ventricle. Conclusions: 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 channel blockers in preventing hypertensive DHF.

AB - Background: The beneficial cardiac effects of some Ca2+ 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). Methods and results: 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 1α, vascular endothelial growth factor, and endothelial nitric oxide synthase in the left ventricle. Conclusions: 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 channel blockers in preventing hypertensive DHF.

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