Biochemical and structural remodeling of collagen in the right ventricular hypertrophy induced by monocrotaline.

Honda, Masaaki; Yamada, Sachiko; Goto, Yasutoshi; Ishikawa, Shigenori; Yoshikane, Hideki; Ishinaga, Yuji; Kuzuo, Hiroshi; Morioka, Shigefumi; Moriyama, Katsutoshi

doi:10.1253/jcj.56.392

Cited by 24 publications

(19 citation statements)

References 22 publications

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“…Daily nicorandil treatment over the course of 3 weeks attenuated MCT-induced reductions in growth (BW values were 10.44% and 14.07% higher than those of rats treated with MCT at weeks 2 and 3, respectively) and this effect was abolished by 5-HD (Figure 1A). These results are in accordance with the literature [26], [27], [28].…”

Section: Resultssupporting

confidence: 94%

Nicorandil Prevents Right Ventricular Remodeling by Inhibiting Apoptosis and Lowering Pressure Overload in Rats with Pulmonary Arterial Hypertension

et al. 2012

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BackgroundMost of the deaths among patients with severe pulmonary arterial hypertension (PAH) are caused by progressive right ventricular (RV) pathological remodeling, dysfunction, and failure. Nicorandil can inhibit the development of PAH by reducing pulmonary artery pressure and RV hypertrophy. However, whether nicorandil can inhibit apoptosis in RV cardiomyocytes and prevent RV remodeling has been unclear.Methodology/Principal FindingsRV remodeling was induced in rats by intraperitoneal injection of monocrotaline (MCT). RV systolic pressure (RVSP) was measured at the end of each week after MCT injection. Blood samples were drawn for brain natriuretic peptide (BNP) ELISA analysis. The hearts were excised for histopathological, ultrastructural, immunohistochemical, and Western blotting analyses. The MCT-injected rats exhibited greater mortality and less weight gain and showed significantly increased RVSP and RV hypertrophy during the second week. These worsened during the third week. MCT injection for three weeks caused pathological RV remodeling, characterized by hypertrophy, fibrosis, dysfunction, and RV mitochondrial impairment, as indicated by increased levels of apoptosis. Nicorandil improved survival, weight gain, and RV function, ameliorated RV pressure overload, and prevented maladaptive RV remodeling in PAH rats. Nicorandil also reduced the number of apoptotic cardiomyocytes, with a concomitant increase in Bcl-2/Bax ratio. 5-hydroxydecanoate (5-HD) reversed these beneficial effects of nicorandil in MCT-injected rats.Conclusions/SignificanceNicorandil inhibits PAH-induced RV remodeling in rats not only by reducing RV pressure overload but also by inhibiting apoptosis in cardiomyocytes through the activation of mitochondrial ATP-sensitive K+ (mitoKATP) channels. The use of a mitoKATP channel opener such as nicorandil for PAH-associated RV remodeling and dysfunction may represent a new therapeutic strategy for the amelioration of RV remodeling during the early stages of PAH.

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Section: Resultssupporting

confidence: 94%

Nicorandil Prevents Right Ventricular Remodeling by Inhibiting Apoptosis and Lowering Pressure Overload in Rats with Pulmonary Arterial Hypertension

et al. 2012

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“…MCT-induced PH is also associated with cardiac remodeling including RV hypertrophy and interstitial fibrosis as evidenced by our data and other studies (Ghodsi and W ill, 1981;Honda et al, 1992). Previously, it was reported that expression of renninangiotensin system, TGF-β1, and ET-1 was enhanced in RV hypertrophy of MCT-induced PH rats (Park et al, 2001).…”

Section: Discussionsupporting

confidence: 85%

Monocrotaline-induced pulmonary hypertension correlates with upregulation of connective tissue growth factor expression in the lung

Lee

Byun²,

Kim³

et al. 2005

Exp Mol Med

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“…Male Sprague-Dawley rats (6 weeks old) received a single subcutaneous injection of either 60 mg/ kg monocrotaline, a pyrrolizine alkaloid extracted from Crotalaria spectabilis, or saline. After 3 weeks, all rats treated with monocrotaline showed progressive pulmonary hypertension and right ventricular (RV) hypertrophy accompanied by heart failure as reported in our previous papers (Ishikawa et al 1991a,b;Honda et al 1992). Briefly, the presence of (i) pleural, peritoneal and pericardial effusion; (ii) high RV pressure, low systemic blood pressure, and tachycardia; (iii) hypoxaemia; (iv) increased plasma catecholamines, renin, and ANP and (v) marked dilatation of RV cavity, was regarded as heart failure.…”

Section: Model Of Congestive Heart Failuresupporting

confidence: 75%

Contrasting Effects of Isoproterenol and Phosphodiesterase I11 Inhibitor on Intracellular Calcium Transients in Cardiac Myocytes From Failing Hearts

Honda¹,

Kuramochi

Ishinaga

et al. 1994

Clin Exp Pharma Physio

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1. Effects of a newly developed phosphodiesterase (PDE) III inhibitor, E-1020, on intracellular calcium transients were compared with those of isoproterenol (ISO) in isolated single myocytes from failing hearts secondary to pulmonary hypertension induced by monocrotaline injection. Myocytes were isolated by enzyme digestion using a Langendorff apparatus. Changes in intracellular calcium concentrations ([Ca2+]i) were recorded using a fura-2 fluorescence microscopic technique. Cyclic AMP contents of the hearts were measured by radio-immunoassay. 2. Myocytes from failing hearts showed Ca2+ transients with a low peak (low amplitude) and delayed decline of Ca2+ transients. Both ISO and E-1020 increased peak [Ca2+]i, max + d[Ca2+]i/dt, and max - d[Ca2+]i/dt in a concentration-dependent manner while both agents decreased T80L (time to 80% decline of amplitude from peak light). The concentrations which increased peak [Ca2+]i by 50% were 1.6 x 10(-9) mol/L of ISO and 2 x 10(-6) mol/L of E-1020. These concentrations increased cAMP in the heart to the same levels. Analysis of the effects of both agents on peak [Ca2+]i versus max - d[Ca2+]i/dt showed that ISO is much more effective on peak [Ca2+]i while E-1020 is more effective on max - d[Ca2+]i/dt. 3. These results showed that the effects of ISO and E-1020 on the parameters of intracellular Ca2+ transients of single myocytes from failing hearts are slightly different, and suggest that E-1020 may improve diastolic function as well as systolic function in failing hearts.

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Biochemical and structural remodeling of collagen in the right ventricular hypertrophy induced by monocrotaline.

Cited by 24 publications

References 22 publications

Nicorandil Prevents Right Ventricular Remodeling by Inhibiting Apoptosis and Lowering Pressure Overload in Rats with Pulmonary Arterial Hypertension

Nicorandil Prevents Right Ventricular Remodeling by Inhibiting Apoptosis and Lowering Pressure Overload in Rats with Pulmonary Arterial Hypertension

Monocrotaline-induced pulmonary hypertension correlates with upregulation of connective tissue growth factor expression in the lung

Contrasting Effects of Isoproterenol and Phosphodiesterase I11 Inhibitor on Intracellular Calcium Transients in Cardiac Myocytes From Failing Hearts

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