Pulmonary hypertension and ECG changes from monocrotaline pyrrole in the rat

Bruner, Leon H.; Hilliker, Katherine S.; Roth, Robert A.

doi:10.1152/ajpheart.1983.245.2.h300

Cited by 31 publications

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“…23,27) Endothelial damage is apparent at an early stage, and the development of PH is observed 14 d after MCT injection. 28) In this study, we also observed the elevation of RVSP, development of RV remodeling, and an increase in lung weight 26 d after MCT injection (Tables 1, 2). These changes indicated typical manifestations of PH similar to the previous study.…”

Section: Discussionsupporting

confidence: 68%

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Acute and Chronic Effects of T-1032, a Novel Selective Phosphodiesterase Type 5 Inhibitor, on Monocrotaline-Induced Pulmonary Hypertension in Rats.

Inoue

Yano

Noto

et al. 2002

Biological & Pharmaceutical Bulletin

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Pulmonary hypertension (PH) is a fatal disease, characterized by the progressive elevation of pulmonary arterial resistance. Although the causes of this disorder are complicated, abnormal vasoconstriction appears to be a primary factor in the development of PH. 1,2) Although some kinds of vasodilators, such as calcium blockers and prostacyclin, have been used in the treatment of PH, 3,4) they cause several side effects due to systemic vasodilation. Recent studies have demonstrated that nitric oxide inhalation produces selective pulmonary vasodilation without affecting systemic blood pressure in patients with PH. 5,6) However, since the safety of nitric oxide inhalation has not been established, 7) its doses have been restricted. Phosphodiesterases (PDEs) are enzymes, which break down cAMP and/or cGMP, and they play a key role in the regulation of intracellular cyclic nucleotide levels. A phosphodiesterase type 5 (PDE5) is classified as cGMP-bind, cGMP-specific phosphodiesterase. 8,9) PDE5 is abundantly expressed in some specific tissues, including the lung and pulmonary artery.10-12) Therefore, the inhibition of PDE5 is considered to produce an increase in cGMP levels in the lung and pulmonary artery. It has been reported that PDE5 inhibitors such as zaprinast, E-4021 and sildenafil preferably dilate the pulmonary artery in vivo and in vitro experimental conditions. [13][14][15][16][17][18] T-1032 (methyl 2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate) is a novel inhibitor of PDE5 (IC 50 ϭ0.001 mM; canine lung). The selectivity for PDE5 over other PDEs in T-1032 is similar to that of sildenafil (IC 50 : PDE1; 3 mM, PDE2; 9.7 mM, PDE3; Ͼ100 mM, PDE4; 3.3 mM).19) T-1032 shows potentiating effects on the nitric oxide/cGMP signaling pathway in isolated rat aorta and rabbit corpus cavernosum. 20) In addition, an intraduodenal administration of T-1032 potentiates the penile tumescence induced by pelvic nerve stimulation, probably through the blockade of PDE5 in anesthetized dogs.21) These results suggest that T-1032 potentiates a nitric oxide/cGMP pathway inhibitor and is orally active compound in animal studies.The acute hemodynamic effects by PDE5 inhibitors on pulmonary circulation have been examined in animal models with PH. 13,15,18) However, only a few studies have reported whether the chronic treatment is effective for improving cardiac remodeling and its related death in an animal model with PH. 22) In this study, we first examined the hemodynamic properties of T-1032 in MCT-induced PH rats, and we next evaluated the chronic effect of T-1032 on cardiac remodeling and its related death in MCT-induced PH rats. MATERIAL AND METHODSThis study was approved by the Animal Research Committee of Tanabe Seiyaku Co., Ltd.Animal Preparation Monocrotaline (MCT, 70 mg/kg) was subcutaneously administered in male Wistar rats weighing 94-107 g, as described previously. 23)Acute Hemodynamic Effects in MCT Rats Twenty-six days after MCT (70 mg/kg) or vehicle...

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Section: Discussionsupporting

confidence: 68%

“…These changes indicated typical manifestations of PH similar to the previous study. 23,27,28) In the acute study, the intravenous administration of T-1032 reduced RVSP at doses of 1-100 mg/kg. A sustained and significant reduction of RVSP was apparent at 1 mg/kg, and RVSP reached a maximal reduction at the dose of 10 mg/kg.…”

Section: Discussionmentioning

confidence: 99%

Acute and Chronic Effects of T-1032, a Novel Selective Phosphodiesterase Type 5 Inhibitor, on Monocrotaline-Induced Pulmonary Hypertension in Rats.

Inoue

Yano

Noto

et al. 2002

Biological & Pharmaceutical Bulletin

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“…Synthetic dehydromonocrotaline reproduces the toxicity of MCT. 27,28 In an isolated liver, dehydromonocrotaline readily conjugates with GSH to form the less toxic secondary metabolite GSDHP, 22 which is excreted in high concentrations into the bile. MCT (0.5 mM) also induces a 30-fold increase in the biliary excretion of GSH in an isolated, perfused liver, which depletes hepatic GSH stores.…”

Section: Discussionmentioning

confidence: 99%

The protective effects of cerium oxide nanoparticles against hepatic oxidative damage induced by monocrotaline

Amin

Hassan²,

Awad³

et al. 2011

IJN

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Objective The objective of the present study was to determine the ability of cerium oxide (CeO 2 ) nanoparticles to protect against monocrotaline (MCT)-induced hepatotoxicity in a rat model. Method Twenty male Sprague Dawley rats were arbitrarily assigned to four groups: control (received saline), CeO 2 (given 0.0001 nmol/kg intraperitoneally [IP]), MCT (given 10 mg/kg body weight IP as a single dose), and MCT + CeO 2 (received CeO 2 both before and after MCT). Electron microscopic imaging of the rat livers was carried out, and hepatic total glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPX), glutathione S-transferase (GST), superoxide dismutase (SOD), and catalase (CAT) enzymatic activities were quantified. Results Results showed a significant MCT-induced decrease in total hepatic GSH, GPX, GR, and GST normalized to control values with concurrent CeO 2 administration. In addition, MCT produced significant increases in hepatic CAT and SOD activities, which also ameliorated with CeO 2 . Conclusions These results indicate that CeO 2 acts as a putative novel and effective hepatoprotective agent against MCT-induced hepatotoxicity.

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“…A subcutaneous injection of monocrotaline induces damage to endothelial cells, followed by new muscularization of the pulmonary vasculature and concomitant elevation of pulmonary arterial pressure, therefore resulting in right ventricular hypertrophy [24,25]. Endothelial damage is apparent at an early stage, and the development of pulmonary hypertension is observed 14 days after monocrotaline injection [26]. Several proteases and inflammatory cytokines, vasoconstrictors such as endothelins or thromboxane A 2 , and vasodilators such as prostacyclin or nitric oxide play various roles in these processes.…”

Section: Discussionmentioning

confidence: 99%

“…Typical tracings of right ventricular pressure in normal rats (Sham), monocrotaline-treated rats (Vehicle), and monocrotaline-treated rats subjected to repeated administration of atorvastatin (Atorva 0-28 ), simvastatin (Simva 0-28 and Simva [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] ) and pravastatin (Prava 0-28 ). Sham: water was administered orally from the time of saline injection to 24 h before measurement of right ventricular pressure.…”

Section: Simva14-28mentioning

confidence: 99%

3-Hydroxy-3-Methylglutaryl-COA Reductase Inhibitors and Phosphodiesterase Type V Inhibitors Attenuate Right Ventricular Pressure and Remodeling in a Rat Model of Pulmonary Hypertension

Satoh

Satoh²

2009

J Pharm Pharm Sci

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-Purpose. We examined the inhibitory effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, a prostacyclin analogue and a phosphodiesterase type V inhibitor on hemodynamic function and cardiac remodeling in rats with monocrotaline-induced pulmonary hypertension. Methods. The rat model of pulmonary hypertension was created by administration of monocrotaline (70 mg/kg, s.c.) to male Wistar rats. A polyethylene tube was introduced into a left carotid artery for measurement of mean arterial pressure (MAP), another into the right ventricle via the right jugular vein for measurement of right ventricular systolic pressure (RVSP).Results. Repeated administration of atorvastatin (2 mg/kg/day, p.o. 0 -28 days) and simvastatin (2 mg/kg/day, p.o. 0 -28 days) significantly reduced RVSP and right ventricular weight (RV)/left ventricular + septum weight (LV + S) without a change in MAP and heart rate. However, repeated administration of pravastatin (4 mg/kg/day, p.o. 0 -28 days) did not reduce the monocrotaline-induced elevation of RVSP and RV/(LV + S) significantly. The reduction of RVSP and RV/(LV + S) induced by a combination of a prostacyclin analogue, beraprost (100 µg/kg/day, 0 -28 days) and simvastatin (2 mg/kg/day, 0 -28 days), was more potent than the effect induced by each drug alone. Sildenafil (5 mg/kg/day, 0 -28 days) tended to reduce RVSP and RV/(LV + S). Repeated combined administration of atorvastatin (2 mg/kg/day, p.o. 0 -28 days) + sildenafil (5 mg/kg/day, p.o. 0 -28 days) significantly reduced lung/body weight. Conclusion. Our present results suggest that repeated administration of the lipophilic HMG-CoA reductase inhibitors, atorvastatin and simvastatin, selectively attenuates the elevation of RVSP, development of pulmonary hypertension and right ventricular remodeling in rats with monocrotaline-induced pulmonary hypertension, and that a combination of HMG-CoA reductase inhibitor and beraprost has a more potent effect than each agent alone. Although the significant inhibitory effect of sildenafil (5mg/kg/day) alone were not observed, higher dosage of sildenafil might attenuate the elevation of RVSP, development of pulmonary hypertension and right ventricular remodeling in rats with monocrotaline-induced pulmonary hypertension. INTRODUCTIONPulmonary hypertension is a serious disease, characterized by progressive elevation of pulmonary arterial resistance, leading to right ventricular failure and death [1]. Although the causes of this disorder are complicated, abnormal vasoconstriction by vascular endothelial injury in pulmonary arterioles, smooth muscle cell proliferation and hypertrophy, contraction of arterioles and remodeling appear to be primary factors. It is reported that release of the vasodilators prostacyclin [2] and nitric oxide [3] decreases, on the other hand, the release of the vasoconstrictor thromboxane A 2 [4] and the expression of endothelin-1 from vascular endothelial cells [5] increases. Therefore, a prostacyclin analogue, epoprostenol, has been administered by cont...

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Pulmonary hypertension and ECG changes from monocrotaline pyrrole in the rat

Cited by 31 publications

References 0 publications

Acute and Chronic Effects of T-1032, a Novel Selective Phosphodiesterase Type 5 Inhibitor, on Monocrotaline-Induced Pulmonary Hypertension in Rats.

Acute and Chronic Effects of T-1032, a Novel Selective Phosphodiesterase Type 5 Inhibitor, on Monocrotaline-Induced Pulmonary Hypertension in Rats.

The protective effects of cerium oxide nanoparticles against hepatic oxidative damage induced by monocrotaline

3-Hydroxy-3-Methylglutaryl-COA Reductase Inhibitors and Phosphodiesterase Type V Inhibitors Attenuate Right Ventricular Pressure and Remodeling in a Rat Model of Pulmonary Hypertension

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