Mouse strain-specific responses of mitochondrial respiratory function and cardiac hypertrophy to isoproterenol treatment / 生理学报

Cardiac hypertrophy is a common pathological process of various cardiovascular diseases and eventually develops into heart failure. This paper was aimed to study the different pathological characteristics exhibited by different mouse strains after hypertrophy stimulation. Two mouse strains, A/J and FVB/nJ, were treated with isoproterenol (ISO) by osmotic pump to induce cardiac hypertrophy. Echocardiography was performed to monitor heart morphology and function. Mitochondria were isolated from hearts in each group, and oxidative phosphorylation function was assayed in vitro. The results showed that both strains showed a compensatory enhancement of heart contractile function after 1-week ISO treatment. The A/J mice, but not the FVB/nJ mice, developed significant cardiac hypertrophy after 3-week ISO treatment as evidenced by increases in left ventricular posterior wall thickness, heart weight/body weight ratio, cross sectional area of cardiomyocytes and cardiac hypertrophic markers. Interestingly, the heart from A/J mice contained higher mitochondrial DNA copy number compared with that from FVB/nJ mice. Functionally, the mitochondria from A/J mice displayed faster O

Cardioprotective effect of methanolic extract of Marrubium vulgare L. on isoproterenol-induced acute myocardial infarction in rats.

Isoproterenol injection (100 mg/kg; sc) produced changes in ECG pattern including ST-segment elevation and suppressed R-amplitude. The methanolic extract of M. vulgare at doses of 10, 20, and 40 mg/kg significantly amended the ECG changes. A severe myocardial necrosis and edematous along with a sharp reduction in the arterial blood pressure, left ventricular contractility (LVdP/dtmax or min), but a marked increase in the left ventricular end-diastolic pressure (LVEDP) were seen in the isoproterenol group. All parameters were significantly improved by the extract treatment. The extract (10 mg/kg) strongly increased LVdP/dtmax. Similarly, treatment with 40 mg/kg of M. vulgare lowered the elevated LVEDP and the heart to body weight ratio. In addition to in vitro antioxidant activity, the extract suppressed markedly the elevation of malondialdehyde levels both in serum and in myocardium. The results demonstrate that M. vulgare protects myocardium against isoproterenol-induced acute myocardial infarction and suggest that the effects could be related to antioxidant activities.

Protective effect of Terminalia chebula against experimental myocardial injury induced by isoproterenol.

Cardioprotective effect of ethanolic extract of Terminalia chebula fruits (500 mg/kg body wt) was examined in isoproterenol (200 mg/kg body wt) induced myocardial damage in rats. In isoproterenol administered rats, the level of lipid peroxides increased significantly in the serum and heart. A significant decrease was observed in the activity of the myocardial marker enzymes with a concomitant increase in their activity in serum. Histopathological examination was carried out to confirm the myocardial necrosis. T. chebula extract pretreatment was found to ameliorate the effect of isoproterenol on lipid peroxide formation and retained the activities of the diagnostic marker enzymes.

Effect of fish oil on mitochondrial respiration in isoproterenol induced myocardial infarction in rats.

Following isoproterenol treatment mitochondrial lipid peroxidation, phosphoslipase activity, lactate and calcium increased significantly, while activities of tricarboxylic acid cycle enzymes, enzymes of respiratory chain and ATP production showed decline. Oxidative phosphorylation was also affected on isoproterenol treatment with significant reduction in all the variables. Fish oil pretreatment in isoproterenol treated rats showed improved mitochondrial energy metabolism. The results suggest cardioprotective effect of fish oil.

Cardioprotective effect of magnesium chloride in experimental acute myocardial infarction.

Cardioprotective role of intravenous administration of magnesium chloride was evaluated in rabbits by biochemical and histopathological parameters. Myocardial damage was induced by injecting (i.v.) isoprenaline 1, 2.5, 5 and 7.5 mg/kg body weight of animal. There was a dose dependent increase in the activity of cardiac enzyme creatinine kinase CK (C Max). Maximal elevation of CK (C Max) was observed with 2.5 mg isoprenaline. The mean T-max (mean of the time duration in hr at which maximum creatinine kinase activity of individual rabbit was observed in a group) shifted early, significantly with 2.5, 5 and 7.5 mg isoprenaline compared to control group. Histopathologically, myocardial damage was quite significant in 2.5 mg isoprenaline subgroup of animals. A mortality of 29% was observed in animals injected with 5 and 7.5 mg isoprenaline, whereas all animals subjected with 1 and 2.5 mg isoprenaline were alive for 72 hr. Considering the data on serial determination of cardiac enzyme CK and histopathological changes, 2.5 mg isoprenaline was chosen as standard dose to study efficacy of cardioprotection by gold standard verapamil and magnesium chloride. Verapamil (5 microM) injected prior to 2.5 mg isoprenaline administration revealed significant reduction of CK (C Max) activity (P < 0.05) compared to animals infused with isoprenaline alone. T-max value did not show any alteration in both the groups. Histopathological findings showed no areas of necrosis and cellular infiltrates in animals primed with 2.5 mg isoprenaline following verapamil. Highly significant reduction in CK (C-max) activity was observed in animals administered with 40 mg magnesium chloride prior to isoprenaline compared to animals treated with isoprenaline alone (P < 0.001). In addition to this, significant delay in T-max of CK activity was observed in group treated with 40 mg magnesium chloride and isoprenaline compared to group treated with only isoprenaline (P < 0.01). The study clearly highlighted and confirmed the valuable role of magnesium chloride as cardioprotective agent.

Effect of alpha-tocopherol on isoproterenol induced myocardial infarction in rats--electrocardiographic biochemical and histological evidences.

The effect of alpha-tocopherol (6 mg/100 g body wt, orally, daily for 90 days) pretreatment in isoproterenol (20 mg/100 g body wt, subcutaneously, twice at an interval of two days at the end of the alpha-tocopherol pretreatment) induced myocardial infarction was studied in rats. Isoproterenol administered rats showed electrocardiographic changes suggestive of myocardial infarction with marked ST segment elevation, Q waves appearance and a significant increase in heart rate. In isoproterenol administered rats, a significant decrease was observed in the activities of marker enzymes such as aspartate amino transferase, alanine amino transferase, lactate dehydrogenase and creatine kinase in heart and aorta with a significant increase in their activities in serum. The levels of lipid peroxides in terms of "TBA reactants" increased significantly in serum, heart and aorta on isoproterenol administration. The histology of heart and aorta showed marked fragmentation of muscle fibres and necrotic lesions in isoproterenol administered rats. alpha-Tocopherol pretreated rats showed a near normal ECG pattern, levels of lipid peroxides, activities of marker enzymes and a near normal histology of heart and aorta on isoproterenol administration.

Effect of nitrendipine, nimodipine and nisoldipine on experimentally induced myocardial infarction in rats.

Cardiac necrosis was produced in rats by administering isoproterenol sulphate (85 mg/kg, sc for 4 days). The myocardial damage was proved by observing the elevated levels of serum aspartate aminotransferase, ++alanine aminotransferase and lactate dehydrogenase and the changes were confirmed by his topathology. Nitrendipine, nimodipine and nisoldipine (10 mg/kg, ip) significantly reduced the elevated levels of these enzymes. The average degree of cardiac necrosis in these rats when observed microscopically and histologically was also found to be significantly reduced on pretreatment with these drugs. Nisoldipine was more effective in preventing cardiac necrosis as compared to nitrendipine and nimodipine.

Do all calcium antagonists have a cardioprotective effect against isoproterenol induced myocardial necrosis in rats?

This study investigated and compared the possible protective effects of five Ca2+ entry blockers: Verapamil, nifedipine, diltiazem, flunarizine and amlodipine against isoproterenol-induced myocardial necrosis in rats. Fifty-six male albino rats were divided into seven equal groups. Group 1 served as control, group 2 received isoproterenol [85 mg/kg body wt. s.c.] for two days to produce myocardial necrosis, other groups received one of the following Ca2+ entry blockers for four successive days: verapamil [5 mg/kg body weight i.p.], nifedipine [0.2 mg/kg i.m.], diltiazem [10 mg/kg i.m.], flunarizine [30 mg/kg orally] and amlodipine [0.5 mg/kg orally]. On the third and fourth days of treatment, animals received isoproterenol in the dose mentioned above. Twenty-four hours later, blood samples were withdrawn from the orbital plexus for the determination of creatine phosphokinase [CPK] activity, aspartate aminotransferase [ASAT] and alanine aminotransferase [ALAT]. The post-ischemic survival rate [PISR] for each group was calculated. Isoproterenol caused a significant increase in CPK, ASAT and ALAT as compared to the control group, the PISR was 0%. Pretreatment with nifedipine, verapamil or diltiazem significantly reduced all the enzyme studied as compared to isoproterenol group, the PISR was 87.5% 75% and 75%, respectively. Amlodipine pretreatment reduced only ASAT, PISR was 25%. On the other hand, flunarizine pretreatment did not significantly change the enzyme studied, the PISR was 12.5%. The results suggested that nifedipine, verapamil and diltiazem have protective effects against isoproterenol-induced myocardial necrosis in rats and that flunarizine and amlodipine were free of these cardioprotective effects

Collagen levels in isoproterenol induced myocardial infarction in rats.

Myocardial infarction was induced in albino rats by the subcutaneous administration of isoproterenol. A significant was observed increase in weight of the myocardium, total protein, DNA levels, neutral salt soluble collagen content, serum and urinary hydroxyproline levels at peak infarction stage in treated rats while the body weight, insoluble and total collagen content of heart were found to be decreased. These results show an early degradation of collagen immediately after myocardial infarction and enhanced synthesis during the different stages of recovery. Histological studies confirmed the incidence of peak infarction after two doses of isoproterenol treatment and recovery to normalcy from the third day onwards.

Failure to reduce experimental myocardial infarct size with ibuprofen pre-treatment in rats.

The prophylactic role of ibuprofen in experimental myocardial infarction has not been reported. Twenty-four rats pre-treated with ibuprofen (30 mg/kg), po, for 21 days were subjected to myocardial infarction by administration of isoprenaline hydrochloride (85 mg/kg), sc, on two consecutive days. An equal number of rats were given saline to serve as control. Heart specimens were taken for macroscopic and microscopic examination after 1 day, 5 days, 12 days and 21 days, following myocardial infarction. Ibuprofen pre-treatment caused a significant increase in infarct size at all the intervals studied (P less than 0.01), indicating that ibuprofen exerted a harmful effect in increasing the size of experimental myocardial infarction.

Production of myocardial lesions in a graded fashion by noninvasive technique in albino rats.

Systematic study of producing graded lesions of myocardium with the use of Isoproterenol (IPT) reveals that mild to severe degree of infarction can be induced by administering the compound for one to four consecutive days in the dose of 85 mg/kg body weight in rats. These findings differ slightly from those of Rona et al. where they have not attempted to produce the lesions in a graded fashion. The experimental period can be reduced to two days by using high dose (170 mg/kg), but such procedure increases significantly the mortality in these animals and lesions are not produced in graded fashion.