Administering endothelin during a myocardial infarction worsens tissue damage
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INSUFFICIENT LEANING
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Retrieved literature indicates that endothelin is upregulated after myocardial infarction and contributes to adverse remodeling and arrhythmias, supporting the premise that endothelin pathways worsen tissue damage, but does not test direct administration of endothelin.
OBJECTIVES Activation of the endothelin (ET) receptor has been shown to exert an arrhythmogenic effect; however, the mechanisms remain unclear. We investigated whether ET receptor antagonists (ERAs) exert antiarrhythmic effects through attenuated sympathetic reinnervation after infarction. METHODS Twenty‐four hours after coronary ligation, male Wistar rats received either vehicle, hydralazine, ABT‐627 (selective ETA receptor antagonist), or bosentan (nonselective ETA/ETB receptor antagonist) for 4 weeks. RESULTS Measurement of myocardial ET‐1 levels at the remote zone revealed a significant increase in vehicle‐treated rats compared with sham‐operated rats. Sympathetic reinnervation and nerve function were parallel to ET‐1 levels. Sympathetic hyperinnervation was blunted after administering either ETA or ETA/ETB blockade to a similar extent, assessed by immunohistochemical analysis of tyrosine hydroxylase, growth associated protein 43 and neurofilament, and Western blot and RT‐PCR of nerve growth factor. Dissociation between the effects of blood pressure and sympathetic innervation was noted, because ERAs and hydralazine reduced arterial pressure similarly. Arrhythmic scores during programmed stimulation in ERA‐treated rats were significantly lower than those treated with vehicle. CONCLUSIONS The ET system, especially via ETA receptors, plays an important role in the sympathetic reinnervation after infarction. Chronic use of either ETA or ETA/ETB antagonists after infarction m
Reactive cardiomyocyte hypertrophy after myocardial infarction (MI) is an important risk factor for arrhythmias. Endothelin (ET)-1 has been implicated in the development of cardiac hypertrophy. We investigated the effect of pravastatin on ventricular hypertrophy during remodeling after MI and whether the attenuated hypertrophic effect was via reduced regional ET-1 expression. After ligation of the anterior descending artery, male Wistar rats were randomized to either vehicle, pravastatin, mevalonate, or a combination of the two drugs for 4 weeks. Sham operation served as controls. Pravastatin decreased cardiomyocyte sizes isolated by enzymatic dissociation at the border zone. The myocardial ET-1 levels at the border zone were 6.3-fold higher (P < 0.0001) in the vehicle group compared with sham group. The increased regional ET-1 levels can be inhibited after pravastatin administration. Immunohistochemical analysis confirmed the localization of ET-1 mainly in the cardiomyocytes. This was paralleled by a 9.8 +/- 2.3-fold upregulation of preproET-1 mRNA assessed by real-time quantitative reverse transcription-polymerase chain reaction in the vehicle-treated rats, which reduced after administering pravastatin. Cardiomyocyte sizes at the border zone correlated positively with regional ET-1 levels (P = 0.001). Arrhythmic scores during programmed stimulation were significantly higher in the vehicle group than in the pravastatin-treated group (3.0 +/- 1.3 vs. 1.3 +/- 1.0, P < 0.0001).
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