The antihypertensive and cardioprotective effects of (-)-MJ-451, an ATP-sensitive K+ channel opener

Yen Mei Lee, Mao Hsiung Yen, Yen Yen Peng, Jeon Rong Sheu, Yao Chang Chen, Ming Jyh Chang, Chen Yu Cheng

Research output: Contribution to journalArticle

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Abstract

ATP-sensitive K+ (K(ATP)) channel openers have been shown to be a potential class of therapeutic agents for the control of cardiovascular diseases, including angina, arrhythmias, and hypertension. In this study, the pharmacological activity of 6-cyano-3S,4R-dihydro-2,2-dimethyl-2H-3-hydroxy-4-[5S-(1-hydroxymethyl)-2-oxo-1-pyrrolidinyl]-1-benzopyran ((-)-MJ-451), a synthetic K(ATP) opener, was evaluated in anesthetized rat models and in isolated rat thoracic rings. Results demonstrated that intravascular injection of (-)-MJ-451 (0.02, 0.05 and 0.1 mg/kg) produced an immediate, dose-related reduction in mean arterial blood pressure in anesthetized spontaneously hypertensive rats (SHR), which persisted for more than 3 h and was not accompanied by reflex tachycardia. The hemodynamic changes were completely abolished by pretreatment with glibenclamide (4 mg/kg, i.v. bolus), a selective K(ATP) channel blocker. In isolated thoracic aorta, (-)-MJ-451 (10 nM-3 μM) produced a concentration-dependent vasodilator effect on the phenylephrine (0.3 μM)-induced vasoconstriction. Moreover, (-)-MJ-451 relaxed the thoracic aorta contracted by low (5, 20 and 30 mM), but not high (40 and 60 mM) concentrations of extracellular potassium. In addition, (-)-MJ-451 showed cardioprotective effects in the rat model of 45-min left coronary artery occlusion followed by 1-h reperfusion. In myocardial ischemia, pretreatment with (-)-MJ-451 (2, 5 and 10 μg/kg, i.v. bolus) significantly reduced the incidence of ventricular fibrillation and the mortality, also reducing the total number of ventricular premature contractions, total duration of ventricular tachycardia and ventricular fibrillation. A significant reduction in infarct size was noted in three (-)-MJ-451 (2, 5 and 10 μg/kg)-treated groups. Also, the cardioprotective effects of (-)-MJ-451 were virtually abolished by pretreating the rats with glibenclamide (4 mg/kg, i.v. bolus). In conclusion, (-)-MJ-451, through opening the K(ATP) channel, exerted antihypertensive and cardioprotective effects. Therefore, it is suggested that (-)-MJ-451 has potential in the treatment of hypertension or acute myocardial infarction. Copyright (C) 2000 Elsevier Science B.V.

Original languageEnglish
Pages (from-to)151-160
Number of pages10
JournalEuropean Journal of Pharmacology
Volume397
Issue number1
DOIs
Publication statusPublished - May 26 2000

Fingerprint

Antihypertensive Agents
Adenosine Triphosphate
Glyburide
Ventricular Fibrillation
Thoracic Aorta
Arterial Pressure
MJ 451
Hypertension
Benzopyrans
Ventricular Premature Complexes
Coronary Occlusion
Phenylephrine
Inbred SHR Rats
Ventricular Tachycardia
Vasoconstriction
Vasodilator Agents
Tachycardia
Reperfusion
Myocardial Ischemia
Reflex

Keywords

  • Arrhythmias
  • Hypertension
  • K(ATP) channel
  • Myocardial ischemia
  • Reperfusion

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

The antihypertensive and cardioprotective effects of (-)-MJ-451, an ATP-sensitive K+ channel opener. / Lee, Yen Mei; Yen, Mao Hsiung; Peng, Yen Yen; Sheu, Jeon Rong; Chen, Yao Chang; Chang, Ming Jyh; Cheng, Chen Yu.

In: European Journal of Pharmacology, Vol. 397, No. 1, 26.05.2000, p. 151-160.

Research output: Contribution to journalArticle

Lee, Yen Mei ; Yen, Mao Hsiung ; Peng, Yen Yen ; Sheu, Jeon Rong ; Chen, Yao Chang ; Chang, Ming Jyh ; Cheng, Chen Yu. / The antihypertensive and cardioprotective effects of (-)-MJ-451, an ATP-sensitive K+ channel opener. In: European Journal of Pharmacology. 2000 ; Vol. 397, No. 1. pp. 151-160.
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AU - Peng, Yen Yen

AU - Sheu, Jeon Rong

AU - Chen, Yao Chang

AU - Chang, Ming Jyh

AU - Cheng, Chen Yu

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KW - Arrhythmias

KW - Hypertension

KW - K(ATP) channel

KW - Myocardial ischemia

KW - Reperfusion

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