Magnesium attenuates isoproterenol-induced acute cardiac dysfunction and β-adrenergic desensitization

Abstract

nervous activation is a crucial compensatory mechanism in heart failure. However, excess catecholamine may induce cardiac dysfunction and ␤-adrenergic desensitization. Although magnesium is known to be a cardioprotective agent, its beneficial effects on acute cardiac dysfunction remain to be elucidated. We examined the effects of magnesium on left ventricular (LV) dysfunction induced by a large dose of isoproterenol in dogs. Sixteen anesthetized dogs underwent a continuous infusion of isoproterenol (1 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) with or without a magnesium infusion (1 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ). The dose response to small doses of isoproterenol (0.025-0.2 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was tested hourly. A large dose of isoproterenol decreased LV systolic function, increased the time constant of LV isovolumic relaxation, and suppressed the dose response to small doses of isoproterenol in a time-dependent manner. Magnesium significantly attenuated isoproterenol-induced LV systolic and diastolic dysfunction and preserved the dose response to isoproterenol. Serum-ionized calcium significantly decreased with a large dose of isoproterenol but was fully maintained at baseline level with magnesium. A large dose of isoproterenol increased serum lipid peroxide levels and serological markers of myocardial damage, which were significantly suppressed by magnesium. In conclusion, magnesium significantly attenuated excess isoproterenol-induced acute cardiac dysfunction and ␤-adrenergic desensitization. calcium overload; free radical; dog, left ventricular; tau SYMPATHETIC ACTIVATION IS a crucial compensatory mechanism in heart failure, and serum catecholamine levels are an indicator of the clinical severity (8). However, excess catecholamine may actually induce cardiac cell injury, leading to cardiac dysfunction (34). This is one of the rationales for the clinical beneficial effects of ␤-adrenergic receptor blockade on the prognosis and cardiac function in chronic heart failure (7, 13, 27, 32). Excess isoproterenol (ISO), a selective ␤-adrenergic receptor agonist, induces myocardial necrosis and apoptosis, interstitial fibrosis, and left ventricular (LV) hypertrophy and dysfunction (14, 36). The mechanism of cardiac dysfunction induced by excess ISO may be attributed to calcium overload (19) and free radical generation (37). Moreover, excess ISO induces ␤-adrenergic desensitization (18), one of the hallmarks of heart failure, which potentially exacerbates cardiac dysfunction.Magnesium is known as a cardioprotective factor in the treatment of hypertension, ischemic heart disease, and chronic heart failure (2, 21, 38, 43). In experiments on cardiac ischemia-reperfusion, magnesium has been reported to reduce myocardial calcium overload (44), free radical generation (11), and myocardial infarct size (26). High magnesium levels have been reported to suppress ␤-adrenergic desensitization (9). However, the beneficial effects of magnesium in acute heart failure remain to be elucidated.The goal of the present study was to investigate whether magnesium prev...

Adrenergic stimulation promotes T-wave alternans and arrhythmia inducibility in a TNF-α genetic mouse model of congestive heart failure

“…These results are also not in disagreement with those in a canine wedge preparation by Wilson et al (45), who used a different model to show that the action potential and Ca 2ϩ alternans in the heart failure hearts occurred at slower heart rates compared with normal hearts. Furthermore, the mechanisms of ␤-adrenergic stimulation by isoproterenol involve an additional influx of Ca 2ϩ into myocytes, overloading the Ca 2ϩ -handling cascades, which are chronically impaired in heart failure (6,12). Thus, Ca 2ϩ alternans and impaired Ca 2ϩ handling could be the driving force behind the TWA observed after the injection of isoproterenol in the present study.…”

Effect of isoproterenol on myocardial perfusion, function, energy metabolism and nitric oxide pathway in the rat heart - a longitudinal MR study

“…In an earlier study, Jin et al . reported that a continuous infusion of a large dose of IsoP (1 µg/kg/min) in dogs induced acute left ventricular dysfunction with leakage of myocardial enzymes and contractile proteins indicating myocardial damage, within 2 h of administration, as well as the release of atrial natriuretic peptide. Interestingly, subcutaneous administration of IsoP at an interval of 24 h for 2 days was shown to decrease the activities of Na + /K + ATPase and Mg 2+ ATPase, whereas the activity of Ca 2+ ATPase was increased in IsoP‐treated rats.…”

Mitochondria play a central role in nonischemic cardiomyocyte necrosis: common to acute and chronic stressor states

“…Because the calcitropic hormones, parathyroid hormone (PTH) and vitamin D, potentiate Ca 2+ overloading and ATP loss, they sensitize cardiomyocytes to catecholamine-induced necrosis [22]. This contrasts to Ca 2+ channel blockers, cations (e.g., Zn 2+ ) which compete with Ca 2+ entry, or β 1 adrenergic receptor antagonists, each of which were cardioprotective in response to catecholamine treatment of rats using isoproterenol (Isop) [45,36,75,16,76]. The multidisciplinary team of talented investigators from the Institute contributed importantly to this “new principle in cardiac pathophysiology” [21].…”