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Is there a Role of Intracellular Magnesium in Prevention of Heart Failure?

Panayotis Fantidis, Eladio Sanchez, Ijaz Khan, Ibrahim Tarhini, Tomás Pineda, José Antonio Corrales and José Ramón Gonzalez

Heart failure, characterized by the reduction in left and /or right ventricular function, is the most common cause of mortality and morbidity in almost around the world. This syndrome is induced by β1-adrenergic receptor (β1-AR) desensitization, which in turn is caused by the reduction in cellular cAMP concentration. Cellular cAMP concentration is modulated by adenylyl cyclases (ACs), a family of enzymes that are strongly activated by intracellular magnesium and circulating levels of the stress-related hormones. Short-term activation of β1-AR signalling pathway by increased levels of these hormones induces an increase in intracellular Mg2+ and cAMP concentrations, which improves cardiac function. Nevertheless, long-term activation of β1-AR signalling pathway by elevated levels of these hormones reduces intracellular Mg2+ and cAMP levels, which deteriorates cardiac function. Intracellular cAMP signalling has a circadian rhythm (CR) in mammals, and CR may modulate diverse phenomena. The loss of CR may per se be a cause of severe diseases. Magnesium can regulate intracellular cAMP production and through this may modulate the CR. Here we propose that longterm activation of β1-AR signalling pathway, and /or the use of diuretics, can induce a progressive reduction of intracellular of magnesium and a subsequent gradual reduction of intracellular cAMP levels. This in turn can cause β1-AR desensitization, the loss of CR of the hormones related with HF, and, finally, HF development. We suggest the therapeutic implications of this mechanism in the prevention of HF.