Abstract
Due to the involvement of the imbalance of Ca<sup>2+</sup> homeostasis in neuronal cells in the pathogenesis of several neurodegenerative disorders such as Alzheimer's Disease (AD), the use of drugs to prevent or attenuate this imbalance emerged as a new therapeutic perspective for this disease.
Highlights
Clinical studies performed since 1970’s have reported that acute and chronic administration of L-type Ca2+ Channel Blockers (CCB) during antihypertensive therapy, such as nifedipine and verapamil, reduces efficiently arterial pressure but produce typical symptoms of the sympathetic hyperactivity such as tachycardia and enhance of catecholamine plasma levels [1]
To investigate the molecular mechanisms involved in the sympathetic hyperactivity induced by CCB, some in vitro studies using isolated smooth muscles richly innervated by sympathetic nerves to exclude the influence of adjusting reflex showed that the contractile responses of these muscles induced by neurotransmitter release from sympathetic nerves were significantly reduced or completely abolished by L-type CCB in high concentrations, but unexpectedly and paradoxically potentiated in low concentrations [2,3,4]
Using classical models for in vitro study of the mechanisms involved in the regulation of the sympathetic activity, we discovered in 2013 that the sympathetic hyperactivity induced by CCB was resultant from its modulatory action on the secretory activity of the sympathetic neurons and adrenal chromaffin cells [5]
Summary
Clinical studies performed since 1970’s have reported that acute and chronic administration of L-type Ca2+ Channel Blockers (CCB) during antihypertensive therapy, such as nifedipine and verapamil, reduces efficiently arterial pressure but produce typical symptoms of the sympathetic hyperactivity such as tachycardia and enhance of catecholamine plasma levels [1]. These advances allowed us to propose that pharmacological modulation of the Ca2+/cAMP signaling interaction produced by combined use of the L-type CCB (used in the antihypertensive therapy), such as isradipine, and cAMP-enhancer compounds (used in the anti-depressive therapy), such as rolipram, could represent a new therapeutic strategy for treatment of AD in humans This pharmacological modulation could attenuate cognitive deficit due to increase in central cholinergic neurotransmission caused by increment in ACh release from cholinergic neurons [7,8,9,10,11,12,13,14].
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