Pharmacology and Toxicology

Biography

Biography: Leandro Bueno Bergantin

Abstract

The calcium paradox phenomenon has been discovered in 1970’s due to experiments performed in vas deferens. Briefly, experimental studies using vas deferens showed that neurogenic responses were completely inhibited by L-type Ca²⁺ Channel Blockers (CCBs) in high concentrations but paradoxically potentiated in low concentrations, so characterized as a calcium paradox phenomenon. In addition, several clinical studies have been reporting that administration of L-type CCBs, drugs largely used for antihypertensive therapy such as Verapamil and Nifedipine, produces reduction in peripheral vascular resistance and arterial pressure, associated with a paradoxical sympathetic hyperactivity. Despite this sympathetic hyperactivity has been initially attributed to adjust reflex of arterial pressure, the cellular and molecular mechanisms involved in this paradoxical effect of the L-type CCBs remained unclear for four decades. We discovered in 2013 that the calcium paradox phenomenon produced by L-type CCBs in vas deferens is due to Ca²⁺/cAMP interaction, which could properly explain the paradoxical sympathetic hyperactivity produced by L-type CCBs in clinical studies. Then, the pharmacological manipulation of the Ca²⁺/cAMP interaction could represent a potential cardiovascular risk for hypertensive patients due to increase of sympathetic hyperactivity. In contrast, this pharmacological manipulation could be a new therapeutic strategy for increasing neurotransmission in psychiatric disorders such as depression and producing neuroprotection in the neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. In fact, CCBs truly show cognitive-enhancing abilities and reduce the risk of dementia, including Alzheimer's, Parkinson’s disease and others. The molecular mechanisms involved in these pleiotropic effects remain under debate whether Ca²⁺/cAMP interaction is involved in CCBs pleiotropic effects deserves special attention. Cellular homeostasis of Ca²⁺ and/or cAMP in these cells could be a novel therapeutic target for medicines. By reducing Ca²⁺ influx, CCBs may increase [cAMP]c by enhancing adenylyl cyclase activity, which increases neuroprotection. cAMP also enhances the release of Ca²⁺ from endoplasmic reticulum, which increases exocytosis. Considering our model in which increment of [cAMP]c stimulates Ca²⁺ release from endoplasmic reticulum, it may be plausible the therapeutic use of the PDE inhibitor rolipram in combination with low doses of CCBs to stimulate neuroprotection and enhance neurotransmission by increasing neurotransmitter release in the areas of central nervous system involved in neurological/psychiatric disorders in which neurotransmission is reduced, including Alzheimer’s and Parkinson’s diseases.