Department of Pharmacology, Universidade Federal de São Paulo, Escola Paulista de Medicina São Paulo, Brazil.
Instituto Teófilo Hernando de I+D del Medicamento, Universidad Autónoma de Madrid Madrid, Spain.
Pharmacol Res Perspect. 2015 Oct;3(5):e00181. doi: 10.1002/prp2.181. Epub 2015 Sep 23.
In this review, we discussed pharmacological implications of the Ca(2+)/cAMP signaling interaction in the antihypertensive and neurological/psychiatric disorders therapies. Since 1975, several clinical studies have reported that acute and chronic administration of L-type voltage-activated Ca(2+) channels (VACCs) blockers, such as nifedipine, produces reduction in peripheral vascular resistance and arterial pressure associated with an increase in plasma noradrenaline levels and heart rate, typical of sympathetic hyperactivity. Despite this sympathetic hyperactivity has been initially attributed to adjust reflex of arterial pressure, the cellular and molecular mechanisms involved in this apparent sympathomimetic effect of the L-type VACCs blockers remained unclear for decades. In addition, experimental studies using isolated tissues richly innervated by sympathetic nerves (to exclude the influence of adjusting reflex) showed that neurogenic responses were completely inhibited by L-type VACCs blockers in concentrations above 1 μmol/L, but paradoxically potentiated in concentrations below 1 μmol/L. During almost four decades, these enigmatic phenomena remained unclear. In 2013, we discovered that this paradoxical increase in sympathetic activity produced by L-type VACCs blocker is due to interaction of the Ca(2+)/cAMP signaling pathways. Then, the pharmacological manipulation of the Ca(2+)/cAMP interaction produced by combination of the L-type VACCs blockers used in the antihypertensive therapy, and cAMP accumulating compounds used in the antidepressive therapy, could represent a potential cardiovascular risk for hypertensive patients due to increase in sympathetic hyperactivity. In contrast, this pharmacological manipulation could be a new therapeutic strategy for increasing neurotransmission in psychiatric disorders, and producing neuroprotection in the neurodegenerative diseases.
在这篇综述中，我们讨论了 Ca(2+)/cAMP 信号相互作用在抗高血压和神经/精神疾病治疗中的药理学意义。自 1975 年以来，几项临床研究报告称，L 型电压激活钙通道 (VACC) 阻滞剂，如硝苯地平的急性和慢性给药会降低外周血管阻力和动脉压，同时增加血浆去甲肾上腺素水平和心率，这是交感神经活性增加的典型表现。尽管这种交感神经活性最初归因于动脉压的反射调节，但涉及 L 型 VACC 阻滞剂这种明显拟交感作用的细胞和分子机制几十年来仍不清楚。此外，使用富含交感神经支配的分离组织进行的实验研究（排除调节反射的影响）表明，在 1 μmol/L 以上浓度时，L 型 VACC 阻滞剂完全抑制神经源性反应，但在 1 μmol/L 以下浓度时却增强。在将近四十年的时间里，这些神秘的现象仍然没有得到解释。2013 年，我们发现 L 型 VACC 阻滞剂引起的这种交感活性的反常增加是由于 Ca(2+)/cAMP 信号通路的相互作用。然后，通过组合用于抗高血压治疗的 L 型 VACC 阻滞剂和用于抗抑郁治疗的 cAMP 积累化合物来药理学操纵 Ca(2+)/cAMP 相互作用，可能会由于交感神经活性增加而给高血压患者带来潜在的心血管风险。相比之下，这种药理学操纵可能是增加精神疾病神经传递和在神经退行性疾病中产生神经保护的新治疗策略。
