Polymorphism of the methylenetetrahydrofolate reductase gene C677T and its influence on the antihypertensive and vascular protective effects of short-term lercanidipine treatment

Objective

To determine whether the antihypertensive and vascular protective effects of short-term treatment with lercanidipine, a calcium channel blocker, are modulated by the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism.

Methods

In a self-controlled study, a total of 143 essential hypertensive patients, all permanent residents of Shanghai, were included. All of them were treated orally with lercanidipine at a single daily fixed dosage of 10 mg for 28 consecutive days and the genotypes of the MTHFR C677T polymorphism were determined. Blood pressures, ankle-brachial index values (ABI), and pulse wave velocity (PWV) were measured at baseline and on the 29th day.

Results

The 110 subjects for whom complete genotype and phenotype information were available were used for final data analysis. Patients with the TT genotype showed higher baseline diastolic blood pressure (DBP) than those with the CC and CT genotypes (P = 0.018). Within each genotype group, SBP, DBP and PWV showed significant difference between baseline and after treatment (P < 0.05). However, ABI showed significant difference between baseline and after treatment only within the CT and TT groups (P < 0.05) but not in the CC group (P > 0.05). Patients with the TT genotype presented a greater reduction in normalized PWV than those with the CC and CT genotypes (P = 0.02). Patients in all genotype groups had statistically similar changes in normalized SBP, DBP and ABI (P > 0.05).

Conclusion

The MTHFR gene polymorphism C677T might be associated with the vascular protective effects of short-term lercanidipine treatment. However, the MTHFR C677T polymorphism might not affect the antihypertensive effects of the lercanidipine treatment.     

Role of the phosphatidylinositol 3-kinase and extracellular signal-regulated kinase pathways in the neuroprotective effects of cilnidipine against hypoxia in a primary culture of cortical neurons

Cilnidipine, a calcium channel blocker, has been reported to have neuroprotective effects. We investigated whether cilnidipine could protect neurons from hypoxia and explored the role of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-related kinase (ERK) pathways in the neuroprotective effect of cilnidipine. The viability of a primary culture of cortical neurons injured by hypoxia, measured by trypan blue staining and lactate dehydrogenase (LDH) assay, was dramatically restored by cilnidipine treatment. TUNEL and DAPI staining showed that cilnidipine significantly reduced apoptotic cell death induced by hypoxia. Free radical stress and calcium influx induced by hypoxia were markedly decreased by treatment with cilnidipine. Survival signaling proteins associated with the PI3K and ERK pathways were significantly increased while death signaling proteins were markedly decreased in the primary culture of cortical neurons simultaneously exposed to cilnidipine and hypoxia when compared with the neurons exposed only to hypoxia. These neuroprotective effects of cilnidipine were blocked by treatment with a PI3K inhibitor or an ERK inhibitor. These results show that cilnidipine protects primary cultured cortical neurons from hypoxia by reducing free radical stress, calcium influx, and death-related signaling proteins and by increasing survival-related proteins associated with the PI3K and ERK pathways, and that activation of those pathways plays an important role in the neuroprotective effects of cilnidipine against hypoxia. These findings suggest that cilnidipine has neuroprotective effects against hypoxia through various mechanisms, as well as a blood pressure-lowering effect, which might help to prevent ischemic stroke and reduce neuronal injury caused by ischemic stroke.     

Cellular interplay in pulmonary arterial hypertension: Implications for new therapies

Pulmonary arterial hypertension (PAH) is a complex and multifactorial disease characterized by vascular remodeling, vasoconstriction, inflammation and thrombosis. Although the available therapies have resulted in improvements in morbidity and survival, PAH remains a severe and devastating disease with a poor prognosis and a high mortality, justifying the need of novel therapeutic targets. An increasing number of studies have demonstrated that endothelial cells (ECs), smooth muscle cells (SMCs) and fibroblasts of the pulmonary vessel wall, as well as platelets and inflammatory cells have a role in PAH pathogenesis. This review aims to integrate the interplay among different types of cells, during PAH development and progression, and the impact of current therapies in cellular modulation. The interplay among endothelial cells, smooth muscle cells and fibroblasts present in pulmonary vessels wall, platelets and inflammatory cells is regulated by several mediators produced by these cells, contributing to the pathophysiologic features of PAH. Current therapies are mainly focused in the pulmonary vascular tone and in the endothelial dysfunction. However, once they have not been effective, novel therapies targeting other PAH features, such as inflammation and platelet dysfunction are emerging. Further understanding of the interplay among different vascular cell types involved in PAH development and progression can contribute to find novel therapeutic targets, decreasing PAH mortality and morbidity in the future.