Normalization of deranged signal transduction in lymphocytes of COPD patients by the novel calcium channel blocker H-DHPM

Investigations on the role of intracellular Ca 2+ ion concentration in the mechanism of development of COPD in smokers and non-smokers were carried out. The intracellular Ca 2+ levels were found to be increased in human lymphocytes in patients with COPD as compared to non-smokers and smokers without COPD. The investigations reveal an association in altered intracellular Ca 2+ regulation in lymphocytes and severity of COPD, by means of significant activation of Protein kinase C and inducible nitric oxide synthase (iNOS). The effect of a novel calcium channel blocker ethyl 4-(4′-heptanoyloxyphenyl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (H-DHPM) as a potential candidate for the treatment of COPD was also investigated. H-DHPM treated cells showed a decrease in intracellular Ca 2+ level as compared to the control cells. Molecular studies were carried out to evaluate the expression profile of NOS isoforms in human lymphocytes and it was shown that H-DHPM decreases the increased iNOS in COPD along with reestablishing the normal levels of endothelial nitric oxide synthase (eNOS). The results of H-DHPM were comparable with those of Amlodipine, a known calcium channel blocker. Calcium channel blocker H-DHPM proves to be a potential candidate for the treatment of COPD and further clinical studies are required to prove its role in the treatment of pulmonary hypertension (PH). ► We found an increased intracellular Ca 2+ in COPD patients as compared to healthy. ► Increased PKC levels and iNOS/eNOS imbalance also correlated with COPD severity. ► Altered parameters were found normalized by a novel Ca 2+ channel blocker, H-DHPM. ► H-DHPM effectively increased eNOS levels by releasing it from caveolin bound form. ► The effects of H-DHPM were found comparative to amlodipine.