Combination of Irbesartan with Amlodipine Enhances Nitrate/Nitrite Generation by Angiotensin II-exposed Endothelial Cells

Background: Endothelial dysfunction is an initial step for atherosclerotic cardiovascular disease and highly prevalent in high-risk patients, such as those with hypertension or chronic kidney disease. Decreased nitric oxide production and/or impaired bioavailability are involved in endothelial dysfunction. Since blood pressure lowering significantly reduces the risk for future cardiovascular events in hypertensive patients, several guidelines recommended combination of anti-hypertensive drugs that had complimentary mode of actions for the treatment of patients with moderate or severe hypertension. However, effects of combination therapy on nitric oxide generation by endothelial cells are not fully understood. Methods: In this study, we examined the effects of amlodipine, a calcium channel blocker, and irbesartan, an angiotensin II type 1 receptor blocker on nitrate/nitrite generation in angiotensin IIexposed human umbilical vein endothelial cells. Compared with control, angiotensin II at 100 nM significantly increased reactive oxygen species generation and reduced mRNA levels of endothelial nitric oxide synthase in endothelial cells, both of which were prevented by 10 nM irbesartan, but not 1 nM amlodipine. Combination of irbesartan with amlodipine further ameliorated the deleterious effects of angiotensin II on endothelial cells. Moreover, although amlodipine or irbesartan treatment alone did not increase nitrate/nitrite generation, combination therapy significantly restored the decreased nitrate/nitrite production by angiotensin II-exposed endothelial cells. Results and Conclusion: The present study suggests that combination of irbesartan with amlodipine could be beneficial against endothelial dysfunction, whose effects may partly be independent on its blood pressure-lowering properties.