Nifedipine Increases Endothelial Nitric Oxide Bioavailability by Antioxidative Mechanisms

Abstract

Abstract-Short-term treatment of the endothelium with dihydropyridine calcium antagonists resulted in an increased release in NO that is not due to a modulation of L-type calcium channels, because macrovascular endothelial cells do not express this channel. We investigated whether long-term (48 hours) treatment of porcine endothelial cell cultures with the dihydropyridine calcium antagonist nifedipine resulted in a similar enhanced NO liberation. Regarding to the underlying mechanism, we examined whether (1) nifedipine changed the mRNA and protein levels of the constitutive endothelial NO synthase (NOS) in endothelial cell cultures or (2) nifedipine exerts an NO protective effect via its antioxidative properties, as revealed in a cell culture model and with native endothelium from porcine coronary arteries. ihydropyridine (DHP)-type calcium antagonists are important drugs in the treatment of hypertension and coronary heart disease. They induce their specific pharmacological effects by binding to L-type calcium channels, 1,2 which results in a reduced calcium influx with impaired electromechanical coupling both in vascular smooth muscle cells and in the heart. 3 A few years ago, however, it was observed that removal of the endothelium or blockade of the guanylate cyclase of the vessel wall reduced the efficacy of the DHP-induced vasorelaxation, 4 which indicated an endothelium-responsive cGMP-mediated process as part of the DHP action. Because macrovascular endothelial cells lack voltage-operated L-type calcium channels, 5,6 the DHPs must exert these effects via other mechanisms. In this context, it is worth mentioning that DHPs may also exert antihrombotic 7,8 and antiatherosclerotic 9,10 effects in different experimental and clinical settings, of which the underlying signal transduction remains obscure.With this background, it is tempting to speculate that NO, one of the most prominent endothelium-derived factors, 11,12 which relaxes smooth muscle cells via the cGMP signal cascade, 13 might be involved in these DHP actions. In fact, in various models, evidence has accumulated that DHPs stimulate the endothelial NO release, 14 -19 which may mediate or at least contribute to the abovementioned calcium channel-independent effects.Up to now, however, all of these findings were obtained only after acute exposure to DHPs (lasting minutes to hours). Because patients usually take calcium antagonists for a longer period of time, we investigated whether long-term treatment of endothelial cell cultures with nifedipine may alter the basal endothelial NO release as well as the expression of the constitutive endothelial NO synthase (ecNOS) mRNA and protein. Furthermore, because NO is rapidly deactivated by reactive oxygen species (ROS) 20 and the DHPs may act as scavengers as known from different in vitro models, [21][22][23] we also determined the antioxidative potency of nifedipine in endothelial cell cultures as well as in native cells to reveal a potential NO-protection effect as an underlying mechanism of the increased ...

Effect of nifedipine on adiponectin in hypertensive patients with type 2 diabetes mellitus

“…This suggests that CR nifedipine may have a beneficial effect on the vascular system beyond its antihypertensive effect. 25,26,[34][35][36] In patients with essential hypertension, platelets appear to be preactivated or hyper-responsive to vasoactive agents. 37 In addition, the activation of platelets contributes to vascular structural changes and the development of atherosclerosis.…”

“…These results suggest that CR nifedipine can improve endothelial function and increase the activity of NO, which regulates platelet activation. 25,26,35,45 It is possible that inhibition of platelet activation improves blood flow in skeletal muscle and thus reduces insulin resistance, resulting in an elevation of circulating adiponectin. 46 The ability of CR nifedipine to inhibit MDMP generation provides additional evidence for the antiatherosclerotic action of this drug.…”

“…24 Nifedipine is a dihydropyridine calcium antagonist that improves endothelial function in patients with hypercholesterolaemia by enhancing NO activity, 25 and it also increases endothelial NO bioavailability by antioxidant mechanisms. 26 In addition, nifedipine influences platelet function and the activity of some chemokines, resulting in this drug showing an antiatherosclerotic effect in hyper-tensive patients with type 2 diabetes. To our knowledge, few studies on the relationship between adiponectin and calcium antagonist have been published.…”

Nifedipine increases energy expenditure by increasing PGC-1α expression in skeletal muscle

“…7,30 Indeed, Iwai et al 17 reported that nifedipine treatment reduced superoxide levels by increasing eNOS activity. However, in our study of eNOS-deficient mice, we found that the nifedipine has eNOS-independent effects on increasing the energy expenditure in skeletal muscle and insulin sensitivity.…”

“…Nifedipine treatment reduces atherosclerotic plaques in cholesterol-fed rabbits, 2,3 and suppresses development and progression of atherosclerosis in hypertensive patients. 4,5 Nifedipine has recently been reported to have pleiotropic effects on endothelial cells, 6,7 cardiac muscle cells, 8,9 mesangial cells [10][11][12] and neurons, 13,14 through mechanisms independent of blocking Ca channels. Previous studies have reported that nifedipine treatment decreases body weight in obese hypertensive humans 15 and rat models.…”