Amlodipine Releases Nitric Oxide From Canine Coronary Microvessels: An Unexpected Mechanism of Action of a Calcium Channel–Blocking Agent
To the Editor:
In a recent interesting article,1 Zhang and Hintze stated that amlodipine but not nifedipine released nitric oxide from canine coronary microvessels and classified this as an unexpected mechanism of action. However, it should be noted that several years ago, the same phenomenon, ie, direct release of NO, was observed with nitrendipine in small porcine coronary arteries, porcine arteria basilaris, and porcine arteria caudalis.2 Similarly, the vasodilating action of nitrendipine, nifedipine, nisoldipine, and nimodipine in guinea pig mesenteric vascular beds was found to be sensitive to l-NG-nitroarginine treatment.3 The latter was more pronounced in smaller arterioles (diameter <350 μm).
Regarding the mechanism of action underlying the release of NO, it was shown recently by use of the fura-2 technique that the calcium antagonist nitrendipine enhances the intracellular calcium concentration in suspensions of cultured endothelial cells.4 This effect was insensitive to thapsigargin but was sensitive to extracellular depletion of calcium, indicating that the observed increase in intracellular calcium concentration was mainly due to an influx of calcium rather than a calcium release from intracellular stores. The elevation of intracellular calcium by nitrendipine could be completely blocked by application of gadolinium, a trivalent lanthanide known to inhibit shear stress–activated cation-selective channels on endothelial cells. In addition, the authors showed that the increase in intracellular [Ca2+] by shear stress was further enhanced in the presence of nitrendipine.4
In summary, the release of NO from vascular endothelium is not unique to amlodipine but seems to be a group phenomenon of 1,4-dihydropyridines. The NO release may be more or less prominent when various substances in various vessel types are compared. As shown, the NO dependence of vasodilation by 1,4-dihydropyridines may also be influenced by the position of the vessels within the vascular tree.3 In addition, this NO-releasing action is not restricted to vascular endothelium but can also be found in platelets, as shown for nifedipine, and contributes to its antiaggregatory effects.5
- Copyright © 1999 by American Heart Association