Effects of Slow, Sustained, and Rate-Tunable Nitric Oxide Donors on Human Aortic Smooth Muscle Cells Proliferation

Smooth muscle cell (SMC) proliferation has been accepted as a common event in the pathophysiology of vascular diseases, including atherogenesis and intimal hyperplasia. Delivery of the nitric oxide synthase (NOS) substrate l‐arginine, pharmacological nitric oxide (NO) donors, NO gas or overexpression of NOS proteins can inhibit SMC proliferation and reduce the injury responses within the blood vessel wall. Although commercial development of NO donors that attempt to provide exogenous delivery of NO has accelerated over the last few years, none of the currently available products can provide controlled, sustained, time‐tunable release of NO. Nitrosamine‐based NO donors, prepared in our laboratory, present a unique and innovative alternative for possible treatments for long‐term NO deficiency‐related diseases, including atherosclerosis, asthma, erectile dysfunction, cancer, and neurodegenerative diseases. A family of secondary amines prepared via nucleophilic aromatic displacement reactions could be readily N‐nitrosated to produce NO donors. NO release takes place in three distinct phases. During the initial phase, the release rate is extremely fast. In the second phase, the release is slower and the rate remains essentially the same during the final stage. These compounds inhibited up to 35% human aortic smooth muscle cell proliferation in a concentration‐dependent manner. A series of N‐nitrosamines were prepared by nitrosation of secondary amines obtained from the following; the reactions of 4,4′‐sulfonylbis(1‐fluoro‐2‐nitrobenzene) with primary amines varying in aliphatic chain lengths, and by the reactions with substituted anilines. These nitrosamines release nitric oxide in a slow, sustained rate tunable manner. The release rate is dependent on the electron withdrawing or donating abilities of the moieties attached to the starting primary amines. The released nitric oxide reduces the proliferation of human aortic smooth muscle cells.