Nitric Oxide: What a Vascular Surgeon Needs to Know

Daniel A. Popowich; Vinit Varu; Melina R. Kibbe

Disclosures

Vascular. 2007;15(6):324-335. 

In This Article

Systemic Delivery

One simple mechanism by which to deliver NO to the body is via inhalational therapy. Inhaled NO has been used clinically in the past to selectively reduce pulmonary vascular resistance in patients with pulmonary hypertension, as well as a potential therapy for patients with acute respiratory distress syndrome. Because the gas is delivered only to the pulmonary system and has a very short half-life, it was thought that there would be no systemic effects of the drug. Subsequently, studies in the mid- to late 1990s suggested that inhaled NO had beneficial antiplatelet and antileukocyte properties without adverse systemic side effects.[22,23]

To test if inhaled NO had any beneficial systemic properties specifically on the vasculature, Lee and colleagues evaluated the effect of inhaled NO on neointimal hyperplasia in rats undergoing carotid balloon injury.[24] Beginning 60 minutes before carotid injury, rats were exposed to air with 0 or 80 ppm of NO for 14 days. Although neointimal hyperplasia was evident in control and treatment groups, a 43% reduction was observed in the NO-treated group. It was also observed that NO did not cause any adverse effects on bleeding time or blood pressure, and the authors speculated that this modality of treatment could represent an adjunct to preventing restenosis after percutaneous transluminal coronary angioplasty (PTCA). Unfortunately, the treatment was required for the full 2 weeks to see any difference between the treatment and the control group, thereby limiting its clinical utility.

Despite some of the early animal studies, investigations with healthy human volunteers failed to reproduce these findings.[25] It was speculated that despite the obvious effects of inhaled NO on the pulmonary vasculature, systemic bioavailability could not be reliably achieved because of the immediate binding and depletion of NO by hemoglobin as soon as it entered the systemic circulation.

Hamon and colleagues tested the ability of orally supplementing l-arginine (2.25%), the precursor to NO, in the drinking water of rabbits to reduce the formation of neointimal hyperplasia after injuring the iliac arteries with a balloon.[26] This amount of l-arginine is approximately sixfold higher than normal daily intake. When the arteries were studied 4 weeks after injury, the l-arginine-fed group exhibited less neointimal hyperplasia and greater acetylcholine-induced relaxation compared with the control animals. The authors speculated that the improved outcomes were due to increased bioavailability of NO secondary to the l-arginine-supplemented diets.

To test the ability of this supplemented diet to reduce neointimal hyperplasia in a vein bypass graft model, Davies and colleagues fed rabbits l-arginine (2.25%) 7 days prior to and 28 days after common carotid vein bypass grafts.[27] A 51% decrease in the formation of neointimal hyperplasia was demonstrated in the l-arginine-fed groups, and their vein grafts exhibited preserved NO-mediated relaxation.

Landis and colleagues performed a similar study in dogs. They placed saphenous veins as interposition grafts into the bilateral femoral arteries of 24 mongrel dogs.[28] A clamp was then placed on one side to reduce the flow in that vein graft by 50%. Twelve dogs were fed a normal diet, and 12 dogs were fed a diet supplemented with l-arginine (200 mg/kg). No protective effect was found with the l-arginine-supplemented diet on the flow-restricted vein grafts. The authors hypothesized that these findings were secondary to other by-products of l-arginine metabolism that have inhibitory effects on NO synthase and detrimental effects on vascular remodeling. Subsequently, Six and colleagues showed that although l-arginine (2.25%) supplementation reduced neointimal hyperplasia, it had no effect on the regrowth of endothelial cells in vivo.[29]

Despite some of the positive findings in animals, similar studies in humans have failed to show any benefit with l-arginine supplementation. Shiraki and colleagues studied the effects of short-term high-dose l-arginine on restenosis after PTCA.[30] Thirty-four patients undergoing cardiac catheterization and PTCA for angina pectoris received 500 mg of l-arginine administered through the cardiac catheter immediately prior to PTCA and 30 g per day of l-arginine administered via the peripheral vein for 5 days after PTCA. No significant statistical differences in restenosis were observed between the two groups (34% vs 44%). The authors speculated that the lack of effect was secondary to the fact that although the levels of l-arginine in the plasma increased significantly, NO and cyclic guanosine monophosphate (cGMP) did not.

Dudek and colleagues examined the long-term effects of l-arginine supplementation in humans undergoing coronary artery stenting.[31] Subjects in the treatment group were given l-arginine intravenously for 12 hours prior to stenting (200 mg/kg), during the procedure (200 mg/kg), through the cardiac catheter (500 mg), and then with oral supplementation for 2 weeks after stenting (6.0 g/d). Again, despite the increased plasma levels of l-arginine seen in the treatment groups, there was no difference in restenosis between the two groups at 7 months measured both by quantitative coronary angiography and intravascular ultrasonography. The authors concluded that chronic administration of l-arginine in human subjects had no effect on the development of neointimal hyperplasia.

Another example of a NO-donating drug is the hybrid drug NO-releasing aspirin. It was originally developed to help combat the ulcerogenic properties of aspirin despite its excellent cardioprotective effects. Furthermore, NO was found to have added protective effects on the vasculature over aspirin alone. Napoli and colleagues examined the effects of a NO-releasing aspirin called NCX-4016 (55 mg/kg) on adult and aging rats using a balloon carotid artery injury model.[32] The drug was shown to reduce the neointimal area in adult (18.2 ± 1.8 vs 31.8 ± 2.9, p < .01) and aging rats (24.1± 1.6 vs 44.9± 3.6, p < .01) compared with untreated controls. The drug was also found to have less ulcerogenic activity compared with aspirin alone (30 mg/kg). The authors proposed that this drug could be used as an adjunct to bypass surgery in older patients and those with gastrointestinal damage.

Shukla and colleagues examined the effect of three different NO-releasing aspirin drugs on human saphenous vein grafts and human VSMCs in vitro.[33] They found that these drugs elicited relaxation of isolated human saphenous vein, promoted cGMP formation, and inhibited VSMC proliferation, whereas aspirin alone had no effect on any of these variables. The authors speculated that these drugs could be used to prevent early and late thrombosis secondary to vein spasm and neointimal hyperplasia.

Two other examples of NO-donating drugs that can be delivered systemically are linsidomine and molsidomine. They are members of the sydnonimine antianginal class of drugs ( Table 1 ). Both drugs have been used as NO donors for the treatment of hypertension and angina. A benefit of their use over the more conventional use of organic nitrates is that there is no demonstrated tolerance to their effectiveness. One of the first studies that examined molsidomine's ability to reduce neointimal hyperplasia after vascular procedures was performed by Groves and colleagues.[34] Carotid angioplasties were performed on pigs to induce vascular injury. The pigs were given either oral molsidomine (0.3 mg/kg every 8 hours) or placebo for 48 hours before the procedure and continued administration until the time of vessel harvesting (7 or 21 days). A significant reduction in VSMC proliferation was seen in the treatment group compared with placebo. Although NO inhibited VSMC proliferation following angioplasty, it had no significant influence on VSMC migration or extracellular matrix production within the intima. Furthermore, this reduction in VSMC proliferation was present only if the internal elastic lamina had not been ruptured by balloon dilation.

One of the only studies that examined the use of these drugs systemically to reduce neointimal hyperplasia in humans was the ACCORD Study.[35] This was a prospective randomized multicenter trial in which 700 patients with stable angina underwent PTCA. It compared the effect of intravenous infusion (1 mg/h) of linsidomine at the time of PTCA and subsequent oral administration of molsidomine (12 mg/day) orally for 6 months with that of oral diltiazem (180 mg/day) alone. All patients received aspirin postoperatively. The study revealed only a moderate improvement in restenosis in the treatment group on long-term angiographic follow-up, but this did not correlate with improved clinical outcome or late lumen loss.

Several years later, Wohrle and colleagues performed a randomized, placebo-controlled, double-blinded trial that compared oral molsidomine with placebo and their ability to inhibit neointimal hyperplasia after PTCA.[36] No statistically significant differences were found between the two groups, although the molsidomine treatment group did have significantly improved angina compared with the placebo group.

Despite the ease of administration, the reliability of drug delivery, and the relative safety of these NO-donating drugs, there are limitations associated with systemic administration. One such limitation is that NO is rapidly inactivated by hemoglobin in the circulating blood, resulting in limited bioavailability. Furthermore, in attempts to increase the amount of drug delivered to obtain the desired clinical effect, unwanted systemic circulatory effects (eg, vasodilation) and unwanted hemostatic effects (eg, bleeding) often preclude administration of biologically effective doses of NO.[37] Because NO produces systemic side effects, lower doses of NO have been used in many of the human studies. One of the reasons for the differences observed between the animal studies and the human studies was the 10- to 50-fold lower doses of drugs used in the human studies compared with the animal studies. Thus, local delivery of NO may achieve improved results.[38]

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