LACK OF CROSS-TOLERANCE TO SHORT-TERM LINSIDOMINE IN FOREARM RESISTANCE VESSELS AND DORSAL HAND VEINS IN SUBJECTS WITH NITROGLYCERIN TOLERANCE

Background: Therapy with nitroglycerin is widely used in the treatment of angina pectoris, but development of tolerance is a major problem. Nitrovasodilators other than nitroglycerin may be less prone to induce vascular tolerance. This investigation was designed to test whether t he alternative nitric oxide donor linsidomine maintains its vasodilato r effects in the presence of nitroglycerin tolerance. Methods: We test ed the vascular effects of nitroglycerin and linsidomine (SIN-1) in fo rearm resistance arteries (venous occlusion plethysmography) and hand veins (venous compliance technique) using a randomized, double-blind p lacebo-controlled regimen in 33 healthy subjects (age range, 22 to 38 years; mean age, 26 years) before and after 7 days of assignment to ei ther I week of nitroglycerin administration (0.83 mg/hr) for induction of tolerance or placebo administration. Results: Vascular responses o f both vascular beds to nitroglycerin (in veins: mean difference, 42.3 %; confidence interval [CI], 3% to 81.7%; p < 0.05; in arteries: mean difference, 65.0%; CI, 38.9% to 91.1%; p < 0.01) but not to linsidomin e (in veins mean difference, -13.8%; CI, -53.5 to 25.8%; not significa nt; in arteries: -19.7%; CI, -33.7% to -5.6%; not significant) were at tenuated in the nitroglycerin patch group, whereas the placebo group s howed no differences to either nitroglycerin (in arteries: mean differ ence, -7.5%; CI, -44.6% to 29.6%; in veins: -10.6%; CI, -58.2% to 36.9 %) or linsidomine (in arteries: 4.5%; CI, -12.8% to 21.7%; in veins: - 13.1%; CI, -4.5% to 29.8%). Conclusion: These results suggest that she a-term administration of sydnonimines can overcome the loss of vascula r relaxation associated with long-term nitroglycerin therapy.