10 mN 10 mN K NTG NE NE K 10 min 10mN T NE NTG 10 min 10 mN K+Verapamil Figure 3.Effects of vasodilators on contractions of human vein segments studied in vitro.Panel A shows contractions induced by two vasoconstrictor agents, norepinephrine (NE)and potassium(K).Panel B shows the relaxation induced by nitroglycerin (NTG),4 umol/L.The relaxation is prompt.Panel C shows the relaxation induced by verapamil,2.2 umol/L.The relaxation is slower but more sustained.(Modified and reproduced,with permission,from Mikkelsen E,Andersson KE,Bengtsson B:Effects of verapamil and nitroglycerin on contractile responses to potassium and noradrenaline in isolated human peripheral veins.Acta Pharmacol Toxicol1978,42:14.) Toxicity.Tolerance A.ACUTE ADVERSE EFFECTS The major acute toxicities of organic nitrates are direct extensions of therapeutic vasodilation:orthostatic hypotension,tachycardia,and throbbing headache.Glaucoma, once thought to be a contraindication,does not worsen,and nitrates can be used safely in the presence of increased intraocular pressure.Nitrates are contraindicated, however,if intracranial pressure is elevated. B.TOLERANCE With continuous exposure to nitrates,isolated smooth muscle may develop complete tolerance (tachyphylaxis),and the intact human becomes progressively more tolerant when long-acting preparations(oral,transdermal)or continuous intravenous infusions are used for more than a few hours without interruption. Continuous exposure to high levels of nitrates can occur in the chemical industry, especially where explosives are manufactured.When contamination of the workplace with volatile organic nitrate compounds is severe,workers find that upon starting their work week(Monday),they suffer headache and transient dizziness.After a day or so, o10 Figure 3. Effects of vasodilators on contractions of human vein segments studied in vitro. Panel A shows contractions induced by two vasoconstrictor agents, norepinephrine (NE) and potassium (K+ ). Panel B shows the relaxation induced by nitroglycerin (NTG), 4 umol/L. The relaxation is prompt. Panel C shows the relaxation induced by verapamil, 2.2 umol/L. The relaxation is slower but more sustained. (Modified and reproduced, with permission, from Mikkelsen E, Andersson KE, Bengtsson B: Effects of verapamil and nitroglycerin on contractile responses to potassium and noradrenaline in isolated human peripheral veins. Acta Pharmacol Toxicol 1978;42:14.) Toxicity  Tolerance A. ACUTE ADVERSE EFFECTS The major acute toxicities of organic nitrates are direct extensions of therapeutic vasodilation: orthostatic hypotension, tachycardia, and throbbing headache. Glaucoma, once thought to be a contraindication, does not worsen, and nitrates can be used safely in the presence of increased intraocular pressure. Nitrates are contraindicated, however, if intracranial pressure is elevated. B. TOLERANCE With continuous exposure to nitrates, isolated smooth muscle may develop complete tolerance (tachyphylaxis), and the intact human becomes progressively more tolerant when long-acting preparations (oral, transdermal) or continuous intravenous infusions are used for more than a few hours without interruption. Continuous exposure to high levels of nitrates can occur in the chemical industry, especially where explosives are manufactured. When contamination of the workplace with volatile organic nitrate compounds is severe, workers find that upon starting their work week (Monday), they suffer headache and transient dizziness. After a day or so