Orally administered nitrates in patients with exertional angina.

hou h the efficacy of sublingual nitroglycerin in relieving anginal attacks in patients with ischemic heart disease remains unquestioned, the role of the orally administered, so-called long-acting, nitrates in preventing angina is less certain. Originally, skepticism concerned whether such agents reach the systemic circulation in active forms.’ Recent studies have demonstrated, however, that within 15 minutes of ingestion, nitrates effect a decrease in left ventricular volume, a fall in systemic arterial pressure, a reflex rise in heart rate, a fall in left ventricular ejection time index, improvement in segmental wall motion, and improvement in exercise capacity. 2,3 Both the magnitude and duration of the effects appear to be doserelated.2 The genesis of the increased exercise capacity following administration of nitrates could involve increased myocardial oxygen supply and/or decreased demand. Both dilatation of coronary arterial stenoses4 and decreased resistance in coronary collaterals3 have been observed following nitrate administration and suggest a role for increased supply. Most evidence, however, suggests that more important factors are the decrease in myocardial wall tension and its attendant deci ease in oxygen demand brought about by nitrateinduced systemic venous and arterial dilatation. This conclusion is supported by the relief of pacing-induced angina by intravenous nitroglycerin after delivery of the drug directly into the coronary arteries failed to relieve the symptom,6 and by the relief of pacinginduced angina by phlebotomy alone.7 The nitrateinduced decrease in left ventricular wall tension and end-diastolic pressure might, of course, not only decrease oxygen demand, but also increase supply by decreasing the resistance to coronary capillary flow, especially in the subendocardial myocardium.8 In contrast to orally-administered nitrates, betaadrenergic blocking agents have received almost universal acceptance as agents effective in preventing exercise-induced angina. Because the drugs decrease myocardial oxygen demand through different mechanisms, beta blockers and sublingually-administered nitrates have been found to have additive salutary effects.9 In this issue of Chest, Bassan and WeilerRavel! (see page 233) describe improved exercise capacity following orally administered isosorbide dinitrate in nine of ten patients whose angina was incompletely relieved by propranolol; in eight of the nine the improvement lasted five to eight hours after a dose of the nitrate that lowered systolic blood pressure 20 mm Hg with the patient sitting. Therefbre, that single doses of orally administered nitrates are effective prophylactic antianginal agents, have a dose-dependent relatively long duration of action, and add significantly to the antianginal effects of beta-adrenergic blocking agents seems well established. Many questions, however, are unanswered. Which oral nitrate is most effective? Isosorbide dinitrate is the most thoroughly researched, but other nitrates seem to have similar 0 Which preparation of an effective nitrate is best absorbed? Isosorbide dinitrate tablets2 and sustained release capsules” have been shown to be effective antianginal agents, but patients often complain that the sustained release tablets appear in their stools. Do sublingual, transmucosal, chewable, or transdermal preparations of long-acting nitrates offer any advantages over the oral ones? The important question of nitrate tolerance continues to be debated. Current evidence suggests that with commonly employed dosing schedules, tolerance to the heniodynamic effects of long-acting nitrates develops within a few days, is never complete, is due to endorgan hyporeactivity and not to accelerated metabolism, and is accompanied by the development of some cross-tolerance to sublingual nitroglycerin.’2 For reaSons yet unexplained, improved exercise tolerance persists despite the blunted hemodynamic response at rest.’3 Nitrate dependence, such as occurs in munitions workers,’4 has not been documented with the therapeuti use of nitrates, but would be difficult to distinguish from progression of underlying ischemic heart disease. Similarly, whether in the clinical setting nitrate-induced dilatation of arteries and arterioles supplying normal myocardium ever steals blood from the already maximally dilated arterioles supplying ischemic areas is unknown.’5 Such considerations prompt caution in the chronic prescription and/or abrupt withdrawal of long-acting nitrates. Finally, the role of long-acting nitrates must be redefined in the presence of the calcium ion antagonists. These latter agents have proved highly effective when, as in patients with Prinzmetal’s variant angina, coronary arterial spasm is a dominant feature. In patients with typical exertional angina, however, the beneficial effects of these drugs, like those of nitrates, may result primarily from systemic vasodilatation, and