One of the mechanisms whereby nitroglycerin is considered to reduce myocardial ischaemia and spasm is its preferential reduction of resistance of large compared with small coronary arteries. Accordingly, the action of nitroglycerin on these two resistance beds was compared with newer coronary vasodilator drugs. Following intracoronary administration of boluses of each drug, large and small vessel coronary resistance was measured in 14 dogs by recording the pressure drop across each vascular bed while flow was held constant. The dose of each drug was given to reduce small vessel resistance by 30% (range means 27 to 32%) which peaked at 5 to 10 s and declined to 8 to 18% at 1 min when reduction in large vessel resistance was at its maximum. At 1 min the large vessel resistance was decreased 56 +/- 5% by nitroglycerin, 23 +/- 5% by nitroprusside, 8 +/- 4% by perhexiline, 0 +/- 5% by verapamil and increased 8 +/- 5% by nifedipine. Nitroprusside reduced the large vessel resistance significantly less than nitroglycerin (P < 0.001) for an equivalent reduction in small vessel resistance. Perhexiline, verapamil and nifedipine did not significantly reduce large vessel resistance and the discrepancy between these results and their antianginal and antispasm effect in humans was not apparent from these experiments. However, a suitable model of coronary spasm in the dog following ergonovine injection could not be created.