To investigate the role that atrial natriuretic peptides (ANP) play in regulating coronary circulation in vivo, we examined the effects of intravenous (iv) ANP and/or HS-142-1 (HS), a specific ANP receptor antagonist, in chronically instrumented dogs on circumflex coronary artery diameter (CoD) and coronary blood flow (CBF). At ANP plasma levels of 366.7, 785.0, and 1850.0 pg/ml, which were induced by continuous iv infusion of ANP at 25, 50, and 100 ng/kg per min respectively, ANP increased CoD by 1.2 +/- 0.3%*, 2.2 +/- 0.5%*, and 2.9 +/- 0.5%*, and decreased mean systemic blood pressure by 2.3 +/- 1.0%, 4.3 +/- 1.5%* and 5.3 +/- 1.8%* (*p < 0.05), respectively. A significant increase in the plasma cGMP level was also observed. However, neither CBF nor heart rate changed significantly. Pretreatment with HS (3 mg/kg) almost completely suppressed these hemodynamic effects of ANP along with inhibiting the increases in the plasma cGMP level. However, under control conditions, HS itself (3 mg/kg, iv) produced no significant changes in coronary parameters. Thus, ANP significantly increased CoD at plasma levels 10- to 20-fold higher than those in the control. These findings suggest that in patients under pathological conditions such as severe congestive heart failure increased endogenous ANP may contribute to the regulation of coronary circulation as a compensatory mechanism. It may also have direct vasodilatory effects on epicardial vessels, since HS suppressed both its coronary effects and the increase in plasma cGMP levels. However, in normal subjects, endogenous ANP may have little direct effect on coronary circulation.