Peripheral vasodilator responsiveness was examined in pacing-induced heart failure (HF) in 11 conscious dogs chronically instrumented for measurement of systemic (total peripheral resistance [TPR]) and local (iliac blood flow) vascular resistance. Dose responses to isoproterenol (ISO), acetylcholine (ACh), and nitroglycerin (NTG) were examined in the same dogs before pacing (control) and after 4 to 7 weeks of rapid ventricular pacing, which induced congestive HF, characterized by increased left ventricular end-diastolic pressure (6.7 +/- 0.4 [control] versus 28 +/- 1.5 [HF] mm Hg) and decreased cardiac output (-30 +/- 5%) and left ventricular dP/dt (-53 +/- 3%), as well as ascites and peripheral edema. In the control state, TPR fell by 57 +/- 2% in response to ISO (100 ng/kg), by 61 +/- 3% in response to ACh (3 micrograms/kg), and by 55 +/- 2% in response to NTG (10 micrograms/kg). In HF, smaller decreases (P < .05) in TPR were observed with the same doses of ISO (-50 +/- 2%) and ACh (-49 +/- 2%) but not with NTG (-58 +/- 3%). Depressed responses to systemic ISO and ACh, but not NTG, were observed in HF in the presence of ganglionic blockade and also after local administration of smaller doses of the drugs in the absence of ganglionic blockade, but where systemic effects were not elicited. Inhibition of nitric oxide synthase increased TPR to a greater degree before HF (+154 +/- 28% [control]) than after (+80 +/- 22% [HF]) and eliminated the depressed responses to ACh but not to ISO. beta-Adrenergic receptor density, as determined by 125I-cyanopindolol binding in membrane preparations from mesenteric vessels was significantly decreased after HF (130 +/- 3 [control] versus 100 +/- 8 [HF] fmol/mg, P < .05) without any change in affinity. Thus, peripheral vascular beta-adrenergic receptor downregulation occurs in HF, independent of altered endothelium-mediated peripheral vasodilation.