It is known that nitric oxide (NO) is an important regulator of coronary blood flow. The impact of obesity on NO-mediated coronary microvascular responses, however, is poorly understood. Thus, NO-mediated vasomotor responses were investigated in pressurized coronary arterioles (~100 µm) isolated from lean (on normal diet) and obese rats (fed with 60% of saturated fat). We found that dilations to acetylcholine (ACh) were not significantly different in obese rats, compared to those of lean controls (control: 83±4%, obese: 85±3% at 1µM), yet inhibition of NO synthesis with L-NAME reduced ACh-induced dilations only in vessels of lean controls. Presence of the soluble guanylate cyclase (sGC) inhibitor, oxadiazolo-quinoxaline (ODQ) elicited similar reduction in ACh-induced dilations in the 2 groups of vessels (control: 60±11%, obese: 57±3% at 1µM). Dilations to NO donors, sodium nitroprusside (SNP) and DETA-NONOate were significantly enhanced in coronary arterioles of obese rats, when compared to those of lean controls (lean: 63±6% and 51±5%, obese: 78±5% and 70±5%, respectively, at 1µM each), whereas dilations to 8-bromo-cGMP were not different in the 2 groups. In the presence of ODQ, both SNP and DETA-NONOate-induced dilations were reduced to a similar level in obese and lean rats. Moreover, in coronary arterioles SNP-stimulated cGMP immunoreactivity and also in carotid arteries cGMP levels were enhanced in obese rats, whereas the protein expression of eNOS and sGC1 subunit were not different in the 2 groups. Collectively, these findings suggest that in coronary arterioles of obese rats the increased activity of sGC leads to an enhanced sensitivity to NO, an adaptive mechanism, which may contribute to the maintenance of NO-mediated dilations and coronary perfusion in obesity.