Nitric oxide and natriuretic peptides are endogenous vasodilators that protect against pulmonary hypertension progression. We compared nitric oxide synthase (NOS) and natriuretic peptides (NPs) expression levels in Holstein heifers with brisket disease and healthy controls located at Lhasa for one year. Physiological parameters, blood pressure and blood gas status were measured. Plasma samples were analyzed for brain NP, C-type NP, adrenomedullin, endothelial NOS (eNOS), inducible NOS (iNOS), total NOS (TNOS) and NOx levels (n = 10/group). We performed histological analyses to detect remodeling of small pulmonary arteries. RT-PCR and Western blots were used to determine lung eNOS and endothelin-1 (ET-1) expression. Respiratory rates, oxygen saturation and blood velocity were significant higher in healthy controls. However, heart rates were higher in heifers with brisket disease. Peripheral arterial pressures were significantly higher in healthy controls than those in cattle with brisket disease. In healthy cattle, plasma NPs, eNOS, iNOS, TNOS and NOx levels were elevated relative to those in cattle with brisket disease. Moreover, eNOS mRNA and protein were highly expressed in healthy control lungs (P < 0.01, P < 0.01, respectively). Immunostaining revealed that eNOS was highly expressed in the intima of pulmonary arterioles. In addition, ET-1 mRNA and protein levels were reduced in healthy cattle compared with those of cattle with brisket disease (P < 0.05, P < 0.01, respectively). Cattle with brisket disease displayed small pulmonary arterial adventitial thickening, proliferation of smooth muscle cells and low eNOS expression in the intima. In conclusion, it is possible that highly expressed NO and NPs dilate vasculature, maintain blood flow and pressure and attenuate vascular remodeling to protect against pulmonary hypertension progression.