Stress may affect gap junction connexin 43 and matrix metalloproteinase-2/9 (MMP-2/9) in cardiacfibroblasts, potentially contributing to worsening cardiac function and arrhythmias. Cardiac fibroblastsisolated from neonatal rat were incubated with isoproterenol at 3×10?7 M to mimic stress and were treatedwith either PD156707 or IRL-1038 (selective antagonists for endothelin A and B receptor respectively) and PU0213 (a dual endothelin A/B receptor antagonist) at 1×108 M, 3×108M or 1×107 M. RT-PCR and estern blotting were conducted. Upregulation of the two endothelin receptors, MMP-2/9 and NADPH xidase subunits (p22phox and p47phox), and downregulation of connexin 43 in cardiac fibroblasts were found in the presence of isoproterenol and were attenuated by the selective blockers PD156707 and IRL-1038 in a dose-dependent manner. IRL-1038 was less effective. CPU0213 appeared to be more effective than the two selective blockers in blocking these changes. Changes in cardiac fibroblasts in response toisoproterenol mediated by upregulation of the endothelin–NADPH oxidase pathway may play a role in deteriorating cardiac function and arrhythmias. The endothelin A receptor has a major role, relative to the endothelin B receptor, in the remodeling of cardiac fibroblasts during isoproterenol stimulation. CPU0213, a dual endothelin receptor A/B blocker, seems to be more effective in normalizing these changes than do the selective endothelin receptor antagonists.