The highly inbred Fisher rat strain demonstrates both hyperresponsiveness of the airways to bronchoconstrictors and increased amounts of airway smooth muscle when compared with Lewis rats. We postulated that the excess airway smooth muscle in Fisher was attributable to a greater sensitivity to endogenous mitogenic stimuli with signaling mechanisms common to contractile stimuli. To test this possibility we investigated differences in the growth response of cultured airway smooth muscle cells (SMC) from these two strains. The Fisher SMC demonstrated an enhanced growth response to fetal bovine serum (FBS), as measured both by cell counting and [3H]thymidine incorporation. The difference in growth response was attributable to a more rapid transition in Fisher than Lewis SMC from the G0/G1 phase to the S phase of the cell cycle. When SMC growth was stimulated by either serotonin, endothelin 1, insulin, platelet-derived growth factor (PDGF), or combinations of the above factors, significant interstrain growth response differences were found only with either human PDGF (AB) or a combination of porcine PDGF (BB) and insulin. A polyclonal antibody to PDGF was less inhibitory to Fisher than Lewis SMC following stimulation with FBS. Thus, interstrain growth differences may reflect different responses to PDGF present in FBS, or to other factors which exert an influence during the G0 or G1 phase of the cell cycle.