Skin fibroblasts from newborn spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were cultured to study their growth rate and their reactivity to various agonists in terms of mitogenic potency and inositol phosphate production. A marked enhancement of nuclear 3H-thymidine incorporation, occurring after stimulation of quiescent fibroblasts by fetal calf serum, correlated with the increased growth rate of these cells with regard to WKY ones. Insulin (1 microgram/ml) and epidermal growth factor (10 ng/ml) induced two and four times greater DNA synthesis in SHR fibroblasts compared to WKY cells, without activating the phospholipase C pathway. In contrast, angiotensin II, bradykinin, vasopressin which stimulated inositol phosphate production, and phorbol-12 myristate 13-acetate were unable to stimulate DNA synthesis. Higher levels of tritiated inositol phosphates were produced in SHR cells after serum, bradykinin and angiotensin II stimulation, but not in WKY cells after vasopressin. This enhanced mitogenic response of SHR skin fibroblasts is probably due to a genomic alteration and appears to be independent of the hyperactivation of the phospholipase C to some vasoactive agonists.