Tyrosine kinases have been implicated in vascular smooth muscle cell proliferation and contraction. Underlying mechanisms may involve Calcium2+-dependent pathways. This study assesses relationships between angiotensin II (Ang II)-stimulated phospholipase C-mediated Calcium2+transients and tyrosine kinase-dependent pathways in vascular smooth muscle cells. Intracellular free Calcium2+concentration ([Ca2+]i) was measured in primary cultured unpassaged vascular smooth muscle cells derived from mesenteric resistance vessels of Wistar-Kyoto rats with the use of fura 2 methodology. [Ca2+]ieffects of Ang II (1 nmol/L) were determined in vascular smooth muscle cells in which tyrosine kinase pathways were stimulated by insulin (70 micro U/mL; 0.5 nmol/L), insulin-like growth factor-I (1 ng/mL; 0.13 nmol/L), or platelet-derived growth factor-BB (1 ng/mL; 0.04 nmol/L) and in cells in which tyrosine kinase was inhibited by specific inhibitors (1 micro mol/L tyrphostin A-23 and genistein). Ang II elicited a rapid and transient [Ca2+] (i) response (from 94 plus/minus 8 to 239 plus/minus 5.8 nmol/L). Activation of the receptor tyrosine kinase by insulin, platelet-derived growth factor, and insulin-like growth factor-I significantly reduced (P < .01) Ang II-induced [Ca2+]ito 161 plus/minus 7, 189 plus/minus 3.7, and 183 plus/minus 5 nmol/L, respectively. In the presence of tyrphostin A-23 and genistein, Ang II-stimulated [Ca2+] (i) remained persistently elevated and failed to return to basal levels. Tyrphostin A-1, the inactive tyrphostin analogue, had no significant effect on Ang II-induced [Ca2+]i. This study demonstrates that activation of tyrosine kinase pathways reduces Ang II-elicited [Ca2+]iresponses, whereas tyrosine kinase inhibition prevents [Ca2+]irecovery after agonist stimulation. Interaction between tyrosine kinase- and phospholipase C-dependent signaling pathways modulates vascular smooth muscle cell [Ca (2+)]iresponses to Ang II. (Hypertension. 1996;27:1097-1103.)