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(Hypertension. 1996;27:1097-1103.)
© 1996 American Heart Association, Inc.

Articles

Tyrosine Kinase Signaling Pathways Modulate Angiotensin II–Induced Calcium ([Ca²⁺]_i) Transients in Vascular Smooth Muscle Cells

R.M. Touyz; E.L. Schiffrin

From the Medical Research Council (MRC) Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal (Quebec, Canada).

Abstract Tyrosine kinases have been implicated in vascular smooth muscle cell proliferation and contraction. Underlying mechanisms may involve Ca²⁺-dependent pathways. This study assesses relationships between angiotensin II (Ang II)–stimulated phospholipase C–mediated Ca²⁺ transients and tyrosine kinase–dependent pathways in vascular smooth muscle cells. Intracellular free Ca²⁺ 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⁺]_i effects of Ang II (1 nmol/L) were determined in vascular smooth muscle cells in which tyrosine kinase pathways were stimulated by insulin (70 µU/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 µmol/L tyrphostin A-23 and genistein). Ang II elicited a rapid and transient [Ca²⁺]_i response (from 94±8 to 239±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⁺]_i to 161±7, 189±3.7, and 183±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⁺]_i responses, whereas tyrosine kinase inhibition prevents [Ca²⁺]_i recovery after agonist stimulation. Interaction between tyrosine kinase– and phospholipase C–dependent signaling pathways modulates vascular smooth muscle cell [Ca²⁺]_i responses to Ang II.

Key Words: angiotensin II • calcium • protein-tyrosine kinase • insulin • platelet-derived growth factor • muscle, smooth, vascular

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