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Effect of tyrosine kinase blockade on norepinephrine-induced cytosolic calcium response in rat afferent arterioles

¹Department of Medical Physiology, Division of Renal and Cardiovascular Research, The Panum Institute, University of Copenhagen, 2200 Copenhagen N, Denmark; and ²Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7545

Submitted 6 June 2003 ; accepted in final form 31 December 2003

We used genistein (Gen) and tyrphostin 23 (Tyr-23) to evaluate the importance of tyrosine phosphorylation in norepinephrine (NE)-induced changes in intracellular free calcium concentration ([Ca²⁺]_i) in rat afferent arterioles. [Ca²⁺]_i was measured in microdissected arterioles using ratiometric photometry of fura 2 fluorescence. The control [Ca²⁺]_i response to NE (1 µM) consisted of a rapid initial peak followed by a plateau phase sustained above baseline. Pretreatment with the tyrosine kinase inhibitor Tyr-23 (50 µM, 10 min) caused a slow 40% increase in baseline [Ca²⁺]_i. Tyr-23 attenuated peak and plateau responses to NE, both by 70%. In the absence of extracellular Ca²⁺ (0 Ca), Tyr-23 reduced the immediate [Ca²⁺]_i response to NE by 60%, indicative of mobilization of internal stores, and abolished the plateau phase. In other arterioles, the [Ca²⁺]_i response to depolarization induced by KCl (50 mM) was not attenuated by Tyr-23, indicating no direct effect on L-type Ca⁺ channels activated by depolarization. The Ca²⁺ channel blocker nifedipine (1 µM) inhibited the NE response by 50%; the effects of nifedipine and Tyr-23 were not additive. Nifedipine had no inhibitory effect after Tyr-23 pretreatment, indicating Tyr-23 inhibition of Ca²⁺ entry. Another tyrosine kinase inhibitor, Gen (5 and 50 µM), did not affect baseline [Ca²⁺]_i. High-dose Gen inhibited the peak and plateau response to NE by 87 and 75%, respectively; low-dose Gen attenuated both responses by 20%. In 0 Ca, Gen (50 µM) abolished the immediate [Ca²⁺]_i mobilization response. Combined nifedipine and Gen (50 µM) inhibited the rapid NE response by 90% in the presence of extracellular Ca²⁺. Gen (50 µM) also inhibited by 60% the [Ca²⁺]_i response to 50 mM KCl, indicating a direct interaction with voltage-sensitive, L-type Ca²⁺ entry channels. These results indicate that tyrosine phosphorylation is an important link in the chain of events leading to -adrenoceptor-induced Ca²⁺ recruitment (both entry and release) in afferent arteriolar smooth muscle cells. Furthermore, different blockers of tyrosine kinase appear to have different modes of action in renal microvessels.

-adrenoceptor; renal circulation; vascular smooth muscle cells; genistein; tyrophostin 23; Ca²⁺ mobilization; Ca²⁺ entry; L-type Ca²⁺ channels

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