Contribution of EGF-Receptor Tyrosine Kinase to Angiotensin II-Induced Renal Arteriolar Constriction
Tyrosine kinase activity has been reported to modulate voltage-gated Ca2+ channels (VGCCs), and has been implicated in both the Ca2+ mobilization and Ca2+ influx responses to angiotensin II (AngII). Because renal afferent arteriolar contractile responses to AngII rely on opening of VGCCs while efferent arteriolar AngII responses arise independent of VGCCs, we designed experiments to determine if AngII contracts these arteriolar segments via a mechanism involving tyrosine kinase activation and to examine the role of VGCCs in this phenomenon. Rats were subjected to acute enalaprilat treatment to decrease endogenous AngII formation prior to harvesting tissue for experiments using the in vitro blood-perfused juxtamedullary nephron technique. Papillectomy was employed to avoid the indirect afferent arteriolar effect of AngII that arises via increased tubuloglomerular feedback sensitivity. Arteriolar lumen diameter responses to 1 and 10 nM AngII were monitored using videomicroscopic methods before and during inhibition of EGF-receptor tyrosine kinase activity (100 μM tyrphostin A23). Afferent arteriolar baseline diameter averaged 23.5 ± 1.2 μm (n = 12) and was unaffected by tyrphostin A23. AngII (10 nM) decreased afferent diameter by 13.7 ± 1.9 μm before and 9.6 ± 1.4 μm during tyrphostin A23 treatment (n = 7; P < 0.05), indicating 28 ± 8% inhibition of AngII-induced constriction. However, tyrphostin A23 did not suppress afferent arteriolar contractile responses to membrane depolarization (20-55 mM bath K+; n = 5). Neither baseline diameter nor AngII responsiveness was altered by exposure of afferent arterioles to tyrphostin A1 (inactive analog). Efferent arteriolar baseline diameter averaged 23.6 ± 1.1 μm (n = 6) and was not influenced by tyrphostin A23, but this agent evoked a 52 ± 9% inhibition of the efferent arteriolar diameter response to 10 nM AngII. These observations indicate that 1) EGF-receptor tyrosine kinase activation contributes to AngII-induced contraction of both afferent and efferent arterioles, and 2) a direct influence of the EGF-receptor tyrosine kinase on VGCCs is not likely involved in the afferent arteriolar response to AngII.