Tyrosine kinase involvement in renal arteriolar constrictor responses to angiotensin II.
Experiments were performed to test the hypothesis that tyrosine kinase activity contributes to renal arteriolar contractile responses to angiotensin (Ang) II. Rats were subjected to short-term enalaprilat treatment to decrease endogenous Ang II formation before tissue was harvested for experiments with the in vitro blood-perfused juxtamedullary nephron technique. Acute surgical papillectomy was used to avoid the indirect afferent arteriolar effect of Ang II that arises through increased tubuloglomerular feedback sensitivity. Arteriolar lumen diameter responses to 1 and 10 nmol/L Ang II were monitored by videomicroscopic methods before and during treatment with various tyrphostin compounds: 100 micromol/L AG18 (broad-spectrum tyrosine kinase inhibitor), 100 nmol/L AG1478 (selective epidermal growth factor receptor tyrosine kinase inhibitor), or 100 micromol/L AG9 (inactive analog). Baseline afferent arteriolar lumen diameter averaged 23.5+/-1.2 micrometer and was not influenced by any tyrphostin. Ang II (10 nmol/L) decreased afferent diameter by 11.1+/-1.0 micrometer under untreated conditions, a response that was not altered by AG9 but significantly blunted by AG18 (34+/-9% inhibition) or AG1478 (52+/-8% inhibition). AG18 did not suppress afferent arteriolar contractile responses to membrane depolarization (20 to 55 mmol/L K(+ )bath). Efferent arteriolar baseline diameter averaged 24.1+/-0.8 micrometer and was unaltered by AG18 or AG1478; however, efferent diameter responses to 10 nmol/L Ang II were diminished 52+/-10% by AG18 and 51+/-13% by AG1478. These observations indicate that Ang II signaling in renal afferent and efferent arteriolar vascular smooth muscle is either mediated or modulated by tyrosine kinase activity, including that of the epidermal growth factor receptor tyrosine kinase.
Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, NE, USA. pkcarmin@unmc.edu
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D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D015773:Enalaprilat; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D018715:Microscopy, Video; D010477:Perfusion; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011799:Quinazolines; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology; D014661:Vasoconstriction
D004791:Enzyme Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; D000804:Angiotensin II; C101044:RTKI cpd; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D015773:Enalaprilat; C060641:tyrphostin A23