Phospholipase C and Src modulate angiotensin II-induced cyclic AMP production in preglomerular microvascular smooth-muscle cells from spontaneously hypertensive rats.
Our previous study indicates that the phospholipase C family (PLC) and Src kinase family (Src) modulate adrenoceptor-induced cAMP production in a negative and positive manner, respectively, in preglomerular vascular smooth-muscle cells (PGSMCs) obtained from spontaneously hypertensive rats (SHR). Because angiotensin II (Ang II) activates PLC and Src, and because PLC and Src inhibit and augment cAMP production, respectively, it is conceivable that the balance between these signal-transduction pathways determines whether Ang II increases or decreases cAMP production in SHR PGSMCs. In SHR PGSMCs, Ang II (500 nM) did not alter cAMP production in the absence or presence of PP1 (100 nM; inhibitor of Src). In the presence of U73122 (3 microM; inhibitor of PLC), Ang II stimulated cAMP production from 2.2 +/- 0.062 to 4.7 +/- 0.73 pmol/well. In another study in U73122-pretreated SHR PGSMCs, Ang II increased cAMP from 3.0 +/- 0.07 to 6.3 +/- 0.40 pmol/well, and this response was blocked by PP1. RT-PCR of 10 isoforms of Scr (Lck, Hck, Frk Fyn, Blk, Lyn, Fgr, Yes, Yrk, and c-Src) indicated that SHR PGSMCs preferentially express Frk, Fyn, Lyn, and c-Src. We conclude that in SHR PGSMCs, inhibition of PLC uncovers a stimulatory effect of Ang II on cAMP production that is mediated by Src family kinases, most likely Frk, Fyn, Lyn, and/or c-Src.
Jackson
Edwin K
EK
Department of Medicine, Center for Clinical Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA. edj@pitt.edu
Gillespie
Delbert G
DG
Jackson
Travis C
TC
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D000242:Cyclic AMP / Q000096:biosynthesis*; D004963:Estrenes / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013050:Spectrometry, Fluorescence; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
D004963:Estrenes; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D000804:Angiotensin II; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D000242:Cyclic AMP; D019061:src-Family Kinases; D010738:Type C Phospholipases; D015056:1-Methyl-3-isobutylxanthine