PI3-kinase inhibitors abolish the enhanced chronotropic effects of angiotensin II in spontaneously hypertensive rat brain neurons.
Angiotensin II (Ang II), acting at Ang II type 1 receptors (AT1Rs), increases the firing rate of neurons from Wistar-Kyoto (WKY) rat brain via protein kinase C (PKC)- and calcium-calmodulin kinase II (CaMKII)-dependent mechanisms. The objectives of this study were twofold; first, to compare the Ang-II-stimulated increase in firing of neurons from WKY and spontaneous hypertensive rats (SHR) and second, to elucidate the signaling mechanisms involved. Action potentials were measured in neurons cultured from SHR and WKY rat brains using the whole cell configuration of the patch-clamp technique in the current-clamp mode. Ang II (100 nM) caused three- and sixfold increases in neuronal firing rate in WKY rat and SHR neurons, respectively; effects that were abolished by the AT1R antagonist Losartan (1 microM). Co-administration of calphostin C (10 microM, a PKC inhibitor) and KN-93 (10 microM, a CaMKII inhibitor) completely blocked this Ang II action in WKY rat neurons, while they caused only a approximately 50% attenuation in SHR neurons. The residual increase in firing rate produced by Ang II in SHR neurons was blocked by inhibitors of phosphatidylinositol 3 kinase (PI3-kinase), either LY 294002 (10 microM) or wortmannin (100 nM). These observations suggest that a PI3-kinase signaling pathway may be responsible for the enhanced chronotropic effect produced by Ang II in SHR neurons.
Sun
Chengwen
C
Department of Physiology and Functional Genomics, College of Medicine and McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, USA.
Du
Jianqing
J
Sumners
Colin
C
Raizada
Mohan K
MK
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000804:Angiotensin II / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D002909:Chronobiology Phenomena / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D000804:Angiotensin II; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors