Endothelin increases nitric oxide-dependent cgmp production in
isolated glomeruli but not in mesangial cells.
Tack, I., E. Marin Castano, C. Pcher, F. Praddaude, J. L. Bascands, G.
Bompart, J. L. Ader & J. P. Girolami.
Inserm U 388, and Department of Physiology, Louis Bugnard
Institute, CHU Rangueil 31054 Toulouse France, Fax : 33 62 17 25 54,
Phone : 33 61 32 22 10
APStracts 3:0177F, 1996.
The ability of endothelins (ET) to modulate nitric oxide-dependent
glomerular guanosine 3O-5O-cyclic monophosphate (cGMP) production has
recently been reported. The aim of this study was to directly
confirm, using an antagonist, the involvement of the ETB receptor
subtype and to investigate the potential role of mesangial cells (MC)
in this endothelin-induced cGMP production. In glomeruli freshly
isolated from rats, endothelin 3 (ET-3) induced a dose-dependent
increase in cGMP content. This increase was inhibited by L-NMMA and
methylene blue and was calcium-dependent. Moreover, the effect of ET
-3 was prevented by two ETB-selective receptor antagonists BQ-788 and
IRL 1038, but not by BQ 123, an ETA-selective receptor antagonist. It
therefore appeared that ET-3 stimulates the glomerular constitutive
NO pathway through activation of the ETB receptor subtype. In
contrast, ET-3 and calcium ionophore had no effect on cGMP formation
in cultured mesangial cells, whereas incubation with sodium
nitroprusside resulted in an approximately 50-fold increase in the
intracellular content of cGMP. However, ET-3 induced a dose-dependent
rise in free MC cytosolic calcium that was abolished by an ETB
antagonist. Moreover, both ETA and ETB receptor mRNA were expressed
in primary cultures of MC. Finally, we failed to detect the presence
of constitutive NO synthase (NOS) as demonstrated by the absence of
L-citrulline forming activity and of the mRNA encoding for
endothelial NOS whereas they were present in isolated glomeruli.
These data indicate that mesangial cells, despite the fact that they
express ETB receptors, are not involved in glomerular NO production
induced by exposure to ET-3 because they do not express constitutive
NO synthase.
Received 29 September 1995; accepted in final form 16 September
1996.
APS Manuscript Number F328-5.
Article publication pending Am. J. Physiol. (Renal Fluid Electrolyte
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 5 November 1996