I. Tack et al., CYCLOSPORINE-A-INDUCED INCREASE IN GLOMERULAR CYCLIC-GMP IN RATS AND THE INVOLVEMENT OF THE ENDOTHELIN(B) RECEPTOR, British Journal of Pharmacology, 121(3), 1997, pp. 433-440
1 A transient two fold increase in the cyclic GMP content was observed
in rat freshly isolated glomeruli 6 to 9 h after a single subcutaneou
s injection of 20 mg kg(-1) cyclosporine A (CsA) in conscious animals.
2 In vitro stimulation with endothelin 3 (ET-3) of isolated glomeruli
obtained from CsA-untreated rats resulted in a dose-dependent increas
e in cyclic GMP content. The increase observed with 10 nM ET-3 was sim
ilar to that observed in glomeruli isolated 9 h after in vivo CsA admi
nistration. 3 The rise in glomerular cyclic GMP content after in vivo
CsA injection was prevented by in vivo treatment with L-NAME (10 mg kg
(-1)) or by in vitro calcium deprivation of the incubation medium. 4 T
he stimulating effects of CsA on glomerular cyclic GMP content were in
hibited by in vivo administration of the ETB receptor antagonist BQ-78
8 (2 mg kg(-1)) but not by the ETA receptor antagonist BQ-123 (2 mg kg
(-1)). 5 The maximum increase in glomerular cyclic GMP content induced
in vitro by acetylcholine (100 mu M) and by ET-3 (100 nM) was slightl
y lower (approximately by 20-25%, P<0.05) in glomeruli from CsA-treate
d rats than in glomeruli from untreated rats. In contrast, the maximum
increase achieved with 1 mu M sodium nitroprusside was similar in bot
h groups. 6 A single subcutaneous injection of CsA did not significant
ly alter the glomerular mRNA expression of constitutive endothelial NO
synthase (eNOS), as evaluated by RT-PCR, whereas the mRNA expression
of the inducible NO synthase (iNOS), which follows pretreatment with l
ipopolysaccharide, was prevented. 7 These results indicate that in viv
o administration of a single dose of cyclosporine A transiently increa
ses the cyclic GMP content of freshly isolated glomeruli, and that act
ivation of ETB receptors and stimulation of the NO pathway are involve
d in this process. Furthermore, a single administration of CsA does no
t impair eNOS mRNA expression and only slightly reduces NO-dependent g
lomerular cyclic GMP production.