Korean J Physiol Pharmacol.  1998 Aug;2(4):471-477.

Acute cyclosporin A-treatment impairs the cytosolic guanylate cyclase-mediated vasodilatation in rat thoracic aorta

• Kook H

Abstract

Cyclosporin A (CsA), a widely used immunosuppressant, is well known to cause nephrotoxicity and hypertension as major side effects. The present study was aimed at investigating the effects of CsA-pretreatment on the activities of cytosolic guanylate cyclase (cGC) in relation to the alteration of relaxant responses in the rat thoracic aorta. CsA (10 micrometer)-preincubation for 90 min significantly attenuated the vasodilatation induced by sodium nitroprusside (SNP), a cytosolic guanylate cyclase activator, shifting the dose-response curve to the right. The increase in cGMP contents induced by SNP was markedly attenuated by CsA. SNP (1 micrometer apprx 1 mM) increased the cGC activity dose-dependently, and the increase was completely abolished by CsA. CsA attenuated the SNP-induced cGC activation dose-dependently. The abolishing effect of CsA-pretreatment on the SNP-induced cGC activation was not affected by washing the preparation, suggesting that the inhibition is irreversible. When CsA was added simultaneously with SNP, cGC activation was not attenuated. 1-(5-isoquinolinylsulfonyl)-2-methyl piperazine (H-7), a protein kinase C (PKC) inhibitor, decreased SNP-induced cGC activation and blocked the CsA-attenuation of cGC activation. These results suggest that CsA directly inhibits cGC participating in the CsA-induced impairment of vasodilatation, and that PKC is involved in the inhibitory action of CsA on cGC.

Keyword

Cyclosporin A; Cytosolic guanylate cyclase; cGMP; Vasodilatation; Rat thoracic aorta

MeSH Terms

Animals
Aorta, Thoracic*
Cyclosporine*
Cytosol*
Guanylate Cyclase
Hypertension
Nitroprusside
Protein Kinase C
Rats*
Vasodilation*
Cyclosporine
Guanylate Cyclase
Nitroprusside
Protein Kinase C