Effects of the immunosuppressant cyclosporin A on neurotransmitter release from peripheral non-adrenergic, non-cholinergic nerves.
This study was undertaken to determine the effect of the immunosuppressant cyclosporin A on neurotransmitter release from non-adrenergic, non-cholinergic nerves (tachykininergic nerves) in the rabbit iris sphincter muscle. Cumulative application of cyclosporin A (0.1 to 10 microM) caused a slow onset of contraction in a concentration-dependent manner. Both FK888 (1 microM) and capsaicin (10 microM), a substance P receptor antagonist and a substance P-depleting agent, respectively, inhibited the contractile effect of cyclosporin A, whereas atropine (1 microM) had no effect. Both cyclosporin A and capsaicin (10 microM) stimulated the release of substance P-like immunoreactivity in the iris. Neither the sodium channel blocker tetrodotoxin (1 microM), the N-type voltage-dependent Ca2+ channel blocker omega-conotoxin GVIA (1 microM) nor the P-type channel blocker omega-agatoxin IVA (0.2 microM) affected cyclosporin A (1 microM)-induced contraction. In contrast, the L-type Ca2+ channel blocker nicardipine (10 microM) inhibited this contractile effect. These results suggest that cyclosporin A stimulates substance P-like tachykinin release by activating L-type voltage-dependent Ca2+ channels, resulting in contraction of the rabbit iris sphincter muscle.
Kageyama
M
M
Ophthalmic Research Division, Santen Pharmaceutical Co., Ltd., Nara, Japan.
Fujita
H
H
Nakata
K
K
Shirasawa
E
E
Kanai
A
A
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D007498:Iris / Q000187:drug effects / Q000294:innervation* / Q000378:metabolism; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation* / Q000378:metabolism; D009412:Nerve Fibers / Q000378:metabolism*; D064729:Neurokinin-1 Receptor Antagonists; D011817:Rabbits; D026941:Sodium Channel Blockers; D013373:Substance P / Q000378:metabolism*
D002121:Calcium Channel Blockers; D004151:Dipeptides; D007166:Immunosuppressive Agents; D007211:Indoles; D018727:Muscarinic Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D026941:Sodium Channel Blockers; C078949:FK 888; D013373:Substance P; D001285:Atropine; D016572:Cyclosporine; D002211:Capsaicin