Nitric oxide-induced ciliary muscle relaxation during contraction with endothelin-1 is mediated through elevation of cyclic GMP.
OBJECTIVE
Nitric oxide (NO) relaxes ciliary smooth muscle, and endothelin-1 (ET-1) is reported to regulate ciliary muscle tone. Despite the physiological significance of nitric oxide and ET-1, very few studies have attempted to characterize the mutual modes of action of these mediators in this tissue. Thus, the present experiments were designed to investigate a possible relaxation mechanism of nitric oxide in bovine ciliary muscle that has been contracted by ET-1.


METHODS
The effects of sodium nitroprusside (SNP), as a nitric oxide donor, methylene blue, as an inhibitor of guanylate cyclase, and 8-bromo-cyclic GMP on the bovine ciliary muscle contracted with ET-1 were examined. The changes in cyclic GMP level and relaxation, in response to SNP alone or in combination with 3-isobutyl-1-methylxanthine (IBMX) as a nonselective inhibitor of phosphodiesterases, were also determined.


RESULTS
Sodium nitroprusside (SNP) produced a concentration-dependent relaxation, which was significantly (p < 0.005) augmented by 10(-5) M 3-isobutyl-1-methylxanthine (IBMX) and significantly (p < 0.005) attenuated by 3 x 10(-5) M methylene blue as an inhibitor of guanylate cyclase. The relaxation in response to SNP was accompanied by an increase in the cyclic 3':5' guanosine monophosphate (cyclic GMP) level, which was again significantly (p < 0.05) augmented by 10(-5) M IBMX and significantly (p < 0.005) attenuated by 3 x 10(-5) M methylene blue. The exogenously applied 8-bromo-cyclic GMP relaxed the ciliary muscle strips during the contraction caused by ET-1.


CONCLUSIONS
These results lead us to assume that NO generated from SNP is closely related to cyclic GMP production via the activation of guanylate cyclase and, in turn, causes a relaxation response in the bovine ciliary muscle contracted with ET-1.
Masuda
H
H
Department of Medicinal Chemistry, Faculty of Medicine, Tokyo Medical and Dental University, Japan.
Tamaoki
S
S
Goto
M
M
Ishida
A
A
Kamikawatoko
S
S
Tokoro
T
T
Azuma
H
H
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002924:Ciliary Body / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004338:Drug Combinations; D019332:Endothelin-1 / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D008751:Methylene Blue / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation; D009569:Nitric Oxide / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology
D004338:Drug Combinations; D019332:Endothelin-1; D010726:Phosphodiesterase Inhibitors; D009599:Nitroprusside; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D008751:Methylene Blue; D015056:1-Methyl-3-isobutylxanthine