Adrenergic Pathways Mediate Circadian IOP Rhythm in Rats

This study sought to define adrenergic receptor mechanisms underlying circadian intraocular pressure (IOP) regulation in rats.

IOP was monitored continuously via wireless telemetry in adult Brown-Norway rats entrained to the ambient light/dark (LD) cycle and then maintained in constant darkness (DD). Agonists and antagonists of β- (isoproterenol and timolol), α1- (phenylephrine and bunazosin), and α2- (brimonidine and yohimbine) receptors were applied topically to the cornea during subjective day (SD) and subjective night (SN) in DD. Drug effects were quantified by short-term changes in mean IOP and long-term changes in IOP rhythmicity.

Animals exhibited a pronounced IOP rhythm in LD that persisted in DD. IOP was significantly reduced after SN instillation of timolol (DSN% = -110% ± 24%), bunazosin (DSN% = -107% ± 13%), yohimbine (DSN% = -106% ± 12%), and brimonidine (DSN% = -94% ± 18%) and was unchanged after SD instillation. Conversely, IOP was significantly elevated after SD instillation of phenylephrine (DSD% = 143% ± 62%) and isoproterenol (DSD% = 62% ± 19%) and was unchanged after SN instillation. None of the drugs altered IOP rhythm period or phase, but bunazosin abolished the rhythm for several days.

Multiple adrenergic receptor pathways participate in the circadian regulation of rat IOP. All are necessary to raise IOP during SN since inactivation of any individual pathway drops IOP fully back to daytime levels. β- and α1-receptor activation is also singularly sufficient to raise IOP during SD to nighttime levels, whereas α2-receptors play a more complex role in IOP regulation.