Aqueous humor cyclic AMP and circadian elevation of intraocular pressure in rabbits.

Rabbits entrained in a daily light-dark environment show a circadian elevation of intraocular pressure (IOP) around the onset of dark. It was reported that concentration of cyclic AMP (cAMP) in aqueous humor increases significantly during this time period. Whether or not the increase of ocular cAMP-mediated activities is related to the circadian elevation of IOP is unclear. Light-dark entrained rabbits maintain the circadian IOP elevation in a constant dark environment. Corresponding to this IOP elevation in the constant dark, no change of aqueous humor cAMP concentration was found. Thus, the circadian IOP elevation in the constant dark is probably unrelated to the cAMP-mediated activities. This finding also suggests that a significant portion of the circadian IOP elevation in the light-dark environment is unrelated to the cAMP-mediated activities.

Adrenergic mechanism in circadian elevation of intraocular pressure in rabbits.

Stimulation of the ocular sympathetic nerves is essential for the circadian elevation of intraocular pressure (IOP) in rabbits. Adrenergic mechanisms that participate in this elevation of IOP around the onset of darkness were investigated using selective adrenergic agents. Unilateral topical administration of 0.0001-0.1% prazosin, an alpha-1-adrenergic antagonist, at the onset of darkness caused a dose-dependent reduction of IOP elevation. After treatment with 0.1% prazosin, the concentration of norepinephrine (NE) in aqueous humor was not changed, but the aqueous humor protein concentration was reduced. The increase of aqueous flow, determined by fluorophotometry, after the onset of darkness was not affected by 0.1% prazosin treatment. Treatment of rauwolscine, an alpha-2-adrenergic antagonist, or timolol, a beta-adrenergic antagonist, was ineffective in reducing the circadian elevation of IOP. Apraclonidine, an alpha-2-adrenergic agonist, with concentrations of 0.0001-1% caused a dose-dependent reduction of IOP elevation. Treatment with 1% apraclonidine caused a 70% reduction of aqueous humor NE, a significant attenuation of the increase of aqueous flow, and no change of aqueous humor protein concentration. These results suggest that both an increase of aqueous outflow resistance (by alpha-1-adrenergic receptors) and an increase of aqueous flow (not exclusively by beta-adrenergic receptors) contribute to the circadian elevation of IOP. Prejunctional alpha-2-adrenergic receptors may serve as an autoregulating mechanism to limit the excess release of NE and hypertensive spike in IOP.

Endogenous hormonal changes and circadian elevation of intraocular pressure.

A unique circadian rhythm of intraocular pressure (IOP) occurs in laboratory rabbits housed in a light-dark environment. The IOP is low in the light and high in the dark. In 32 rabbits studied, the IOP was 18.7 +/- 0.3 mm Hg (mean +/- the standard error of the mean) at 2 hr before the onset of dark and 24.9 +/- 0.6 mm Hg at 2 hr into the dark. The changes in endogenous hormones corresponding to this elevation of IOP were studied. Concentrations of norepinephrine (NE), epinephrine (Epi), corticosterone, and melatonin in the plasma and NE and melatonin in the aqueous humor were determined. Changes in plasma catecholamines were variable and statistically insignificant. A decrease of plasma corticosterone and an increase of plasma melatonin in the dark were observed. Norepinephrine and melatonin levels in the aqueous humor increased in the dark. In ten rabbits with unilateral transection of the cervical sympathetic trunk, the elevation of IOP was absent only in the decentralized eye. The changes in plasma NE, Epi, and melatonin levels from the light to the dark phase were insignificant. The plasma corticosterone level decreased. In the dark phase, aqueous humor NE level in the decentralized eye was significantly lower than that in the intact eye. Melatonin levels in these two eyes were indifferent. In 22 rabbits housed in a constant dark environment, aqueous humor NE concentration increased corresponding to the circadian elevation of IOP. The authors conclude that the activation of ocular sympathetic nerves is directly related to the circadian elevation of IOP.

Central cholinergic stimulation affects ocular functions through sympathetic pathways.

Intracerebroventricular (ICV) injection of carbachol into the third ventricle of conscious rabbits increased pupil size and intraocular pressure (IOP). A significant increase of pupil size by 0.6-1.3 mm for 60-90 min was observed with the dose of 1 microgram and an increase of IOP by 1.1-1.9 mmHg for 15-60 min was observed with doses over 10 ng. These responses were due to central cholinergic stimulation; mydriasis was eliminated by ICV injection of atropine and the elevation of IOP was significantly reduced by ICV injections of atropine and hexamethonium. Transection of the cervical sympathetic trunk eliminated the mydriasis. The efferent pathway for the mydriasis is via the cervical sympathetic nerve. The elevation of IOP was significantly reduced but not eliminated in the decentralized eye. Plasma epinephrine (Epi) and norepinephrine (NE) increased at 30 min after the ICV injection of 1 microgram carbachol. It is hypothesized that the elevation of IOP is due mainly to the stimulation of ocular sympathetic nerves and the increase of circulating catecholamines. Topical treatment of 0.01% timolol significantly reduced the IOP elevation, indicating the involvement of ocular beta-adrenergic mechanism in the elevation of IOP.

Intramuscular injection of chlorpromazine decreases intraocular pressure by lowering systemic blood pressure.

Intramuscular injection of chlorpromazine in rabbits caused a significant decrease in intraocular pressure (IOP). The dose-response curve was generated. The threshold dose was 0.1 mg/kg (approximately 0.35 mg per rabbit) and 10 mg/kg chlorpromazine produced the maximal response which lasted for several hours. This decrease in IOP was not due to the release of pituitary prolactin by a central dopaminergic-2 antagonistic activity of chlorpromazine. Intracerebroventricular (i.c.v.) injection of chlorpromazine also caused a decrease in IOP. The threshold dose was 0.33 mg per rabbit. This high i.c.v. threshold dose indicates that no direct central mechanism is responsible for the decrease of IOP after an i.m. injection of chlorpromazine. Intravitreal injection of 0.35 mg chlorpromazine caused significant miosis without any change in IOP. It appears that direct mechanisms of chlorpromazine in ocular tissues do not decrease IOP. After an i.m. injection of 0.1 or 10 mg/kg chlorpromazine, systemic blood pressure (BP) was lowered in a similar pattern as the decrease in IOP. Neither IOP nor BP was affected by an i.m. injection of a subthreshold chlorpromazine dose of 0.01 mg/kg. These observations suggest that the decrease in IOP after an i.m. injection of chlorpromazine is mainly due to the decrease of BP.

Thyrotropin releasing hormone increases intraocular pressure. Mechanism of action.

Intravenous injections of 1-100 micrograms thyrotropin releasing hormone (TRH) in rabbits elevated intraocular pressure (IOP). The 2-5 mm Hg increase of IOP lasted for less than 2 hr. No change of pupil size was observed. This IOP elevation was not due to a direct effect of TRH on ocular tissues since intravitreal injections of 0.1 and 1 micrograms TRH did not change IOP. Concentrations of thyroid stimulating hormone (TSH), triiodothyronine (T-3), epinephrine (Epi) and norepinephrine (NE) in the plasma were elevated at 30 min after an i.v. injection of 10 micrograms TRH. Plasma levels of prolactin and thyroxine were not changed. Bolus i.v. injections of 0.1-1 micrograms TSH and 0.1-1 micrograms T-3, which would produce an equivalent increase of relevant hormones in the circulation, did not increase IOP. However, similar i.v. injections of 10-100 ng Epi and 100 ng NE caused a 1.5-3 mm Hg IOP elevation for 15-30 min. Thus, the IOP elevation following TRH administration probably is caused by the increase of circulating endogenous catecholamines and not by the stimulation of the TSH-thyroid hormone axis. Heart rate, but not blood pressure, was increased with 10 micrograms TRH. After unilateral transection of the cervical sympathetic trunk, the IOP elevation in the decentralized eye was larger than that in the intact eye. Topical treatment of 0.1% or 1% timolol in the decentralized eye inhibited the IOP elevations in both eyes, but 0.1% prazosin was not effective. Topical 1% atropine and atropine given subcutaneously at 0.6 mg/kg decreased the bilateral IOP elevations. These observations indicate that beta-adrenergic and muscarinic mechanisms, not an alpha-1-adrenergic mechanism, are involved.

Intravitreal human chorionic gonadotropin decreases intraocular pressure in rabbits: mechanism of action.

Intravitreal injection of purified human chorionic gonadotropin (hCG) in rabbits decreased intraocular pressure (IOP). A dose-dependent decrease in IOP was observed with intravitreal hCG concentrations at 30 nM and 100 nM. The onset of this effect was later than 10 hr following the injection and it lasted for more than 24 hrs. The purified beta-subunit of hCG caused a similar decrease in IOP with a short duration. The threshold intravitreal concentration was 10 nM. Unlike the intact hCG, the hCG beta-subunit was inactive as a gonadotropic agent to activate the adenylate cyclase in the rat testis. Intravitreal injection of rabbit luteinizing hormone, which was active as a gonadotropic agent, had no effect on IOP in 4 intravitreal concentrations ranging from 1 nM to 30 nM. These observations indicate that the mechanism of IOP decrease by intravitreal hCG is not related to its gonadotropic action. The IOP decrease in rabbits due to intravitreal hCG or its beta-subunit is probably related to a contaminant or an immune reaction.

Extra-pituitary action of luteinizing hormone releasing hormone on intraocular pressure.

Luteinizing hormone releasing hormone (LHRH) given intraventricularly caused a delayed, significant decrease of intraocular pressure (IOP) in adult female rabbits for a prolonged period, but only elevated plasma gonadotropins for a few hrs. Intravenous injections of LHRH caused a similar elevation of plasma gonadotropins without any effect on IOP. It indicates that LHRH initiates a mechanism in the central nervous system to decrease IOP, which is unrelated to the conventional LHRH-gonadotropin axis.

Central nervous system and peripheral mechanisms in ocular hypotensive effect of cannabinoids.

Systemic administration of cannabinoids decreases intraocular pressure (IOP). To determine whether the mechanism of action originates in the central nervous system, we administered various cannabinoids into the cerebral ventricles of conscious New Zealand albino rabbits. When delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-tetrahydrocannabinol, cannabinol, and cannabidiol were given intravenously, only delta 9-THC produced dose-dependent ocular hypotension and miosis. Bolus administration into the cerebral ventricles or ventriculocisternal perfusion of delta 9-THC did not change IOP or pupil size. In urethane-anesthetized rabbits, IOP and blood pressure were lowered by intravenous administration of delta 9-THC but not by bolus cerebral administration. These observations indicate that the action of cannabinoids on IOP does not originate in the central nervous system. Alteration of blood pressure may be involved in the mechanism of ocular hypotension induced by delta 9-THC.