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innervation as well as humoral mechanisms to maintain a steady‐state IOP. Adrenergic regulation of AH formation is complex and the role of some receptor subtypes remains unclear. The β‐adrenergic antagonists, such as timolol, lower IOP by decreasing AH production. During sleep, AH formation decreases ~50% via modulation of the β‐arrestin/cAMP signaling pathway by β‐adrenergic receptors in humans and reducing the ocular hypotensive effects of timolol when instilled at night. Thus, IOP exhibits a circadian rhythm, which varies depending on whether animals are nocturnal or diurnal. For example, diurnal species such as dogs and nonhuman primates exhibit the greatest IOP during the early day, while in nocturnal species such as cats and rats IOP peaks at night.

      Cholinergic regulation of AH formation and composition is similarly ambiguous. For example, parasympathomimetic nerve stimulation or drugs have been demonstrated to increase, decrease, or not change the rate of AH production; these differences are likely due to species and technique‐related effects. Cholinergic agents may regulate amino acid transport from the blood to the AH as well as modulate inorganic ion concentrations within the AH. In aggregate, these studies suggest that the influence of parasympathetic drugs such as pilocarpine is relatively minor in AH formation and that their efficacy in decreasing IOP is likely due to increased AH outflow.

      Aqueous Humor Outflow

      Structural and Biomechanical Attributes

Schematic illustration of chemical composition of the aqueous humor and lens.
Dog Cat Rabbit Cow Horse Nonhuman primate
Estimated normal IOP (mmHg) 15–18 17–19 15–20 20–30 17–28 13–15
C” outflow (μl/mmHg/min by tonography) 0.24–0.30 0.27–0.32 0.22–0.28 0.90 0.24–0.28
Uveoscleral outflow (μl/min) 15% 3% 13% 30–65%
Episcleral venous pressure (mmHg) 10–12 8 9 10–11
Aqueous formation (μl/min) 5.22 6.00–7.00 1.84 2.75

      Other studies suggest that the main site of resistance to outflow is the endothelial lining of the AAP and its ECM. However, the site of filtration may be different from the site of flow resistance. AH transport through the endothelium of the AAP (or Schlemm's canal in nonhuman primates and domestic chickens) is thought to occur via transcellular pores, large vacuoles, or pinocytotic vesicles. However, paracellular routes between the endothelial cells of Schlemm's canal have also been proposed and may be pressure sensitive, particularly at higher IOPs.

      Fluid Dynamics

      As the ciliary body produces AH, the tissues comprising the ICA resist AH outflow, thus generating IOP. Steady‐state IOP occurs when the rates of AH inflow and outflow are equivalent. The AH exits the eye by passive bulk flow via two routes in the ICA:

      1 The traditional or conventional pathway, which involves passage through the TM, AAP, scleral venous plexus, veins of the episclera and conjunctiva (anterior) or vortex veins (posterior), and systemic venous circulation.

      2 The uveoscleral or nonconventional pathway, which involves passage through the iris root, anterior face of the ciliary body muscle, supraciliary or suprachoroidal space, and out through the sclera (and perhaps the optic nerve head).

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