the ciliary muscle, modify its extracellular matrix, and increase uveoscleral outflow (Weinreb et al., 2002) and that pilocarpine in monkeys contracts the ciliary muscle and reduces uveoscleral outflow (Bill, 1967a), it was predicted that the two drugs would not have an additive IOP eVect. This prediction proved to be true when pilocarpine and prostaglandin F2a were used in combination therapy in monkeys (Crawford and Kaufman, 1987; Camras et al., 1990). However, latanoprost was additive in humans treated with a variety of cholinergic agonists, including pilocarpine, carbachol, phospholine iodide (Villumsen and Alm, 1992; Fristro¨m and Nilsson, 1993; Patelska et al., 1997; Shin et al., 1999; Kent et al., 1999), or physostigmine (Linde´n and Alm, 1997b). In a clinical study (Toris et al., 2001) to explain the IOP additivity of latanoprost and pilocarpine, it was found that latanoprost when used alone increased uveoscleral outflow and pilocarpine when used alone increased outflow facility. Additivity of latanoprost and pilocarpine was achieved because pilocarpine did not block the uveoscleral outflow increase induced by latanoprost, and latanoprost appeared to potentiate the trabecular outflow facility increase induced by pilocarpine.

Reports of aqueous flow eVects of pilocarpine are mixed. One study found no eVect of pilocarpine on aqueous flow (Toris et al., 2001) when given to ocular hypertensive patients four times daily for a week and another study found that pilocarpine (Nagataki and Brubaker, 1982) increases aqueous flow in healthy volunteers. The eVect was small and of little clinical significance.

F. Experimental Drugs

New classes of drugs are under investigation as potential therapies to increase IOP and treat hypotony or decrease IOP and treat glaucoma. Discussed below are studies of some promising new classes of drugs aVecting aqueous humor dynamics.

1. Dopaminergic Agonists and Antagonists

The six types of dopamine receptors (D1, D2a, D2b, D3, D4, and D5) are metabotropic G–protein coupled receptors with dopamine as their endogenous ligand. D1 and D5 typically are excitatory and the rest are inhibitory. Growing evidence suggests a role for dopamine receptors in the modulation of IOP. D1 receptor blockade [SDZ PSD 958 (Pru¨nte et al., 1997)], D2 receptor stimulation [quinpirole (Pru¨nte et al., 1997)], and D3 receptor stimulation [PD128,907 (Chu et al., 2004) and 7 hydroxy 2 dipropylaminotetralin (Chu et al., 2000)] contribute to IOP lowering in rabbits. A possible mechanism for this IOP decrease is a reduction in aqueous flow (Chu et al., 2000; Reitsamer and Kiel, 2002b). In rabbits, high doses of dopamine decrease

aqueous flow (Reitsamer and Kiel, 2002b) in a manner similar to brimonidine, that is, by reducing ciliary blood flow (Reitsamer et al., 2006). Interestingly, low doses of dopamine increase rather than decrease aqueous flow (Reitsamer and Kiel, 2002b). Evidence in rabbits suggest that D1 receptors are not involved in the outflow of aqueous humor. Tonographic outflow facility was unchanged in rabbits treated with a mixed D1 receptor antagonist and D2 receptor agonist (Pru¨nte et al., 1997). The D1 receptor antagonist, SCH 23390, binds to sites within the epithelium of the ciliary processes, but not in the iridocorneal angle (Mancino et al., 1992).

Clinical studies have found that the selective D1 receptor agonist, fenoldopam, increases IOP in healthy humans (Piltz et al., 1998) and fenoldopam, along with another selective D1 receptor agonist, 3B90, increase IOP in patients with primary open angle glaucoma (Virno et al., 1992). Additionally, D1 receptors have been found in human uvea and sclera (Cavallotti et al., 1999), suggesting an outflow eVect, unlike in rabbits. Obviously, further research is needed to elucidate the role of dopamine in the regulation of aqueous humor dynamics.

Ibopamine, a prodrug of N methyldopamine with a adrenergic properties, is under development for the purpose of increasing IOP to treat hypotony. Ibopamine apparently increases IOP by stimulating aqueous humor production. Two studies (Virno et al., 1997; Azevedo et al., 2003) compared the IOP and aqueous flow eVect of multiple drops of topical ibopamine in healthy volunteers and patients with glaucoma. In both studies, a significant increase in aqueous humor production was found in both groups of subjects but only the glaucoma group had the expected increase in IOP. These puzzling findings were explained in a third study (McLaren et al., 2003). It was observed that ibopamine caused mydriasis that can interfere with the fluorophotometric method to measure aqueous flow. The eVect of mydriasis on aqueous flow was evaluated in 24 healthy subjects treated with either tropicamide or ibopamine to create mydriasis, dapiprazole to block the mydriasis, or placebo. It was found that a rapid transient doubling of aqueous flow was an artifact of increased fluorescein clearance from the anterior chamber back through the dilated pupil. Ibopamine coupled with dapiprazole did increase aqueous flow compared with tropicamide coupled with dapiprazole, but the increase was slight and would not have been detected as an increase in IOP in the healthy subjects. The increased IOP in the glaucoma patients treated with ibopamine was due to the poor outflow facility in these patients.

2. Angiotensin AT1 Receptor Antagonists

The renin–angiotensin system is a hormone system that helps to regulate blood pressure and extracellular volume in the body. Angiotensin I is formed by the action of renin on angiotensinogen and then is converted to