but increases outßow resistance, resulting in an initial short-term decline in IOP and an eventual gradual return to basal IOP levels [22]. Sympathetic beta-adrenergic mechanisms acting at the level of the ciliary processes are involved in increased aqueous production. In rabbits, it has been shown that both an outßow resistance increase mediated by alpha-adrenergic mechanisms and an aqueous inßow increase mediated by beta-adrenergic mechanisms cause the nocturnal IOP rise [205, 406].

Sensory Þbers from the trigeminal ganglion that contain SP and CGRP also innervate the ciliary body and vessels, ciliary processes, iris stroma and vessels, limbal vessels, and/or the trabecular meshwork in guinea pigs, rats, squirrels, rabbits, pigs, cats, monkeys, and humans [20, 23, 74, 143, 198, 202, 224, 236, 319, 342, 343, 346, 347, 359Ð363, 380]. Double-label studies show that the SP and CGRP typically co-occur in single Þbers in these regions [193]. SP and CGRP are common in neurons of the trigeminal ganglion [380], and trigeminal ganglionectomy or transection of the ophthalmic nerve (plus maxillary nerve) eliminates SP and CGRP from the anterior uvea and limbal vessels [362, 363, 380]. Consistent with its SP+ input, rat and rabbit iris possess SP receptors [68], and consistent with its CGRP+ input, the iris and ciliary body in pig, guinea pig, and cat possess CGRP receptors [138]. Sensory Þbers such as those of the trigeminal nerve send a central message of hot, cold, pain, or touch and can elicit ocular reßexes, such as blinking and tearing in response to their activation [23, 103]. Peripheral Þbers can also participate in antidromic responses in which they release SP and CGRP and cause local irritation responses, which include a vascular component [23]. For example, stimulation of the ophthalmic nerve in rabbits causes blood ßow increases in the iris and ciliary body, IOP increases, increased extravasation of albumin in the iris and ciliary body, increased albumin in the aqueous, and pupil constriction [338]. Ocular irritation or injection of CGRP into the eye of rabbits increases iridial and ciliary body blood ßow and causes blood-retinal barrier breakdown, IOP rise, and pupil constriction [188]. The SP released from the ophthalmic nerve endings does not appear to contribute to the blood-retinal barrier

breakdown, but the CGRP does [13, 36]. The ocular irritation response involves edema and vasodilation to wash away irritants. In monkeys and cats, however, trigeminal nerve stimulation or SP and/or CGRP injection into the eye causes lesser effects on iridial and ciliary body blood ßow and blood-aqueous barrier integrity than they do in rabbits [10, 37, 262]. SP and CGRP also exert an effect on aqueous production and aqueous outßow in monkeys, cats, and rabbits, although the nature of the effects and the mechanisms underlying them may vary among species [12, 189, 262, 340, 377]. For example, an effect on IOP can be mediated by a vasodilatory effect of trigeminal sensory Þbers on the arteries of the ciliary processes and/or the episcleral veins of the outßow channel.

12.4Neural Control of Blood Flow in Orbital Glands

The orbit also contains various glandular structures that are responsible for lubricating the cornea and washing away small debris that might injure the cornea. These structures include the lacrimal gland (which is located laterally in the orbit and secretes tears that lubricate and moisturize the cornea), the Meibomian glands of the tarsal plates of the eyelids (which secrete an oily ßuid that coats the cornea and limits dehydration), goblet cells of the conjunctival fornices (which secrete mucin to aid in limiting corneal dehydration), and the Harderian gland, which is a sebaceous gland that acts as an accessory to the lacrimal gland in most mammalian species and is very prominent in birds, where it is located medially in the orbit and is larger than the lacrimal gland [63, 266, 273]. The blood supply to the lacrimal gland arises from the ophthalmic artery via the lacrimal artery, while the blood supply to the Harderian gland arises from a more medial and posterior branch of the ophthalmic artery (in birds, it arises from the ophthalmotemporal artery). The blood supply to the Meibomian glands and goblet cells is via branches of the palpebral arteries to the eyelids. Secretion from these glands is under neural control, as is blood ßow to and within these glands.

For example, Ruskell has shown that the lacrimal gland in primates is innervated by parasympathetic and sympathetic nerve Þbers. In an early study [300], he showed parasympathetic terminals from the PPG to the lacrimal gland in rabbits. In a later study, he showed that rami from the PPG (presumably secretomotor) and perivascular nerves traveling on the lacrimal artery both enter the lacrimal gland in humans [299]. The PPG neurons projecting to the lacrimal gland appear to arise from a different part of the PPG than those to the iris [357]. Ruskell [296] showed sympathetic terminals that arise from the superior cervical ganglion on arteries, veins, and capillaries in the lacrimal gland of monkeys. Ven der Werf and coworkers [18, 381] conÞrmed that the PPG and superior cervical ganglion innervate the lacrimal gland in monkey using retrograde labeling methods, and they also showed trigeminal sensory innervation. The PPG and superior cervical ganglion innervation of lacrimal gland has been conÞrmed by immunolabeling, retrograde labeling, and/or anterograde labeling for diverse rodent species as well, including guinea pig, rat, and/or mouse [19, 71, 72, 311, 357, 376]. The PPG Þbers in rodents are cholinergic and contain VIP and nNOS as well, and they and the sympathetic input end near acinar cells, as well as on blood vessels. In mouse at least, parasympathetic and sympathetic Þbers innervate different parts of the mouse lacrimal gland and thus different secretory cells [71, 72].

The autonomic innervation of the lacrimal gland regulates both blood ßow and tear secretion in the gland. Reßecting its secretomotor role, transection of preganglionic input to the PPG has been shown to cause dry eye in rabbits [372]. Cholinergic mechanisms are involved in the secretomotor role of PPG input to the lacrimal gland [231]. Additionally, VIP released from PPG terminals has a secretomotor role in lacrimal gland function, since VIP causes lacrimal gland tear secretion in rats, rabbits, and pigs [68, 321, 341]. Nilsson [256] showed that activation of PPG input to the eye via facial nerve stimulation also increases blood ßow in rabbit lacrimal gland. The increase at 2-Hz stimulation was nearly completely blocked by NOS inhibition, but only reduced at 5 Hz, implying a greater role

for NO at low stimulation frequencies and a greater role for VIP at high frequencies. Subsequently, Nilsson (2000) provided further evidence for frequency-dependent roles of NO, VIP, and cholinergic mechanisms in vasodilation in lacrimal glands from studies in cats. Facial nerve stimulation at 5 Hz yielded increases in blood ßow in lacrimal gland that could be greatly reduced by NOS inhibition alone (with LNA), and further reduced by combined NOS inhibition and muscarinic blockade with atropine. This result suggests a prominent role of NO in lacrimal gland vasodilation at 5 Hz, involving both NO release from PPG terminals and acetylcho- line-evoked NO release from endothelium. The fact that LNA alone did not entirely block lacrimal gland vasodilation at 5 Hz suggests some role of VIP at this frequency as well. At 10 Hz, facial nerve stimulation-evoked increases in glandular blood ßow were greatly attenuated but not completely blocked by combined LNA and atropine. Moreover, the facial nerve stimulationevoked increases in glandular blood ßow at 10 Hz were no more reduced by combined LNA and atropine than by NOS inhibition alone, and atropine alone did not reduce the vasodilation at all. These results suggest a role of neurally derived NO in vasodilation in lacrimal gland at 10 Hz, as well as a role for an additional vasodilator that is presumably VIP. Yasui et al. [402] showed that 20-Hz facial nerve stimulation yielded both blood ßow increases and tear secretion from lacrimal gland in cats. The tear secretion at this frequency was greatly dependent on muscarinic cholinergic mechanisms since it was blocked with scopolamine, while the blood ßow increase was not blocked by scopolamine. Thus, lacrimal vasodilation mediated by the PPG input at a 20-Hz activation frequency may occur via VIP but not via acetylcholine-evoked release of endothelially derived NO, and secretion may be mainly cholinergic in its basis. Given the prominent role of muscarinic mechanisms in lacrimal secretion, the contributions of VIP and NO to such secretion may occur (at least in part) via their effects on blood ßow. Finally, consistent with regionally differential parasympathetic and sympathetic innervation of mouse lacrimal gland, both beta-adrenergic and cholinergic