Ординатура / Офтальмология / Английские материалы / Age-Related Changes of the Human Eye_Cavallotti, Cerulli_2008

of Helsinki and in conformity with the ARVO Statement on the Use of Human Subjects in Ophthalmic and Vision Research applied by all ethical committees.

All patients were divided into four groups: the first group of 200 patients was treated with local or systemic administration of a calcium channel blocker; the second group of 200 patients was treated with oral or systemic administration of β-blockers; the third group of 100 patients was treated with systemic administration of ACE inhibitors; and the fourth group of 100 patients was treated with a diuretic drug (acetazolamide). All patients were subjected monthly to measurements of their systemic blood pressure, intraocular pressure, and visual field.

Results

Our results are summarized in Table 17.1. The oral administration of a calcium channel blocker (nitrendipina) in subjects with moderate essential hypertension and without ocular hypertonia causes systemic effects with a moderate decrease of ocular pressure, while local instillation causes a remarkable hypotensive effect. The scotoma in glaucomatous subjects with normal pressure gets better after the administration of calcium channel blockers, showing that the peripheral vascular reaction enhances the optical nerve blood flow. The oral administration of β-blockers is also correlated with a reduction of the IOP, especially if the β-blocker reduces systemic blood pressure.

Nadolol, a long half-life, nonselective β-blocker, in a single oral dose of 20 or 40 mg, may result in a remarkable decrease of the IOP during the whole day. It has been demonstrated that the systemic administration of ACE inhibitors is also effective in reducing the IOP by some mechanisms which, although not known yet, seem to act on the posterior ciliary arteries, shunting the blood to the ciliary body. Finally, acetazolamide, a diuretic usually used to reduce systemic blood pressure, can be used to reduce the IOP. On the other hand, if perfusion pressure is reduced as a consequence of hypertension treatment, the damage to the visual field could be accelerated.

Table 17.1 Values of arterial blood pressure, intraocular pressure, and visual field before and after a treatment of six months with an antihypertension drug

Discussion

Among all possible risk factors for glaucoma, particular attention is given to systemic hypertension. Several studies have shown a relation between nontreated systemic hypertension and ocular hypertension, even if there is not a direct relationship between blood pressure and ocular perfusion pressure because of the autoregulation of the ocular vessels.

Moreover, researchers have demonstrated a higher correlation between low diastolic blood pressure and intraocular pressure (IOP), with prevalence of a low pressure in chronic glaucoma. The influence of antihypertensive drugs on the IOP should not be underestimated, since these drugs can influence the progression of glaucoma damage.

The vascular autoregulation is the vessels’ capability of keeping blood flow constant despite modification in PP. Retinal and choroid blood flow depends on perfusion pressure and vascular resistance, i.e., the vessels’ diameter.

The PP can be considered as the difference between the mean arterial pressure (MAP) and the intraocular pressure (IOP). MAP is the sum of the diastolic pressure (DBP) and a third of the difference between systolic (SBP) and diastolic blood pressure: MAP = DBP + (SBP - DBP)/3.

Vessel diameter depends on smooth cells’ contractility and the action of pericytes, which are in turn regulated by several factors, including neurotransmitters and systemic or local vasoactive substances such as endothelins and nitric oxide.

At a microstuctural level, retinal arterioles have no precapillary sphincters and receive no innervation from the autonomic nervous system, although α and β adrenergic and angiotensine receptors have been found on pericytes. Retinal autoregulation is based on changes in resistance that are obtained through changes in contractility of retinal arterioles. It depends on metabolic (pCO2, pO2, pH …) and myogenic mechanisms.

It seems clear, from what we said about the role of blood pressure as a risk factor for glaucoma, that the possible influence of antihypertensive drugs on the IOP and in the progression of the glaucomatous damage should not be underestimated. Hypertensive patients with glaucoma can consume drugs belonging to different classes. Calcium channel blockers, β-blockers, ACE inhibitors, and diuretics are of particular importance in cases of concomitant cardiovascular diseases.

Since the early 1980s, experiments on animals and humans to estimate the efficacy of calcium channel blockers in glaucoma patients have been performed.

In 1983 Monica et al26 demonstrated that, in patients with moderate hypertension27 and without ocular hypertonia, oral administration of nitrendipine 20 mg caused systemic effects (a reduction in peripheral resistance, cardiac output, and ejection fraction) as well as a significant, though moderate, decrease in intraocular pressure (despite the absence of a basal hypertonia).28

On the other hand, in 1988 Abelson29 didn’t confirm the different activity of oral and topical use of calcium channel blockers other studies had found.30 In fact, while in humans a dose of nitrendipine consumed per os has a hypotensive effect at the

ocular level, a local instillation caused marked ocular hypertension. Abelson et al29 showed that an instillation of verapamil 1.25 mg/ml caused a significant reduction of the intraocular pressure lasting about 10 hours. The efficacy of topical medication was not dependent on cardiovascular changes, suggesting that the observed effects were not consequences of the systemic vasodilatation, as happens with the oral route. The hypotensive effect seemed to be linked to local dilatation of veins and arteries.31 Verapamil inhibits intracellular calcium uptake by inactivation of its ATP-dependent channels, located on the inner side of the cells’ membrane. This reduction of calcium entrance in muscular cells inhibits contraction, so causing vasodilation.32 A local reduction of blood pressure causes a reduction in aqueous production that induces hypotonia. Verapamil can also interfere with the calciumdependent gap junctions between pigmented and unpigmented cells of the ciliary epithelium, so altering permeability and inhibiting aqueous outflow.32

It seems clear so far that calcium has many effects on the aqueous dynamic. Among them, a hydrostatic component mediated by an effect on blood pressure and ciliary body perfusion, and an osmotic component caused by an effect on active secretion of sodium, calcium, and other ions from the ciliary epithelium.

It is important to notice that different subclasses of calcium channel blockers can have different effects: for example, diltiazem doesn’t reduce intraocular pressure as do verapamil and nitrendipine, these sharing the same ocular effect despite different cardiovascular effects.33 The only difference between the last two drugs (that have a hypotensive effect when instilled) and diltiazem is that diltiazem doesn’t have a negative inotropic effect. How this is related to the lack of ocular hypotensive effects is not known.

Beside these effects on ocular tone, calcium channel blockers can enhance the optical nerve’s blood flow, an effect that can be positive in patients with normal pressure glaucoma.

In recent studies calcium channel blocker effects were evaluated in patients with normal pressure glaucoma and chronic simple glaucoma who were receiving calcium channel blockers for extraocular reasons.

These studies are characterized by a long follow-up. Netland34 found a significant difference in the progression of visual field defects and in the optical nerve damage between subjects with normal pressure glaucoma, who had a better prognosis, and those with chronic simple glaucoma. The authors and Kitazawa suggested using calcium channel blockers, in patients with normal pressure glaucoma, to slow the progression of the campimetric damage.

Patients with normal pressure glaucoma are more exposed to vascular damage of the optical nerve than those with chronic simple glaucoma. The alteration of the optical disk found in these patients is caused by an ischemic degeneration. However, it is not clear if ischemia is mechanically induced by the high intraocular pressure or by a primary vascular damage of the optical nerve. The presence of ischemic damages and the association to migraine and Raynaud’s phenomenon, as already noticed, suggest an associated or primary vascular anomaly. This is the reason why the use of calcium channel blockers could prevent vasospasm and enhance blood flow in the head of the optical nerve.22

In a number of patients with defects of the visual field of unknown etiology, the history of very cold hands is rather characteristic. In these cases the study of finger circulation, through the topical cold test and the capillaroscopy, is advisable.19

These tests, inducing an intense vasospasm, will confirm the hypothesis that visual defects are related to a vasospastic syndrome. Glasser and Flammer35 noticed that visual field defects worsened as hands were dipped into cold water and scotoma improved after the administration of calcium channel blockers, so demonstrating that a peripheral vasculature reaction to the drug accompanied an increase in the optical nerve’s blood flow.

To evaluate the effects of β-blockers on blood and ocular pressure, these drugs were used in patients with both systemic and ocular hypertension. When blood pressure was within normal values (SBP<160 mmHg and DBP< 90 mmHg) the IOP was significantly reduced,36 but when systemic hypertension did not respond to β-blockers, even the IOP was scarcely modified.

Nadalol is a nonselective β-blocker that has no intrinsic adrenergic activity and no effect as a membrane stabilizer, four times stronger than propranolol, with the longest half-life (20–24 hours) among β-blockers. It is easily absorbed by the whole gastrointestinal tract, has its maximun effect in 3–4 hours and can be administered once daily.37,38 IOP reduction is dose-related: 20–40 mg/day per os can have a therapeutic role in glaucoma. The nadolol ocular hypotensive effect in normotensives is considerable for as long as 24 hours, at all dosages used. The reduction of the IOP at 24 hours with both dosages is lower than that observed after 3 hours following drug intake. This suggests that a single 20 mg or 40 mg dose of nadolol can completely block the adrenergic receptors for a 24-hour period. According to Williamson,39 20 mg of nadolol twice daily, instead of 40 mg once daily, could result in a substantial decrease of the IOP.

Studies on β-blockers in chronic simple glaucoma have compared the effects of a single dose per os with those of a topical application of timolol twice daily.40 The absolute reduction of the IOP obtained with the oral route was the same as with the topical route of timolol. Higher doses, such as those used for systemic hypertension (80 mg) were not necessary. Nadolol efficacy was well maintained for rather a long period. The oral route for the treatment of glaucoma would be more suitable than the topical one in patients who already receive β-blockers for cardiovascular diseases and in those who, for any reason, cannot instill ocular drops.

Using autoradiographic techniques, β2 receptors have been identified in the optical nerve’s head. Since stimulation of β2 receptors causes vasodilatation and their inhibition blocks vasodilatation, there is concern about the possibility that a prolonged use of β-blockers could have an ischemic effect on the ocular disk with a reduced vasodilatation response to tissue needs (altered autoregulation).

The third antihypertensive class we will focus on are the ACE inhibitors. The presence of precursors and enzymes that are necessary for angiotensin II production in the eye suggests that this organ could have its own renin-angiotensin system.41,42,43 This hypothesis has physiologic and pathophysiologic implications. Kaufman and Barany44 demonstrated that angiotensin I increases the aqueous outflow. This in turn suggested that angiotensin II could be involved in IOP regulation,

in that its inhibition could cause an IOP reduction. Costagliola et al45 demonstrated that captopril reduced the IOP in all patients examined: 10 controls; 10 hypertensives with normal IOP; 10 normotensives with open-angle glaucoma; and 10 hypertensives with open-angle glaucoma. In this study, hypertensive patients were selected to evaluate whether captopril modification of the IOP was mediated by a reduction of pressure in the episcleral veins and the consequent increase in trabecular outflow. The absence of a correlation between blood pressure and IOP makes it unlikely. Other mechanisms should explain this ocular hypotensive effect. Moreover, the optical nerve blood flow through the posterior ciliary arteries is sensible to angiotensin II.46 The angiotensin II vasoconstriction effect on ocular vasculature could divert blood to the ciliary body; this would implement its metabolic activities and, in the end, its aqueous production. The captopril-induced block of the octapeptide production would then reduce aqueous production with a consequent IOP reduction.

Nonetheless, ACE inhibitors have other properties. For example, they enhance bradikinin cleavage that is involved in endogenous prostaglandin synthesis.47,48 Prostaglandins are powerful ocular hypotensive agents, and captopril effects on the IOP could be mediated by the increased production of endogenous prostaglandins that enhance the uveoscleral defluxion.

Among diuretics, which are not commonly used to reduce blood pressure, acetazolamide, an inhibitor of the carbonic anhydrase, reduces the IOP interfering with aqueous production, presumably inhibiting the enzyme of the ciliary epithelium.49 From all we have said, it seems that systemic antihypertensive drugs have a modulatory effect on the IOP and then on the visual field. The IOP also depends, at least in part, on high blood pressure control. If the perfusion pressure is reduced

by antihypertensive treatment, visual field loss can be accelerated.

References

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14.Leske MC and Podgot MJ (1983) Intraocular pressure, cardiovascolar risk variables and visual field defects. Am. J. Ophthalmol. 118:280-287

15.Klein BEK, Klein R, Sponsel W, et al. (1992) Prevalence of glaucoma. The Beaver Dam Eye Study. Ophthalmology 99:1499-1504

16.Morgan RW and Drance SM (1975) Chronic open-angle glaucoma and ocular hypertension an epidemiology study. Br. J. Ophthalmol. 59:211-215

17.Katz J and Sommer A (1988) Risk factors for primary open angle glaucoma. Am. J. Prev. Med. 4:110-114

18.Carter CJ, Brooks DE, Doyle DL and Drance SM (1990) Investigation into a vascular etiology for low-tension glaucoma. Ophthalmology 97:49-55

19.Drance SM (1977) Is ischemia the villain in glaucomatous cupping and atrophy? In: Brockhurst RJ, Bonchoff SA, Hutchinson BJ and Lessel S (eds) Controversy in Ophthalmology. Kluger Philadelphia, 292-300

20.Spaeth GL (1975) Fluorescein angiography its contributions towards understanding the mecchanisms of visual loss in glaucoma. Trans. Am. Ophthalmol. Soc. 73:491-553

21.Chumbley LC and Brubaker RF (1976) Low-tension glaucoma. Am. J. Ophthalmol. 81:764-767

22.Phelps CD and Corbett JJ (1985) Migraine and low-tension glaucoma a case control study. Invest. Ophthalmol. Vis. Sci. 26:1105-1108

23.Sisler HA (1972) Comparative ophtalmodinamometry using scleral pressure, suction and corneal pressure units. Am. J. Ophthalmol. 74:964-966

24.Demmailly P, Aubuer G and Abadie P (1987) Timolol and functional perimetric prognosis of primary open angle glaucoma. J. Fr. Ophtalmol. 71:766-771

25.Kaiser HJ, Flammer J, Stumplig D and Hendrickson P (1994) Long-term visual field follow-up of glaucoma patients treated with beta blockers. Surv. Ophthalmol. 38 (Suppl. May):156-160

26.Monica LM, Hesse RJ and Messerli FM (1983) The effect of a calcium channel blocking agent on intraocular pressure. Am. J. Ophthalmol. 96:814

27.Ventura HO, Messerli FH, Oighman W, et al. (1983) Immediate hemodynamic effects of new calcium channel bloking agent (nitrendipine) in essential hypertension. Am. J. Cardiol. 51:783-791

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29.Abelson MB, Gilbert CM and Smith LM (1998) Sub-stained reduction of intraocular pressure in humans with the calcium channel blocker verapamil. Am. J. Ophthalmol. 105:155-159

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40.Williamson J, Young JDH, Atta H, et al. (1985) Comparative efficacy of orally and topically administered b-blockers for chronic simple glaucoma. Br. J. Ophthalmol. 69:41-45

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The prevalence of dry eye increases with age,2-5 consistent with previous reports that the quality and quantity of tear fluid normally decreases with age.6-13 Moreover, dry eye is one of the most common ocular problems in the world.2-5 Clarification of the mechanisms involved in the associations between aging and the lachrymal gland is thus extremely important.14

Anatomy of the Lachrymal Gland

Gross Anatomy of the Lachrymal Gland

The human lachrymal gland consists of the main lachrymal gland and the accessory lachrymal gland. The main lachrymal gland resides in the superior temporal orbit and comprises palpebral and orbital lobes, which are continuous with each other at the lateral edge of the aponeurosis of the levator palpebrae superiosis.15-18 The orbital lobe lies in the lachrymal fossa on the anterior lateral part of the orbit. The palpebral lobe lies below the aponeurosis of the levator palpebrae superiosis and is in contact with the superior and lateral fornices of the conjunctiva. Excretory ducts arising from the palpebral and orbital lobes open into the superior conjunctival fornix.

The accessory lachrymal gland comprises histologically identifiable small glands located in the lamina propria of the conjunctiva.15,16 Human accessory lachrymal glands are divided into two types: glands of Krause, and glands of Wolfring. Glands of Krause are located in the lamina propria of the fornix, while glands of Wolfring reside in the edge of the tarsus. Ducts of both glands open onto the conjunctival surface. Other vertebrates also have accessory lachrymal glands in the conjunctiva. For instance, the nictitating membrane is well known as a site containing accessory lachrymal glands.

Most animal studies have used lachrymal glands from rodents and rabbits. The anatomy of lachrymal glands from those animals differs substantially from that in humans. In rodents, the lachrymal gland consists of the intraorbital, exorbital, and Harderian glands. The exorbital gland is found under the skin on the lateral side of the face near the ear. The rabbit also has a lachrymal and Harderian gland, both located within the orbit. The Harderian gland produces mainly lipids.

Histology of the Lachrymal Gland

The lachrymal gland is composed of many lobules separated from one another by loose connective tissue. Each lobule displays a tubuloacinar structure with numerous acini and intralobular ducts. The acini appear as rosettes of polarized pyramid-shaped acinar cells with a central lumen. Acinar cells include numerous periodic acid-Schiff (PAS)-positive secretory granules, indicating an

abundance of glycoproteins. Various lachrymal proteins are synthesized and secreted by these acinar cells. Myoepithelial cells are flattened and distributed surrounding the acini and intercalated ducts, and contain many myofilaments in the cytoplasm that are thought to squeeze secretory products down the lumen.

The intraand interlobular ducts comprise 2–3 layers of epithelial cells and lack myoepithelial cells. Ductal epithelial cells have small amounts of granules in the cytoplasm that differ from granules in acinar cells. In rodents, enzyme Na+-K+- ATPase involved in fluid and ion transport is present in the basolateral membranes of intraand interlobular ductal cells, not in acinar cells.19

The connective tissue contains interlobular ducts, vessels, nerve fibers, fibroblasts, plasma cells, lymphocytes, macrophages, and mast cells. Plasma cells secrete immunoglobulin (Ig)A, which is important in protecting the ocular surface from infection. The conjunctiva and lachrymal gland are commonly thought to represent a mucosa-associated lymphoid tissue (MALT), representing the immune system located at mucosal surfaces.20,21

The accessory lachrymal gland is histologically and histochemically identical to the main lachrymal gland.22 However, the gland of Krause is very small and usually comprises only one lobule. The extent to which the accessory lachrymal gland contributes to total tear volume remains unclear, but that main lachrymal gland is generally considered the major fluid-secreting organ.

Innervation of the Lachrymal Gland

The lachrymal gland is innervated by both parasympathetic and sympathetic divisions of the autonomic nervous system.23-25 Parasympathetic nerves are predominantly developed in the gland and release acetylcholine, whereas sympathetic nerves are less abundant and release norepinephrine. Parasympathetic cholinergic nerves also contain neuropeptides such as vasoactive intestinal polypeptide (VIP), substance P (SP) and neuropeptide Y. Sympathetic adrenergic nerves also contain neuropeptide Y. Autonomic nerve endings are innervated not only in acinar cells, but also in myoepithelial cells, ductal cells, and blood vessels.26,27 Sensory nerves, as a division of the trigeminal nerve, also innervate the gland and release SP and calcitonin gene-related peptide (CGRP), but have the least dense innervation.

Parasympathetic, sympathetic, and sensory innervations play complex stimulatory and inhibitory roles in the secretory function of the lachrymal gland. Although neural control of lachrymal secretions includes emotional responses, as in crying, the most well documented control involves stimulation to the ocular surface, cornea, and conjunctiva, activating afferent sensory nerves on the ocular surface and leading to activation of the efferent sympathetic and parasympathetic nerves in the gland to stimulate secretion. The generally accepted concept is that components of the ocular surface (cornea, conjunctiva, and Meibomian glands), the main and accessory lachrymal glands, and interconnecting innervation act as a functional unit.28,29