Effects of caffeinated coffee consumption on intraocular pressure, ocular perfusion pressure, and ocular pulse amplitude: a randomized controlled trial.

PURPOSE: To examine the effects of caffeinated coffee consumption on intraocular pressure (IOP), ocular perfusion pressure (OPP), and ocular pulse amplitude (OPA) in those with or at risk for primary open-angle glaucoma (POAG). METHODS: We conducted a prospective, double-masked, crossover, randomized controlled trial with 106 subjects: 22 with high tension POAG, 18 with normal tension POAG, 20 with ocular hypertension, 21 POAG suspects, and 25 healthy participants. Subjects ingested either 237 ml of caffeinated (182 mg caffeine) or decaffeinated (4 mg caffeine) coffee for the first visit and the alternate beverage for the second visit. Blood pressure (BP) and pascal dynamic contour tonometer measurements of IOP, OPA, and heart rate were measured before and at 60 and 90 min after coffee ingestion per visit. OPP was calculated from BP and IOP measurements. Results were analysed using paired t-tests. Multivariable models assessed determinants of IOP, OPP, and OPA changes. RESULTS: There were no significant differences in baseline IOP, OPP, and OPA between the caffeinated and decaffeinated visits. After caffeinated as compared with decaffeinated coffee ingestion, mean mm Hg changes (± SD) in IOP, OPP, and OPA were as follows: 0.99 (± 1.52, P<0.0001), 1.57 (± 6.40, P=0.0129), and 0.23 (± 0.52, P<0.0001) at 60 min, respectively; and 1.06 (± 1.67, P<0.0001), 1.26 (± 6.23, P=0.0398), and 0.18 (± 0.52, P=0.0006) at 90 min, respectively. Regression analyses revealed sporadic and inconsistent associations with IOP, OPP, and OPA changes. CONCLUSION: Consuming one cup of caffeinated coffee (182 mg caffeine) statistically increases, but likely does not clinically impact, IOP and OPP in those with or at risk for POAG.

Brimonidine 0.2% versus apraclonidine 0.5% for prevention of intraocular pressure elevations after anterior segment laser surgery.

OBJECTIVE: To compare the efficacy of brimonidine 0.2% with apraclonidine 0.5% in preventing intraocular pressure (IOP) elevations after anterior segment laser surgery. DESIGN: Double-masked, randomized clinical trial. PARTICIPANTS: Sixty-six patients underwent either laser peripheral iridotomy, argon laser trabeculoplasty, or neodymium:yttrium-aluminum-garnet laser capsulotomy. INTERVENTION: Eyes received either one drop of brimonidine 0.2% or apraclonidine 0.5% before laser surgery. MAIN OUTCOME MEASURES: Intraocular pressure, heart rate, and blood pressure were measured before laser surgery and at 1 hour, 3 hours, 24 hours, and 1 week after laser surgery. RESULTS: Before the laser treatment, 33 patients (50.0%) received brimonidine 0.2% and 33 patients (50.0%) received apraclonidine 0.5%. Eight of 33 patients (24.2%) in the brimonidine-treated group and 9 of 33 patients (27.3%) in the apraclonidine group had postoperative IOP increases of 5 mmHg or more. This was not statistically different (P = 0.80). By the time of last follow-up examination, 3 of 33 patients (9.1%) in the brimonidine-treated group and 3 of 33 patients (9.1%) in the apraclonidine group had IOP increases of 10 mmHg or more. This was also not statistically different (P > or = 0.95). The mean IOP reduction from baseline in the brimonidine group (-2.8 +/- 2.8 mmHg) was not statistically different (P = 0.55) compared with the mean IOP reduction in the apraclonidine group (-3.6 +/- 3.3 mmHg). There were no statistically significant changes in mean heart rate or blood pressure in either group except for a slight reduction in diastolic blood pressure at 1 hour (P = 0.005) in the brimonidine group (-5.2 +/- 7.4 mmHg) compared with the apraclonidine group (-0.2 +/- 6.4 mmHg). There were no clinically significant side effects noted in either group. CONCLUSIONS: A single preoperative drop of brimonidine 0.2% is as effective as apraclonidine 0.5% in preventing IOP elevation immediately after anterior segment laser surgery.

Postoperative sympathetic ophthalmia.

Although uncommon, SO is a fearful postoperative complication because of its potential to blind both eyes. It can result not only from penetrating ocular surgery but also from nonpenetrating ocular procedures. Thus, it is important to consider in any patient who has undergone ocular surgery and develops bilateral uveitis, particularly because prompt, sufficient treatment is required to maximize visual outcome. It is also important to note that the disease may present with a spectrum of clinical findings, none of which is pathognomonic. Thus, suspicion is important for making the diagnosis. Treatment should address the T-cell-mediated nature of the disease. With appropriate treatment, visual acuity of no less than 20/60 is likely. However, before the start of treatment, which consists of immunosuppressants, infection must be ruled out and potential side effects of treatments must be considered. Furthermore, any patient with a history of SO needs ample immunosuppressant coverage for ocular procedures. Better understanding of the pathogenesis of the disease may lead to safer treatments that result in improved visual outcome and a cure. Meanwhile, because of its relapsing nature, SO requires continual, close surveillance, even after many years of quiescence.

The effects of FK506 on retinal ganglion cells after optic nerve crush.

PURPOSE: The purpose of this study was twofold: to determine whether immunophilins were present in the rat retina and to determine the physiologic consequence of their presence. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis were performed on rat retinal tissue, and the immunophilin FKBP12 was found to be present in retina. Immunohistochemical studies showed the presence of FKBP12 in retinal ganglion cells (RGCs). In rats, optic nerve crush was performed on one side and a sham operation on the other side. By gavage, animals were given 5 mg/kg per day of the FKBP12 ligand FK506 in sterile phosphate-buffered saline (PBS) or in PBS alone. Eight days after nerve crush, the total number of back-labeled RGCs was estimated from retinal wholemounts. RESULTS: In control eyes, the number of labeled ganglion cells was 74,104 +/- 4,166 (mean +/- SEM) in rats receiving vehicle and 74,993 +/- 3,098 in animals receiving FK506 daily. Eight days after optic nerve crush, 27,775 +/- 3,332 labeled ganglion cells were counted in retinas of animals receiving vehicle (n = 11), whereas 33% more ganglion cells (37,118 +/- 2,475) were counted in animals receiving FK506 daily (n = 11). This difference was statistically significant (P < 0.05). CONCLUSIONS: The data presented demonstrate that the immunophilin FKBP12 is present in retina and specifically in RGCs. In addition, the FKBP12 ligand FK506 confers neuroprotection on RGCs after optic nerve crush. This neuroprotection may occur as a result of FK506's ability to interfere with apoptotic mechanisms after optic nerve crush.

Thy-1 is critical for normal retinal development.

In the mammalian retina, Thy-1, the most abundant mammalian neuronal surface glycoprotein, is found predominantly if not exclusively on retinal ganglion cells. We hypothesized that Thy-1 plays a significant role in retinal development. Neurite outgrowth of retinal ganglion cells from Thy-1(-) mice over multiple substrates was compared to that seen with wild-type controls. Adult mouse retinas were histologically compared between Thy-1(-) and three strains of Thy-1 positive mice. Thy-1(-) retinal ganglion cells had significantly less neurite outgrowth than controls. The inner nuclear, inner plexiform, ganglion cell and outer segment/pigment epithelium layers were thinner in Thy-1(-) retinae than in controls. Thy-1 appears to be critical for normal retinal development.

Vascular endothelial growth factor-induced migration of vascular smooth muscle cells in vitro.

Angiogenesis is a complex process that includes recruitment and proliferation of mural cells-smooth muscle cells (SMC) and pericytes. Vascular endothelial growth factor (VEGF) has been shown to play an important role in angiogenesis and is an endothelial cell chemoattractant. In addition, certain VEGF isoforms have been implicated in the normal formation of smooth muscle cell-surrounded arteries. Because VEGF's role as a mural cell chemoattractant had not been explored, we examined the ability of VEGF to influence vascular SMC migration in vitro. A Boyden chamber migration assay demonstrated that VEGF (0-100 ng/ml) caused a dose-dependent migration of SMC. VEGF did not cause proliferation of SMC. Reverse transcriptase-polymerase chain reaction analysis demonstrated the presence of both KDR and flt mRNA, two known VEGF receptors, in SMC cultures. Western blot analysis of SMC lysates confirmed these data, revealing bands migrating at approximately 200 kDa and slightly below 200 kDa consistent with KDR and flt. These observations demonstrate that VEGF receptors are present on SMC, and that VEGF can act as an SMC chemoattractant.

Lidocaine toxicity to rat retinal ganglion cells.

PURPOSE: To examine the effects of the local anesthetic, lidocaine, on rat retinal ganglion cells (RGC) in vitro and in a modified in vivo assay. METHODS: For in vitro experiments, RGC were dissociated from freshly harvested Long Evan's rat pup retinas. The RGC were incubated overnight with varying concentrations of lidocaine (0.5-12.0 mM). Surviving cells were assayed at 24 hours. In an in vivo assay, 7-day-old Long-Evans rat pups were anesthetized and 2 microl of lidocaine (final intraocular concentration: 0.03-15 mM) or vehicle was injected intravitreally. Intravitreal coinjection of nimodipine or MK801 (dizocilpine) were also performed in a subset of animals. A week after injection, rat pups were sacrificed and each retina removed, dissociated and plated separately. RGC survival was immediately assessed. Living RGC were identified on the basis of morphology and counted in a masked fashion. RESULTS: Lidocaine is toxic in a dose dependent fashion to RGC in vitro. Lower concentrations (0.5 mM and 1.0 mM) were non-toxic; 2.0, 6.0 and 12.0 mM lidocaine killed 25%, 88% and 99% of the RGC respectively. Intravitreal lidocaine was also toxic to RGC in a dose dependent fashion. Lidocaine concentrations of 3.0 mM, 7.5 mM and 15 mM killed 25%, 38% and 44% of the RGC. This effect was blocked by the simultaneous administration of either nimodipine or MK801. CONCLUSIONS: Lidocaine is toxic to RGC both in vitro and in vivo. This effect is blocked in vivo by the simultaneous administration of agents known to block glutamate mediated neuronal death, suggesting that excitotoxicity may be involved in this process.

Cation channel control of neurite morphology.

The development of neuronal polarity and morphology is essential for a functioning nervous system. The present study was undertaken to explore whether blockade of specific channels alter neuronal morphology. Retinal ganglion cells were cultured in the presence of antagonists to NMDA, AMPA/kainate, L-, N-, P-, and Q-type voltage-dependent calcium channels (VDCCs). Five parameters were measured under these conditions: the number of neurites at the cell body, total neurite length, the length of the longest neurite, the number of branch points per neurite, and the diameter of the cell soma. Antagonists to NMDA and L-type VDCCs reduce the number of neurites at the cell body; antagonists to P- and Q-type VDCCs increase the number of neurites. Antagonists to the N-type VDCCs increase total neurite outgrowth, while antagonists to the NMDA and P-type channels reduce total neurite length. Antagonists to the NMDA and L-type channels increase the length of a single neurite, while decreasing the number of branch points; antagonists to the P- and Q-type VDCCs do essentially the opposite-increase the number of neurites, while decreasing the length of each. Blockade of one or more cation channels in developing retinal ganglion cells significantly perturbs neurite morphology. This study may help elucidate part of the role that cation channel signaling plays in neuritic development.

Nitrate therapy may retard glaucomatous optic neuropathy, perhaps through modulation of glutamate receptors.

Nitrates have been a major part of the internist's pharmacopoeia for more than 100 years, predominantly for the relief of anginal symptoms. The effects of nitroglycerin on the eye and specifically on intraocular pressure has been investigated with diverse results. However, nitroglycerin may also serve to protect retinal ganglion cells against glutamate mediated toxicity--a form of cell death that may be critical in glaucomatous blindness. Consequently, we therefore sought to evaluate whether nitroglycerin preparations, taken for non-ophthalmic reasons, had an effect on glaucomatous damage.

Excitatory mechanisms in retinal ganglion cell death in primary open angle glaucoma (POAG).

Glaucoma is a leading cause of blindness worldwide and the second leading cause of irreversible blindness in the United States. The most common form of glaucoma, primary open angle glaucoma, is characterized by a chronically elevated intraocular pressure in the absence of any demonstrable structural abnormalities in the eye. The pathologic hallmark of glaucomatous optic neuropathy is the selective death of retinal ganglion cells, generally attributed to an elevated intraocular pressure. However, the histopathology of glaucomatous injury is strikingly similar to the pattern seen with the administration of toxic levels of glutamate. We have found that glaucoma is associated with elevated levels of intraocular glutamate-to a level toxic to ganglion cells. We propose that an elevation of vitreal glutamate may be responsible, at least in part, for the loss of ganglion cells seen in open angle glaucoma.

Color Doppler ultrasound analysis of ocular circulation after topical calcium channel blocker.

PURPOSE: To investigate the effect of topical administration of the calcium channel blocker verapamil on intraocular pressure and retrobulbar hemodynamics. METHODS: In this randomized, prospective, double-masked study, we examined the effects of single-dose topical administration of verapamil in ten normal human volunteers by using color Doppler ultrasound imaging to measure hemodynamic parameters. Limitations of this study include single-dose application of verapamil and relatively small sample size. RESULTS: No systemic effect on heart rate or blood pressure was detected after administration of topical verapamil. The intraocular pressure significantly decreased compared with baseline two hours after topical 0.125% and 0.25% verapamil (P = .015 and .040, respectively). Pourcelot's ratio, an index of vascular resistance, measured in the central retinal artery was significantly reduced after topical application of 0.125% verapamil (P = .008). The change in Pourcelot's ratio primarily resulted from an increased end diastolic velocity in the central retinal artery. No significant differences compared with baseline values were detected in the color Doppler ultrasound measurements of the posterior ciliary arteries and the central retinal vein two hours after topically administered verapamil. CONCLUSIONS: Topical administration of verapamil decreases intraocular pressure and alters ocular hemodynamics, reducing the vascular resistance index in the central retinal artery.

Vascular tone influences arterial pressure lability after sinoaortic deafferentation.

Sinoaortic deafferentation (SAD) results in increased variability of arterial pressure. The purpose of this study was to investigate the contribution of nonneurogenic, peripheral vasomotor mechanisms to this arterial pressure lability. In rats with SAD, ganglionic blockade combined with either captopril or a V1-vasopressin receptor antagonist reduced the high lability. Under these conditions, continuous infusions of phenylephrine and the endogenous vasoconstrictors angiotensin II, epinephrine, and vasopressin increased lability, suggesting that the level of vascular tone is important for maintaining lability. Hemodynamic changes in individual vascular beds did not correlate with pressure lability; however, the sum of the changes in resistance, an estimate of changes in total peripheral resistance, was significantly correlated. These results suggest that 1) direct actions of endogenous vasoconstrictors can induce marked variations of arterial pressure, presumably by sustaining a high background of vascular tone, and 2) variations in resistance of individual vascular beds do not account for the lability of arterial pressure evoked by infusion of vasoconstrictors. We conclude that vascular tone of neural and/or humoral origin is critical for the generation of fluctuations in arterial pressure associated with deafferentation of baroreceptors.

Role of renal nerves in experimental hypertension: evaluation of neurogenic mechanisms.

To evaluate neurogenic mechanisms underlying variations in arterial pressure associated with removal of baroreflexes, renal sympathetic nerve activity (RSNA) was recorded in conscious unrestrained rats 1 day and 14 days following sinoaortic deafferentation (SAD) or sham operation. Fluctuations in RSNA and heart rate (HR) were correlated stastistically with moment to moment changes in pressure. One day and 14 days after SAD, the lability of mean arterial pressure (MAP) was increased, whereas the lability of RSNA and HR were reduced at 1 day and unchanged at 14 days. Arterial pressure and RSNA were negatively correlated in sham rats, however in rats with SAD negative correlations were virtually absent and positive correlations appeared only infrequently. These results indicate that SAD reduces variability of both RSNA and HR and that lability of arterial pressure appears to not be driven by variations in sympathetic discharge. To examine the central origins of RSNA in anesthetized rats we blocked neuronal transmission in two vasomotor regions of rostral medulla, rostral ventrolateral medulla (RVLM) and rostral ventromedial medulla (RVMM) using bilateral microinjections of lidocaine. Blockade of either or both RVLM and RVMM produced an equivalent marked reduction in arterial pressure but reduced RSNA to only 40% of control. Ganglionic blockade had little additional effect on arterial pressure but abolished the residual RSNA. These findings suggest that a substantial fraction of RSNA may be non-vasomotor in function and that this activity may originate from spinal sites or from supraspinal sites other than RVLM or RVMM.

Differential regulation of sympathetic nerve activity by lateral and medial subregions of the rostral ventral medulla.

Microinjections of lidocaine were used to examine the contributions of two subregions of the RVM, RVLM (2 mm lateral to midline) and RVMM (1 mm lateral to midline) to the maintenance of AP and SNA in urethane-anesthetized rats. Lidocaine microinjected into either site reduced AP to similar levels. Blockade of RVLM and RVMM produced a small further reduction in AP and essentially abolished neurogenic maintenance of AP. Blockade of either RVLM or RVMM elicited similar falls in RSNA. In contrast, inactivation of RVLM elicited larger falls in lumbar chain (LSNA) and splanchnic (SSNA) SNA than did inactivation of the RVMM. Combined blockade of RVLM and RVMM essentially eliminated LSNA, while RSNA and SSNA were reduced only 60%. From these data we conclude that (1) RVLM and RVMM contribute equally to the neurogenic maintenance of AP; (2) RVLM and RVMM differentially control the activity of individual sympathetic nerves; and (3) a substantial portion of RSNA and SSNA originates outside the RVM and may not be involved in vasomotor control.

Regional hemodynamic responses to central administration of corticotropin-releasing factor (CRF).

Central administration of corticotropin-releasing factor (CRF) produces a marked increase in both mean arterial pressure and heart rate. These increases appear to be mediated almost exclusively by an activation of the sympathetic nervous system. We studied the hemodynamic mechanisms of the response by determining the contribution of the major vascular beds to the increase in arterial pressure. Experiments were done in conscious, freely moving, male Sprague-Dawley rats. Animals were prepared for measurement of regional blood flow using miniaturized pulsed Doppler flow probes placed on the renal, mesenteric and abdominal aortic arteries. Intracerebroventricular injection of CRF (28.5-570 pmol) produced a dose-dependent increase in both mean arterial pressure and heart rate. A significant increase in vascular resistance was observed in the mesenteric and renal but not in the hindquarter vascular bed at the highest dose of CRF. These data indicate that vasoconstriction in the renal and mesenteric circulations contributes to the centrally mediated pressor effect of CRF.