Physiology and Pharmacology Episcleral Venous Pressure and IOP Responses to Central Electrical Stimulation in the Rat

PURPOSE. Histological evidence suggests a role for the central nervous system in controlling episcleral venous pressure (EVP). Based on prior studies that identified candidate regions in the brain stem, the present study assessed the effect of electrical stimulation at the location of the superior salivatory nucleus (SSN) on EVP in rats. METHODS. Male Sprague-Dawley rats (n ¼ 11) were anesthetized using pentobarbital sodium (50 mg/kg intraperitoneally initially, supplemented intravenously [IV] as needed) and paralyzed with gallamine triethiodide (1 mg/kg, IV). The animals were artificially ventilated and the femoral artery and vein were cannulated for blood pressure measurement and drug administration. Carotid blood flow was measured with an ultrasound flow probe and heart rate with a cardiotachometer. IOP was measured through a cannula in the vitreous compartment and EVP was measured through a micropipette in episcleral veins using the servonull technique. After a craniotomy was performed, a unipolar stainless steel electrode was inserted into the brainstem at the coordinates of the SSN using a stereotactic instrument. Stimulations were performed at 20Hz, 9 lA, 1 ms pulse duration, and 200 pulses. RESULTS. Stimulation at the SSN coordinates increased IOP from 10.6 6 0.4 to 11.8 6 0.6 mm Hg (P < 0.01) and EVP from 7.8 6 1.3 to 10.7 6 1.1 mm Hg (P < 0.01). Mean arterial pressure, carotid blood flow, and heart rate remained unaltered. CONCLUSIONS. The present study indicates that the SSN may participate in regulating EVP. Keywords: episcleral venous pressure, superior salivatory nucleus, stimulation, IOP S teady-state IOP can be described by the Goldmann equation as the relationship between aqueous flow, uveoscleral outflow, outflow facility, and episcleral venous pressure (EVP). 1,2 EVP is the pressure that has to be overcome for fluid to leave the eye via the trabecular outflow pathway and, in humans under normal conditions, EVP accounts for roughly 60% of IOP. Despite its importance for IOP homeostasis, the physiology of the episcleral venous pressure is poorly understood. The current de facto standard for measuring EVP is the venomanometer described by Zeimer et al. 12 Recently, a study by Samuels et al. The brainstem, however, appears to be the first relay station for nerves supplying the eye, and, thus, the nuclei there are likely to be more specialized than higher-order centers in the diencephalon. METHODS The study was approved by the institutional animal care and use committee of the University of Texas Health Science Center at San Antonio and conducted in accordance with the ARVO guidelines for animal use in vision research. All animals were euthanized with an anesthetic overdose at the end of the experiment without regaining consciousness. Animal Preparation Male Sprague Dawley rats (n ¼ 11, 305.4 6 8.6 g) were anesthetized using pentobarbital sodium (Sigma-Aldrich, 50 mg/kg intraperitoneally, supplemented intravenously as needed). A tracheotomy was performed and the animal was respire

Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% for TBLH-BMD, and 39% for TB-LM, with a shared genetic component of 43%. We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: _WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5_. Variants in the _TOM1L2/SREBF1_ locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that _SREBF1_ is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10−8), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P <5 x 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.Peer reviewe

Large meta-analysis of genome-wide association studies identifies five loci for lean body mass

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 x 10(-8)) or suggestively genome wide (p < 2.3 x 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/ near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/ near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass

Episcleral Venous Pressure Responses to Topical Nitroprusside and N-Nitro-l-arginine Methyl Ester

Episcleral venous pressure is a key component of aqueous dynamics and intraocular pressure homeostasis, but little is known about its physiology and pharmacology. This study indicates that nitric oxide is an important modulator of episcleral venous pressure

A rabbit model to study orbital venous pressure, intraocular pressure, and ocular hemodynamics simultaneously

PURPOSE. To measure orbital venous pressure (OVP) and determine the effects of changes in mean arterial pressure (MAP) on OVP, intraocular pressure (IOP), episcleral venous pressure (EVP), and ciliary and choroidal blood flows. METHODS. The experiments were performed in anesthetized rabbits. In all animals, MAP, IOP, and OVP were measured by direct cannulation of the central ear artery, the vitreous, and the orbital venous sinus, respectively. Laser Doppler flowmetry was used to measure choroidal blood flow in one group, and ciliary blood flow in a second group. A servonull micropressure system was used to measure EVP in a third group. The protocol for all three groups entailed varying MAP mechanically with occluders on the aorta and vena cava. RESULTS. The OVP and IOP relationship correlated linearly (r ϭ 0.99) during mechanical manipulation of MAP. EVP also correlated well with OVP (r ϭ 0.9). Resistance calculations based on choroidal and ciliary blood flows and the pressure gradients indicate active adjustment of arterial resistance and passive changes in venous resistance in response to changing MAP in both circulations. CONCLUSIONS. The rabbit orbital venous sinus permits continuous measurements of OVP. The present findings show that OVP is not static and suggest that OVP may play an important role in IOP homeostasis and ocular hemodynamics. (Invest Ophthalmol Vis Sci. 2002;43:3728 -3734) B ecause the veins draining the eye are small or difficult to reach without disturbing the eye and orbit, measurements of venous pressure outside the eye are not performed routinely. However, as the downstream recipient of conventional aqueous outflow and the efflux of the ocular circulations, the orbital venous system&apos;s physiology is intertwined with aqueous dynamics and ocular hemodynamics. In the case of the episcleral veins, the episcleral venous pressure (EVP) is the pressure head that must be overcome for aqueous passage through the trabecular pathway, and so the EVP is acknowledged as a key determinant of steady state intraocular pressure (IOP). 1 However, although EVP is often measured in studies of drug effects on aqueous dynamics, 2 it has rarely been manipulated experimentally, aside from studies of pseudofacility. 3 In contrast to EVP and aqueous dynamics, the effects of orbital venous pressure (OVP) on ocular hemodynamics are less clear. To the best of the authors&apos; knowledge, the only information in the literature comes from the study by Bill 4 in which the blood flow from a cannulated vortex vein was measured as the cannula pressure was varied while holding IOP constant at different levels. Otherwise, we are aware of no studies in which blood flow in an ocular circulation was measured while OVP was varied or measured. Given the paucity of information about OVP, we sought a method to measure it. We found that the rabbit&apos;s skull offers a unique opportunity to measure OVP by direct cannulation of the orbital venous sinus through the posterior supraorbital foramen. This article presents the results of continuous measurements of OVP, EVP, IOP, mean arterial pressure (MAP), and choroidal and ciliary blood flows. The relationships between these parameters obtained during mechanical manipulation of MAP over a wide range show that OVP is not static and that it may play an important role in ocular hydrodynamics. METHODS All animal procedures were approved by the Institutional Animal Care and Use Committee and conducted in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. At the end of the experiment, all animals were killed with an overdose of anesthetic without regaining consciousness. Animal Preparation New Zealand albino rabbits (2-3 kg, n ϭ 25) of both sexes were housed for 1 to 3 days in the vivarium with access to food and water ad libitum before the experiments. The animals were anesthetized with pentobarbital sodium (30 mg/kg, intravenously, supplemented as needed) and paralyzed with gallamine triethiodide (1 mg/kg) to eliminate eye movement. The animals were intubated through a tracheotomy and ventilated with room air. Expired PCO 2 was monitored (Normocap 200; Datex, Tewksbury, MA) and maintained at 40 to 45 mm Hg. A heating pad was used to maintain normal body temperature (38 -39°C). All intravenous injections were given through cannulas placed in the marginal ear veins. The right eye and the right orbital venous sinus were used in all experiments. To estimate the ocular arterial pressure (AP) and ensure the adequacy of anesthesia, a catheter was inserted into the right ear artery and connected to a pressure transducer positioned at the same height above the heart as the eye. After the initial surgical preparation, the animals were mounted in a stereotaxic head holder, and the right eye was cannulated with a 23-gauge needle inserted into the vitreous cavity through the pars plana to measure the IOP with a pressure transducer. To avoid the rabbit ocular trauma response 5 and release of prostaglandins, 6,7 the right eye was anesthetized topically with lidocaine before cannulation and care was taken not to disturb the cornea and anterior chamber. Measurement of OVP The orbital venous sinus covers most of the backside of the rabbit eye