The Association of Urinary Sodium Excretion with Glaucoma and Related Traits in a Large United Kingdom Population

Purpose: Excessive dietary sodium intake has known adverse effects on intravascular fluid volume and systemic blood pressure, which may influence intraocular pressure (IOP) and glaucoma risk. This study aimed to assess the association of urinary sodium excretion, a biomarker of dietary intake, with glaucoma and related traits, and determine whether this relationship is modified by genetic susceptibility to disease. Design: Cross-sectional observational and gene-environment interaction analyses in the population-based UK Biobank study. Participants: Up to 103 634 individuals (mean age: 57 years; 51% women) with complete urinary, ocular, and covariable data. Methods: Urine sodium:creatinine ratio (UNa:Cr; mmol:mmol) was calculated from a midstream urine sample. Ocular parameters were measured as part of a comprehensive eye examination, and glaucoma case ascertainment was through a combination of self-report and linked national hospital records. Genetic susceptibility to glaucoma was calculated based on a glaucoma polygenic risk score comprising 2673 common genetic variants. Multivariable linear and logistic regression, adjusted for key sociodemographic, medical, anthropometric, and lifestyle factors, were used to model associations and gene-environment interactions. Main Outcome Measures: Corneal-compensated IOP, OCT derived macular retinal nerve fiber layer and ganglion cell-inner plexiform layer (GCIPL) thickness, and prevalent glaucoma. Results: In maximally adjusted regression models, a 1 standard deviation increase in UNa:Cr was associated with higher IOP (0.14 mmHg; 95% confidence interval [CI], 0.12–0.17; P < 0.001) and greater prevalence of glaucoma (odds ratio, 1.11; 95% CI, 1.07–1.14; P < 0.001) but not macular retinal nerve fiber layer or ganglion cell-inner plexiform layer thickness. Compared with those with UNa:Cr in the lowest quintile, those in the highest quintile had significantly higher IOP (0.45 mmHg; 95% CI, 0.36–0.53, P < 0.001) and prevalence of glaucoma (odds ratio, 1.30; 95% CI, 1.17–1.45; P < 0.001). Stronger associations with glaucoma (P interaction = 0.001) were noted in participants with a higher glaucoma polygenic risk score. Conclusions: Urinary sodium excretion, a biomarker of dietary intake, may represent an important modifiable risk factor for glaucoma, especially in individuals at high underlying genetic risk. These findings warrant further investigation because they may have important clinical and public health implications. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article

Rate of decrease of myocardial O2 consumption due to cardiac arrest in anesthetized goats

The rate of change of myocardial O2 consumption, MVO2, has been measured during the transition from beating to cardiac arrest. Cardiac arrest was achieved by destruction of the bundle of His by injection of formalin and induced by 25 s interruption of pacing. The left main coronary artery was perfused under constant pressure and the great cardiac vein was drained under controlled pressure. The arterio-venous O2 content difference, [O2](a-v), and coronary arterial and venous flows, CAF resp CVF, were continuously measured. The MVO2 transient was calculated using the following equation based on a 3 compartment model: MVO2 = CAF . [O2](a-v) - (Vc + Vv) . d[O2]v/dt - (Vc . Vv/CVF) . d2[O2]v/dt2 where Vc and Vv are the capillary and the venous blood volume as function of time and [O2]v is the venous oxygen content. A 7th order polynoma was fit to the [O2]v-data and the fitted equation was differentiated analytically to obtain the first and second order derivatives. The MVO2 decreased from 94 +/- 5 microliters O2/s/100 g (mean +/- SE) before cardiac arrest to 15.4 +/- 5 microliters O2/s/100 g after 15 s of cardiac arrest. The change in MVO2 (50% in 3.8 +/- 0.3 s) preceded the change in venous oxygen content (50% in 12.7 +/- 0.5 s) and the change in coronary resistance (50% in 14.9 +/- 0.9). These results are in accordance with the hypothesis that interstitial O2 concentration is a major determinant of coronary resistanc

Intramyocardial blood volume change in first moments of cardiac arrest in anesthetized goats

The effect of cardiac relaxation on the intramyocardial blood volume was studied by measuring the integrated difference between arterial inflow and great cardiac venous outflow. In nine anesthetized goats, the left main coronary artery was perfused under constant pressure. The great cardiac vein was drained under pressure control. The venous flow signal was amplified so that the integrated intramyocardial blood volume was constant in the beating heart. With normal vasomotor tone, the mean change in vascular volume was 3.01 +/- 0.18 (SE) ml/100 g left ventricle (LV); 67% of the volume change was achieved in 1.60 +/- 0.09 s. For the fully dilated bed (adenosine infusion), the values were 4.13 +/- 0.33 ml/100 g and 0.96 +/- 0.06 s, respectively. The volume change could be correlated with the venous pressure during cardiac arrest (Pvd) and the change in mean left ventricular pressure after cardiac arrest (r = 0.95). The correlation improved when data were selected for Pvd less than 6 mmHg to r = 0.98. We assumed that the change in vascular transmural pressure can be approximated as half the mean left ventricular pressure change. The intramyocardial vascular compliance was then estimated as 0.104 +/- 0.012 and 0.146 +/- 0.028 ml X mmHg-1 X 100 g-1 for control and adenosine conditions, respectively. The long time constants excluded the large epicardial veins as the site of volume change; they were much longer than the duration of diastole in the beating heart. We conclude that the intramyocardial vascular compartment is capable of volume expansion on the order of 20% of its normal volume when myocardial compression by ventricular systole is suspende

Stopped-flow epicardial lymph pressure is affected by left ventricular pressure in anesthetized goats

We measured epicardial lymph pressure (Plymph) in the anesthetized goat (n = 5 goats). To study the transmission of systolic left ventricular pressure (PLV) to Plymph, the effect of an increase in PLV caused by clamping of the descending aorta on Plymph was evaluated. Peak systolic PLV was 131 +/- 4 (+/- SE) mmHg during control (43 beats) and 188 +/- 4 mmHg when elevated due to aortic clamping (157 beats). Peak systolic Plymph was 24.8 +/- 1.0 and 34.8 +/- 1.1 mmHg during control and elevated PLV, respectively. In the first beat of elevated PLV, peak Plymph did not change, although the pressure waveform did. In the subsequent beats, Plymph increased proportionally with increased PLV. When PLV was decreased back to control, Plymph also decreased but did not reach control level until after three beats. The relationship between normalized Plymph and normalized PLV is given by Plymph = 0.70 x PLV + 0.09. The results show that PLV does affect Plymph in a normal beating hear

Persistent GnRH receptor activation in pituitary αT3-1 cells analyzed with a label-free technology.

The gonadotropin-releasing hormone (GnRH) receptor is a drug target for certain hormone-dependent diseases such as prostate cancer. In this study, we examined the activation profiles of the endogenous ligand, GnRH and a well-known marketed analog, buserelin using a label-free assay in pituitary αT3-1 cells with endogenous GnRH receptor expression. This whole cell impedance-based technology allows for the real-time measurement of morphological cellular changes. Both agonists dose-dependently decreased the impedance as a result of GnRH receptor activation with potencies of 9.3±0.1 (pEC50 value, buserelin) and 7.8±0.06 (pEC50 value, GnRH). Subsequently, GnRH receptor activation was completely abolished with a selective Gαq inhibitor, thereby confirming the Gαq-coupling of the GnRH receptor in pituitary αT3-1 cells. Additionally, we observed continued responses after agonist stimulation of αT3-1 cells indicating long-lasting cellular effects. Wash-out experiments demonstrated that the long-lasting effects induced by GnRH were most likely caused by rebinding since over 70% of the original response was abolished after wash-out. In contrast, a long receptor residence time was responsible for the prolonged effects caused by buserelin, with over 70% of the original response remaining after wash-out. In summary, we validated that impedance-based label-free technology is suited for studying receptor-mediated activation in cell lines endogenously expressing the target of interest. Moreover, this real-time monitoring allows the examination of binding kinetics and its influence on receptor activation at a cellular level.</p

Persistent GnRH receptor activation in pituitary αT3-1 cells analyzed with a label-free technology.

The gonadotropin-releasing hormone (GnRH) receptor is a drug target for certain hormone-dependent diseases such as prostate cancer. In this study, we examined the activation profiles of the endogenous ligand, GnRH and a well-known marketed analog, buserelin using a label-free assay in pituitary αT3-1 cells with endogenous GnRH receptor expression. This whole cell impedance-based technology allows for the real-time measurement of morphological cellular changes. Both agonists dose-dependently decreased the impedance as a result of GnRH receptor activation with potencies of 9.3±0.1 (pEC50 value, buserelin) and 7.8±0.06 (pEC50 value, GnRH). Subsequently, GnRH receptor activation was completely abolished with a selective Gαq inhibitor, thereby confirming the Gαq-coupling of the GnRH receptor in pituitary αT3-1 cells. Additionally, we observed continued responses after agonist stimulation of αT3-1 cells indicating long-lasting cellular effects. Wash-out experiments demonstrated that the long-lasting effects induced by GnRH were most likely caused by rebinding since over 70% of the original response was abolished after wash-out. In contrast, a long receptor residence time was responsible for the prolonged effects caused by buserelin, with over 70% of the original response remaining after wash-out. In summary, we validated that impedance-based label-free technology is suited for studying receptor-mediated activation in cell lines endogenously expressing the target of interest. Moreover, this real-time monitoring allows the examination of binding kinetics and its influence on receptor activation at a cellular level

Cardiac contraction and intramyocardial venous pressure generation in the anaesthetized dog.

1. Two hypotheses relating to the influence of contraction of the heart on coronary venous pressure (Pv) were tested. The first assumes a direct transmission of left ventricular pressure (PLV). According to the alternative hypothesis the Pv is caused by cyclical changes in the elastance of the surrounding tissue. 2. A small epicardial vein was cannulated retrogradely in eight open-chest dogs deeply anaesthetized with fentanyl. The duration of diastoles was varied after induction of a heart block with formaldehyde. Coronary arterial inflow and perfusion pressure were controlled by a perfusion system connected to the left main coronary artery by a Gregg cannula. Stopped-flow Pv was studied with intrinsic coronary tone (IT) and after maximal dilatation with adenosine. 3. The Pv pulse in the first contraction after a long diastole was not significantly correlated to the PLV pulse, with a slope of 0.5, in any dog, either with IT or during adenosine treatment. Comparing the first contraction after the long diastole with the last beat before, systolic Pv pulse decreased significantly in seven out of eight dogs, but systolic PLV pulse increased in five dogs and was unaltered in three dogs in both conditions. In contrast, end-diastolic Pv was significantly correlated to the systolic Pv in each individual animal under either condition. 4. The results indicate that pressure generation in the small coronary veins can be explained on the basis of the time-varying elastance hypothesis and that a direct transmission of PLV to Pv is absent