Decrease In Outflow Resistance Research Articles

Downregulation of COL12A1 and COL13A1 by a selective EP2 receptor agonist, omidenepag, in human trabecular meshwork cells.

Omidenepag isopropyl (OMDI) is an intraocular pressure (IOP)-lowering drug used to treat glaucoma. The active form of OMDI, omidenepag (OMD), lowers elevated IOP, the main risk factor for glaucoma, by increasing the aqueous humor outflow; however, a detailed understanding of this mechanism is lacking. To clarify the IOP-lowering mechanism of OMDI, the effects of OMD on the mRNA expression of the extracellular matrix, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) were evaluated in human trabecular meshwork cells. Under 2D culture conditions, the mRNA expression of FN1, COL1A1, COL1A2, COL12A1, and COL13A1 decreased in a concentration-dependent manner after 6 or 24 h treatment with 10 nM, 100 nM, and 1 μM OMD, while that of COL18A1 decreased after 6 h treatment with 1 μM OMD. Significant changes in expression were observed for many MMP and TIMP genes. Under 3D culture conditions, the extracellular matrix-related genes COL12A1 and COL13A1 were downregulated by OMD treatment at all three concentrations. Under both 2D and 3D culture conditions, COL12A1 and COL13A1 were downregulated following OMD treatment. Reduction in the extracellular matrix contributes to the decrease in outflow resistance, suggesting that the downregulation of the two related genes may be one of the factors influencing the IOP-lowering effect of OMDI. Our findings provide insights for the use of OMDI in clinical practice.

A Novel 8-mm Schlemm's Canal Scaffold Reduces Outflow Resistance in a Human Anterior Segment Perfusion Model

To study the effect on outflow facility and outflow resistance of a nitinol microstent implanted into Schlemm's canal. Using a constant pressure perfusion method, outflow facility and outflow resistance were measured in 26 pairs of dissected anterior segments from donated human eyes. Measurements were made at perfusion pressures of 10, 20, 30 and 40 mm Hg. The Hydrus Microstent was placed in Schlemm's canal of one eye and the contralateral eye underwent a sham procedure. Outflow facility and outflow resistance were measured again after the microstent implantation or sham procedure. The Hydrus Microstent significantly increased outflow facility from 0.33 ± 0.17 μL/min/mm Hg to 0.52 ± 0.19 μL/min/mm Hg (P < 0.001). Outflow resistance was significantly reduced from 4.38 ± 3.03 mm Hg/μL/min at baseline to 2.34 ± 1.04 mm Hg/μL/min (P < 0.001) with the microstent. There was a linear correlation between outflow resistance at baseline and decrease in outflow resistance with the microstent (R(2) = 0.89, P < 0.0001). The increase in outflow facility and decrease in resistance supports the potential use of the Hydrus Microstent as a surgical option to reduce intraocular pressure (IOP). The IOP-lowering effect may be higher in eyes with higher outflow resistance (and IOP) as compared with eyes with lower outflow resistance (and IOP).

Latrunculin B effects on trabecular meshwork and corneal endothelial morphology in monkeys

To determine the mechanism of latrunculin B (LAT-B)-induced decrease in outflow resistance and the effect of LAT-B on the cornea, structural changes of the trabecular meshwork (TM) and the corneal endothelium following LAT-B were studied in the live monkey eye. LAT-B (0.5 μM) and vehicle were administered by anterior chamber exchange and infusion with cationized and non-cationized gold solution in opposite eyes. The eyes were fixed by infusing Ito's solution and enucleated. Anterior segments were quadrisected and embedded in Epon-Embed 812. Morphology of the TM and the corneal endothelium was studied by light and electron microscopy. LAT-B-induced morphological changes in the TM included: (1) loss of microfilament integrity in cells, especially in TM cells on the collagen beams; (2) development of numerous cytoplasmic projections of the sub-canalicular cells (SUB); (3) reorganization of intermediate filaments in Schlemm's canal inner wall (IW) cells; (4) massive ‘ballooning’ of the juxtacanalicular (JXT) region, leading to a substantial expansion of the space between the IW of Schlemm's canal and the trabecular collagen beams; and (5) retention of extracellular matrix (ECM), trapped between the SUB cell layer and IW cells. No detrimental effects on tight junctions, giant vacuoles, and cell–cell and cell–ECM adhesions were observed. Endocytosis of gold particles was not affected. Morphology of the corneal endothelium of the LAT-B-treated eye was unchanged. In conclusion, TM changes in the LAT-B-treated eye suggest that the expansion of the JXT space may account for the decrease in outflow resistance induced by latrunculins. The outflow-effective concentration of LAT-B administered intracamerally does not significantly affect the corneal endothelium.

Effect of age on outflow resistance washout during anterior chamber perfusion in rhesus and cynomolgus monkeys

When aqueous humour outflow resistance is measured by two-level constant pressure perfusion in non-human primate eyes, a progressive decrease in outflow resistance, known as the ‘washout effect’ occurs with time. The effect of age on total outflow resistance washout (the reciprocal of outflow facility (OF)) was determined in rhesus and cynomolgus monkeys. In cynomolgus monkeys, the effect of time between exchange of the anterior chamber (AC) contents and post-exchange OF measurements on outflow resistance was also examined. Total OF was determined at baseline in one eye of 35 rhesus monkeys aged 4–29 yrs, and in 27 cynomolgus monkeys, aged 3–17 yrs, at baseline and after 10 min AC exchange with 1 or 2 ml Bárány's perfusand or in Bárány's containing 0.01–1% dimethyl sulfoxide (DMSO) or Tris base. Resistance washout did not differ with age at baseline in rhesus or cynomolgus monkeys. Similarly, no changes were found when comparing post-exchange resistance washout vs. age in cynomolgus monkeys that had undergone AC exchange with Bárány's perfusand only or Bárány's containing 0.01–1% DMSO or Tris base. Rate of resistance washout decreased with increased length of time between exchange of the AC contents and post-exchange outflow facility readings (−0.0004±0.0092 mmHg min −1 μl −1 yr −1; p=0.016). Several explanations for these findings are plausible.

Cardiac natriuretic peptides: a physiological lineage of cardioprotective hormones?

Vertebrate hearts from fish to mammals secrete peptide hormones with profound natriuretic, diuretic, and vasodilatory activity; however, the specific role of these cardiac natriuretic peptides (NPs) in homeostasis is unclear. NPs have been suggested to be involved in salt excretion in saltwater teleosts, whereas they are proposed to be more important in volume regulation in mammals. In this review, we consider an alternative (or perhaps complementary) function of NPs to protect the heart. This hypothesis is based on a number of observations. First, evidence for NPs, or NP-like activity has been found in all vertebrate hearts thus far examined, from osmoconforming saltwater hagfish to euryhaline freshwater and saltwater teleosts to terrestrial mammals. Thus the presence of cardiac NPs appears to be independent of environmental conditions that may variously affect salt and water balance. Second, cardiac stretch is a universal, and one of the most powerful, NP secretagogues. Furthermore, stretch-induced NP release in euryhaline teleosts appears relatively independent of ambient salinity. Third, excessive cardiac stretch that increases end-diastolic volume (EDV) can compromise the mechanical ability of the heart by decreasing actin-myosin interaction (length-tension) or through Laplace effects whereby as EDV increases, the wall tension necessary to maintain a constant pressure must also increase. Excessive cardiac stretch can be produced by factors that decrease cardiac emptying (i.e., increased arterial pressure), or by factors that increase cardiac filling (i.e., increased blood volume, increased venous tone, or decreased venous compliance). Fourth, the major physiological actions of cardiac NPs enhance cardiac emptying and decrease cardiac filling. In fish, NPs promote cardiac emptying by decreasing gill vascular resistance, thereby lowering ventral aortic pressure. In mammals a similar effect is achieved through pulmonary vasodilation. NPs also decrease cardiac filling by decreasing blood volume and increasing venous compliance, the latter producing a rapid fall in central venous pressure. Fifth, the presence of NP clearance receptors in the gill and lung (between the heart and systemic circulation) suggest that these tissues may be exposed to considerably higher NP titers than are systemic tissues. Thus, a decrease in outflow resistance immediately downstream from the heart may be the first response to increased cardiac distension. Because the physiology of cardiac NPs is basically the same in fish and mammals, we propose that the cardioprotective effects of NPs have been well preserved throughout the course of vertebrate evolution. It is also likely that the cardioprotective role of NPs was one of the most primordial homeostatic activities of these peptides in the earliest vertebrates.

Hemodynamic evaluation of the addition of isosorbide-5-mononitrate to nadolol in cirrhotic patients with insufficient response to the ?- blocker alone

The association beta-blockers plus isosorbide-5-mononitrate (I5M) has been proposed for the treatment of portal hypertension in patients with insufficient response to beta-blockers alone, according to hemodynamic criteria. The mechanism of action in these patients is not clearly defined. Fifteen patients with cirrhosis and esophageal varices were evaluated by hepatic venous pressure gradient (HVPG) measurement and duplex-Doppler ultrasonography before and after 1 month of treatment with nadolol. Nine patients who did not exhibit a decrease in HVPG to 12 mm Hg or a percent decrease greater than 20% were classified as poor responders, and were studied again with the same methodology after 3 months of chronic administration of nadolol + I5M 20 mg twice per day. In poor responders, mean HVPG decrease after nadolol was 8.9% +/- 2.8%, and after the combination, it was 25.7% +/- 1.7% (P = .004). All patients except one became good responders to the association. Portal blood flow (PBF) decreased significantly after nadolol (P = .004), and remained unchanged after the addition of nitrates. Resistance to portal blood flow (RPBF) increased after nadolol (P = .02) and returned to baseline values during combined treatment (P = .03). In good responders, an adequate decrease in HVPG was associated with a decrease in PBF (P = .06) but no change in RPBF. A wide spectrum of combined changes in PBF and in RPBF after nadolol was observed in poor responders, ranging from no change in either parameter to a marked decrease in PBF counterbalanced by a marked increase in RPBF. The addition of I5M was followed in most cases by larger effects on resistance than on flow. Doppler parameters were not significantly correlated with the HVPG response to nadolol alone or associated with I5M. It is concluded that good hemodynamic responders to nadolol differ from poor responders in the lack of increase in RPBF after the drug. The addition of nitrates to nadolol is effective in decreasing portal pressure in most poor responders to nadolol alone. A decrease in outflow resistance is the main mechanism involved.

Hemodynamic evaluation of the addition of isosorbide-5-mononitrate to nadolol in cirrhotic patients with insufficient response to the beta- blocker alone

The association beta-blockers plus isosorbide-5-mononitrate (I5M) has been proposed for the treatment of portal hypertension in patients with insufficient response to beta-blockers alone, according to hemodynamic criteria. The mechanism of action in these patients is not clearly defined. Fifteen patients with cirrhosis and esophageal varices were evaluated by hepatic venous pressure gradient (HVPG) measurement and duplex-Doppler ultrasonography before and after 1 month of treatment with nadolol. Nine patients who did not exhibit a decrease in HVPG to 12 mm Hg or a percent decrease greater than 20% were classified as poor responders, and were studied again with the same methodology after 3 months of chronic administration of nadolol + I5M 20 mg twice per day. In poor responders, mean HVPG decrease after nadolol was 8.9% +/- 2.8%, and after the combination, it was 25.7% +/- 1.7% (P = .004). All patients except one became good responders to the association. Portal blood flow (PBF) decreased significantly after nadolol (P = .004), and remained unchanged after the addition of nitrates. Resistance to portal blood flow (RPBF) increased after nadolol (P = .02) and returned to baseline values during combined treatment (P = .03). In good responders, an adequate decrease in HVPG was associated with a decrease in PBF (P = .06) but no change in RPBF. A wide spectrum of combined changes in PBF and in RPBF after nadolol was observed in poor responders, ranging from no change in either parameter to a marked decrease in PBF counterbalanced by a marked increase in RPBF. The addition of I5M was followed in most cases by larger effects on resistance than on flow. Doppler parameters were not significantly correlated with the HVPG response to nadolol alone or associated with I5M. It is concluded that good hemodynamic responders to nadolol differ from poor responders in the lack of increase in RPBF after the drug. The addition of nitrates to nadolol is effective in decreasing portal pressure in most poor responders to nadolol alone. A decrease in outflow resistance is the main mechanism involved. (Hepatology 1997 Jul;26(1):34-9)

Excimer laser photoablative filtration surgery: histology and ultrastructure in 4 human cadaver eyes.

The purpose of this study was to verify the feasibility of ab externo layer-by-layer excimer laser photoablative removal of limbal tissue down to the trabecular meshwork and to assess the damage caused by this procedure to the neighbouring structures. Excimer laser photoablation (193 nm) can remove layers of corneal tissue effectively with little or no damage to the adjacent areas. Previous experimental studies have demonstrated a decrease in outflow resistance after ab-externo photoablative removal of juxtacanalicular tissue. We have performed ab-externo photoablative removal of limbal tissue overlying the trabecular meshwork in four freshly enucleated eyes from our Eye Bank. The beam of an excimer laser (wavelength 193 nm; fluence 180 mJ/Sq.cm) was shaped using a metal mask with a rectangular opening of 1.2 x 2.5 mm. After removing the conjunctiva, photoablation was carried out at maximum surgical microscope magnification (40 x) until trabecular meshwork appeared at the bottom of the crater. Light microscopy showed that craters had smooth walls and their base reached the Schlemm's canal area; all structures appeared of normal morphology. Transmission electron microscopy showed a thin layer of amorphous material or pseudomembrane on the side walls of the crater; corneoscleral collagen fibers were abruptly interrupted and undistorted. At the bottom of the crater the trabecular meshwork and Schlemm's canal tissues appeared normal.

Developmental changes in cerebrospinal fluid pressure and resistance to absorption in rats

Cerebrospinal fluid (c.s.f.) pressure and resistance to absorption have been studied in exteriorised fetuses (18 to 21 days gestation) from pregnant rats anaesthetised with pentobarbitone and in similarly anaesthetised postnatal rats at 1, 5, 10 and 30 days after birth and in adults. The resting c.s.f. pressure was low in fetuses (17–21 mm H 2O) and it rose to 26–27 mm H 2O at 1 and 5 days after birth. By 10 days after birth the pressure was 34 mm H 2O after which time there was no further change. The plateau pressure response to different infusion rates was linear, but only up to pressures around 7-fold higher than the resting c.s.f. pressure. Hence, resistance to absorption was calculated for plateau pressures up to 140 mm H 2O in fetuses, to 200 mm H 2O in 1- and 5-day rats and to 240 mm H 2O for 10-day, 30-day and adult rats. Resistance to absorption was not significantly different for the two measurement sites (lateral ventricle and subarachnoid space) at any age studied, showing that fluid can move freely through the ventricular system in young rats. The resistance to absorption was low in the fetuses, 10.8 and 16.3 mm H 2O min/μl at 18–19 and 20–21 days gestation, respectively. There was a sharp increase in resistance to 39.2 mm H 2O min/μl at 1 day after birth and thereafter there was a decrease to 6.8 mm H 2O min/μl at 30 days and this was similar to adult values. This decrease in outflow resistance from the first day after birth may be related to the increase in c.s.f. pressure and secretion rate that occur after birth in the rat.

Air Trabeculotomy

Retrograde air injection into an episcleral aqueous vein of ten rhesus monkey eyes resulted in multiple microscopic ruptures in the inner canal wall and trabecular meshwork, without trabecular detachment or damage to the other canal walls and the surrounding tissues. After air trabeculotomy, a 41% decrease in outflow resistance was observed.