Hypertensive Rabbits Research Articles

Effect of ophthalmic preparation of methyldopa on induced ocular hypertension in rabbits.

Glaucoma is a type of ocular disorder with multifaceted etiologies characterized by progressive optic nerve damage and ultimately loss of visual field. Thisstudy aimed to evaluate the possible intraocular pressure (IOP) lowering effect of an ophthalmic preparation of methyldopa (MD) in corticosteroid-induced ocular hypertension in rabbits. Forty New Zealand white male rabbits were assigned to the experiment and then randomly divided into five groups (n = 8). Ocular hypertension was induced by weekly subconjunctival injection of betamethasone suspension in both eyes. Animal groups included the control (healthy) group, which received the ophthalmic vehicle only; the standard (timolol) group, which received 0.5% timolol eye drops (ED); and the MD groups, which received 0.5%, 1%, and 2% of methyldopa ophthalmic preparation. Treatments were applied to the right eye twice daily for 7 days, whereas the left eye served as a control and was given only distilled water. IOP was recorded and ocular reflexes were observed. Weekly subconjunctival injections of betamethasone resulted in a significant elevation in the IOP (P ≤ 0.001) that was reduced after treatments with timolol 0.5% and MD at different concentrations. Timolol showed the highest reduction (P ≤ 0.001) in the mean IOP with a 30% reduction. MD showed a concentration-dependent reduction with the highest reduction (P ≤ 0.01) observed at 2% compared to the induced/distilled water (DW) eyes and no significant difference compared to the timolol 0.5% (P ≥ 0.05) with a 24.2% reduction in the mean IOP. Methyldopa managed to reduce the IOP in the chronic model of glaucoma, making MD a promising addition to the anti-glaucoma medications.

Low-intensity focused ultrasound combined with microbubbles for non-invasive downregulation of rabbit carotid body activity in the treatment of hypertension.

Targeting the carotid body (CB) is a new approach in treating hypertension. This study investigates the efficacy and safety of ultrasound combined with microbubbles in targeting CB to treat hypertension. Twenty-seven hypertensive rabbits were randomly assigned to three groups: microbubbles only (sham group, n = 11), ultrasound plus microbubbles (LIFU group, n = 11), and bilateral carotid sinus nerve denervation (CSND group, n = 5). Four weeks post-intervention, blood pressure, hypoxic ventilatory response (HVR), blood pressure variability (BPV), heart rate variability (HRV), biochemical indicators, neurohormones, and histopathology were assessed in all groups. The results indicated significant reductions in systolic and diastolic blood pressure in the LIFU and CSND groups post-intervention, along with decreases in BPV, HRV, and catecholamines. HVR results showed a 35.10% reduction in CB activity in the LIFU group compared to the sham group, which was significantly lower than the reduction in the CSND group compared to the sham group (73.85%). Histopathology and transmission electron microscopy confirmed CB damage and cell apoptosis, with immunofluorescence showing a reduction in type I and II cells. In conclusion, LIFU combined with microbubbles can reduce blood pressure by lowering CB and sympathetic nerve activity.

Acetazolamide encapsulation in elastin like recombinamers using a supercritical antisolvent (SAS) process for glaucoma treatment

Glaucoma, the second most common cause of blindness worldwide, requires the development of new and effective treatments. This study introduces a novel controlled-release system utilizing elastin-like recombinamers (ELR) and the Supercritical Antisolvent (SAS) technique with supercritical CO2. Acetazolamide (AZM), a class IV drug with limited solubility and permeability, is successfully encapsulated in an amphiphilic ELR at three different ELR:AZM ratios, yielding up to 62 %. Scanning electron microscopy (SEM) reveals spherical microparticles that disintegrate into monodisperse nanoparticles measuring approximately 42 nm under physiological conditions. The nanoparticles, as observed via Transmission Electron Microscopy (TEM) and Atomic Force Microscopy (AFM), do not exhibit aggregates, a fact confirmed by the zeta potential displaying a value of –33 mV over a period of 30 days. Transcorneal permeation tests demonstrate a 10 % higher permeation level compared to the control solution, which increases to 30 % after 2 h. Ocular irritation tests demonstrate no adverse effects or damage. Intraocular pressure (IOP) tests conducted on hypertensive rabbits indicate greater effectiveness for all three analyzed formulations, suggesting enhanced drug bioavailability during treatment. Consequently, the combination of recombinant biopolymers and high-pressure techniques represents a promising approach for advancing glaucoma therapy, emphasizing its potential clinical significance.

Effect of nadolol in treatment of induced ocular hypertension in rabbits

In glaucoma, as optic neuropathy gradually proceeds unnoticed by the patient, early detection and treatment is of paramount importance in arresting or controlling the progress of damage. To explore effects of topical nadolol on intraocular pressure (IOP) ocular hypertensive eyes of rabbits. A group of 36 males of the rabbits were included in this study. Induction of ocular hypertension was achieved by injection of hydroxy propyl methylcellulose in the anterior chamber of rabbits right eye. The present study was designed to evaluate the possible beneficial therapeutic effect. The included rabbits were divided into distilled water group, timolol (0.25% and 0.5%) groups, and nadolol (0.25% and 0.5%). Each of drug eye drops (including distilled water) were instilled into right eyes 3 times/day for 10 days therapeutically. The rabbits had been examined for the IOP, pupil diameter, light reflex, corneal reflex, and conjunctival redness prior to instillation of drugs and along the trial period. Results: Ocular hypotensive effects of nadolol (0.25%) and (0.5%) eye drops were more efficient than that of distilled water (P<0.01). Furthermore, nadolol eye drop was more efficient than timolol eye drop (0.01>P>0.05) in its ocular hypotensive effect in both concentrations along the trial period. In both parts of the present study and regarding each of mean pupil diameter, light reflex, corneal reflex and conjunctival redness, nadolol (0.25% or 0.5%) eye drops had no significant adverse effect (P > 0.05). Conclusions: Nadolol eye drops instilled 3 times / day had an obvious beneficial, safe, and tolerable therapeutic ocular hypotensive effects on hydroxy propyl methyl cellulose - induced ocular hypertension in rabbits.

Deteriorated Vascular Homeostasis in Hypertension: Experimental Evidence from Aorta, Brain, and Pancreatic Vasculature.

Hypertension, as a primary risk factor for many fatal disorders, is prevalent in the elderly. There is wide literature on hypertension dealing with its biological and/or biochemical aspects; however, limited research is available on the multifactorial nature of hypertension from a mechanobiological standpoint. This study intended to study in parallel histopathological alterations and deviated protein expressions with the mechanical behavior of the hypertensive tissues. The Goldblatt (2K1C) method was chosen for induction of renovascular hypertension in rabbits. The microstructural and immunohistological characteristics of the aortic, pancreatic, and brain vasculature were investigated. The mechanical properties of the aortic tissue were also evaluated using biaxial tensile tests. Our findings indicated severe hypertrophy of the hypertensive vessels and declined content of intact smooth muscle cells. Most of the collagen I content of the wall was compromised and less functional type III collagen was highly expressed. Reversed collagen I to collagen III ratio was the main contributor to the hypertrophic and less stiff hypertensive vessel walls. The multifactorial nature of hypertension is illustrated, and smooth muscle cell detachment is identified as the sign of described degenerative cascades all along the arterial tree.

Effects of exogenous hydrogen sulfide on pulmonary hypertension in rabbits with endotoxic shock

Objective: To investigate the effects of exogenous hydrogen sulfide (H2S) on pulmonary vascular reactivity induced by endotoxic shock (ES) in rabbits. Methods: In this experiment, the model of endotoxic shock (ES) was induced by injection of lipopolysaccharides (LPS) to New Zealand big eared white rabbit through jugular vein (8 mg/0.8 ml/kg), the intervention was performed by H2S donor(sodium hydrosulfide, NaHS) which was injected intraperitoneally (28 μmol/kg) 15 min in advance. New Zealand rabbits were randomly divided into 4 groups(n=8):control group, LPS group, LPS+NaHS group and NaHS group. The changes of mean arterial pressure (MAP) and mean pulmonary arterial pressure (MPAP) were detected. The tension of pulmonary artery ring (PARs) was detected byin vitro vascular ring technique. The ultrastructure of pulmonary artery wall and pulmonary artery endothelial cells were observed by light microscope and scanning electron microscope. Results: ①MAP was decreased while MPAP was increased in rabbits after LPS injection, and ES animal model was established successfully. Compared with LPS group, mPAP of rabbit in LPS+NaHS group was decreased significantly (all P＜0.05). ②Compared with normal control group, pulmonary artery of rabbits in LPS group had an increased contractile response to phenylephrine (PE) and a decreased relaxation response to acetylcholine (ACh) (both P＜0.01); Compared with LPS group, pulmonary artery of rabbits in LPS+NaHS group had a decreased contractile response to PE and an increased relaxation response to ACh (both P＜0.05). ③Under light microscope, the structure of vascular endothelial cells was continuous in the normal control group, the elastic fibers were intact in the subcutaneous layer, and the smooth muscle layer was arranged neatly. LPS can shed some of the pulmonary artery endothelial cells, break the subcutaneous elastic fibers, and disorder the smooth muscle layer structure. Compared with LPS group, the injury of pulmonary artery wall in LPS+NaHS group was ameliorated. The morphology of pulmonary artery wall was normal in NaHS group. It is showed that some endothelial cells of pulmonary artery were missing in LPS group by Scanning electron microscopy. The morphology of pulmonary artery endothelial cells in LPS+NaHS group was similar to that in the control group: slightly widened intercellular space was observed, and no cell exfoliation was observed. Conclusion: These results suggest that exogenous H2S can protect pulmonary artery endothelial cells and regulate the reactivity changes of pulmonary artery during ES, which may be one of the mechanisms reducing PAH in ES rabbits.

Ocular Hypotensive Effects of Sacubitril and Valsartan Eye Drops on Ocular Normotensive and Betamethasone-Induced Ocular Hypertensive Rabbits

Ocular Hypotensive Effects of Sacubitril and Valsartan Eye Drops on Ocular Normotensive and Betamethasone-Induced Ocular Hypertensive Rabbits

The Intraocular Pressure Lowering Effect of a Dual Kinase Inhibitor (ITRI-E-(S)4046) in Ocular Hypertensive Animal Models.

PurposeThe purpose of this study was to develop a preclinical compound, ITRI-E-(S)4046, a dual synergistic inhibitor of myosin light chain kinase 4 (MYLK4) and Rho-related protein kinase (ROCK), for reducing intraocular pressure (IOP).MethodsITRI-E-(S)4046 is an amino-pyrazole derivative with physical and chemical properties suitable for ophthalmic formulation. In vitro kinase inhibition was evaluated using the Kinase-Glo Luminescent Kinase Assays. A comprehensive kinase selectivity analysis of ITRI-E-(S)4046 was performed using the KINOMEscan assay from DiscoverRx. The IOP reduction and tolerability of ITRI-E-(S)4046 were assessed in ocular normotensive rabbits, ocular normotensive non-human primates, and ocular hypertensive rabbits. In vivo studies were conducted to assess drug concentrations in ocular tissue. The adverse ocular effects of rabbit eyes were evaluated following the OECD405 guidelines.ResultsITRI-E-(S)4046 showed highly selective kinase inhibitory activity against ROCK1/2, MYLK4, and mitogen-activated protein kinase kinase kinase 19 (MAP3K19), with high specificity against protein kinase A, G, and C families. In ocular normotensive rabbits and non-human primates, the mean IOP reductions of 0.1% ITRI-E-(S)4046 eye drops were 29.8% and 28.5%, respectively. In hypertonic saline-induced and magnetic beads-induced ocular hypertensive rabbits, the mean IOP reductions of ITRI-E-(S)4046 0.1% eye drops were 46.9% and 22.0%, respectively. ITRI-E-(S)4046 was well tolerated with only temporary and minor signs of hyperemia.ConclusionsITRI-E-(S)4046 is a novel type of highly specific ROCK1/2 and MYLK4 inhibitor that can reduce IOP in normotensive and hypertensive animal models. It has the potential to become an effective and well-tolerated treatment for glaucoma.

The Impact of several Antihypertensive drugs and Medicinal herbs on Induced hypertension in rabbits

Objective: To assess the antihypertensive efficacy of the medicinal plants used Hibiscus subdariffa, Plantago major, Teucrium polium. Moreover, we aim to Investigate the mechanisms of actions of tested agents. Design: Induced hypertension in experimental animals is tested against several drugs and medicinal plants extracts. Animals and materials: Hypertension was induced in experimental rabbits with phenylephrine 0.2mg/kg i.v. with increasing the dose (until Blood pressure>130/90mmHg). Rabbits were divided to 7 groups: Control, atenolol, furosemide, candesartan, Hibiscus subdariffa, Plantago major, Teucrium polium. ANOVA with Dunnett's test was implemented for statistical calculations with p<0.05 as significance level. Results: Candesartan was the most effective in lowering both systolic and diastolic blood pressure. Concerning the blood flow, candesartan was found to be the most significantly effective drug in increasing blood flow followed by furosemide and Hibiscus subdariffa respectively. Concerning the urine output furosemide was found to be the most significantly effective drug in increasing urine output followed by Hibiscus subdariffa. The aqueous extracts of Plantago major and Teucrium polium showed no significant effect. Conclusions: Hibiscus subdariffa is effective as diuretic agent at the concentration mentioned. Its action involves diuretic and vasodilator effect. While aqueous extracts of Plantago major and Teucrium polium are not effective.

Suberoylanilide hydroxamic acid (SAHA) inhibits transforming growth factor-beta 2-induced increases in aqueous humor outflow resistance

Transforming growth factor-beta 2 (TGF-β2) is highly concentrated in the aqueous humor of primary open-angle glaucoma patients. TGF-β2 causes fibrosis of outflow tissues, such as the trabecular meshwork (TM), and increases intraocular pressure by increasing resistance to aqueous humor outflow. Recently, histone deacetylase (HDAC) activity was investigated in fibrosis in various tissues, revealing that HDAC inhibitors suppress tissue fibrosis. However, the effect of HDAC inhibitors on fibrosis in the eye was not determined. Here, we investigated the effect of suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor, on TGF-β2-induced increased resistance to aqueous humor outflow. We found that SAHA suppressed TGF-β2-induced outflow resistance in perfused porcine eyes. Moreover, SAHA cotreatment suppressed TGF-β2-induced ocular hypertension in rabbits. The permeability of monkey TM (MTM) and Schlemm’s canal (MSC) cell monolayers was decreased by TGF-β2 treatment. SAHA inhibited the effects of TGF-β2 on the permeability of these cells. TGF-β2 also increased the expression of extracellular matrix proteins (fibronectin and collagen type I or IV) in MTM, MSC, and human TM (HTM) cells, while SAHA inhibited TGF-β2-induced extracellular matrix protein expression in these cells. SAHA also inhibited TGF-β2-induced phosphorylation of Akt and ERK, but did not inhibit Smad2/3 phosphorylation, the canonical pathway of TGF-β signaling. Moreover, SAHA induced the expression of phosphatase and tensin homolog, a PI3K/Akt signaling factor, as well as bone morphogenetic protein 7, an endogenous antagonist of TGF-β. These results imply that SAHA prevents TGF-β2-induced increases in outflow resistance and regulates the non-Smad pathway of TGF-β signaling in TM and MSC cells.

Formulation and Characterization of Acetazolamide/Carvedilol Niosomal Gel for Glaucoma Treatment: In Vitro, and In Vivo Study.

Acetazolamide (ACZ) is a diuretic used in glaucoma treatment; it has many side effects. Carvedilol (CAR) is a non-cardioselective beta-blocker used in the treatment of elevated intraocular pressure; it is subjected to the first-pass metabolism and causes fluids accumulation leading to edema. This study focuses on overcoming previous side effects by using a topical formula of a combination of the two previous drugs. Sixty formulations of niosomes containing Span 20, Span 60, Tween 20, and Tween 60 with two different ratios were prepared and characterized. Formulation with the lowest particle size (416.30 ± 0.23), the highest zeta potential (72.04 ± 0.43 mv), and the highest apparent coefficient of corneal permeability (0.02 ± 0.29 cm/h) were selected. The selected formula was incorporated into the gel using factorial design 23. Niosomes (acetazolamide/carvedilol) consisting of Span 60 and cholesterol in the molar ratio (7:6), HMPC, and carbopol with two different ratios were used. The selected formula was subjected to an in vivo study of intraocular pressure in ocular hypertensive rabbits for 60 h. The sustained gel formula of the combination decreased (IOP) to normal after 1 h and sustained efficacy for 4 days. Histological analysis of rabbit eyeballs treated with the selected formula showed improvement in glaucomatous eye retinal atrophy.

In vivo experimental study of acute intraocular hypertension in rabbit based on particle image velocimetry technique

At present, there are few in vivo experimental studies on anterior chamber flow field, and the relevant technologies are not mature. This study explores the experimental method and key techniques of particle image velocimetry (PIV) for the in vivo measurement of anterior chamber flow field with slow flow velocity in the rabbit with acute intraocular hypertension. The experimental process can be divided into three parts: model construction of rabbit eye with acute intraocular hypertension, in vivo eyeball preparation, and PIV setup. The following key techniques were mainly investigated: the optimal injection strategy of fluorescent particles and the correction strategy for image acquisition errors caused by the effects of image refraction and respiration. The results showed that the best injection method was that 15 μL of fluorescent particles solution was slowly injected into the anterior chamber through the lower part of iris and then the rabbit was released and waited for 13 h. In this way particles were completely distributed in the anterior chamber with the help of the aqueous humor circulation, and then in vivo PIV experiment could be performed. The eyeball should be covered with a square flume filled with ultrasonic coupling gel for the sake of imaging during the experiment. The Maximal Information Coefficient algorithm could be applied to correct the measured results before post-processing calculation. The results indicated that feasible injection strategy of fluorescent particles and the correction strategy for image acquisition are critical to obtain nice experiment effects for the in vivo PIV measurement of anterior chamber flow field in the rabbit with acute intraocular hypertension.

Treatment of Obstructive Sleep Apnea-Hypopnea Syndrome With a Mandible Advanced Device Increases Nitric Oxide Release and Ameliorates Pulmonary Hypertension in Rabbits

To investigate the effects of mandible advanced device (MAD) therapy for obstructive sleep apnea-hypopnea syndrome (OSAHS) on nitric oxide (NO) release and changes in pulmonary artery pressure and structure. Thirty male New Zealand white rabbits were randomly divided into OSAHS, MAD, and control groups (n=10 per group). The soft palate of rabbits in the OSAHS and MAD groups was injected with hydrophilic polyacrylamide gel to induce OSAHS. The MAD group wore a MAD, and the control group was not treated. Cone-beam computed tomography scans and polysomnography recordings were performed to confirm successful model establishment. All rabbits slept in a supine position for 4 to 6hours daily and were observed for 8 consecutive weeks. The pulmonary artery pressure was measured by right heart catheterization. Pulmonary artery morphometry was analyzed by hematoxylin and eosin staining. NO levels in plasma and lung homogenate supernatants were detected by Griess reaction assay kits. The OSAHS group exhibited higher pulmonary artery pressure (57.74±1.79mm Hg) than the MAD (19.99±2.04mm Hg) and control (14.49±0.54mm Hg) groups. The media thickness percentage of the pulmonary artery was higher in the OSAHS group (46.89±2.72%) than the control group (15.87±1.18%) and was markedly reduced by MAD (21.64±1.45%). Blood oxygen saturation was positively correlated with the NO concentration in both the lung and plasma, and the NO concentration was negatively correlated with the media thickness percentage and media section percentage. OSAHS induced a decrease in NO and pulmonary hypertension, which was relieved by MAD therapy.

Estimation of the vascular resistance amplifier in the renal vascular bed in conscious hypertensive rabbits: comparison with the total peripheral vasculature

ObjectivesThe vascular amplifier in hypertension is a result of structural changes in resistance arteries. We estimated the vascular amplifier hypertensive:normotensive (H:N) ratio in the renal bed compared with the total peripheral bed in conscious rabbits during infusion of vasoconstrictor and vasodilator stimuli. MethodsRabbits were subjected to bilateral renal cellophane wrap or sham operation. A perivascular ultrasonic flow probe was implanted on the left renal artery to measure renal blood flow. A catheter was inserted into the thoracic aorta for agonist administration. Blood pressure, heart rate and renal blood flow were measured on three separate days in conscious rabbits with intact effectors, ganglionic block or neurohumoral block. Dose-response curves were constructed to intra-arterial infusion of noradrenaline, angiotensin II, adenosine and acetylcholine. ResultsResting renal vascular resistance in hypertensive rabbits was markedly decreased by ganglionic block and further by neurohumoral block. With effectors intact, ganglionic block or neurohumoral block, the H:N ratio for renal vascular resistance was 2.32, 1.72 or 1.72, respectively. The ratio was generally maintained during the infusion of constrictor and dilator drugs although distortions occurred at higher concentrations of constrictor or dilator drugs. ConclusionsEstimation of the renal resistance amplifier in renal wrap hypertension with neurohumoral block accords with our earlier estimates of the total peripheral resistance amplifier (1.79). This vascular resistance amplifier is consistent with a decrease in internal radius through structural remodelling in the renal vascular bed as is reflected in the total arterial circulation in hypertension.

Fetal growth and well-being in a study of maternal hypertension in rabbits.

Obtaining growth and physiologic data in the postnatal laboratory animal is common. However, monitoring growth in utero is far more difficult, with little data available except upon termination of pregnancy. High-resolution ultrasound was used to monitor growth, morphology, and fetal well-being in normotensive and hypertensive rabbits (21 fetuses) at day 16, 20, and 26 of the 32 day gestational period. Set protocols, comparable to those routinely assessed in humans, were devised and followed for each examination. Birth weight was greater in offspring of hypertensive as compared to normotensive mothers (p < 0.001); however, litter size was reduced. The greater birth weight was reflected in growth parameters measured throughout gestation indicating the predictive value of ultrasound. High-resolution ultrasound was a reliable and sensitive method for biometric and morphologic assessment of the fetal rabbit, demonstrating that growth trajectory of offspring of hypertensive mothers may be altered early in gestation.

Effect of topically applied nimodipine on the intraocular pressure on ocular normotensive and betamethasone-induced hypertensive eyes in rabbits

Glaucoma is a leading cause of irreversible blindness worldwide. Lowering intraocular pressure (IOP) is the only strategy documented to delay the appearance and retard the progression of vision loss. The present investigation was conducted to evaluate the effect of topical nimodipine (0.5%) drop on IOP of both normotensive and induced -hypertensive eyes in rabbits. Thirty six rabbits were included in the present study .Two groups (each group contains 6 rabbits) were used to evaluate the effect of nimodipine, one as a normotensive group and the other for induction of hypertensive. Nimodipine ophthalmic solutions were instilled twice daily for 7 days in both normotensive and induced -hypertensive eyes (that induced by weakly subconjunctival injection of 0.7 ml of betamethasone suspension for 4 weeks). On the other hand another two groups were used to evaluate the effect of (twice daily instillation for 7 days) of Timolol and distilled water (DW). IOP measured by Schiotz tonometer daily at about the same time (9.0 am) to avoid IOP diurnal fluctuation. The main findings of the present study were the followings: Nimodipine (0.5%) was very effective in lowering IOP in both normotensive and ocular hypertensive rabbits. Mean IOP decreased after one day of nimodipine instillation by (1.5 ± 0.43 mmHg) in normotensive eyes and by (4.5± 1.45 mmHg) in hypertensive eyes. A significant results (P ≤ 0.05) were obtained when compared the results of nimodipine with DW (as a negative control group), on the other hand no significant differences were obtained when compared with that of Timolol (as a positive group). The results obtained in this study provide experimental evidences for the effectiveness of nimodipine (0.5%) ophthalmic solutions in the reduction of IOP. In addition to above nimodipine in applied doses were found to have tolerable ocular hypotensive effect.

Antioxidant status in rabbit aqueous humor after instillation of ascorbyl laurate-based nanostructures.

The aim of this work was evaluate the antioxidant effect of ascorbyl laurate (ASC12) based nanostructures applied topically to the cornea of ocular normotensive and hypertensive rabbits. The ASC12 was chosen for its capacity to form liquid lyotropic crystal and keeps its free radical trapping power. The hypertension model was performed in six rabbits and was obtained by the application of intracameral injections of alpha-chymotrypsin in the right eye. A single 50 ml dose of ascorbyl laurate coagel 2% w/v (COA-ASC12) was applied topically to the cornea of six normotensive and six hypertensive rabbits. The aqueous humor samples were obtained before and after instillation of COA-ASC12 at different times (2 h and 4 h). Antioxidant capacity was determined via the reduction reaction with iron and tripyridyltriazine (FRAP) and the total proteins were measured using the Bradford reagent. The kinetic antioxidant capacity in the aqueous humor of normotensive and hypertensive rabbits showed a maxim increment at 4 h instillation. Also, the antioxidant capacity in the aqueous humor of hypertensive rabbits was ten times lower than in normotensive rabbits. This type of nanostructures has the potential to significantly improve the topical formulation for the prophylaxis and treatment of several eye diseases.

Renovascular Hypertension Aggravates Atherosclerosis in Cholesterol-Fed Rabbits

Background: Hypertension is a major risk factor for atherosclerotic disease. However, it is still not clear whether mechanical stress caused by hypertension directly affects the atherosclerotic development in the aorta and coronary arteries. Objectives and Methods: We generated a hypertensive (HTN) rabbit model by surgical removal of the left kidney and partial ligation of the right renal artery. After a 16-week cholesterol diet, we compared aortic and coronary atherosclerosis of HTN rabbits with those of normotensive rabbits. Results: Hypertension did not affect lipid and apolipoprotein levels in plasma but led to a 3.0-fold increase in aortic atherosclerosis and a 1.7-fold increase in coronary atherosclerosis compared with control rabbits. Enhanced atherosclerosis in HTN rabbits was caused by significant increases in macrophages and smooth muscle cells in the lesions. Furthermore, oxidized LDL contents in the lesions were significantly increased in HTN rabbits. In addition, HTN rabbits exhibited prominent hyaline arteriolosclerosis in coronary arterioles. Conclusions: These results indicate that hyper tension not only enhances atherosclerosis in large arteries including the aorta and coronary arteries but also affects hyaline arteriolosclerosis in small arteries.

A Highly Selective Rho-Kinase Inhibitor (ITRI-E-212) Potentially Treats Glaucoma Upon Topical Administration With Low Incidence of Ocular Hyperemia.

The purpose of this study was to investigate the IOP-lowering effects of the ITRI-E-212, a new Rho-associated protein kinase (ROCK) inhibitor. ITRI-E-212 improved fluid outflow through the trabecular meshwork and reduced IOP with transient and mild conjunctival hyperemia. ITRI-E-212 can potentially be developed into new antiglaucoma agents. ITRI-E-212 was selected from more than 200 amino-isoquinoline structures because of its adequate solubility and drug-loading percentage in eye drops. ITRI-E-212 has less than 50% inhibitory concentration (IC50) against ROCK2. The in vitro kinase inhibition was evaluated using the ADP-Glo kinase assay. A comprehensive analysis of the kinase inhibitor selectivity of ITRI-E-212 was performed using the KINOMEscan methodology. The IOP-lowering effect and tolerability of ITRI-E-212 were investigated in normotensive and ocular hypertensive rabbits. The pharmacokinetics study was performed in vivo in the aqueous humor (AH), and hyperemia was assessed. ITRI-E-212 showed high in vitro inhibitory activity against ROCK2 and high specificity against AGC kinases. The mean IOP-lowering effect of ITRI-E-212 in normotensive and ocular hypertensive models was 24.9% and 28.6%, respectively; 1% ITRI-E-212 produced notable reductions in IOP that were sustained for at least 6 hours after each dose once per day. Only transient, mild hyperemia was observed. The compound extracted from the AH reached 78.4% ROCK2 kinase inhibition at 1 hour after dose administration and was sustained for 4 hours. ITRI-E-212 is a novel and highly specific ROCK2 inhibitor with the ability to lower IOP in animal models. It has favorable pharmacokinetic and ocular tolerability profiles with only minimal conjunctival hyperemia.

Formulation and Characterization of Carvedilol Leciplex for Glaucoma Treatment: In-Vitro, Ex-Vivo and In-Vivo Study.

This study evaluated the efficacy of cationic nanoparticle (leciplex) to deliver carvedilol to ocular surface for glaucoma treatment as recent studies pointed out the effect of topical carvedilol on intraocular pressure, therefore carvedilol loaded leciplex formulae were prepared using soy phosphatidyl choline (SPC) and cationic surfactant (CTAB/DDAB) and characterized for morphology, entrapment efficiency, particle size, zeta potential and ex-vivo corneal permeation. Then the selected formula was evaluated via in-vivo studies in comparison with carvedilol solution. Leciplex nanoparticles appeared spherical in shape with entrapment efficiency exceeded 95% in all formulae. Leciplex formula composed of SPC and DDAB in (1:1) molar ratio showed the smallest particle size (16.04 ± 1.2 nm), highest zeta potential value (53.9 ± 0.91 mv) and highest apparent corneal permeability coefficient (0.1157 cm/h). Carvedilol leciplex reduced intraocular pressure (IOP) to normal range in ocular hypertensive rabbits after 30 min and duration of action lasted for 24 h, while carvedilol solution reduced IOP to normal value after 60 min and duration of action lasted for 6 h. Furthermore, histological examination of eyeballs of rabbits treated with carvedilol leciplex showed improvement of retinal atrophy of glaucomatous eyes. This study concluded that leciplex improve transcorneal permeation and bioavailability of carvedilol.