Effects of peripherally and centrally applied ghrelin on the oxidative stress induced by renin angiotensin system in a rat model of renovascular hypertension.

BACKGROUND: Renovascular hypertension (RVH) is a result of renal artery stenosis, which is commonly due to astherosclerosis. In this study, we aimed to clarify the central and peripheral effects of ghrelin on the renin-angiotensin system (RAS) in a rat model of RVH. METHODS: RVH was induced in rats by partial subdiaphragmatic aortic constriction. Experiment A was designed to assess the central effect of ghrelin via the intracerebroventricular (ICV) injection of ghrelin (5 µg/kg) or losartan (0.01 mg/kg) in RVH rats. Experiment B was designed to assess the peripheral effect of ghrelin via the subcutaneous (SC) injection of ghrelin (150 µg/kg) or losartan (10 mg/kg) for 7 consecutive days. Mean arterial blood pressure (MAP), heart rate, plasma renin activity (PRA), and oxidative stress markers were measured in all rats. In addition, angiotensin II receptor type 1 (AT1R) concentration was measured in the hypothalamus of rats in Experiment B. RESULTS: RVH significantly increased brain AT1R, PRA, as well as the brain and plasma oxidative stress. Either SC or ICV ghrelin or losartan caused a significant decrease in MAP with no change in the heart rate. Central ghrelin or losartan caused a significant decrease in brain AT1R with significant alleviation of the brain oxidative stress. Central ghrelin caused a significant decrease in PRA, whereas central losartan caused a significant increase in PRA. SC ghrelin significantly decreased PRA and plasma oxidative stress, whereas SC losartan significantly increased PRA and decreased plasma oxidative stress. CONCLUSIONS: The hypotensive effect of ghrelin is mediated through the amelioration of oxidative stress, which is induced by RAS centrally and peripherally.

Comparison of the antinociceptive effect of systemic versus intrathecal magnesium sulphate on spinal morphine analgesia.

The aim of this work was to compare the possible antinociceptive effect of the intravenous (IV) versus the intrathecal (IT) administration of magnesium sulphate prior to spinal morphine analgesia. This research was conducted in two sets: First; experimentally, to compare the antinociceptive effect of IT magnesium sulphate (375 µg/rat) versus IP magnesium sulphate 100 mg/kg), prior to IT morphine (10 µg/rat). Pain was assessed using Randall-Selitto testing, the hot-plate, and formalin tests. A non-significant difference in the nociceptive threshold was observed between IT and IP magnesium sulphate administration prior to IT morphine in rats. Second: clinically, in patients undergoing orthopedic surgery, who received either an IT mixture of 1 mg of morphine with 3 mL hyperbaric 0.5% bupivacaine, an IT mixture of morphine with bupivacaine and 50 mg of magnesium sulphate, or an IT mixture of morphine bupivacaine plus IV 20 mg/kg of magnesium sulphate as a loading dose over 15 min prior to surgery, followed by infusion at a rate of 10 mg/kg/h. Pain was evaluated using a visual analog pain scale (VAS) score at one hour, 6 h and 12 h postoperatively. The use of IT or IV magnesium sulphate, in addition to the spinal morphine caused a significant decrease in the VAS score in the 6(th) and 12(th) post-operative hours with a non-significant difference between both routes. In conclusion the efficacy of systemic magnesium sulphate to potentiate the analgesic effect of intrathecal morphine is a promising and attractive route of choice for postoperative pain relief during spinal anesthesia. Opioid analgesia could be prolonged and the incidence of motor paralysis, common with the intrathecal route of magnesium sulphate administration, reduced.

Biochemical and histological impact of direct renin inhibition by aliskiren on myofibroblasts activation and differentiation in bleomycin induced pulmonary fibrosis in adult mice.

Aliskiren is a drug classified as a direct renin inhibitor. The renin-angiotensin system plays an important role in pulmonary fibrogeneses. This study aimed to investigate the impact of aliskiren on pulmonary fibrosis induced by bleomycin. Forty adult mice were divided into group I (control), group II (aliskiren 25mg/kg/day IP), group III (bleomycin 0.035U/g intraperitoneally twice weekly for 4 weeks) and group IV (aliskiren+bleomycin). Plasma renin activity (PRA), lung content of hydroxyproline and transforming growth factor-ß1 (TGF-ß1) were assayed. Lung paraffin sections were prepared for histological study and immunohistochemical detection of alpha smooth muscle actin (αSMA) as a marker for myofibroblasts activation and differentiation. Bleomycin induced a significant elevation of PRA with a significant increase in hydroxyproline and TGF-ß1 in group III. Microscopically, pulmonary fibrosis was evident in the form of areas of collapsed alveoli, intense inflammatory cells infiltrations, excess accumulation of collagen, and excessively encountered αSMA positively immune-stained myofibroblasts, compared to a negative immune-reaction in groups I and II. In group IV, aliskiren resulted in a significant decrease in PRA, TGF-ß1 and hydroxyproline, with an attenuation of pulmonary fibrosis and a decrease in αSMA positively immune-stained myofibroblasts. In conclusion, renin inhibition by aliskiren attenuated pulmonary fibrosis through decreasing TGF-ß1 and myofibroblasts activation and differentiation.

Evaluation of osteoporosis risk associated with chronic use of morphine, fentanyl and tramadol in adult female rats.

Opioid use in the management of chronic pain is widespread. However, it is a recognized risk factor for the development of osteoporosis. The hypothesis of this study was to evaluate the effect of various analgesic drugs; morphine, fentanyl and tramadol, on the bone of adult female rats. Forty rats were divided into 4 groups; Control, morphine (8 mg/kg), fentanyl (32 µg/kg) and tramadol (10 mg/kg) groups. After 90 days of treatment, the serum calcium, alkaline phosphatase, osteocalcin and estradiol were assayed and the bones were prepared for histomorphometric study. In comparison to the control group, morphine and fentanyl groups showed a significant biochemical and histological osteoporotic changes while treatment with tramadol leads to non-significant osteoporotic effect. In conclusion, tramadol had the least osteoporotic effect as compared to morphine or fentanyl on chronic administration suggesting the safety use of tramadol in the treatment of patients with chronic pain particularly in association with osteoporosis.

The possible role of L-carnitine on the skeletal muscle of ovariectomized rats.

Low muscle strength is observed during the peri-and postmenopausal periods, when the secretion of ovarian hormones is drastically reduced. It is also a predictive of adverse health events as well as incident mobility limitation and disability. The objective of the present study is to study the biochemical and the histological changes in the skeletal muscle of premature menopause-induced rats and the possible protective role of L-carnitine. Ovariectomized (OVX) rats were gavaged with L-carnitine (100 mg/kg) daily for 60 days starting from the second post-operative day. Serum levels of estradiol and markers of skeletal muscle damage (creatine kinase and lactic dehydrogenase activities) were determined. Light and electron microscopic study of the quadriceps femoris muscle (QFM) specimens were done. OVX rats showed significant decrease in the serum estradiol level with significant increase the markers for skeletal muscle damage. Histopathological examination of the QFM showed degenerated myofibers, apoptotic changes and compensatory hypertrophy. Degenerated mitochondria, multiple lysosomes and lipid droplets among the damaged myofibrils were also noticed. L-carnitine administration to the OVX rats resulted in non-significant change in the serum estradiol level with significant attenuation of skeletal muscle damage either biochemically or histopathologically. In conclusion, L-carnitine administration recovered muscle degeneration after ovariectomy. This finding suggested that L-carnitine could be recommended in the management of post-menopausal myopathy.

Effect of preischemic treatment with fenofibrate, a peroxisome proliferator-activated receptor-α ligand, on hepatic ischemia-reperfusion injury in rats.

Liver ischemia/reperfusion (I/R) injury is a serious clinical problem. The reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-α) are important mediators in liver I/R injury. This study was designed to investigate the effect of preischemic treatment with fenofibrate (Peroxisome proliferator-activated receptor- α agonist) on the oxidative stress and inflammatory response to hepatic I/R injury in rats. Hepatic I/R was induced by clamping the blood supply of the left lateral and median lobes of the liver for 60 min, followed by reperfusion for 4 h. Each animal group was pretreated with a single dose of fenofibrate (50 mg/kg body weight) intraperitoneally 1 h before ischemia. At the end of reperfusion, blood samples and liver tissues were obtained to assess serum alanine aminotransferase (ALT), TNF-α, hepatic malondialdehyde (MDA) and superoxide dismutase activity (SOD). Liver specimens were obtained and processed for light and electron microscopic study. Hepatic I/R induced a significant elevation of serum ALT and TNF-α with significant elevation of hepatic MDA and reduction of SOD activity. Histopathological examination revealed hepatic inflammation, necrosis and apoptosis. Preischemic treatment with fenofibrate at a dose of 50 mg/kg significantly attenuated the biochemical and structural alterations of I/R-induced liver injury.

Effect of peroxisome proliferator-activated receptor gamma agonist (pioglitazone) and methotrexate on disease activity in rheumatoid arthritis (experimental and clinical study).

OBJECTIVE: To investigate the combined effect of both pioglitazone and methotrexate on disease activity of rheumatoid arthritis in a biphasic study; experimental and clinical. METHODS: EXPERIMENTALLY: 50 rats were divided into 5 equal groups; controls, experimental arthritis, methorexate treated (0.1 mg/Kg daily), pioglitazone-treated (10 mg/kg daily), and methotrexate and pioglitazone treated. Clinically: forty-nine diabetic rheumatoid arthritis patients were included. Patients group consisted of 28 patients and they received pioglitazone 30 mg orally beside their usual treatment. Control group consisted of 21 patients and they continued their usual treatment plus placebo. Disease activity was assessed using DAS28 score. Patients were followed up for 3 months. RESULTS: Pioglitazone produced a significant improvement of serum oxidative stress parameters (P < 0.05), and inflammatory cytokines in the treated arthritic group (P < 0.05). Clinically, the pioglitazone treated group showed significant improvement in DAS28 (P = 0.001) and C-reactive protein (P < 0.0001) compared to placebo group. CONCLUSION: The concomitant use of the PPAR γ agonist pioglitazone and methotrexate appears to be promising therapeutic strategy for rheumatoid arthritis patients.

Effect of celecoxib on the antihypertensive effect of losartan in a rat model of renovascular hypertension.

Certain nonsteroidal anti-inflammatory drugs have been reported to elevate blood pressure in some hypertensive patients, who are either untreated or treated with antihypertensive agents. This study was undertaken to determine the effect of a selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, on the antihypertensive effects of the angiotensin II type 1 receptor (AT1) antagonist, losartan potassium. We studied the effect of oral treatment with losartan (30 mg/kg), celecoxib (3 mg/kg), and their combination on the mean arterial blood pressure (MAP), plasma renin activity (PRA), and plasma prostaglandin E2 (PGE2) in male Sprague-Dawley rats with renovascular hypertension (RVH) induced by partial subdiaphragmatic aortic constriction. Treatment was continued for 7 days after aortic coarctation. Aortic coarctation led to significant increases in the MAP, PRA, and plasma PGE2. In RVH rats, losartan treatment caused a significant decrease of MAP with a significant increase in both plasma PGE2 and PRA. Celecoxib caused a nonsignificant change in MAP with a significant decrease in the raised levels of plasma PGE2 and PRA. Concomitant administration of celecoxib and losartan did not significantly affect the lowering effect of losartan on MAP with a subsequent significant decrease in the plasma PGE2 and PRA in RVH rats. Therefore, celecoxib could be used in renin-dependent hypertensive patients who receive losartan, without fear of a rise in their blood pressure.