Lisinopril alters contribution of nitric oxide and K(Ca) channels to vasodilatation in small mesenteric arteries of spontaneously hypertensive rats.

To investigate lisinopril effect on the contribution of nitric oxide (NO) and K(Ca) channels to acetylcholine (ACh)-induced relaxation in isolated mesenteric arteries of spontaneously hypertensive rats (SHRs). Third branch mesenteric arteries isolated from lisinopril treated SHR rats (20 mg/kg/day for ten weeks, SHR-T) or untreated (SHR-UT) or normotensive WKY rats were mounted on tension myograph and ACh concentration-response curves were obtained. Westernblotting of eNOS and K(Ca) channels was performed. ACh-induced relaxations were similar in all groups while L-NMMA and indomethacin caused significant rightward shift only in SHR-T group. Apamin and TRAM-34 (SK(Ca) and IK(Ca) channels blockers, respectively) significantly attenuated ACh-induced maximal relaxation by similar magnitude in vessels from all three groups. In the presence of L-NMMA, indomethacin, apamin and TRAM-34 further attenuated ACh-induced relaxation only in SHR-T. Furthermore, lisinopril treatment increased expression of eNOS, SK(Ca) and BK(Ca) proteins. Lisinopril treatment increased expression of eNOS, SK(Ca), BK(Ca) channel proteins and increased the contribution of NO to ACh-mediated relaxation. This increased role of NO was apparent only when EDHF component was blocked by inhibiting SK(Ca) and IK(Ca) channels. Such may suggest that in mesenteric arteries, non-EDHF component functions act as a reserve system to provide compensatory vasodilatation if (and when) hyperpolarization that is mediated by SK(Ca) and IK(Ca) channels is reduced.

Lisinopril indifferently improves heart rate variability during day and night periods in spontaneously hypertensive rats.

The aim of this work was to investigate the effect of 10 weeks of lisinopril treatment to spontaneously hypertensive rats (SHRs) on day/night variations of blood pressure, heart rate and autonomic cardio-regulation parameters. Male SHR with surgically implanted radio-telemetry implant that provided direct measurements of arterial pressure and electrocardiogram wave were used. Animals were allocated to two groups (n=5 each). The first group was treated with lisinopril (20 mg/kg by gavage) daily for 10 weeks (treated group); whereas the second was gavaged daily with tap water (untreated group). Arterial blood pressure, ECG and other telemetry parameters were recorded at the start and at the end of 10-week treatment. Collected data were analyzed using specialized software and were statistically tested. In addition to the expected lowering of blood pressure, spectral analysis of R-R intervals revealed that lisinopril treatment for 10 weeks significantly caused 2-3 fold increase in heart rate variability (HRV) during both active and inactive periods. However, R-R interval durations demonstrated variable distribution patterns during those periods. The cause of observed distribution pattern of R-R intervals during active and inactive periods may be of significance to better understand HRV changes and warrants further investigations.

Ontogenic aspects of cisplatin-induced nephrotoxicity in rats.

A multi-age rat model was evaluated to identify a potential age-related difference in kidney injury following administration of cisplatin (CP). Different age groups of Wistar rats (aged 3, 7, 11 and 24 weeks) were given CP intraperitoneally (6 mg/kg) and sacrificed 6 days thereafter. CP-induced nephrotoxicity caused significant decreases in body weight, creatinine clearance, urine osmolality, plasma total anti-oxidant status, cortical glutathione (GSH) concentration and superoxide dismutase activity. It increased kidney weight and plasma concentrations of creatinine and urea. It increased urinary N-acetyl-beta-D-glucosaminidase activity and protein concentration. Most of the above actions were more marked as the animals advanced in age, except for the changes in GSH, which were similar in all age groups. CP produced necrosis in renal tubules and epithelial vacuolization, the extent of which was more evident as the rats grew older. Renal CP concentration was increased with the increased age of the animal, and the cortical CP concentration in 3 week-old rats was nearly half that of 24 week-old rats. This study showed that the vulnerability profile of each age group was different, suggesting that a multi-age pediatric/geriatric animal model is appropriate to assess, more completely, age-dependent changes in drug toxicity.

The ameliorative effect of cysteine prodrug L-2-oxothiazolidine-4-carboxylic acid on cisplatin-induced nephrotoxicity in rats.

Pathogenesis of nephrotoxicity of the synthetic anticancer drug cisplatin (CP) involves generation of reactive oxygen species and free radicals in the kidney cortex, and cysteine prodrug l-2-oxothiazolidine-4-carboxylic acid (OTC) has been confirmed to have a strong antioxidant action. Therefore, in the present work, we aimed at testing the possible protective or palliative effect of OTC on CP nephrotoxicity in rats. OTC was given at an oral dose of 150 mg/kg/day for 7 days. On day 7, some of these rats were given a single intraperitoneal injection of CP (or vehicle) at a dose of 6 mg/kg. Rats were killed, blood and urine samples were collected, and the kidneys were removed 6 days after CP treatment. Nephrotoxicity was evaluated histopathologically by light microscopy, and biochemically by measuring the concentrations of creatinine and urea in serum, reduced glutathione (GSH) concentration and superoxide dismutase (SOD) activity in renal cortex, and by urinalyses. CP significantly increased the concentrations of urea and creatinine (P < 0.05) by about 128% and 170% respectively. CP treatment reduced cortical GSH concentration by about 34% (P < 0.05), and the activity of SOD by about 28% (P < 0.05). CP treatment significantly increased urine volume and N-acetyl-beta-D-glucosaminidase (NAG) activity, and significantly decreased osmolality and protein concentrations. OTC significantly mitigated all these effects. Sections from saline- and OTC-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This appeared to be lessened when CP was given simultaneously with OTC. The concentration of CP in the cortical tissues was not significantly altered by OTC treatment. The results suggested that OTC had ameliorated the histopathological and biochemical indices of nephrotoxicity in rats. Pending further pharmacological and toxicological studies, OTC may potentially be useful as a nephroprotective agent.

Genetic variations related to hypertension: a review.

Hypertension is a complex multifactorial disorder with genetic, environmental and demographic factors contributing to its prevalence. The genetic element contribution to blood pressure variation ranges from 30 to 50%. Therefore, identifying hypertension susceptibility genes will help understanding the pathophysiology of the disease. In addition to the potential impact of genomic information in selecting antihypertensive drug therapy, it may also help in recognizing those at risk of developing the disease, which may lead to new preventive approaches. Several strategies and methods have been used to identify hypertension susceptibility genes. Currently, genetic analysis of such data produced complex results, which makes it difficult to draw final conclusion on the use of genomic data in management of hypertension. This review attempts to summarize present known genetic variations that may be implicated in the pathogenesis of hypertension and to discuss various research strategies used to identify them. It also highlights some of the opportunities and challenges, which may be encountered in interpreting the value of these genetic variations to improve management of hypertension.

The effect of a strongly basic alkaloidal fraction of Rhazya stricta, a traditional medicinal plant, on cytochrome P450-mediated metabolism of theophylline in mice.

The strongly basic alkaloidal fraction of the traditional medicinal plant Rhazya stricta (RS) was given orally to mice, in a single dose of 10 mg/kg (group 1) or, twice daily for 3 days at the same dose (group 2). A third group (control) received normal saline. Liver homogenates from all animals were used to assess the microsomal activity of cytochrome P450 and its isoforms as well as its catalytic activity (using theophylline as a substrate). RS alkaloidal fraction had no significant effect on the total amount of microsomal cytochrome P450, but it caused a significant increase in the cytochrome P450 isoforms CYPs 1A1 and 1A2. It also significantly increased the concentrations of some metabolites of theophylline. These results suggest that RS has the potential to interact with other drugs that are biotransformed by cytochrome P450, when given concomitantly with it.

Central nervous system activity of Leucas inflata Benth. in mice.

The analgesic activity of the methanol and acetone extracts of Leucas inflata L. (family Labiatae) was evaluated in mice using different experimental models. The effect of the two extracts on pentobarbitone-sleeping time, motor activity, sensorimotor coordination, carrageen induced inflammation, and brewer's yeast-induced pyrexia has also been investigated. The two crude extracts have been phytochemically analyzed and some constituents isolated and characterized. These included stigmasterols, a chromone and coumarins. Extracts of L. inflata L., given at single oral doses of 0.25, 0.5, 1.0 or 2.0 g/kg, significantly and dose-dependently, reduced formalin-induced pain, acetic acid induced abdominal constrictions and increased the reaction time in the hot-plate test. Both extracts caused significant and dose-related impairment in the sensorimotor control and ambulatory and total motor activity of treated mice. Both extracts exhibited anti-inflammatory action by reducing paw edema of treated mice. The extracts did not significantly affect the rectal temperature of normothermic mice. However, they were effective in preventing Brewers yeast induced pyrexia. It is concluded that the crude methanol and acetone extract of L. inflata has CNS depressant properties, manifested as antinociception and sedation. Both extracts have anti-inflammatory and antipyretic actions.

Some effects of Salvia aegyptiaca L. on the central nervous system in mice.

Salvia aegyptiaca L. is used for treating various unrelated conditions that include nervous disorders, dizziness, trembling, diarrhoea and piles. This work examines some effects of the crude acetone and methanol extracts of the plant given at single oral doses of 0.25, 0.5, 1 or 2 g/kg, on the central nervous system (CNS) in mice. The extracts were also tested for anti-inflammatory and antipyretic actions. Several models of nociception have been used to examine the analgesic effect of the extract. In treated mice, the extracts caused dose-related inhibition of acetic acid-induced abdominal constriction, and significantly reduced formalin-induced pain. Treatment with the extracts at doses of 0.5 and 1 g/kg significantly increased the reaction time in the hot-plate test. In treated mice both extracts caused significant and dose-related impairment of the sensorimotor control and motor activity. Treatment with both extracts did not significantly affect the rectal temperature of normothermic mice. The methanol extract (0.5 and 1.0 g/kg) did not affect the rectal temperature of hyperthermic mice, but the acetone extract was effective in significantly reducing the rectal temperature of hyperthermic mice, 0.5 and 1 h after administration of the extract at doses of 0.25-2 g/kg. It is concluded that the crude methanol and acetone extracts of S. aegyptiaca have CNS depressant properties, manifested as antinociception and sedation. Both extracts have some anti-inflammatory and antipyretic actions. On the whole, the acetone extract appeared to be slightly more effective than the methanol extract in this regard.

Effect of Rhazya stricta Decne on monoamine oxidase and cholinesterase activity and brain biogenic amine levels in rats.

The effect of treatment with the medicinal plant Rhayva stricta Decne, on monoamine oxidase (MAO) and cholinesterase activity, and on the concentration of brain biogenic amines was studied in rats. R. stricta extract, at doses of 0.2 and 0.5 g kg(-1), significantly (P < 0.05-0.01) increased the hepatic and cerebral activity of MAO by 36-127%. The higher doses used (2.0 and 8.0 g kg(-1)) produced smaller (10-26%) and statistically insignificant increases in MAO activity in liver and brain. Cholinesterase activity in blood, liver and brain was not significantly influenced by treatment with R. stricta. The concentrations of the measured biogenic amines (noradrenaline, adrenaline, 5-hydroxytryptamine and dopamine) were significantly lowered in rats treated with R. stricta. The observed increase in MAO activity may be responsible for the lowered biogenic amines levels and may, in part, be responsible for the pharmacological effects of R. stricta extract in rats.

Antioxidant action of extract of the traditional medicinal plant Rhazya stricta Decne. in rats.

The effects of a leaf extract of the traditional medicinal plant Rhazya stricta (0.25, 1.0 and 4.0 g/kg/day for 3 days) on reduced glutathione (GSH), lipid peroxidation (LP) and ascorbic acid (AA) concentrations in the liver and kidneys were studied in rats 24 h after the last dose. The plant extract, at a dose of 0.25 g/kg, did not significantly affect the concentrations of GSH, LP or AA in the liver or kidneys. At a dose of 1.0 g/kg, the plant extract significantly increased the GSH concentration in the liver, but did not affect the GSH concentration in the kidneys, or LP or AA in the liver or kidneys. The plant extract (4.0 g/kg) significantly increased the GSH and decreased LP peroxidation, but did not affect the AA concentrations in the liver and kidneys. It may be concluded that the R. stricta extract, at some of the doses used, has antioxidant actions in the rat.

Phytochemistry, pharmacology and toxicity of Rhazya stricta decne: a review.

Phytochemical, pharmacological and toxicological properties of the medicinal plant Rhazya stricta Decne. are reviewed. Several types of alkaloids and a few flavonoids have been isolated and their structures and stereochemistry characterized. However, in most cases the biological activity of these compounds has not been studied. Most of the pharmacological activity of the plant resides in its alkaloidal fractions which cause depression of the central nervous system and hypotension. Extracts of R. stricta appear to have low toxicity, although its use in pregnant women may be inadvisable.

Mechanism of the hypotensive action of Rhazya stricta leaf extract in rats.

The hypotensive action of Rhazya stricta lyophilized leaf extract was found to be partly caused by the electrolyte content of the extract, and partly caused by a strongly basic alkaloidal fraction (AF). AF (0.05-1.6 mg animal(-1)) caused a dose-dependent reduction in mean arterial blood pressure (MAP) of urethane-anaesthetized rat preparations. In naiuml;ve pithed rats, AF administration (0.5-2.0 mg animal(-1)) significantly increased MAP. In pithed or spinalized rats made normotensive by noradrenaline infusion, AF (0.25 mg animal(-1)) did not cause any significant changes. Direct intracerebroventricular injection of AF (0.1-0.4 mg) markedly and significantly reduced MAP. It is suggested that the hypotensive action of AF to be mediated by a central mechanism.

The effect of Rhazya stricta Decne, a traditional medicinal plant, on spontaneous and drug-induced alterations in activity of rats.

The effect of acute and chronic treatment of rats with a lyophilized extract of the leaves of the medicinal plant Rhazya stricta on total and ambulatory activity was studied. Given acutely at single oral doses of 1, 2, 4, and 8 g/kg, the extract produced dose-dependent decreases in total activity and ambulatory activity. Diazepam (20 mg/kg, orally) produced a decrease in rat activity comparable to that produced by a dose of 1 g/kg of the extract. When given daily at an oral dose of 2 g/kg for 21 consecutive days, the extract produced, on the last day of treatment, significant decrease in activity amounting to about 30% of control activity levels. Subcutaneous (SC) treatment of rats with caffeine (7.5, 15, and 30 mg/kg), dose-dependently and significantly increased total activity and ambulatory activity. These effects were dose-dependently attenuated when the extract was given concomitantly with caffeine at oral doses of 1, 2, and 4 mg/kg. Treatment of rats with zoxazolamine alone (10, 20, or 40 mg/kg, SC) or R. Stricta (1 and 4 g/kg orally) alone significantly decreased total and ambulatory activities. Concomitant treatment with zoxazolamine and R. Stricta decreased the rats activity to a greater degree than with either treatment given alone.

The in vivo interaction between gliclazide and glibenclamide and insulin on glucose disposal in the rat.

Many reports suggest that extrapancreatic actions contribute to the antidiabetic effect of sulphonylurea drugs (SUs). In this work, the ability of two SUs, namely, gliclazide and glibenclamide, to augment insulin action was studied in vivo. Both drugs elevated the plasma concentration of immunoreactive insulin (IRI) and lowered the plasma concentrations of glucose and non-esterified fatty acids (NEFA) in normal intact rats. These changes were not reproduced in alloxan-diabetic or eviscerated rats. The actions of insulin on plasma glucose and NEFA were not augmented by gliclazide in alloxan-diabetic rats. Neither gliclazide nor glibenclamide (given acutely and for 30 days) augmented the actions of exogenously administered insulin in reducing plasma glucose or NEFA concentrations in intact or eviscerated animals. It was concluded that these SUs do not produce their acute or chronic effects on blood glucose by augmenting the actions of insulin.

The effect of gentamicin on acetylsalicylic acid-induced platelet antiaggregatory action in mouse pial arterioles.

Gentamicin (G) treatment (5, 20, 40 and 80 mg kg[-1] day[-1] given intramuscularly for 6 days) was shown to cause a dose-related platelet proaggregatory effect in mouse pial microcirculation. This was associated with a reduction in mouse renal function, indicated by high plasma creatinine and urea concentrations. When G was given at the same doses but as a single injection, it caused no change in renal function or platelet aggregation. Gentamicin (20 and 80 mg kg/day, given intramuscularly for 6 days) significantly (P < 0.05) impeded the platelet antiaggregatory effect of acetylsalicylic acid (100 mg kg[-1], intraperitoneally).

Effect of extract of Rhazya stricta, a traditional medicinal plant, on rat brain tribulin.

Rhazya stricta leaves, which have both antidepressant and sedative properties in animal models, are widely used in folk medicine in the Arabian peninsula. In this study, the effects of oral administration of leaf extracts on rat brain tribulin levels [endogenous monoamine oxidase (MAO) A and B inhibitory activity], were determined. In an acute study, low doses brought about an increase in MAO A inhibitory activity, while intermediate doses caused a significant reduction. The highest doses had no significant effects on activity. There were no significant effects on MAO B inhibitory activity at any dose. Subchronic administration (21 days) caused a significant decrease in MAO A inhibitory activity, most prominent at low dosage, and an increase in MAO B inhibitory activity. Acute intramuscular administration also resulted in a similar pattern. Such paradoxical effects were at least partially explained when different extracts of the leaves were used; a weakly basic chloroform fraction caused an increase in MAO A inhibitory activity, whereas butanol extracts brought about a decrease. These fractions had no significant effects on MAO B inhibitory activity. The findings show that Rhazya stricta leaves contain at least two different components that affect MAO inhibitory activity in opposite directions. It may be that the antidepressant and sedative actions of the plant are explicable in terms of these different components.