Co-administration of metformin and/or glibenclamide with losartan reverse NG-nitro-l-arginine-methyl ester-streptozotocin-induced hypertensive diabetes and haemodynamic sequelae in rats.

Over the years, there have been opinions on whether to reduced blood pressure (BP) to a different levels in patients with diabetes mellitus. Hence, this study investigated the efficacy of the co-administration of losartan (angiotensin receptor blocking antihypertensive agent) with metformin and/or glibenclamide (antidiabetic agents) on hypertensive-diabetic experimental rats induced by NG-nitro-l-arginine-methyl-ester hydrochloride (l-NAME), and streptozotocin (STZ). STZ (45 mg/kg, i.p.)-induced diabetic rats combined with l-NAME (40 mg/kg, p.o.)-induced hypertension were allotted into different groups. Group 1 received distilled water (10 mL/kg) and served as normal control, group 2 comprised hypertensive diabetic rats with distilled water, groups 3-5 were hypertensive-diabetic rats but received combination treatments of losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide daily for 8 weeks, respectively. Our finding revealed no changes in the body weights, but there was a significant increase in fasting blood sugar levels in l-NAME - STZ-induced hypertensive-diabetes, which were lowered by losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide treatments. Moreover, the increased systolic-BP, mean arterial pressure but not diastolic-BP and heart rate by l-NAME + STZ were attenuated more significantly by losartan + metformin + glibenclamide between weeks 2-8 relative to hypertensive-diabetic control. l-NAME + STZ-induced elevated levels of lactate dehydrogenase and creatinine kinase, were differentially reversed by losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide. However, l-NAME + STZ-induced decreased nitrite level was significantly restored by all treatments, suggesting increased nitrergic transmission. Additionally, l-NAME + STZ-induced degeneration of pancreatic islet and myocardial cells were dramatically alleviated by losartan + metformin + glibenclamide treatments. Our findings suggest hyperglycemia with raised systolic-BP should be managed with losartan combined with both metformin and glibenclamide than single combination of losartan with antidiabetics.

Dimethyl fumarate confers neuroprotection by casein kinase 2 phosphorylation of Nrf2 in murine intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Edema formation, inflammation and increased blood-brain barrier permeability contribute to poor outcomes after intracerebral hemorrhage (ICH). This study examined the therapeutic effect of dimethyl fumarate (DMF), a fumaric acid ester that activates nuclear factor erythroid-2 related factor 2 (Nrf2) and Nrf2 heterodimerization effector protein musculo-aponeurotic fibrosarcoma-G (MAFG) in a murine ICH model. METHODS: Male CD-1 mice (n=176) were subjected to intrastriatal infusion of bacterial collagenase (n=126), autologous blood (n=18) or sham surgery (n=32). Four (4) animals not subjected to ICH (naive) were also included in the study. After ICH, animals either received vehicle, dimethyl fumarate (10 mg or 100 mg/kg) or casein kinase 2 inhibitor (E)-3-(2,3,4,5-tetrabromophenyl)acrylic acid (TBCA). Thirty-two mice also received scrambled siRNA or MAFG siRNA 24h before ICH. Brain water content and neurological function were evaluated. RESULTS: Dimethyl fumarate reduced Evans blue dye extravasation, decreased brain water content, and improved neurological deficits at 24 and 72 h after ICH. Casein kinase 2 inhibitor TBCA and MAFG siRNA prevented the effect of dimethyl fumarate on brain edema and neurological function. After ICH, ICAM-1 levels increased and casein kinase 2 levels decreased. Dimethyl fumarate reduced ICAM-1 but enhanced casein kinase 2 levels. Again, casein kinase 2 inhibitor TBCA and MAFG siRNA abolished the effect of dimethyl fumarate on ICAM-1 and casein kinase 2. Dimethyl fumarate preserved pNrf2 and MAFG expression in the nuclear lysate after ICH and the effect of dimethyl fumarate was abolished by casein kinase 2 inhibitor TBCA and MAFG siRNA. Dimethyl fumarate reduced microglia activation in peri-hematoma areas after ICH. The protective effect of dimethyl fumarate on brain edema and neurological function was also observed in a blood injection mouse model. CONCLUSION: Dimethyl fumarate ameliorated inflammation, reduced blood-brain barrier permeability, and improved neurological outcomes by casein kinase 2 and Nrf2 signaling pathways after experimental ICH in mice.

Efficacy of initiating therapy with amlodipine and hydrochlorothiazide or their combination in hypertensive Nigerians.

In order to evaluate whether amlodipine or hydrochlorothiazide would be preferable to initiate therapy, 90 untreated hypertensive Nigerians of both genders aged 31-86 years with blood pressure >160/90 and ≤180/120 mm Hg were recruited into a randomized 48-week study. Patients, 30 each in amlodipine, hydrochlorothiazide, and amlodipine-hydrochlorothiazide groups, were treated, respectively, with amlodipine 5 mg for 6 weeks and the dose increased to 10 mg till week 12, after which hydrochlorothiazide 25 mg was added; hydrochlorothiazide 25 mg till week 6, after which amlodipine 5-10 mg was added; and amlodipine 5-10 mg + hydrochlorothiazide 25 mg. Body mass index, blood pressure, heart rate, and 24-hour urine volume were evaluated at baseline and at the end of weeks 1, 3, 6, 12, 24, 36, and 48. The primary efficacy variables were decreased in mean trough sitting diastolic and systolic blood pressure such that blood pressure < 140/90 mm Hg was regarded as normalized. At week 48 in the amlodipine group, 27 patients versus 25 patients in the hydrochlorothiazide group had diastolic blood pressure <90 mm Hg (90% vs. 83.3%; P <.03). In the amlodipine group, 23 patients versus 20 patients in the hydrochlorothiazide group had blood pressure < 140/90 mm Hg (76.7% vs. 66.7%; P <.01). In the amlodipine-hydrochlorothiazide group, 27 patients (90%) and 15 patients (50%) had diastolic blood pressure <90 mm Hg and blood pressure < 140/90 mm Hg, respectively. This study has demonstrated that a regimen of amlodipine to which hydrochlorothiazide is subsequently added provides superior efficacy on blood pressure control when compared with a regimen of hydrochlorothiazide to which amlodipine is subsequently added or with ab initio amlodipine-hydrochlorothiazide combination therapy.

Evaluation of the potassium channel activator levcromakalim (BRL38227) on the lipid profile, electrolytes and blood glucose levels of streptozotocin-diabetic rats.

BACKGROUND: Levcromakalim is a vasorelaxant used in the management of hypertension in diabetes mellitus. Thus, the effects of levcromakalim were investigated in streptozotocin (STZ)-diabetic rats. METHODS: Diabetes was induced in Wistar albino rats with a single injection of STZ (60 mg/kg, i.p.) following chronic (4 weeks) treatment with levcromakalim (75 µg/kg per day). Rats were then divided into the following groups (n = 5 in each group): (i) a normal saline (2 mL/kg)-treated group; (ii) a 5 mg/kg glibenclamide-treated group; (iii) 350 mg/kg metformin-treated group; and (iv) 5, 10, 20 and 40 IU/kg insulin-treated groups. Rats were transferred to metabolic cages and the lipid profile, plasma and urine electrolytes and blood glucose levels were determined 24 h after drug administration. RESULTS: Levcromakalim treatment significantly reduced total cholesterol, low-density lipoprotein (LDL), and triglyceride levels in diabetic rats (all P < 0.05 compared with untreated diabetic rats). In addition, levcromakalim reduced plasma sodium, bicarbonate, and chloride levels, but increased urinary bicarbonate and chloride levels, in diabetic rats (all P < 0.05 compared with untreated diabetic rats). Levcromakalim significantly inhibited the effects of glibenclamide, metformin, and low-dose (20 IU/kg) insulin treatment in diabetic rats (all P < 0.05). Only 40 IU/kg insulin produced significant reductions in hyperglycemia in levcromakalim-treated diabetic rats. CONCLUSION: Levcromakalim induced resistance to glibenclamide, metformin, and low-dose insulin treatment in diabetic rats, leading to persistent hyperglycemia. However, reductions in LDL, total cholesterol and triglyceride levels following chronic levcromokalim treatment may decrease the risk of cardiovascular disease in diabetic rats.

Oxytocin inhibiting effect of the aqueous leaf extract of Ficus exasperata (Moraceae) on the isolated rat uterus.

The leaves of Ficus exasperata Vahl Enum. Pl. vahl (Moraceae) are used by traditional healers in Southern Nigeria and some parts of Africa to avoid preterm births. However, previous reports showed that the plant also exhibited uterine contractions at specific concentrations. This study is therefore aimed at investigating the purported uterine inhibitory aspect of the plant on the isolated rat uterus. The aqueous extract (AET) was tested on rhythmic spontaneous uterine contractions. Concentration-response relationships were obtained for oxytocin (OT), acetylcholine (ACh) and ergometrine (EGM), in the presence or absence of fixed concentrations of AET. Salbutamol (SBL) and verapamil (VER) were used as positive controls. AET, at 1.0 x 10(-2) mg/mL, significantly increased (p < 0.05) the EC50 of oxytocin-induced contractions but had no significant effect on ACh, EGM and spontaneous uterine contractions. However, SBL and VER significantly increased (p < 0.01) the EC50, of OT, ACh and EGM and significantly inhibited (p < 0.01) the frequency and amplitude of spontaneous uterine contractions. The aqueous leaf extract of F. exasperata inhibits oxytocin-induced uterine contractions at the concentration shown in this study. This observation may explain its folkloric use in counteracting preterm contractions and alleviating dysmenorrhoea.

Oxytocic effects of the aqueous leaf extract of Costus lucanusianus - family Costaceae on isolated non-pregnant rat uterus.

Costus lucanusianus J. Braun (Costaceae) is a climbing herb, found mainly in the Niger Delta region of Nigeria. This plant is locally used in situations of pains, inflammation, dysmenorrhoea and in pyrexia. The purpose of this study was to investigate this claim with view to validating scientifically the ethno-medicinal usage. The aqueous extract was subjected to pharmacological testing in vitro on a piece of isolated rat uterus previously pretreated with 1 mg/kg stilbestrol for 24 h. The dose response curves of oxytocin and that of the extract were first obtained. The effects of antagonists like atropine (1 mg) and salbutamol (2 microg) on the dose response curve of the extract were also investigated. Possible synergy was investigated via co-administration of the extract and oxytocin. Finally the proximate analysis of the extract was investigated. The aqueous extract of C. lucanusianus and oxytocin both produced a dose dependent contraction of the uterus. An effect of 0.63+/-0.06 g force of uterine contraction produced by 12.5 mg of the extract was increased to 1.37+/-0.09 g when 200 mg of the extract was administered. Oxytocin at 0.16 i.u was observed to produce a similar force of contraction with 200 mg of the aqueous extract. Synergy was established as co administration of the extract at 200 mg and oxytocin at 0.08 i.u, produced higher contractile effect, significantly higher (p<0.05) than when either the extract (200mg) or oxytocin (0.08 i.u) was administered alone. Both atropine and salbutamol significantly (p<0.0001) inhibited the contractile effect produced by the extract. The inhibitory effect showed by atropine on the contractile effect of the extract seems to suggest the involvement of muscarinic receptors. The proximate analysis carried out in this study is used to establish the identity of the crude drug sample. A moisture content of 10.047 % was obtained. The total ash is a measure of the non-volatile inorganic constituents remaining after ashing. The values of 3.42 % were obtained.

Analgesic activity of aqueous extract of Stereospermum kunthianum (Cham, Sandrine Petit) stem bark.

The analgesic activity of the aqueous extract of Stereospermum kunthianum stem bark was studied using the acetic acid-induced writhing, the hot plate test, tail flick test, and formalin pain test in mice or rats. The aqueous extract (100, 200 or 400 mg/kg) produced a significant (p<0.001) dose-dependent inhibition of abdominal writhes in mice. The results of the hot plate test showed a dose-related and time-dependent significant (P<0.001) increase in pain threshold in mice 60 minutes after treatment at all the doses used in the study. The extract (100, 200 or 400 mg/kg) showed significant (p <0.05) dose-dependent increase in tail flick latency in rats and also inhibited both phases of the formalin pain test in mice with a more intense effect on the first phase than the second phase. The results indicate that the aqueous extract of Stereospermum kunthianum stem bark possesses analgesic activity which is mediated through both central and peripheral mechanisms. This is a possible rationale for its use in traditional human medicine for pain relief.

Pharmacognosy and hypotensive evaluation of Ficus exasperata Vahl (Moraceae) leaf.

There is already a literature report on the anti-ulcer effect of water extract of Ficus exasperata. Some communities in Edo and Delta States of Nigeria use the decoction of the leaf as hypotensive crude drug. Verification of this claim and also the microscopy and other pharmacognostic parameters which can be used to establish the identity of the leaf were carried out. The microscopy of the leaf powder revealed the presence of straight walled epidermal cells, cone or nail shaped trichomes or epidermal hairs, clustered or prismatic calcium oxalate crystals of varying dimensions. The percentage weight loss on drying was 9.84 +/- 0.08 whereas water and alcohol extractive values were 5.29 +/- 0.07 and 2.21 +/- 0.11, respectively. The ash value was 30.68 +/- 0.44 whereas the acid insoluble ash and water soluble ash values were 17.87 +/- 0.37 and 16.73 +/- 0.13, respectively. Preliminary phytochemistry of leaf showed that it contains tannins, flavonoids and saponins with no traces of alkaloids or anthraquinones. The water extract showed a dose related reduction in mean arterial blood pressure. At 10 mg/kg, a reduction of 16.6 +/- 1.1 mmHg was observed, whereas at 30 mg/kg, a fall in mean arterial pressure of 38.3 +/- 0.6 mmHg was obtained. The hypotensive effect of the extract was significantly reduced with a prior administration of 2.5 mg of either atropine or chlorpheniramine. This suggests the probable stimulation of muscarinic receptors in the heart or release of histamine into the circulatory system thereby causing the initial fall in blood pressure.

Increased superoxide dismutase and Na+, K+-ATPase activities in aortic strips from potassium-adapted rats: implication for altered vascular reactivity.

The contributions of superoxide dismutase (SOD) and Na(+), K(+)-ATPase to the altered vascular reactivity in potassium-adapted rats were investigated to test the hypothesis that smooth muscle hyperpolarisation may be involved. Isometric contractions to noradrenaline (NA), 5-hydroxytryptamine (5-HT), and relaxations to acetylcholine (ACh), levcromakalim (LEV) and sodium nitroprusside (SNP), were measured in aortic rings from potassium-adapted rats. Pieces of the aortae were also excised from the animals and assayed for SOD and Na(+), K(+)-ATPase. Maximum contractile responses were significantly attenuated (P<0.05) in aortic rings from the potassium-adapted rats to NA and 5-HT, while relaxations were also significantly augmented (P<0.05) in the same rings to LEV and SNP, but not to ACh. Both SOD and Na(+), K(+)-ATPase activities were significantly higher (P<0.05) in the aortae from the potassium-adapted rats compared to controls. It is concluded that the alteration in vascular smooth muscle reactivity may be due to hyperpolarisation caused by the activities of SOD and Na(+), K(+)-ATPase.