EFFECT OF CHRONIC TREATMENT WITH AMLODIPINE IN NON-INSULIN-DEPENDENT DIABETIC RATS

We have investigated the effects of amlodipine on streptozotocin- (STZ) induced neonatal non-insulin-dependent diabetes mellitus (NIDDM) rats. NIDDM was induced by intraperitoneal injection of STZ (70 mg kg⁻¹) to 5-day-old rat pups. The animals were weaned at 30 days and maintained with food and waterad libitumfor 3 months. Amlodipine (5 mg kg⁻¹p.o.) was administered for 6 weeks after the animals were confirmed diabetic (3 months after the STZ injection). A group of control animals were also maintained and this group received citrate buffer 5 days after birth. Fasting- and fed-glucose levels in NIDDM rats were significantly higher than control rats. Treatment with amlodipine reduced the elevated fasting- and fed-glucose levels significantly. Results of the oral glucose tolerance test (OGTT) revealed that glucose tolerance is impaired in the NIDDM rats. There was a marked increase in glucose levels after oral administration of glucose in the control NIDDM rats. Increased glucose levels were found to be associated with increased insulin levels. Treatment with amlodipine in the NIDDM rats caused a decrease in insulin release, however, glucose levels were found to be lowered significantly indicating that amlodipine causes an increase in insulin sensitivity. In conclusion, our data indicated that amlodipine increases insulin sensitivity in neonatal-STZ NIDDM rats.     

Evidence for α2-Adrenoceptor Agonist Activity of Minoxidil*

The present investigation was undertaken to study the mechanism of action of minoxidil using various smooth muscle preparations. Minoxidil (4.7 × 10^?6 m to 4.7 × 10^?4 m ) produced a concentration-dependent inhibition of field stimulation-evoked responses in rat anococcygeus muscle and vas deferens. The inhibition produced by minoxidil was antagonized by yohimbine (2.5 × 10^?7 m ). Minoxidil (1.4 × 10^?5 m to 4.7 × 10^?4 m ) also produced a concentration-dependent relaxation in oestrogen-primed potassium chloride-depolarized rat uterus. These responses were blocked not only by yohimbine but also by glibenclamide (202 × 10^?8 m ). Our results suggest that minoxidil possesses α₂-adrenoceptor agonist activity in addition to potassium-channel-opening activity.     

Anti-ulcer Activity of Cromakalim (BRL 34915), a Potassium-channel Opener,Against Experimentally Induced Gastric and Duodenal Ulcers in Rats and Guinea-pigs

The effect of cromakalim, a potassium-channel opener, was studied on pylorus ligation-induced, aspirin-induced and water-immersion plus restraint stress-induced gastric ulcers in rats and on histamine-induced duodenal ulcer in guinea-pigs. Pretreatment with cromakalim (50–500 μg kg^?1, p.o.) resulted in a significant reduction in the incidence of gastric and duodenal ulceration in each model. The anti-ulcer activity of cromakalim was comparable with that of cimetidine. Cromakalim at 100, 250 and 500 μg kg^?1 caused a reduction in the volume of the gastric content in pylorus-ligated rats, and a dose of 250 μg kg^?1 resulted in a significant reduction in total acidity (28.81 ± 11.73 mEq L^?1, P < 0.02) in the pylorus ligation model. A significant reduction in total acid output was observed at doses of 250 μg kg^?1 (84.27 ± 22.33 mEqH+, P < 0.02) and 500 μg kg^?1 (120.17 ± 24.49 mEq H+, P < 001) in pylorus-ligated rats. A significant reduction in the ulcer index in pylorus-ligated rats was observed at all cromakalim doses: 50 μg kg^?1 (0.23 ± 009, P < 0.05), 100 μg kg^?1 (0.15 ± 0009, P < 0.02), 250 μg kg^?1 (0.12 ± 0.05, P < 0.01) and 500 μg kg^?1 (0.14 ± 0.03, P < 0.02). A significant reduction in the ulcer index of aspirin-treated rats was also observed at all cromakalim dose levels: 50 μg kg^?1 (0.39 ± 0.03. P < 0.01), 100 μg kg^?1 (0.28 ± 0.06, P < 0.01), 250 μg kg^?1 (0.22 ± 0.04, P < 0.001) and 500 μg kg^?1 (0.28 ± 0.03, P < 0.01). In the water-immersion plus restraint stress-induced gastric ulcer model, cromakalim significantly reduced gastric ulceration at all the dose levels: 50 μg kg^?1 (28.2 ± 2.12, P < 0.001), 100 μg kg^?1 (20.24 ± 1.71, P < 0.01), 250 μg kg^?1 (19.95 ± 1.46, P < 0.001) and 500 μg kg^?1 (21.61 ± 3.00, P < 0.001) but there was no consistent reduction of gastric bleeding. In addition to gastric ulcers, duodenal lesions were also reduced by pretreatment with cromakalim at all dose levels: 50 μg kg^?1 (97.87 ± 20.03 mm², P < 0.02). 100 μg kg^?1 (70.72 ± 12.82 mm², P < 0.02), 250 μg kg^?1 (48.32 ± 8.42 mm², P < 0.01) and 500 μg kg^?1 (55.50 ± 12.50 mm², P < 0.01). Cromakalim at a dose of 100 μg kg^?1 also reduced total acidity (99.36 ± 9.12 mEq L^?1, P < 0.02) and total acid output (172.22 ± 45.33 mEq of H+, P < 0.05) in this model. These findings demonstrate the anti-ulcer activity of cromakalim in different experimental models and suggest its potential use in ulcer therapy.