effect of calcium channel blockers amlodipine, lacidipine and diltiazem on thermal and visceral pain in mice

The effect of the calcium channel blockers amlodipine, lacidipine and deltiazem was studied after subcutaneous [s.c.] injection in mice using the hot plate and abdominal stretching assays. In the hot-plate test of thermal pain, amlodipine [0.43 and 0.86 mg/kg], lacidipine [0.17 and 0.35 mg/kg] or deltiazem [5.2 and 10.4 mg/kg], produced a dose-related reduction in nociceptive responses. In the acetic acid-induced abdominal constrictions test of visceral pain, amlodipine, lacidipine or deltiazem at the above doses, reduced the number of abdominal constrictions dose-dependently. The inhibition of writhing response by the three drugs was reduced by co-administration of the muscarinic acetylcholine receptor antagonist atropine [1 mg/kg, s.c.], enhanced by co-administration of the alpha-1 adrenoceptor blocker prazosin [1 mg/kg, s.c.], whilst the analgesic effect of lacidipine and deltiazem was reduced by the alpha-2 adrenoceptor blocker yohimbine [5 mg/kg, s.c.]. The analgesic effect of both amlodipine and Iacidipine was unaffected, but that of deltiazem was reduced by the beta adrenoceptor antagonist propranolol [1 mg/kg, s.c.]. The non-selective opioid receptor antagonist naloxone [5 mg/kg, i.p.] enhanced the analgesic effect of amlodipine, but reduced that of deltiazem. Meanwhile, lacidipine anti-nociception was reduced by the non-selective adenosine receptor antagonist theophylline [20 mg/kg, s.c.]. These data suggest that the calcium channel antagonists amlodipine, Iacidipine or deltiazem have analgesic effects in thermal and visceral pain models in mice. Data also indicate that muscarinic acetylcholine receptors mediate at least in part the visceral analgesic effect of these drugs. The antinociceptive effect of lacidipine involves adenosine receptors. The antinociceptive effect of deltiazem involves opioid, alpha-2 and beta adrenoceptors

Effect of Ramipril, Valsartan, Candesartan and Lacidipine on inflammation and gastric ulcer in rats

The present study investigated and compared the effect of the angiotensin converting enzyme inhibitor ramipril and the angiotensin II receptor blockers valsartan and candesartan and the calcium channel blocker lacidipine on inflammation and gastric ulcer in rats. The acute inflammation was induced by intraplantar injection of carrageenan [1%] in the rat hind paw. Gastric ulcer was evoked by s.c. indomethacin [20 mg/kg]. When given s.c. 30 min prior to induction of inflammation, ramipril [0.23 and 0.45 mg/kg], valsartan [7.5 and 15 mg/kg], candesartan [0.72 and 1.44 gm/kg] failed to reduce paw oedema response. Meanwhile, lacidipine at the lower dose of 0.18 mg/kg displayed mild anti-inflammatory activity up to 1 hr, reducing paw odema by 26.7% for 1 hr post-carrageenan, while a higher dose of 0.36 mg/kg inhibited oedema formation by 33.5, 31, 23.6 and 22.3% at 1, 2, 3 and 4 hr post-carrageenan, respectively. The acute gastric mucosal lesions evoked by indomethacin in the rat were aggravated by co-administration of ramipril 0.23 and 0.45 mg/kg, valsartan 7.5 and 15 mg/kg, lacidipne 0.18 and 0.36 mg/kg and candesartan 0.72 mg/kg, but reduced by candesartan 1.44 mg/kg. Findings in the present study do not favor an anti-inflammatory activity for ramipril, valsartan and candesartan, but indicates an antioedema effect for lacidipine at the doses employed. These agents are likely to adversely affect gastric mucosal integrity and enhance the indomethacin-induced gastric injury

Effect of hypoglycaemia induced by different agents on thermal nociception in mice

Peripheral neuropathy is a well-recognized complication of diabetes mellitus and achieving glycaemic control is presumed to be important in reducing its severity and progression. Meanwhile, the effect of hypoglycaemia on pain perception is less well studied. The current study compared the effects of four classes of oral hypoglycemics namely the sulfonylureas "glimepiride and glibenclamide", the biguanide "metformin", and the meglitinide analogue "repaglinide", besides the insulin sensitizer "rosiglitazone", in addition to insulin, sucrose and alloxan, on thermal pain using the hot-plate test in mice. Drugs were given 30 min prior to testing and blood glucose level determination. Alloxan was given 2hr before the assay. Glimepiride and glibenclamide [in two dose levels each] produced a reduction in nociceptive responses increasing hot-plate latency by 45.5-68.6% and by 18.1-12.8%, respectively, compared with pre-drug basal values. Hot-plate latency was increased by 66.2-32.8% following metformin. Rosiglitazone and repaglinide resulted in 26.7-39% and 50.1-43.1% increase in hot-plate latency, respectively. Insulin administered subcutaneously at 3 IU/kg decreased the nociceptive response by 19.5%, while a higher dose of 12 IU/kg caused 5.7% decrease in pain threshold. Hot-plate latency was also increased by oral [by 31.3-22.8%] or i.p. [by 50.1-37%] administration of 5% and 10% sucrose, respectively. Pain threshold decreased by 39.2% by alloxan [120 mg/kg, i.p.] and by 18.7% after both alloxan and glibenclamide [2.5 mg/kg, i.p.]. In case of glimepiride, insulin or alloxan treatment, correlation analysis showed relationship between the hot-plate latency and blood glucose level; R = 0.52, 0.51 and 0.72, respectively. It is concluded that within a certain range, reduction in blood glucose level impairs the perception of a thermal noxious stimulus

The effect of non-selective and selective Cox-2 inhibitors on bile secretion in the rat

The effect of the non-selective cyclo-oxygenase inhibitors indomethacin. Diclofenac, sulindac, tolmetin, piroxicam and the selective cyclo-oxygenase type 2 [COX-2] inhibitors celecoxib and rofecoxib on biliary secretion was studied in urethane anaesthetised rats. Drugs were intraperitonealIy administered prior to bile duct cannulation and bile collection. Bile secretions were collected at 30-min intervals for 4 h following drug administration. Bile flow was determined. In addition, total proteins, cholesterol, total, lipids, glucose and several hepatic enzymes were assessed in bile. Results indicated that basal bile secretion was unchanged after diclofenac, but decreased after piroxicam, indomethacin, tolmetin, celecoxib and rotecoxib administration by 23-25%. In contrast, bile flow was increased by 39.3-66.6% after the administration of sulindac. The concentration of cholesterol in bile was increased by all NSAIDs examined. Cholesterol secretion into bile was increased by indomethacin, Piroxicam, high dose sulindac, celecoxib and rofecoxib. All NSAIDs in the study decreased lipid secretion into bile to variable extent. Protein secretion was unchanged by most drugs, but increased by diclofenac and small dose rofecoxib and decreased by tolmetin. These data collectively suggest that NSAIDs alter biliary secretion and composition which is likely to have important clinical implications. Data also suggest that preferential COX-2 inhibition did not result in marked difference compared with conventional NSAIDs as regards the effect on bile flow, cholesterol or biliary lipid secretion