Effect of the Angiotensin Converting Enzyme Inhibitor 'Ramipril' and the Angiotensin Ⅱ Receptor Blockers 'Valsartan and Candesartan' on Thermal and Visceral Pain in Mice

摘要

The effect of the angiotensin converting enzyme inhibitorrn"Ramipril" and the angiotensin Ⅱ receptor blockers "Valsartan and Candesartan" on the sensation of pain was studied using the hot plate and abdominal stretching assays in mice. In the hot-plate test (thermal pain), ramipril (0.22 & 0.44 mg/kg, s.c.) and valsartan (6.9 & 13.8 mg/kg, s.c), but not candesartan (0.69 & 1.38 mg/kg, s.c), produced a dose-related reduction in nociceptive responses. Ramipril and valsartan, in the same doses, also reduced the number of abdominal constrictions induced by i.p. acetic acid injection. Candesartan in smaller doses (0.69 & 1.38 mg/kg, s.c.) was without effect. The inhibition of writhing response by ramipril (0.22 mg/kg, s.c.) was reduced by co-administration with the beta-adrenoceptor blocker propranolol (1 mg/kg, s.c.) and by the opioid antagonist naloxone (5 mg/kg i.p.). The antinociceptive effect of valsartan (13.8 mg/kg, s.c.) was reduced by propranolol (1 mg/kg, s.c), atropine (1 mg/kg, s.c), but not by naloxone. On the other hand, the antinociceptive effect of ramipril was increased by alpha-2 adrenoceptor antagonist "yohimbine" (5 mg/kg, s.c), but unaffected by the alpha 1-adrenoceptor antagonist prazosin (1 mg/kg, s.c.) or by adenosine receptor antagonist, theophylline (20 mg/kg, s.c). Meanwhile, valsartan antinociception was increased by yohimbine or prazosin, but unaffected by theophylline. These data suggest that the angiotensin Ⅱ receptor blockers "valsartan and candesartan" have differing effect on visceral pain. The data also indicates that beta-adrenoceptors mediate at least in part the analgesic effect of the angiotensin converting enzyme inhibitor "ramipril" and the angiotensin Ⅱ receptor blocker valsartan. The analgesic effect of ramipril was reversed by naloxone, an opioid antagonist, while that of valsartan was reversed by atropine; a muscarinic acetylcholine receptor antagonist.