Background: The present study was attempted to compare enalapril, an angiotensin-converting enzyme inhibitor withlosartan an angiotensin II (Ang II) receptor blocker in the inhibitory effects on the secretion of catecholamines (CA) fromthe perfused model of the rat adrenal gland. Methods: The adrenal gland was isolated and perfused with Krebs-bicarbonate.
CA was measured directly by using the fluorospectrophotometer. Results: Both enalapril and losartan during perfusion intoan adrenal vein for 90 minutes inhibited the CA release evoked by acetylcholine (ACh), 1.1-dimethyl-4-phenyl piperazinium(DMPP, a selective Nn agonist), high K+ (a direct membrane-depolarizer), 3-(m-chloro-phenyl-carbamoyl-oxy-2-butynyltrimethylammonium (McN-A-343, a selective M1 agonist), and Ang II in a time-dependent manner. Also, in the presence ofenalapril or losartan, the CA release evoked by veratridine (an activator of voltage-dependent Na+ channels),6-dimethyl-3-nitro-4-(2-trifluoromethyl–phenyl)-pyridine-5-carboxylate (BAY-K-8644, an L-type Ca2+ channel activator),and cyclopiazonic acid (a cytoplasmic Ca2+-ATPase inhibitor) were significantly reduced. Based on the same concentrationof enalapril and losartan, for the CA release evoked by ACh, high K+, DMPP, McN-A-343, Ang II, veratridine,BAY-K-8644, and cyclopiazonic acid, the following rank order of inhibitory potency was obtained: losartan > enalapril. Inthe simultaneous presence of enalapril and losartan, ACh-evoked CA secretion was more strongly inhibited compared withthat of enalapril- or losartan-treated alone. Conclusions: Collectively, these results demonstrate that both enalapril andlosartan inhibit the CA secretion evoked by activation of both cholinergic and Ang II type-1 receptors stimulation in theperfused rat adrenal medulla. When these two drugs were used in combination, their effects were enhanced, which may alsobe of clinical benefit. Based on concentration used in this study, the inhibitory effect of losartan on the CA secretion seemsto be more potent than that of enalapril.
목적: 본 연구는 흰쥐부신의 관류모델에서 카테콜아민(catecholamines, CA) 분비에 대한 안지오텐신 II (angiotensin II, Ang II) 전환효소억제제인 enalapril과 안지오텐신Ⅱ 수용체 차단제인 losartan의 억제작용을 비교하는데 목적이 있다.
방법: 부신을 적출하여 Krebs-bicarbonate 액으로 관류하였으며 CA는 형광분석기를 이용하여 직접 측정하였다.
결과: Enalapril과 losartan은 다 같이 부신정맥 내로 90 분간 관류하는 동안 아세틸콜린(acetylcholine, ACh), 선택성 Nn 수용체 작용제(1.1-dimethyl-4-phenyl piperazinium, DMPP), 고칼륨(직접 막탈 분극제), 선택성 M1 수용체 작용제(3-(m-chloro-phenyl-carbamoyl-oxy-2-butynyl-trimethyl ammonium, McN-A-343) 및 Ang II에 의한 CA분비작용을 시간의존적으로 억제하였다. 또한 enalapril이나losartan 존재상태에서 veratridine(전압의존성 Na통로 활성화제), L형 칼슘통로활성화제(6-dimethyl-3-nitro-4-(2-trifluoromethyl- phenyl)-pyridine-5-carboxylate, BAY-K-8644), cyclopiazonic acid(세포질내형질세망 Ca2+ ATPase 억제제)에 의한 CA분비가 유의하게 억제되었다. Enalapril과losartan의 동일 농도를 근거로 보면, ACh, 고칼륨, DMPP, McN-A-343, AngⅡ, veratridine, BAY-K-8644 및 cyclo- piazonic acid의 CA분비에 대한 억제작용을 비교하면losartan >enalapril이다. Enalapril과 losartan 동시 존재상태에서 ACh의 CA분비작용은 enalapril이나 losartan 단독처치의 경우에 비교하여 현저히 억제되었다.
결론: 위의 결과를 종합하여보면, enalapril과 losartan은흰쥐관류 부신수질에서 콜린수용체 및 AngII수용체(Ang II type-1) 흥분에 의한 CA분비를 다 같이 억제하며, 두약물은 병용시 억제효과가 상승되었으며 이는 임상적으로 유용하다고 생각된다. 본 연구에서 사용한 농도를 근거로 보면 CA분비에 대한 losartan의 억제작용이 enalap- ril보다 더욱 강력한 것으로 생각된다.