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Abstract
Background:
The present study was attempted to compare enalapril, an angiotensin-converting enzyme inhibitor with losartan an angiotensin II (Ang II) receptor blocker in the inhibitory effects on the secretion of catecholamines (CA) from the 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 into an 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-butynyl–trimethyl ammonium (McN-A-343, a selective M1 agonist), and Ang II in a time-dependent manner. Also, in the presence of enalapril 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 Ca – 2+ channel activator), and cyclopiazonic acid (a cytoplasmic Ca2+-ATPase inhibitor) were significantly reduced. Based on the same concentration of 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. In the simultaneous presence of enalapril and losartan, ACh-evoked CA secretion was more strongly inhibited compared with that of enalapril- or losartan-treated alone.
Conclusions:
Collectively, these results demonstrate that both enalapril and losartan inhibit the CA secretion evoked by activation of both cholinergic and Ang II type-1 receptors stimulation in the perfused rat adrenal medulla. When these two drugs were used in combination, their effects were enhanced, which may also be of clinical benefit. Based on concentration used in this study, the inhibitory effect of losartan on the CA secretion seems to be more potent than that of enalapril.
References
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Fig. 1.
Time-course effects of losartan or enalapril on the secretory responses of CA evoked by acetylcholine from the isolated perfused rat adrenal glands. The CA secretion by a single injection of (ACh, 5.32 × 10-3 M) in a volume of 0.05 mL was evoked at 15 minutes intervals during loading with losartan (50 μM) or enalapril (50 μM) for 90 minutes as indicated by the arrow marks. Columns and vertical lines represent mean ± standard error. Numbers in the parenthesis indicate number of rat adrenal glands. Ordinate: the amounts of CA secreted from the adrenal gland (% of control). Abscissa: collection time of perfusate (minutes). Statistical difference was obtained by comparing the corresponding control with losartan- or enalapril-treated group (**), and by comparing the losartan-treated group with enalapril-treated group (a). ACh-induced perfusates were collected for 4 minutes. **p < 0.01, ap < 0.05. CA, catecholamines; ACh, acetylcholine.
Fig. 2.
Time-course effects of losartan or enalapril on high potassium-evoked catecholamines (CA) secretion from the isolated perfused rat adrenal glands. The CA secretion by a single injection of high potassium (56 mM) in a volume of 0.05 mL was evoked at 15 minutes intervals during loading with losartan (50 μM) or enalapril (50 μM) for 90 minutes as indicated by the arrow mark. Other legends are the same as in Fig. 1. High potassium-induced perfusates were collected for 4 minutes. **p < 0.01, ap < 0.05.
Fig. 3.
Time-course effects of losartan or enalapril on 1.1-dimethyl-4 -phenyl piperazinium iodide (DMPP)-evoked catecholamines (CA) secretion from the isolated perfused rat adrenal glands. The CA secretion by perfusion of DMPP (10-4 M) for 2 minutes was induced at 20 minutes intervals during loading with losartan (50 μM) or enalapril (50 μM) for 90 minutes as indicated by the arrow mark. DMPP-induced perfusates were collected for 8 minutes. Other legends are the same as in Fig. 1.*p < 0.05, **p < 0.01, ap < 0.05.
Fig. 4.
Time-course effects of losartan or enalapril on McN-A-343-evoked catecholamines (CA) secretion from the isolated perfused rat adrenal glands. The CA secretion by perfusion of 3-(m-chlloro-phenyl- carbamoyl-oxy-2-butynyl-trimethyl ammonium chloride (McN-A-343, 10-4 M) for 4 minutes was induced at 15 minutes intervals during loading with losartan (50 μM) or enalapril (50 μM) for 90 minutes as indicated by the arrow mark. McN-A-343-induced perfusates were collected for 4 minutes. Other legends are the same as in Fig. 1. *p < 0.05, **p < 0.01. ap< 0.05, bp < 0.01.
Fig. 5.
Time-course effects of losartan or enalapril on angiotensin II-evoked catecholamines (CA) secretion from the perfused rat adrenal glands. The CA secretion by perfusion of angiotensin II (10-7 M) for 4 minutes was induced at 15 minutes intervals during loading with losartan (15 μM) or enalapril (15 μM) for 90 minutes as indicated by the arrow mark. Angiotensin II-induced perfusates were collected for 4 minutes. Other legends are the same as in Fig. 1. **p < 0.01. bp < 0.01.
Fig. 6.
Time-course effects of losartan or enalapril on 6-dimethyl-3-nitro-4-(2-trifluoromethyl-phenyl)-pyridine-5-carboxylate (BAY-K-8644)-evoked catecholamines (CA) secretion from the perfused rat adrenal glands. The CA secretion by perfusion of BAY-K-8644 (10-5 M) for 4 minutes was induced at 15 minutes intervals during loading with losartan (15 μM) or enalapril (15 μM) for 90 minutes as indicated by the arrow mark. Bay-K-8644-induced perfusates were collected for 4 minutes. Other legends are the same as in Fig. 1. **p < 0.01, bp < 0.01.
Fig. 7.
Time-course effects of losartan or enalapril on cyclopiazonic acid-evoked catecholamines (CA) secretion from the perfused rat adrenal glands. The CA secretion by perfusion of cyclopiazonic acid (10-5 M) for 4 minutes was induced at 15 minutes intervals during loading with losartan (15 μM) or enalapril (15 μM) for 90 minutes as indicated by the arrow mark. Cyclopiazonic acid-induced perfusates were collected for 4 minutes. Other legends are the same as in Fig. 1. *p < 0.05, **p < 0.01, bp < 0.01.
Fig. 8.
Time-course effects of losartan or enalapril on veratridine-evoked catecholamines (CA) secretion from the perfused rat adrenal glands. The CA secretion by perfusion of veratridine (10-5 M) for 4 minutes was induced at 15 minutes intervals during loading with losartan (15 μM) or enalapril (15 μM) for 90 minutes as indicated by the arrow mark. Veratridine-induced perfusates were collected for 4 minutes. Other legends are the same as in Fig. 1. *p < 0.05, **p < 0.01, bp < 0.01.
Fig. 9.
Comparative time-course effects of losartan, enalapril and losartan + enalapril on acetylcholine-evoked catecholamines (CA) secretion from the perfused rat adrenal glands. The CA secretion by a single injection of acetylcholine chloride (5.32 × 10-3 M) in a volume of 0.05 mL was evoked at 15 minutes intervals during loading with losartan (50 μM) or enalapril (50 μM), losartan (50 μM) + enalapril (50 μM) for 90 minutes as indicated by the arrow mark. Acetlcholine-induced perfusates were collected for 4 minutes. Other legends are the same as in Fig. 1. **p < 0.01 enalapril-treated group vs. losartan-treated group or enalapril + losartan-treated group.
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