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Abstract
The aim of the present study was to examine the effects of ketamine, a dissociative anesthetics, on secretion of catecholamines (CA) secretion evoked by cholinergic stimulation from the perfused model of the isolated rat adrenal gland, and to establish its mechanism of action, and to compare ketamine effect with that of thiopental sodium, which is one of intravenous barbiturate anesthetics. Ketamine (30 ~ 300 μ M), perfused into an adrenal vein for 60 min, dose- and time-dependently inhibited the CA secretory responses evoked by ACh (5.32 mM), high K+ (a direct membrane-depolarizer, 56 mM), DMPP (a selective neuronal nicotinic NN receptor agonist, 100 μ M) and McN-A-343 (a selective muscarinic M1 receptor agonist, 100 μ M). Also, in the presence of ketamine (100 μM), the CA secretory responses evoked by veratridine (a voltage-dependent Na+ channel activator, 100 μM), Bay-K-8644 (an L-type dihydropyridine Ca2+ channel activator, 10 μM), and cyclopiazonic acid (a cytoplasmic Ca2+-ATPase inhibitor, 10 μM) were significantly reduced, respectively. Interestingly, thiopental sodium (100 μM) also caused the inhibitory effects on the CA secretory responses evoked by ACh, high K+, DMPP, McN-A-343, veratridine, Bay-K-8644, and cyclopiazonic acid. Collectively, these experimental results demonstrate that ketamine inhibits the CA secretion evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors and the membrane depolarization from the isolated perfused rat adrenal gland. It seems likely that the inhibitory effect of ketamine is mediated by blocking the influx of both Ca2+ and Na+ through voltage-dependent Ca2+ and Na+ channels into the rat adrenal medullary chromaffin cells as well as by inhibiting Ca2+ release from the cytoplasmic calcium store, which are relevant to the blockade of cholinergic receptors. It is also thought that, on the basis of concentrations, ketamine causes similar inhibitory effect with thiopental in the CA secretion from the perfused rat adrenal medulla.
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Fig. 1.
Concentration-dependent effects of ketamine on the secretory responses of catecholamines (CA) from the perfused rat adrenal glands evoked by acetylcholine (ACh, Upper) and by high K+ (Lower). CA secretion by a single injection of ACh (5.32×10−3 M) or K+ (56 mM) in a volume of 0.05 ml was evoked at 15 min intervals after preloading with 30, 100 and 300 μM of ketamine, respectively, for 60 min as indicated at an arrow mark. Numbers in the parenthesis indicate number of rat adrenal glands. Vertical bars on the columns represent the standard error of the mean (S.E.M.). Ordinate: the amounts of CA secreted from the adrenal gland (% of control). Abscissa: collection time of perfusate (min). Statistical difference was obtained by comparing the corresponding control with each concentration-pretreated group of ketamine. Pefusates induced by ACh and high K+ were collected for 4 minutes, respectively. ∗∗p<0.01.
Fig. 2.
Concentration-dependent effects of ketamine on the CA secretory responses evoked by DMPP (Upper) and McN-A-343 (Lower) from the perfused rat adrenal glands. The CA secretory responses by the perfusion of DMPP (10−4 M) and McN-A-343 (10−4 M) for 4 min at 20 and 15 min intervals were induced after preloading with 30, 100 and 300μM of ketamine for 60 min, respectively. Pefusates induced by DMPP and McN-A-343 were collected for 8 and 4 minutes, respectively. Other legends are the same as in Fig. 1. ∗∗P<0.01. ns: Statistically not significant.
Fig. 3.
Time course effect of ketamine on the CA release evoked by Bay-K-8644 (Upper) and cyclopiazonic acid (Lower) from the perfused rat adrenal glands. Bay-K-8644 (10−5 M) and cyclopiazonic acid (10−5 M) were perfused into an adrenal vein for 4 min at 15 min intervals after preloading with 100μM of ketamine for 60 min, respectively. Other legends are the same as in Fig. 1. ∗P<0.05, ∗∗P<0.01. ns: Statistically not significant.
Fig. 4.
Time course effect of ketamine on the CA release evoked by veratridine from the perfused rat adrenal glands. Veratridine (10−4 M) was perfused into an adrenal vein for 4 min at 15 min intervals after preloading with 100μM of ketamine for 60 min. Other legends are the same as in Fig. 1. ∗∗P<0.01.
Fig. 5.
Time course effect of of thiopental on the secretory responses of catecholamines (CA) from the perfused rat adrenal glands evoked by acetylcholine (ACh, Upper) and by high K+ (Lower). CA secretion by a single injection of ACh (5.32×10−3 M) or K+ (56 mM) in a volume of 0.05 ml was evoked at 15 min intervals after preloading with 100 μM thiopentall for 60 min as indicated at an arrow mark. Other legends are the same as in Fig. 1. ∗∗P<0.01.
Fig. 6.
Time course effect of of thiopental on the CA secretory responses evoked by DMPP (Upper) and McN-A-343 (Lower) from the perfused rat adrenal glands. The CA secretory responses by the perfusion of DMPP (10−4 M) and McN-A-343 (10−4 M) for 4 min at 20 and 15 min intervals were induced after preloading with 100μM thiopental for 60 min, respectively. Other legends are the same as in Fig. 1. ∗∗P<0.01. ns: Statistically not significant.
Fig. 7.
Time course effect of thiopental on the CA release evoked by Bay-K-8644 (Upper) and cyclopiazonic acid (Lower) from the perfused rat adrenal glands. Bay-K-8644 (10−5 M) and cyclopiazonic acid (10−5 M) were perfused into an adrenal vein for 4 min at 15 min intervals after preloading with 100μM of thiopental for 60 min, respectively. Other legends are the same as in Fig. 1. ∗P<0.05, ∗∗P<0.01. ns: Statistically not significant.
Fig. 8.
Time course effect of thiopental on the CA release evoked by veratridine from the perfused rat adrenal glands. Veratridine (10−4 M) was perfused into an adrenal vein for 4 min at 15 min intervals after preloading with 100μM of thiopental for 60 min. Other legends are the same as in Fig. 1. ∗∗P<0.01.
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