Effects in cats of atipamezole, flumazenil and 4-aminopyridine on stress-related neurohormonal and metabolic responses induced by medetomidine, midazolam and ketamine

Abstract

This study aimed to investigate the antagonistic effects of a fixed dose of atipamezole (ATI), flumazenil (FLU) and 4-aminopyridine (4AP), both alone and in various combinations, on key stress-related neurohormonal and metabolic changes induced by medetomidine (MED), midazolam (MID) and ketamine (KET) in healthy cats. Seven cats were used consistently in eight investigation groups. Cats were administered a mixture of 0.05 mg/kg MED and 0.5 mg/kg MID followed 10 mins later by 10 mg/kg KET intramuscularly. Twenty minutes after KET injection, the cats were intravenously injected with either a physiological saline solution at 0.1 ml/kg (control) or one of the seven variations of experimental drugs, alone or in combination: ATI, FLU, 4AP, ATI + FLU, FLU + 4AP, ATI + 4AP and ATI + FLU + 4AP. Blood samples were collected 10 times during the 24 h test period. Plasma glucose, insulin, cortisol, epinephrine, norepinephrine and non-esterified fatty acid levels were measured. The administration of MED + MID + KET resulted in hyperglycaemia and decreases in epinephrine, norepinephrine, cortisol and non-esterified fatty acid levels. FLU or 4AP alone or FLU + 4AP did not effectively antagonise the effects induced by MED + MID + KET but enhanced the hyperglycaemia. ATI alone was effective in antagonising these effects. Compared with non-ATI regimens, combinations with ATI were more effective in antagonising the effects induced by MED + MID + KET; however, ATI + FLU + 4AP caused large increases in cortisol, epinephrine and norepinephrine concentrations. ATI, both alone and in combination, is effective in antagonising the neurohormonal and metabolic effects of MED + MID + KET in cats. However, ATI + FLU + 4AP is not suitable because of large stress-related hormonal responses.

Figure 1

(a) Changes in plasma non-esterified fatty acid (NEFA) concentrations after administration of antagonists, either alone or in combination, in seven cats anaesthetised with medetomidine, midazolam and ketamine (MED + MID + KET). Each point and vertical bars show the mean ± SD. (b) Area under the curve (AUC) data from 0–6 h for NEFA values after administration of antagonists. Each vertical bar indicates the mean and SD. a = Significantly different from control; b = significantly different from atipamezole (ATI); c = significantly different from flumazenil (FLU); d = significantly different from 4-aminopyridine (4AP); e = significantly different from ATI + FLU; f = significantly different from ATI + 4AP; g = significantly different from FLU + 4AP. The significance level is P <0.00625

Figure 2

(a) Changes in plasma glucose concentrations after administration of antagonists, either alone or in combination, in seven cats anaesthetised with medetomidine, midazolam and ketamine (MED + MID + KET). (b) Area under the curve (AUC) data from 0–6 h for glucose values after administration of antagonists. Plots, abbreviations and footnotes (a–g) are as described in Figure 1

Figure 3

(a) Changes in plasma insulin concentrations after administration of antagonists, either alone or in combination, in seven cats anaesthetised with medetomidine, midazolam and ketamine (MED + MID + KET). (b) Area under the curve (AUC) data from 0–6 h for insulin values after administration of antagonists. Plots, abbreviations and footnotes (a–g) are as described in Figure 1

Figure 4

(a) Changes in plasma cortisol concentrations after administration of antagonists, either alone or in combination, in seven cats anaesthetised with medetomidine, midazolam and ketamine (MED + MID + KET). (b) Area under the curve (AUC) data from 0–6 h for cortisol values after administration of antagonists. Plots, abbreviations and footnotes (a–g) are as described in Figure 1

Figure 5

(a) Changes in plasma epinephrine concentrations after administration of antagonists, either alone or in combination, in seven cats anaesthetised with medetomidine, midazolam and ketamine (MED + MID + KET). (b) Area under the curve (AUC) data from 0–6 h for epinephrine values after administration of antagonists. Plots, abbreviations and footnotes (a–g) are as described in Figure 1

Figure 6

(a) Changes in plasma norepinephrine concentrations after administration of antagonists, either alone or in combination, in seven cats anaesthetised with medetomidine, midazolam and ketamine (MED + MID + KET). (b) Area under the curve (AUC) data from 0–6 h for norepinephrine values after administration of antagonists. Plots, abbreviations and footnotes (a–g) are as described in Figure 1