The inhibitory effect of fentanyl, nicomorphine and 6-nicotinoyl morphine on phrenic nerve activity in relation to their cardiovascular effects in the anaesthetized cat.

The inhibitory effects of the morphine-like drugs fentanyl, nicomorphine (3,6-dinicotinoyl morphine, Vilan) and its active metabolite 6-nicotinoyl morphine (6-NM) on phrenic nerve activity (PNA) were quantified. Therefore, the drugs were simultaneously infused into the left and right vertebral artery of anaesthetized cats. Previously we demonstrated that drugs, administered via these arteries, accumulate within the pontomedullary region, whereas only insignificant amounts reach higher brain areas and peripheral structures. The results were compared with the effects of i.v. administration. It is shown that fentanyl already inhibits PNA after 60 ng via the vertebral arteries. Nicomorphine and its metabolite have much less influence on respiration (factor 564 and 47, respectively). The difference in potency between nicomorphine and 6-NM was less after i.v. injection, indicating that nicomorphine needs metabolization in order to unfold full biological activity. Haemodynamic parameters are not affected after central administration even when PNA is almost completely depressed. After i.v. injection of relatively high doses, blood pressure falls, but probably not by an interaction with opiate receptors in the lower brain stem, since it could not be reversed by intravertebral naloxone.

Depressor effects, drug concentration and cholinesterase activities in the brain after administration of paraoxon in the cat.

After simultaneous administration of paraoxon into both the left and right vertebral artery (4-8 micrograms) or into a femoral vein (150-550 micrograms.kg-1) of the anaesthetized cat, dose-dependent drug concentrations are measured in various brain regions. These amounts induce inhibition of brain acetylcholinesterase activity and dose-dependent depressor effects. Although paraoxon is rapidly eliminated from the CNS, enzyme activity remains at a low level. After central application of paraoxon into both vertebral arteries no detectable amounts are found in the hypothalamus and acetylcholinesterase activity in that brain region is not or only slightly affected. Curves representing the relationship between the decrease in blood pressure and the concentration of paraoxon or enzyme inhibition in the medulla oblongata are steep. Also, a steep dose-response curve for the depressor response to paraoxon is found. A reduction of brain enzyme activity to about 35% has no influence on blood pressure. However, inhibition by 65-100% induces dose-dependent depressor effects. The results support earlier findings that the depressor response to paraoxon is mediated by a central mechanism. This site of action is probably located within the medulla oblongata region.

The effects of paraoxon on blood pressure in the anaesthetized and in the conscious rat.

1 Intravenous administration of paraoxon (150-825 mug/kg) to anaesthetized rats induced long-lasting, dose-dependent pressor effects. Only after injection of 825 mug/kg paraoxon was the pressor response followed by a depressor effect and a bradycardia that could be blocked by N-methylatropine. Intracerebroventricular injection of paraoxon into anaesthetized rats also induced pressor effects.2 In order to elucidate the mechanism of the pressor action rats were given dexetimide, N-methylatropine, mecamylamine, phentolamine, prazosin, yohimbine, atenolol and metoprolol. If treatment with these drugs resulted in a low initial blood pressure, vasopressin was infused to elevate blood pressure to normal levels. The influence of adrenalectomy, pretreatment with reserpine and midcollicular transection was also examined.3 The pressor effect of paraoxon was not influenced by N-methylatropine or mecamylamine. However, a combination of these drugs as well as dexetimide, phentolamine or prazosin combined with yohimbine, reduced or prevented the pressor effect.4 In conscious rats the effects of paraoxon and the action of antimuscarinic drugs upon the pressor response were similar to those observed in anaesthetized animals.5 Acetylcholinesterase activities were measured in various brain regions and in whole blood. Paraoxon concentrations within the CNS were also measured.6 It is concluded that the pressor effect of paraoxon in anaesthetized and conscious rats is mediated by a central mechanism, although a contribution of peripheral acetylcholinesterase inhibition in sympathetic ganglia to this pressor effect cannot be ruled out.

The pressor effects of paraoxon in the pithed rat.

1 In pithed rats paraoxon 825 microgram/kg induced a short-lasting pressor effect. Lower doses of the drug were ineffective. 2 The pressor effect was prevented by N-methylatropine, dexetimide and alpha-receptor blocking agents but not by mecamylamine. 3 When blood pressure of pithed rats was elevated either by the continuous infusion of vasopressin or by electrical stimulation of the pithing rod, both 275 and 825 microgram/kg paraoxon induced further pressor effects. The effectiveness of various receptor blocking agents was similar to that observed in pithed rats without vasopressin. 4 It is concluded that the pressor effect of paraoxon is mediated by ganglionic muscarinic receptors. Stimulation of these receptors by accumulated acetylcholine results in an increase in postganglionic sympathetic activity and causes pressor effects. 5 The peripheral action of paraoxon is compared with its action in intact anaesthetized animals.

The central effects of paraoxon on blood pressure of rabbits after intravenous administration or infusion via a vertebral artery.

In the present study paraoxon (28-825 micrograms/kg, i.v.) was administered into rabbits treated with N-methylatropine (1 mg/kg). In urethane-anaesthetized rabbits pressor and depressor effects were observed. In pentobarbitone-anaesthetized rabbits, however, only depresssor effects were noticed. Dexetimide (0.25-0.5 mg/kg) prevented the pressor and depressor action of paraoxon. Furthermore, paraoxon (83-825 micrograms) was infused into a vertebral artery of pentobarbitone-anaesthetized animals. After administration via this route the depressor effect was similar to i.v. administration. 30 min after administration of paraoxon acetylcholinesterase activity was determined in the medulla oblongata, the pons and the hypothalamus. The enzyme has to be inhibited almost completely to induce an effect on blood pressure. It is concluded that the vascular effects of paraoxon seem to be mediated by a mechanism involving stimulation of central muscarinic receptors, probably by accumulated acetylcholine, which in turn induces a decrease in blood pressure.

Inhibition of efferent sympathetic nerve activity by centrally administered paraoxon in the cat.

We recently found that central administration of the cholinesterase inhibitor paraoxon lowered blood pressure substantially. It was postulated that the decrease in pressure was mediated by a reduction of sympathetic outflow. In the present study, efferent splanchnic nerve activity in anaesthetized and paralysed cats was recorded, and quantified by measuring the variance of signal amplitude. After administration of 8 micrograms paraoxon into the vertebral arteries, blood pressure and splanchnic nerve activity decreased simultaneously. A mean fall of 46 +/- 6% and 45 +/- 13% (mean +/- S.E.M.) respectively was reached within 12 min and was maintained during the period studied (30 min). When the effect of paraoxon was antagonized by dexetimide, both blood pressure and splanchnic nerve activity returned to control values. Since previous work has shown that the depressor action could not be prevented by efferent vagal blockade it seems likely that the fall in blood pressure after paraoxon was mainly caused by a decreased sympathetic outflow. In addition, we varied the amplifier band width in recording splanchnic nerve activity. The measurement of frequencies between 10 and 225 Hz appeared to be sufficient for studying the change in activity after paraoxon.

Central effects of paraoxon on haemodynamics in the cat.

Application of paraoxon into the left vertebral artery (8--80 micrograms) or both the left and right vertebral artery (4--8 micrograms) of the anaesthetized cat evoked dose-dependent depressor effects, whereas heart rate was not influenced significantly. Also after systemic administration of paraoxon (150--825 micrograms . kg-1), while peripheral muscarinic receptors were blocked, depressor effects were still observed. Dose-response curves for the depressor response to paraoxon were established. Infusion of low doses of dexetimide via the vertebral artery prevented the hypotensive action of paraoxon. The distribution of this antimuscarinic drug in the brain was investigated. The depressor effect of paraoxon can be attributed to both a decrease in peripheral resistance and cardiac output. Decerebration and midcollicular transection were carried out in order to elucidate the site and mechanism of action. The depressor effect of paraoxon seems to be mediated by a central mechanism of action located within the lower brain stem. It is concluded that stimulation of muscarinic receptors in the pontomedullary region gives rise to the observed changes in haemodynamic parameters. Muscarinic receptors in the hypothalamus seem to be of minor importance for the hypotensive action of paraoxon.