Effects of a new centrally acting muscle relaxant, NK433 (lanperisone hydrochloride) on spinal reflexes.

(-)-(R)-2-methyl-3-(1-pyrrolidinyl)-4'-trifluoromethylpropiophenone++ + monohydrochloride, lanperisone hydrochloride (NK433) administered intravenously or orally depressed the mono- and polysynaptic reflex potential, dorsal root reflex potential, flexor reflex mediated by group II afferent fibers, patellar and flexor reflexes. These effects were reduced by spinal transection. NK433 inhibited the facilitation of the flexor reflex mediated by group II afferent fibers that was induced by intrathecal administration of noradrenaline-HCl. (+)-(1R,2R)-2-methyl-3-(1-pyrrolidinyl)-1-(4-trifluoromethylphenyl)-1-pr opanol (LPS-9)-HCl, a metabolite of NK433, also inhibited the spinal reflexes. Given orally, NK433 had effects more than three times stronger and tending to be longer-lasting than those of eperisone-HCl. These results suggest that NK433 exerts a non-selective inhibition on spinal reflexes and that inhibition of the descending noradrenergic tonic facilitation within the spinal cord is involved in the mechanism of spinal reflex depression by NK433. LPS-9 could contribute to the potent activity of NK433 after oral administration.

[Effectiveness of NKH477, a novel forskolin derivative, in rat cardiac preparations with desensitized beta-adrenoceptors].

Effects of prolonged noradrenaline infusion on the density of cardiac beta-adrenoceptors, phosphodiesterase (PDE) and adenylate cyclase (AC) activities, and the ability of NKH477, 6-(3-dimethylaminopropionyl) forskolin hydrochloride, to increase tension development and heart rate were studied in rat cardiac preparations. Noradrenaline infusion (400 micrograms/kg/hr, s.c.) for 7 days significantly decreased cardiac beta-adrenoceptor density (Bmax), whereas the binding affinity (Kd) of the ligand was unchanged. The basal cardiac PDE activity was increased in treated rats, whereas there was no difference in the basal cardiac AC activity between treated and untreated rats. Significant decreases in basal developed tension and heart rate were observed in the left and right atrial muscles from treated rats, respectively. The positive inotropic and chronotropic potencies of NKH477 were unaffected by noradrenaline infusion, whereas the positive inotropic potencies of isoproterenol and 3-isobutyl-1-methylxanthine were significantly reduced. Thus, NKH477 appears to be superior to beta-adrenoceptor agnosits or PDE inhibitors as a cardiotonic drug in the treatment of heart failure accompanied by beta-adrenoceptor downregulation.

Effects of 6-(3-dimethylaminopropionyl)forskolin hydrochloride on energy metabolism in dog hearts in situ.

The effect of NKH477 (6-(3-dimethylaminopropionyl)forskolin hydrochloride, CAS 138605-00-2) [formula: see text], a newly developed forskolin derivative, on mechanical function, carbohydrate metabolism and energy metabolism was examined in the dog heart, and compared with that of dobutamine. Intravenous injection of NKH477 (10 or 30 micrograms/kg) or dobutamine (1 or 3 micrograms/kg) increased the maximum rate of rise of left ventricular pressure (LVdP/dtmax), producing a positive inotropic effect. The duration of the effect of NKH477 was longer than that of dobutamine. In addition, NKH477 (10 or 30 micrograms/kg) increased heart rate (positive chronotropic effect). Nevertheless, neither NKH477 (10 or 30 micrograms/kg) nor dobutamine (1 or 3 micrograms/kg) modified the tissue levels of adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, creatine phosphate and lactate. Glycolytic flux (as expressed by the ratio of ([glucose-6-phosphate] + [fructose-6-phosphate]) / [fructose-1,6-diphosphate]) and redox state (as expressed by the ratio of [lactate] / [pyruvate]) in the myocardial cells were not influenced by NKH477 (10 or 30 micrograms/kg) or dobutamine (1 or 3 micrograms/kg). These results suggest that NKH477 produces both positive inotropic and positive chronotropic effects, while it does not interfere with the myocardial energy and carbohydrate metabolism.

Effects of NK433, a new centrally acting muscle relaxant, on masticatory muscle reflexes in rats.

The effects of (-)-(R)-2-methyl-3-(1-pyrrolidinyl)-4'- trifluoromethylpropiophenone monohydrochloride (NK433), a novel centrally acting muscle relaxant, on masticatory muscle reflexes were investigated in rats. NK433 inhibited the monosynaptic tonic vibration reflex of the masseter muscle and the polysynaptic tonic periodontal masseteric reflex. These reflexes are increased by gamma-motor activity. NK433 had a weak inhibitory effect on the polysynaptic jaw opening reflex evoked by electrical stimulation of the tooth pulp, which is little related with gamma-motor activity. Eperisone-HCl depressed the three types of masticatory muscle reflexes. When intravenously administered, eperisone-HCl was equipotent to NK433, but the effect of eperisone-HCl was shorter-lasting than that of NK433. The effect of intragastrically administered NK433 on the periodontal masseteric reflex was about three times stronger than that of eperisone-HCl. These results suggest that NK433 inhibits masticatory muscle reflexes controlled by the gamma-motor system and thus may ameliorate the temporomandibular joint syndrome in man.

Pharmacological properties of NK433, a new centrally acting muscle relaxant.

The pharmacological properties of NK433 ((-)-(R)-2-methyl-3-(1-pyrrolidinyl)-4'-trifluoromethylpropiophenone+ ++ monohydrochloride), a novel muscle relaxant, were investigated. NK433 inhibited intercollicular decerebrate rigidity (gamma-rigidity) and anemic decerebrate rigidity (alpha-rigidity) dose dependently. NK433 was stronger in inhibiting gamma-rigidity than alpha-rigidity. NK433 inhibited the increase in muscle spindle discharges induced by pinna pinching (gamma-activity) without affecting muscle spindle discharges or neuromuscular transmission. At muscle relaxant doses in decerebrate rigidities, NK433 did not affect the muscle tone induced by morphine-HCl nor that of normal animals. These results suggest that NK433 selectively depresses the excessive muscle tone of decerebrate rigidities through its effects on the central nervous system, and inhibition of gamma-activity causes a preferential depression of gamma-rigidity in comparison to alpha-rigidity. In i.v. experiments, the effects of NK433 on decerebrate rigidities were similar to those of eperisone-HCl and tolperisone-HCl, but in p.o. experiments, NK433 was at least 3 times as potent as eperisone-HCl and tolperisone-HCl.

The effects of centrally acting muscle relaxants on the intrathecal noradrenaline-induced facilitation of the flexor reflex mediated by group II afferent fibers in rats.

The effects of centrally acting muscle relaxants on the flexor reflex mediated by group II afferent fibers (group II flexor reflex) in anesthetized intact rats and on the intrathecal noradrenaline-HCl-induced facilitation of the group II flexor reflex in anesthetized spinal rats were investigated. In anesthetized intact rats, mephenesin, tolperisone-HCl, chlorpromazine-HCl and baclofen inhibited the group II flexor reflex dose-dependently, whereas the inhibitory effect of tizanidine-HCl was bell-shaped. The effect of diazepam tended to be saturated. In anesthetized spinal rats, mephenesin, tolperisone-HCl, chlorpromazine-HCl, diazepam and baclofen also depressed the group II flexor reflex, but tizanidine-HCl slightly increased it. The intrathecal noradrenaline-HCl-induced facilitation of the group II flexor reflex was not affected by mephenesin or diazepam, but was inhibited by tizanidine-HCl, tolperisone-HCl, chlorpromazine-HCl and baclofen. These results suggest that compounds with centrally acting muscle relaxant activity depress the group II flexor reflex in different manners, and the inhibition of descending noradrenergic tonic facilitation within the spinal cord participates in the depressant action of the group II flexor reflex produced by tolperisone-HCl, tizanidine-HCl, chlorpromazine-HCl and baclofen.

Intrathecal noradrenaline facilitates and inhibits the flexor reflex mediated by group II afferent fibers via alpha 1- and alpha 2-receptors, respectively.

The effects of intrathecal noradrenaline (NA) on the flexor reflex mediated by group II afferent fibers (group II flexor reflex) were investigated in anesthetized spinal rats. Low doses (0.01 and 0.1 mumol) of NA-HCl inhibited the group II flexor reflex, while high doses (1 and 10 mumol) facilitated it. In rats pretreated with the selective alpha 2-antagonist yohimbine-HCl (0.1 mumol), the effect of NA-HCl (0.1 mumol) shifted from inhibition to facilitation. Intravenous administration of prazosin-HCl (0.1 and 1 mg/kg, i.v.), a selective alpha 1-antagonist, dose-dependently antagonized the facilitation of the group II flexor reflex induced by NA-HCl in rats pretreated with yohimbine-HCl. The selective alpha 1-agonist methoxamine-HCl (1 mumol) and the alpha 2-agonist clonidine-HCl (0.1 mumol) facilitated and inhibited the group II flexor reflex, respectively. The effects of clonidine-HCl and methoxamine-HCl were almost the same as those of NA-HCl at doses of 0.1 and 10 mumol, respectively. NA-HCl (1 and 10 mumol) and methoxamine-HCl (1 mumol) increased the spontaneous electromyogram (EMG) spikes of the muscle tibialis anterior. The time course of the increase in the spontaneous EMG spikes was similar to that observed in the group II flexor reflex. These results suggest that NA facilitates and inhibits the group II flexor reflex via alpha 1- and alpha 2-receptors, respectively, and one of the mechanisms of the facilitatory effects is the elevation of excitability of the alpha-motoneuron.

The flexor reflex mediated by group II afferent fibers: effects of morphine-HCl and mephenesin.

The effects of morphine-HCl and mephenesin on the flexor reflex mediated by group II afferent fibers were investigated. The flexor reflex was recorded by means of the electromyogram (EMG) evoked in the muscle tibialis anterior by stimulation of the ipsilateral tibial nerve in urethane-alpha-chloralose anesthetized rats. Afferent volleys corresponding to the phasic EMG component of the flexor reflex with 7.6-msec latency (flexor EMG: fEMG) were also recorded using the double volley technique. The threshold of the afferent volleys mediating the fEMG was approximately twice as high as that of the most excitable afferent volleys, which were considered the spikes of group I afferent fibers, and the conduction velocity of the afferent volleys was 39.9 +/- 3.2 m/sec. Morphine-HCl (5 mg/kg, i.v.) did not change the amplitude of the fEMG, but mephenesin (40 and 80 mg/kg, i.v.) depressed it dose-dependently. These results suggest that the fEMG is a flexor reflex mediated by group II afferent fibers, which is not affected by morphine-HCl but depressed by mephenesin.