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Biomedical subjects

W F Riker

Publications and source records attributed to W F Riker.

16 recordsLinked to original sources
PubMed1992

Neuromuscular pharmacology in rat neonates: development of responsiveness to prototypic blocking and reversal drugs.

The neonatal pharmacology of neuromuscular drugs was studied in vivo in newborn rats and in vitro in neonatal phrenic nerve-hemidiaphragm preparations. Drugs used to probe neuromuscular development in rat neonates were physostigmine, edrophonium, neostigmine, 4-aminopyridine, d-tubocurarine (dTc), and succinylcholine. The prejunctional actions of these drugs were monitored in relation to neonatal age by the appearance of stimulus-evoked repetitive discharge initiated by motor nerve endings and the occurrence and magnitude of the resulting enhancement of twitch tension. The occurrence and incidence of drug-induced fasciculations also served to track the development of functional motor nerve endings. Each of these prejunctional actions was inoperative until the third neonatal week, indicative of incomplete motor nerve development. In contrast, 4-aminopyridine, a nonanticholinesterase, evoked these prejunctional actions in 1-wk-old rat neonates. Neostigmine and edrophonium antagonized dTc as early as the first week; presumably, postsynaptic maturation had reached a functional level. 4-Aminopyridine also antagonized dTc at week 1. Rat neonates showed resistance to dTc blockade when tested by neonatal phrenic nerve-hemidiaphragm preparations in vitro. Relationships between age and 85%-95% transmission block declined to the adult level by week 5. This result indicates that in rat neonates, pharmacodynamic rather than pharmacokinetic mechanisms predominate in the development of responsiveness to dTc.

4-Aminopyridine↗
PubMed1990

The interactions of ouabain with post-tetanic and facilitatory drug potentiations at cat soleus neuromuscular junctions in vivo.

Cat soleus motor nerve terminals, after high frequency conditioning, generate a post-tetanic repetition (PTR) which leads to a post-tetanic (PTP) of the muscle response. This property enables quantitative assessment of enhancement or depression of this nerve terminal excitability in vivo. The present study focuses on ionic mechanisms underlying the PTRs produced in this neuromuscular system either by high frequency stimulation or edrophonium. Ouabain was used as a specific probe for inhibition of Na(+)-K+ ATPase and its known consequences on Na+ and Ca2+ translocation. Ouabain pretreatment doubled the duration over which single stimuli, following either high frequency or edrophonium conditioning produced PTR. Ouabain in the doses used had no effect per se but as a function of dose augmented the frequency dependent responses. This pointed to Na+ loading of nerve terminals via high frequency stimulation plus ouabain inhibition of Na(+)-K+ ATPase. Ouabain potentiation of PTR responses evidently depends on exchange of intra-terminal sodium for external calcium. Thus, calcium entry blockers, Mn2+, and Co2+ suppressed or abolished the potentiations both before and after ouabain. Diphenylhydantoin, a Na+ and Ca2+ blocker, acted similarly. The effects of stimulation frequency, ouabain and the sequence of events leading to PTR in the soleus neuromuscular system appeared in general no different from those derived from the many in vitro microphysiologic studies of this phenomenon. Thus, EPPs were augmented and prolonged. It was concluded that intracellular Ca2+ is critical for regulating the stability of systems in which repetitive firing is both a normal and abnormal function.

Animals↗
PubMed1988

Motor nerve ending disorder in myasthenia gravis.

Mild myasthenia gravis patients were compared with normals with respect to the capacity of their motor nerve endings (MNEs) to generate a neostigmine-induced postactivation repetition (PAR). Dose-response analyses of PAR recorded from muscle electrically and by contractile measurement disclose a loss of this pharmacologic responsiveness in myasthenia. Since mild myasthenics transmitted nerve impulse trains of 20 to 200 Hz, as did normals, it was evident that PAR is transmitted insofar as it can be generated by MNEs. The dose-response analyses support this. These data indicate an MNE disorder in the disease.

Action Potentials↗
PubMed1986

Succinylcholine: mechanism of fasciculations and their prevention by d-tubocurarine or diphenylhydantoin.

Administration of d-tubocurarine (dTC) or diphenylhydantoin (DPH) was evaluated as a pretreatment to prevent succinylcholine (Sch) evoked fasciculations. Experiments were designed to determine the nature of the drug-drug interactions, sites of interaction, and site of fasciculation suppression. Sch is known to evoke repetitive discharge generation by motor nerve terminals (MNTs). Transmission of these prejunctional discharges causes fasciculations. A cat soleus neuromuscular preparation in situ, which enables recording of nerve action potentials initiated by MNTs, their transmitted muscle action potentials, and the resultant contractile responses, was used to explore Sch effects before and after iv pretreatment with dTC or DPH. dTC is known to act prejunctionally to suppress repetitive discharges initiated by facilitatory drugs and tetanic conditioning of MNTs. Accordingly, pretreatment with dTC 50 micrograms X kg-1 suppressed the Sch-induced MNT repetitive discharging and correspondingly suppressed generalized fasciculations without affecting twitch. This dTC dose, however, also reduced Sch blocking potency by 33%, slowed its rate, and shortened block duration. These latter effects represent competitive postjunctional antagonism. DPH is also known to suppress MNT repetitive discharging. Correspondingly, Sch-induced repetitive firing and ensuing fasciculations were suppressed by DPH (30 mg X kg-1) without affecting twitch. Unlike dTC, this DPH dose increased Sch blocking potency by 50%, increased the initial rate of block, and did not alter block duration. These DPH effects were dose-dependent and within the anticonvulsant range for cats. Therefore, patients with anticonvulsant levels of DPH may not require pretreatment before Sch.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Myokymia and impaired muscular relaxation with continuous motor unit activity.

We have studied two cases of the syndrome of myokymia and impaired muscular relaxation with continuous motor unit activity. Both patients complained of muscle twitching, weakness, stiffness, and hyperhydrosis during their illness. Myokymia was present over the entire body in both. On repetitive testing of muscle strength each patient showed initial fatigue followed by increasing strength as he continued his efforts. Both patinets improved on phenytoin therapy at high blood levels. Nerve conduction velocities were decreased. Electromyograms showed continuous electrical activity at rest which persisted during sleep and spinal anaesthesia but was diminished by curare. Intravital staining with methylene blue in one case demonstrated sprouting and beading of motor nerve terminals with multiple innervation of muscle fibres. The neurophysiological and pathological findings in these two cases indicate an abnormality of peripheral nerve in this disorder.

Adult↗
PubMed1978

The neuropathology of DFP at cat soleus neuromuscular junction.

The fine structure of the cat soleus neuromuscular junction was studied following a single intra-arterial injection of di-isopropylfluorophosphate (DFP) into the right femoral artery. DFP induced separate subacute and delayed morphologic changes in soleus non-myelinated motor nerve terminals. Three days after DFP administration motor nerve terminals were reduced in number. Subacute DFP damage was also noted in the subneural apparatus and in the immediate subjacent muscle. Both pre- and post-junctional subacute changes were resolved two weeks post-DFP. One week following this initial regeneration, soleus motor nerve terminals underwent a delayed transient degeneration, followed by reinnervation of damaged endplates 6--8 weeks following DFP. Quantitative analysis of methylene blue-stained intramuscular nerves indicated that both subacutely and chronically denervated soleus muscle fibres were reinnervated by regeneration of the original motor axon. Reinnervation by means of collateral sprouting was insignificant. This mechanism of reinnervation and the rapidity with which it occurred suggests that both subacute and delayed soleus motor nerve damage is initiated from local actions of DFP on the non-myelinated terminal. The subacute reaction probably results from a direct cytotoxic action of DFP at pre- and post-junctional sites. The delayed nerve terminal degeneration may also stem from an acute effect not immediately detrimental to nerve function.

Animals↗
PubMed1977

Effects of a single methylprednisolone dose on a facilitatory response of mammalian motor nerve.

Long-term glucocorticoid dosing directly enhances a facilitatory function of cat soleus motor nerve terminals. Posttetanic potentiation (PTP) of soleus contraction is a manifestation of this prejunctional facilitation. The present study demonstrates that the same enhancement of facilitation is produced with a single large intravenous dose methylprednisolone. The single dosing method, however, showed an initial suppression of facilitation that neared recovery in four hours. Thereafter, the characteristic augmentation of prejunctional facilitation emerged, peaking in 24 hours. Return to control required four days. Knowledge of this time course enabled centrally disconnected motor nerve endings to be identified as the site of both phases of the steroid action. Since the neuromuscular facilitation studied is equivalent to that triggered by neostigmine-like drugs, the results infer that the antimyasthenic effect of glucocorticoids may involve a direct action on motor nerve endings.

Animals↗
PubMed1977

Glucocorticoid effects on the edrophonium responsiveness of normal and degenerating mammalian motor nerve terminals.

An intensive short-term triamcinolone regimen in cats preserves the prejunctional actions of edrophonium in degenerating motor nerves. These edrophonium actions include the induction of a stimulus-dependent afterdischarge and the initiation of fasciculations. The relationship between fasciculations and stimulus-dependent afterdischarge is discussed. The glucocorticoid preservation of these edrophonium effects is like that previously reported for the preservation of posttetanic facilitation in motor nerves equally compromised. The results therefore show that glucocorticoid and facilitatory drug actions synergize to increase facilitation in degenerating but still functional motor nerves. This drug synergy is comparable to that which occurs in normal motor nerves. This interaction may provide a basis for effectively combining glucocorticoid and facilitatory drugs in the treatment of myasthenia gravis.

Animals↗
PubMed1975

Glucocorticoids and mammalian motor nerve excitability.

Short-term treatment of cats with high doses of triamcinolone and related steroids strikingly increased the capacity of soleus motoneurons to generate posttetanic stimulus-bound repetition (SBR) and the obligatory postetanic potentiation (PTP) of muscle. The edrophonium chloride (Tensillon)-induced SBR and twitch potentiation were likewise augmented. These effects reflect an increase in the excitability of the motoneuron. This glucocorticoid effect suggests that the motoneuron is the site of the antimyasthenic action of the hormone. Certainly, the enhanced SBR is a neuronal representation of the adverse epileptogenic action of the glucocorticoids. The glucocorticoid effect on motoneuron outlasts the dosing period, suggesting an underlying alteration in the neuron. Other glucocorticoids caused the same effects, but varied in their potencies. Mineralocorticoids were less effective. The single androgen that was tested proved to be minimally effective.

Animals↗
PubMed1975

Motor nerve terminal response to edrophonium in delayed DFP neuropathy.

A localized peripheral neuropathy was induced in cats with di-isopropyl fluorophosphate (DFP). Soleus nerve-muscle preparations, and the motor nerve terminals in particular, were evaluated for responsiveness to edrophonium (200 mug/kg i.v.). Potentiation of contractile strength was absent 24 hr after DFP, and showed a trend toward recovery 7-14 days post-DFP; it then fell to about 25% of normal 3 weeks following DFP administration. During the ensuing 5 weeks this aspect of edrophonium responsiveness was largely regained. The underlying post-drug repetition which gives rise to the potentiated responses was not demonstrable in either the nerve or muscle 3 weeks after DFP, but was again observed 8 weeks after poisoning. These findings suggest a delayed peripheral neuropathy indicative of a trophic deprivation and further illustrate a motor nerve terminal deficit as the initial function alteration in DFP neuropathy.

Action Potentials↗
PubMedDate not supplied

A benzodiazepine-anticholinergic drug synergism in the prevention of stress-induced gastric mucosal erosion in mice.

Chlordiazepoxide and clidinium each, as a function of dose, prevent stress-induced gastric mucosal erosion in mice. Clidinium was 2.5 times more potent than chlordiazepoxide. When used in a combination of 2 parts chlordiazepoxide and 1 part clidinium, the protective effect was nearly five times greater than that produced by clidinium alone. Furthermore, the combination dosing proved nearly three times more potent than the potency that was predicted from simple additivity of the individual drug effects. This potentiation appears related to the number of ways in which the combination treatment can decrease autonomic input to the gastric mucosa. Thus, the peripheral cholinergic blockade by clidinium may be potentiated by a central chlordiazepoxide suppression of both sympathetic and parasympathetic activities. Therefore, the combined use of these drugs in the therapy of stress-induced gastric disorder appears to have a rational pharmacologic basis.

Animals↗