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Biomedical subjects

B E Waud

Publications and source records attributed to B E Waud.

15 recordsLinked to original sources
PubMed1985

Interaction among agents that block end-plate depolarization competitively.

The influence of gallamine, metocurine, pancuronium, and tubocurarine on depolarization of a mammalian muscle end-plate region was examined to determine whether the antagonists given in combination exerted a degree of block consistent with the simple classical competitive model. Depolarization was produced by carbachol in isolated guinea pig lumbrical muscles and recorded by the moving fluid electrode technique. The dose-response values obtained were fitted to a regression embedded in a split plot factorial experimental design such as both to control and to measure effects of variation among preparations, order of administration, time, and level of block. Of the six possible pairings of the four drugs, four showed the simple additivity expected from a competitive mechanism, while two (pancuronium plus metocurine and metocurine plus gallamine) showed potentiation beyond additivity. In these latter two pairs the combination shifted the carbachol dose-response curve, respectively, 41 and 21% further than predicted from the classical model. The significance of this deviation in the light of alternative receptor models is discussed, and a model consistent with the observed results is outlined.

Animals↗
PubMed1979

Effects of volatile anesthetics on directly and indirectly stimulated skeletal muscle.

Isolated guinea pig nerve-lumbrical muscle preparations were exposed to halothane, methoxyflurane, isoflurane, enflurane, fluroxene, and diethyl ether. The temporal courses of the effects on indirectly and directly elicited twitch responses were determined over a range of concentrations for each agent. When the anesthetics were compared at concentrations equivalent in terms of minimum alveolar concentration (MAC), a spectrum was observed in which halothane, methoxyflurane and isoflurane depressed the indirect twitch response at 3.5--5 MAC and the direct twitch response at 8--10 MAC. Diethyl ether and fluroxene depressed the indirect twitch response at 2--3.5 MAC and the direct twitch response at 3--6 MAC. Enflurane depressed the indirect response at 1.5--2.5 MAC and the direct response at 6--8 MAC. When the anesthetics were compared at concentrations equivalent in terms of their abilities to depress end-plate depolarization, however, all anesthetics were equipotent. Depression of the indirect twitch response occurred only when anesthetic concentrations were great enough to depress depolarization by 50 per cent.

Anesthetics↗
PubMed1979

Decrease in dose requirement of d-tubocurarine by volatile anesthetics.

Volatile anesthetics are known to decrease the requirements for neuromuscular blocking agents. To obtain a quantitative measure of the extent of this drug interaction, studies were performed on isolated guinea pig nerve--lumbrical muscle preparations exposed to methoxyflurane, halothane, isoflurane, diethyl ether, fluroxene, and enflurane in concentrations equal to MAC. From the relationship between indirect twitch height and d-tubocurarine concentration, the concentration depressing the twitch height by 50 per cent was determined. In the presence of MAC levels of anesthetic, the ED50 was decreased by the following fractional amounts: methoxyflurane, 0.311; halothane, 0.334; isoflurane, 0.335; diethyl ether, 0.462; fluroxene, 0.580; enflurane, 0.697. Comparison of the fractional decrease of d-tubocurarine dose requirement by an anesthetic at MAC and previously obtained values for the fractional depression of end-plate depolarization by an anesthetic at MAC showed that the more the anesthetic depresses depolarization, the smaller the d-tubocurarine dose requirement. Thus, clinically observed decreases in dose requirements may be explained by the effects of the anesthetics on chemosensitivity of the end-plate region.

Anesthetics↗
PubMed1977

Kinetic analysis of the AH8165-receptor interaction at the mammalian neuromuscular junction.

The effect of a new neuromuscular blocking agent, AH8165, on carbachol-induced end-plate depolarization was measured in isolated guinea pig lumbrical muscles. The results showed that the kinetics were competitive (parallel shift of dose-response curves to the right and a slope of Schild plot of 1.09 +/- 0.07) and the AH8165-receptor dissociation constant was estimated as 0.337 +/- 0.008 muM. Once the dissociation constant was known, the fraction of receptors occupied by any given concentration of AH8165 could be determined. This fractional receptor occupancy was then compared with the indirect twitch response in an isolated guinea pig nerve-lumbrical muscle preparation. These measurements of the effect of AH8165 on the margin of safety of neuromuscular transmission gave values comparable to those obtained with d-tubocurarine, i.e., the twitch remained normal until 75-80 per cent of the receptors were blocked and was abolished when 90-95 per cent of the receptors were occluded. Thus, the neuromuscular blocking action of AH8165 appears to be consistent with a simple postsynaptic competitive interaction with the transmitter.

Animals↗
PubMed1977

Potencies of neuromuscular blocking agents at the receptors of the atrial pacemaker and the motor endplate of the guinea pig.

Drug receptor dissociation constants (KB) were determined for four neuromuscular relaxants at the cardiac pacemaker as well as at the motor endplate. The ratios KB(atrium)/KB(lumbrical) were found to be high for d-tubocurarine and dimethyltubocurarine, 264 and 136, respectively. Thus, interaction at muscarinic sites would occur only with large doses of these drugs. In contrast, the ratios were low for pancuronium and gallamine, 5.3 and 2.4, respectively. Hence, the concentrations of these drugs needed for clinical neuromuscular blockade would occupy appreciable fractions of cardiac muscarinic receptors, and thus might produce vagal blockade and thereby produce the tachycardia seen clinically with these two agents.

Chemoreceptor Cells↗
PubMed1975

The effects of diethyl ether, enflurane, and isoflurane at the neuromuscular junction.

The actions of diethyl ether, enflurane, and isoflurane at the neuromuscular junction were examined in isolated guinea pig lumbrical muscles. These anesthetics depressed the ability of carbachol to depolarize the endplate region; this depression of depolarization did not show competitive kinetics. None of the anesthetics altered the affinity of the acetylcholine receptor for d-tubocurarine, i.e., the dissociation constant of d-tubocurarine was unchanged. Since diethyl ether, enflurane, and isoflurane produced no observable alteration of the receptor, the antagonism of the drug-induced depolarization of the neuromuscular junction appears to be exerted at a stage subsequent to reaction with the receptor. (Key words: Anesthetics, volatile, diethyl ethers; Anesthetics, volatile, euflurane; Anesthetics, volatile, isoflurane; Neuromuscular relaxants, d-tubocurarine; Neuromuscular junction.).

Acetylcholine↗
PubMed1975

Depolarization block and phase II block at the neuromuscular junction.

The effects of repeated doses of decamethonium or succinylcholine in muscles of the cat, dog, and rabbit have been examined. In particular, the relation of degree of neuromuscular block to intensity of the electrical change at the end-plate region has been found to be more consistent when the peak spatial gradient of depolarization is used as a measure of electrical effect than when the peak depolarization is used; the reason for this difference is discussed. A plot of twitch height against electrical change provides a convenient frame of reference for following the development of phase II block quantiatively. Examples presented show that the extent and kinetics of phase II block can vary considerably among species or among muscles in a given species.

Anesthesia, Intravenous↗
PubMed1975

In vitro measurement of margin of safety of neuromuscular transmission.

The margin of safety of neuromuscular transmission was measured in isolated guinea pig lumbrical muscles. Twitch height of an indirectly stimulated muscle was reduced stepwise by suitable concentrations of tubocurarine for comparison with the associated occlusion of receptors by the drug. Receptor occlusion was estimated from the effect of tubocurarine on carbachol depolarization measured extracellularly by the moving-fluid electrode technique. Roughly 75-80% of the receptor pool had to be blocked before the twitch height began to fall, and 90-95% had to be blocked before the twitch response was completely abolished. These results agree well with those found previously in vivo. Thus, the present results add further support to the earlier measurements. In particular, artifacts that might have been present because of the complex pharmacokinetic situation in vivo have been ruled out.

Animals↗
PubMed1975

A comparison of the potencies of a series of barbiturates at the neuromuscular junction and on the central nervous system.

The ability of a series of barbiturates to depress the depolarizing action of carbachol at the end-plate of guinea-pig lumbrical muscle was studied. The compounds studied were: amorbarbital, aprobarbital, barbital, barbituric acid, butabarbital, butalbital, dimethylbutylethyl barbituric acid, hexobarbital, mephobarbitak, secobarbital, thiamylal, and thiopental. The depressant activity was sensitive to small changes in structure of the compounds strongly suggesting that a specific receptor site was involved in the interaction of the drug with the tissue. The observed relative potencies on the motor end-plate were compared with their anesthetic potencies assayed on tadpoles. The two potencies went hand-in-hand for all the compounds studied, including the convulsant member of the series.

Animals↗