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Biomedical subjects

A M SHANES

Publications and source records attributed to A M SHANES.

At least 19 recordsLinked to original sources

Membrane permeability: monolayer relationships.

A model of permeation of living membranes is proposed in which penetration by polar molecules takes place through islands composed of limited numbers of lipoidal molecules in a state comparable to that of certain compressed monolayers. These islands are visualized as scattered within a rigid, relatively impervious matrix. Relationships for penetration of monolayers by gases have been applied to this membrane model. Calculations on this basis demonstrate that the permeabilities relative to water are described at least as well by this model as by that assuming rigid pores of 4.25 A radius.

Cell Biology↗

Quantitative molecular approach to the permeability changes of excitation.

Functional relationships, available from only a few monolayer studies, can be applied to a relatively simple model of the excitable membrane to give permeability-potential curves quite similar to the conductance-potential curves obtained experimentally in voltage-clamped giant axons. Contrary to the usual view in terms of "carrier systems," the present model considers the permeability to sodium and potassium to be reduced by the increase in the surface pressure induced by large lipophilic cations and anions in the outer layer of the lipoidal bimolecular leaflet constituting the living membrane; hence, the increase in permeability during depolarization, for example, is due to a decrease in the amount of the organic anions in this layer, whereas the decrease in sodium permeability during inactivation is caused by a rise in content of organic cations. The present proposal has the advantage that it is in keeping with known phenomena observed in simple physico-chemical systems as well as in excitable systems; moreover, the current actually transferred by the postulated lipophilic ions can be negligible compared to that transferred by the inorganic cations they control. The latter situation, as well as the steepness of the permeability-potential relationships obtained, have been pointed out to be critical requirements of a satisfactory molecular hypothesis.

Axons↗

Calcium flux and contractility in guinea pig atria.

The calcium in guinea pig atria can be divided into three components by kinetic studies with Ca(45): (a) a rapidly exchangeable fraction with a half-time of 4.5 minutes; (b) a slowly exchangeable fraction with a half-time of 86 (or 168) minutes; and (c) an inexchangeable fraction. In Krebs-Henseleit solution containing 2.5 mM calcium, the calcium content of the tissue at rest remains constant, the flux being about 0.02 micromicromol/cm(2)-second. An increase or a decrease in extracellular calcium concentration by 1.25 mM causes a proportionate change in influx. A large increase in Ca(45) entry, equivalent to as much as 0.55 micromicro/mol/cm(2) accompanies a contraction. When the strength of contraction is varied by stimulating at different frequencies or in solutions containing calcium at different concentrations, the increment of Ca(45) uptake per beat changes proportionally with the strength of the beat. Total atrial calcium is not increased by stimulation; however, the increase in outflux of Ca(45) during contraction that this constant tissue calcium implies could not be demonstrated under the experimental conditions employed. The observations are discussed in the light of the possible role of calcium transfer in excitation-contraction coupling.

Calcium↗

Radiocalcium release by stimulated and potassium-treated sartorius muscles of the frog.

Stimulation of frog (Rana pipiens) sartorius muscle accelerates release of Ca(45), but only during the period of stimulation. No appreciable difference is obtained in the calcium released per impulse whether stimulation is at a rate of 20/sec. or 0.5/sec. However, prior stimulation may appreciably increase the loss per impulse. In unfatigued muscles, the minimum amount of calcium liberated during an isotonic twitch is estimated to be about that previously calculated to enter, viz. 0.2 micromicromole/cm(2). The time course of radiocalcium release during potassium depolarization depends on the nature of the contracture. When contracture is isometric, the rate of escape is doubled and declines only slowly; if isotonic, the rate is quadrupled but declines in a few minutes to a level maintained at about double that before potassium. The minimal calcium release during the first 10 minutes of potassium treatment is estimated to be about the same in both cases and about one-half to one-third the uptake. This, and especially the close equality of calcium entry and exit during electrical stimulation, are pointed out as not necessarily inconsistent with a transitory net entry of calcium, comparable to the influx, into restricted regions of the individual fibers.

Animals↗

Interactions of veratrum alkaloids, procaine, and calcium with monolayers of stearic acid and their implications for pharmacological action.

The interactions of veratridine, cevadine, veracevine, and veratramine with monolayers of stearic acid show marked differences. Veratridine and cevadine, at concentrations that are known from potential, ionic flux, and other measurements to affect living membranes, react strongly with the film and appear to cause an "interfacial dissolution" whereby both the alkaloid and the stearate leave the surface. Veracevine at the same concentration does not interact with the film. The veratramine reaction is weak, much like that of the local anesthetic procaine. The veratridine and cevadine effects are antagonized by 10(-3)M Ca(++), low pH, and 3.7 and 7.4 x 10(-3)M procaine. These differences among the veratrum alkaloids and the antagonisms parallel effects observed in living systems. Such parallelism suggests that similar physical interactions are involved in the stearate film and in natural membranes.

Anesthetics, Local↗

Antagonism of veratrine by calcium ion in monolayers of stearic acid.

Force-area diagrams for monolayers of stearic acid on Ringer's solution demonstrate a competition between veratrine and calcium for carboxyl groups of the films. The competition occurs at customary concentrations. Local anesthetics act quite differently. The interactions suggest those observed less directly in living cells and therefore indicate that such surface films may serve as models for the study of drug and ion effects.

Calcium↗

The distribution and kinetics of release of radiocalcium in tendon and skeletal muscle.

The distribution of Ca(45) in frog (Rana pipiens) sartorius muscle, after 4 hours' exposure to Ringer's solution containing radiocalcium, has been analyzed by observing the kinetics of escape of the radioisotope into a non-radioactive Ringer's solution with calcium present or absent and by assuming that the tendon of Achilles is a satisfactory model of the extent of the uptake and release of Ca(45) by the interstitial connective tissue (c.t.). In a Ringer's solution containing 1 mM/liter calcium, the exchangeable calcium distribution in micromoles per gram wet weight is as follows: (a) Aqueous phase of c.t. space: 0.16; (b) bound to c.t.: 0.16; (c) bound to surface of fibers: 0.13, of which 0.03 is displaced only by self-exchange, whereas the rest, as in c.t., can be displaced by other ions; and (d) in myoplasm: 0.33. The kinetics of Ca(45) exit suggests that in infinite time of exposure to Ca(45) the myoplasmic component would rise to 0.85. In the muscles, the half-time of the quickly emerging Ca(45) averages about 3 minutes, whereas the time constant of the slowly released component is about 500 minutes. In the tendons the percentage rate of escape falls exponentially, the half-time of emergence being about 10 minutes.

Animals↗

Anesthetic and calcium action in the voltage-clamped squid giant axon.

Changes in spike configuration and in the inward and outward currents of voltage-clamped axons agree in indicating that the increases in permeability to sodium and potassium ions during activity are depressed by procaine and cocaine and augmented by calcium. At low levels of depolarization, the effect of the multivalent ion is similar to that of the local anesthetics, in keeping with their similar effects on the threshold of excitability. The reduction of membrane conductance at rest requires a higher concentration of the drugs than that needed to affect the increase in permeability with activity.

Anesthetics, Local↗

Calcium influx in skeletal muscle at rest, during activity, and during potassium contracture.

Calcium influx in the sartorius muscle of the frog (Rana pipiens) has been estimated from the rate of entry of Ca(45). In the unstimulated preparation it is about equal to what has been reported for squid giant axons, but that per impulse is at least 30 times greater than in nerve fibers. The enhanced twitch when NO(-) (2) replaces Cl(-) in Ringer's is associated with at least a 60 per cent increase in influx during activity, whereas this anion substitution does not affect the passive influx significantly. Calcium entry during potassium contracture is even more markedly augmented than during electrical stimulation, but only at the beginning of the contracture; thus, when a brief Ca(45) exposure precedes excess K(+) application, C(45) uptake is increased three- to fivefold over the controls not subjected to K(+), whereas when C(45) and K(+) are added together, no measurable increase in Ca(45) uptake occurs. These findings are in keeping with the brevity of potassium contracture in "fast (twitch)" fibers such as in sartorius muscle.

Calcium↗

The influence of high hydrostatic pressure on cocaine and veratrine action in a vertebrate nerve.

The application of high hydrostatic pressure to toad sciatic nerve causes a gain in sodium and a loss of potassium which are not affected by cocaine. However, cocaine action is enhanced by high pressure when counteracting veratrine depolarization and when blocking the action potential. Various effects of elevated pressure on the after-potentials are presented and the role of ions in these processes is discussed.

Action Potentials↗