Physiological limitations to underwater exploration and work.
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Administration, Inhalation↗
Biomedical subjects
P B Bennett
Publications and source records attributed to P B Bennett.
Nonstationary fluctuation analysis of the delayed rectifier K channel in cardiac Purkinje fibers. Actions of norepinephrine on single-channel current.
We have studied the large increase in macroscopic potassium channel current caused by catecholamines in mammalian cardiac cells. An increase in macroscopic K current could result from either an increase in the single-channel current or by an increase in the number of channels that are open. Therefore, we have measured nonstationary potassium current fluctuations under voltage clamp conditions to determine whether norepinephrine increases the current through this channel. The single-channel current (at a potential of -30 mV in 4 mM external [K]) was estimated to be 3.7 pA and was not altered by concentrations of norepinephrine up to 2 microM. The spectral density of the current fluctuations were fitted well by a sum of 2 Lorentzians with corner frequencies that correspond with the measured time constants for deactivation of the macroscopic K current tails. We conclude that the increase in macroscopic K current caused by norepinephrine in these cells is not the result of an increase in single-channel conductance and therefore must involve an increase in the number of open K channels.
Animals↗
Temperature and voltage dependence of sodium channel blocking and unblocking by O-demethyl encainide in isolated guinea pig myocytes.
O-demethyl encainide (ODE) is a metabolite of encainide with potent antiarrhythmic effects. We studied block of sodium channels by ODE in isolated guinea pig ventricular myocytes, using both direct measurement of whole cell sodium current and Vmax. Specifically, we examined whether block by ODE was use-dependent, whether ODE blocked activated or inactivated channels, and whether ODE's effect depended on membrane potential. At cold temperatures (15-20 degrees C), ODE was a potent blocker of activated cardiac sodium channels, with little or no effect on inactivated channels. At these temperatures, there was no detectable diastolic recovery from block. Repeated depolarizations produced use-dependent unblocking, which increased as the holding potential was made more negative. At warmer temperatures, use-dependent unblocking was increased, the availability curve of sodium channels for use-dependent unblocking was less shifted toward negative potentials, and diastolic recovery from block became detectable, albeit slow (tau approximately 25 s). Our findings demonstrate that electrophysiologic effects of agents such as ODE may be both quantitatively and qualitatively different at cold temperatures than at normal body temperature. One should be cautious about extrapolating electrophysiologic data obtained at cold temperatures to clinical situations.
Anilides↗
Effect of epidural lidocaine on spinal cord blood flow.
The effect of epidural lidocaine on spinal cord blood flow (SCBF) was measured in mongrel dogs. Spinal evoked potentials were used to measure spinal cord conduction and enabled us to time the measurement of SCBF associated with maximum reduction in latency and amplitude of spinal evoked potentials produced by instillation of 5 ml of 2% lidocaine in the epidural space. We used the radioactive microsphere technique to quantitate SCBF in the cervical, upper thoracic, lower thoracic, and lumbar regions of the spinal cord. A narcotic/relaxant technique was used to eliminate SCBF changes associated with other anesthetic agents. Other parameters known to affect SCBF were kept constant and within normal physiologic values. As compared with saline solution controls, there were significant decreases in SCBF in all the four areas of spinal cord in animals given epidural lidocaine, most marked in the lumbar area.
Anesthesia, Epidural↗
Competition between lidocaine and one of its metabolites, glycylxylidide, for cardiac sodium channels.
The modulated receptor hypothesis states that sodium channels have a specific receptor for antiarrhythmic drugs. Therefore, two agents that block sodium channels by binding to this receptor are expected to compete for occupancy. Glycylxylidide (GX) is a deethylated metabolite of lidocaine that accumulates in patients on lidocaine therapy. In single, voltage-clamped cardiocytes, GX, like lidocaine, blocked cardiac sodium channels in a use-dependent manner. However, its kinetics of recovery from block were markedly different from lidocaine: at potentials between -80 and -100 mV, GX-blocked channels recovered faster and more completely than lidocaine-blocked channels but recovered more slowly at more negative potentials (-120 to -140 mV). If lidocaine and GX compete for a common receptor, then there are conditions in which addition of a "faster" drug to a "slower" drug will produce less block than the slower drug alone. At potentials between -120 and -140 mV, addition of GX (slower drug) to lidocaine always increased the level of block, but addition of lidocaine to GX decreased the block in four of nine experiments and did not increase it in three of nine experiments. Conversely, at potentials between -80 and -100 mV, addition of lidocaine (slower drug) to GX always increased block, whereas addition of GX to lidocaine reduced the level of block in five of 16 experiments and did not increase it in seven of 16 experiments. Thus, upon addition of more blocker, the sodium current increased in 36% of cases or did not decline in 76% of cases. These results can be explained by the modulated receptor hypothesis with two drugs competing for the same receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Quinidine delays IK activation in guinea pig ventricular myocytes.
A major action of the antiarrhythmic agent quinidine is prolongation of cardiac repolarization. In these experiments, the time-dependent effects of quinidine on the delayed rectifier potassium current, IK, a current contributing to cardiac repolarization, were investigated in acutely disaggregated guinea pig ventricular myocytes using the whole-cell recording configuration of the patch-clamp method. The effect of quinidine on IK was dependent on the duration of depolarization. After long (2,000 msec) pulses, IK was reduced by 30 +/- 27% (SD; n = 8, paired) by 10 microM quinidine; in contrast, after short (100 msec) pulses, the drug decreased IK 65 +/- 35% (p less than 0.05). This effect was found both in paired experiments as well as when quinidine-pretreated cells were compared to non-pretreated cells. Quinidine significantly delayed IK activation (9 +/- 20 msec at baseline vs. 44 +/- 25 msec in drug, p less than 0.05), but did not alter the subsequent time course of activation (time constant 659 +/- 118 msec). These findings are consistent with the hypothesis that quinidine promotes occupancy of a channel state from which opening does not occur.
Animals↗
Block and enhancement of cardiac ion channel currents by des-oxo-amiodarone.
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Amiodarone↗
Rat brain catecholamine release at 1, 10, 20, and 100 ATA heliox, nitrox, and trimix.
The pattern of neurotransmitter release in the rat caudate and hypothalamus was studied following exposure to pressure in combination with various gas mixtures. The caudate was selected for its control of extrapyramidal motor output. The hypothalamus was studied because of its involvement in autonomic responses. The neurotransmitters chosen for study were norepinephrine (NE) and dopamine (DA). Change of neurotransmitter concentration from control values and neurotransmitter turnover rate were chosen as measures of neuronal activity in the selected brain regions. Exposure to 100 ATA heliox resulted in a significant (P less than 0.05) increase in hypothalamic DA concentrations; however, NE concentrations remained relatively unchanged. One hundred ATA heliox produced the opposite effect on caudate DA concentrations; these values dropped to 1% of chamber control values. High partial pressures of nitrogen as seen with 100 ATA trimix and 20 ATA nitrox resulted in significant decreases in both DA and NE concentrations (both P less than 0.05) in the hypothalamus. These same exposures also produced significant decreases in DA concentrations in the caudate (P less than 0.05). Regional (caudate vs. hypothalamus) changes in neurotransmitter release in response to different pressures and/or gas mixtures may offer explanations for the physiologic and neurologic changes observed during nitrogen narcosis and high pressure nervous syndrome.
Animals↗
Catecholamines modulate the delayed rectifying potassium current (IK) in guinea pig ventricular myocytes.
The effects of isoproterenol and norepinephrine on the delayed, outward potassium current, IK, were tested in single, dialyzed guinea pig heart cells where complications from a restricted extracellular space are minimized and internal K concentration is controlled. The average IK reversal potential in control cells was -80 +/- 2.1 mV (N = 4; [K]o = 4.5 mM; [K]i = 120 mM) indicating a high degree of K selectivity (PNa/PK less than or equal to 0.01). In paired experiments, both isoproterenol and norepinephrine increased IK without changing the reversal potential, indicating that the selectivity of the channels is not altered by these agents. The results explain the shortening of action potential duration observed at high concentrations (Quadbeck and Reiter, 1975); and suggest that an increase in IK by catecholamines may serve to limit the degree of calcium current-induced action potential prolongation during increased sympathetic tone and rapid heart rates.
Action Potentials↗
Evaluation of the efficacy and tolerance of the antiarrhythmic agent transcainide (R 54718).
The antiarrhythmic efficacy of transcainide has been studied in 41 patients. It abolished ventricular arrhythmias in 10 out of 12 patients after i.v. administration and in 11 out of 14 after oral administration. It also reduced ventricular arrhythmias during recovery from exercise. The maximum intravenous dose prolonged the PR-interval by 43% and QRS-duration by 37%. Side-effects observed in 6 out of 41 patients included Mobitz Type I AV block, complete bundle branch block, hypotension and increased arrhythmia frequency. Transcainide is a promising new antiarrhythmic drug which should be used with caution in patients with conduction disorders and impaired cardiac function. Its value and safety in the chronic oral treatment of life-threatening arrhythmias remains to be established.
Administration, Oral↗
Sodium channel block by a potent, new antiarrhythmic agent, transcainide, in guinea pig ventricular myocytes.
Transcainide is a new lidocaine analog that has been shown to suppress a range of cardiac arrhythmias in an initial clinical trial. We have evaluated the effects of transcainide on sodium channel current in guinea pig ventricular myocytes using the whole-cell patch-clamp technique. Reduction of sodium current by transcainide was concentration dependent, with an ED50 of approximately 0.5 microM (n = 9). This reduction of the sodium current exhibited little use dependence, and block did not accumulate even after 10-Hz pulse trains. Moreover, little or no recovery from block was observed even when cells were hyperpolarized to -160 mV for 1 min. We observed no reversal of sodium channel block after superfusing cells up to 1 h in drug-free solution. Thus, transcainide, unlike many other clinically useful antiarrhythmic agents, blocked sodium channels with very little time dependence or voltage dependence. These novel electrophysiological properties of transcainide may endow the agent with a unique spectrum of efficacy against certain arrhythmias. At the same time, the great potency of transcainide and its lack of reversibility, at least within an hour, mandate that the drug should be used with great caution.
Animals↗
Use of EEG digital filtering and display for HPNS diagnosis.
Divers show symptoms of a condition known as the high pressure nervous syndrome (HPNS) at depths greater than about 180 m. A symptom that possibly lends itself to an objective diagnosis is a change in the frequency content of the EEG signal with increased slow wave (theta, 4-8 Hz) and decreased fast wave (alpha, 8-13 Hz) activity. Therefore, a method was developed, first, to obtain the power in the EEG frequency bands by digital filtering and, second, to display band-indices and ratios during a dive, in a format suitable for rapid appraisal. The formulas for the cascaded 2nd order Butterworth bandpass filters are given together with the corresponding FORTRAN program. EEG signals from 3 subjects taped during the Duke University Atlantis IV dive to a depth of 650 m were analyzed and displayed by the above method as well as by a Fast Fourier Transfer signal analyzer. The results suggest the theta: alpha ratio, which is a one-parameter EEG evaluation in the frequency domain, is a valuable descriptor for the objective HPNS diagnosis.
Computers↗
Delayed rectification in the calf cardiac Purkinje fiber. Evidence for multiple state kinetics.
We have investigated the delayed rectifier current (Ix) in the calf cardiac Purkinje fiber using a conventional two-microelectrode voltage clamp arrangement. The deactivation of Ix was monitored by studying decaying current tails after the application of depolarizing voltage prepulses. The reversal potential (Vrev) of these Ix tails was measured as a function of prepulse magnitude and duration to test for possible permeant ion accumulation- or depletion-induced changes in Vrev. We found that prepulse-induced changes in Vrev were less than 5 mV, provided that prepulse durations were less than or equal to 3.5 s and magnitudes were less than or equal to +35 mV. We kept voltage pulse structures within these limits for the remainder of the experiments in this study. We studied the sensitivity of Vrev to variation in extracellular K+. The reversal potential for Ix is well described by a Goldman-Hodgkin-Katz relation for a channel permeable to Na+ and K+ with PNa/PK = 0.02. The deactivation of Ix was always found to be biexponential and the two components shared a common reversal potential. These results suggest that it is not necessary to postulate the existence of two populations of channels to account for the time course of the Ix tails. Rather, our results can quantitatively be reproduced by a model in which the Ix channel can exist in three (two closed, one open) conformational states connected by voltage dependent rate constants.
Animals↗
Central and peripheral causes of hyperreflexia in humans breathing 5% trimix at 650 m.
To clarify the mechanism of increased stretch reflex responsiveness in deep divers (hyperbaric hyperreflexia), comparative studies of stretch (T) and Hoffmann (H) reflexes were done on three men breathing 5% N2-0.5 bar O2-balance He at pressures up to 650 m of seawater (msw) (Atlantis IV simulated dive, F.G. Hall Laboratory, Duke Medical Center). Electromyography revealed increases at depth of up to 160% in the T reflex recruitment ratio (T reflex/Mmax) compared with surface controls. The H reflex recruitment ratio (Hmax/Mmax) did not change significantly. It is concluded that hyperbaric hyperreflexia is mainly due to increased muscle spindle sensitivity, presumably arising as a central effect on gamma-motoneuron activity. However, a purely peripheral effect of pressure on the spindle end-organ itself is not ruled out. Increases of 100-200% in muscle twitch peak force are reported and provide evidence that pressure can act directly on peripheral physiology. Postreflex clonic potentials (rebounds) during voluntary plantar flexion were significantly increased both in amplitude and number, leading to sustained clonus in one subject. In this respect, 5% N2 was less effective than 10% N2 of Atlantis III in controlling underdamping of the reflex loop. Conversely, the twitch contraction rate and clonic frequency in this study were only half as slowed compared with results from the earlier dive.
Central Nervous System↗
Effects of halothane and hydrostatic pressure on sodium channels in squid axon.
The effects of halothane and hydrostatic compression have been studied on the voltage-dependent sodium conductances in the squid giant axon. Compression to 150 atmospheres reduced the time course of both the activation and inactivation phases of the sodium current, reduced the amplitude of the peak inward current, and shifted the sodium reversal potential in a slightly hyperpolarizing direction. Halothane also depressed the sodium current amplitude and shifted the reversal potential but did not alter the membrane kinetics. Subsequent compression to 100 ATA did not restore the inward current flux to its control value, nor reverse the shift in the sodium reversal potential. We conclude that pressure and halothane do not act antagonistically at common sites in this preparation.
Animals↗
EEG and evoked potential changes during gas- and liquid-breathing dives to 1000 msw.
To test the hypothesis that compression in helium gas and compression without gas (hydrostatic compression) both produce the same neurological symptoms of high pressure nervous syndrome (HPNS), groups of 4 to 5 dogs were exposed to one of the following: (a) a 2-h surface control breathing He-O2 gas; (b) compression to 700-1000 msw breathing He-O2 gas; (c) a 2-h liquid-breathing control [ventilation with warmed (38 degrees C), oxygenated fluorocarbon liquid, FC-80]; and (d) "near hydrostatic" compression to 700-1000 msw while being ventilated with liquid from a sealed reservoir. Power spectra obtained from scalp-recorded EEG signals revealed a significant compression-related shift of power from the normally dominant 5-8 Hz band to the 8-11 Hz band. This effect was greatest at 600 msw and occurred equally in both dive groups. At very high pressures (greater than 900 msw) power in this 6-10 Hz range became reduced whereas 16-22 Hz activity increased as the EEG flattened. Somatosensory evoked potentials (SEPs) were elicited by subdermal electrical stimulation in the foreleg (n = 120). The latency of P1 (approximately 31 ms) did not change in any group; transmission time to cortex was unaltered by time or pressure. However, the "late-wave" P4 (approximately 250 ms) was slowed by 32-35 ms at 1000 msw in both groups (P less than 0.003 in He-O2). Since these main symptoms were provoked equally in both He-O2 and FC-80 dive groups, helium pressure did not play a significant role in the etiology of HPNS in this animal model. It is concluded that the HPNS is primarily a result of excessive pressure per se or rate of change of pressure per se.
Animals↗
Probing the limits of human deep diving.
Divers breathing compressed air are restricted to 45 m depth because of the narcotic effects of nitrogen and toxic action of oxygen at increased pressures. Substitution of oxygen-helium for compressed air has permitted divers to reach 600 m. However, at depths greater than 160 m, signs and symptoms of the high pressure nervous syndrome (h.p.n.s.) occur, with tremors, myoclonic jerking, nausea, vomiting, fatigue, somnolence, e.e.g. changes, dyspnoea, and poor sleep with nightmares. It has been the objective of this Laboratory to ameliorate the symptoms of pressure-induced h.p.n.s. by the addition of small amounts of 'narcotic' nitrogen to the oxygen-helium mixture to form the Trimix breathing gas. In 1973, comparative experiments with oxygen-helium and the same divers, during compressions in only 33 min to 219.5 m and 305 m, showed such Trimix to be effective with 10% (by volume) nitrogen. Simulated dives, termed ATLANTIS, have been made with Trimix over the last 4 years to depths in excess of 610 m for 11 days, 650 m for 4 days and 686 m for 1 day. The objectives were to determine the effects of either slow or rapid rates of compression, and either 5% or 10% (by volume) nitrogen in Heliox, on the presence of h.p.n.s. or nitrogen narcosis. Measurements were made of intellectual and psychomotor performance, electrophysiological function of the brain and reflexes, lung and cardiovascular function, including arterial gas analysis at rest and work, blood chemistry and psychiatric and psychological status. The results permit the conclusion that divers may be compressed safely to depths as great as 686 m. The technique requires a slow exponential compression over days, with frequent stages lasting 14 h or more, the use of 5-8% (by volume) nitrogen in Heliox and careful selection of the divers.
Atmospheric Pressure↗
Decompression from a deep nitrogen/oxygen saturation dive--a case report.
Ten divers participated in a 4.5 d nitrogen/oxygen saturation dive to 165 fsw. There were daily 2 h excursions to 61 msw (200 fsw). The divers breathed air during the excursions and 0.51 bar (0.5 atm) oxygen in nitrogen at 50.3 msw (165 fsw). The final decompression began 6 h after the last excursion. The oxygen partial pressure was 0.51 bar (0.5 atm) from 50.3 to 13.7 msw (165 to 45 fsw), and air was used from 13.7 msw (45 fsw) to the surface. By 6.1 msw (20 fsw), four divers had developed decompression sickness. A fifth diver developed decompression sickness during a commercial air flight 68 h after surfacing. Comparison of ascent rates for this dive and for air or nitrogen/oxygen saturation dives reported in the literature suggests that deeper dives require slower rates of ascent. Dives shallower than 30.5 msw (100 fsw) had a mean ascent rate of 1 msw/h (3.2 fsw/h) and 14 decompression incidents in 107 man-exposures. Dives deeper than 30.5 msw (100 fsw) had a mean rate of 0.76 msw/h (2.5 fsw/h) and 14 incidents in 45 man-exposures.
Adaptation, Physiological↗