PubMed Health⌕ Search

Biomedical subjects

T F McDonald

Publications and source records attributed to T F McDonald.

At least 19 recordsLinked to original sources
PubMed1991

Marijuana-derived material-induced changes in monkey ciliary processes differ from those in rabbit ciliary processes.

The morphologic changes in ciliary processes and the associated intraocular pressure (IOP) were observed in owl and squirrel monkeys after intravitreal (IVT) and intravenous (IV) injections of water soluble marijuana-derived material (MDM). The response in monkeys differed from that reported in rabbits wherein IV injection induced severe ciliary swelling and a significant decrease in IOP. Only moderate swelling occurs in monkey processes after IV injection of relatively high dose of MDM, and this change, which includes disruption of the basal lamina of the pigment epithelium, is not associated with a change in IOP. Severe swelling occurs in the crests of monkey ciliary processes after IVT injection, which is accompanied by a fall in IOP. The difference in the response in monkey versus rabbit ciliary processes after IV injection of MDM may be due to a more compact stroma in the monkey processes.

Animals↗
PubMed1990

A dual-pipette technique that permits rapid internal dialysis and membrane potential measurement in voltage-clamped cardiomyocytes.

Guinea pig ventricular myocytes were voltage-clamped and dialysed using two glass patch pipettes (P1, P2) with tip openings of around 2 microns. A substantial improvement in the efficacy of dialysis from P2 was achieved by the application of positive pressure (15-30 cm H2O) to P2, and similar negative pressure to P1. Evidence of enhanced dialysis was obtained by measuring the effect on Ca channel current of P2 dialysates containing Ca, cAMP, GTP [gamma-S], trypsin, or the catalytic subunit of protein kinase A. Times to maximum response were 3-5 times shorter than those calculated or observed by others using a single-pipette method. The speeding-up was verified in comparative experiments with 100 microM GTP [gamma-S] dialysates; maximum stimulation of ICa occurred after 1.3-1.8 min with the dual-pipette method, versus 8.2 min with a single pipette. Other advantages of the dual-pipette method include the option of following a control dialysis from P1 with a test dialysis from P2, and the measurement of actual membrane potential. The disadvantages are that the rate of success is lower than with single-pipette experiments, and that smaller cardiomyocytes are difficult subjects.

Animals↗
PubMed1990

Whole-cell calcium current in guinea-pig ventricular myocytes dialysed with guanine nucleotides.

1. Whole-cell calcium current (ICa) was recorded in guinea-pig ventricular myocytes superfused with Na+,K(+)-free solution and dialysed with a substrate-free solution (minimum intracellular solution, MICS). A dual tight-seal pipette method was often used to permit pressure-enhanced dialysis of a test solution after a given pre-dialysis. 2. In dual-pipette experiments, test dialysates contained 100 mM-GTP-gamma-S (guanosine 5'-O-(3-thiotriphosphate] or 100 microM-GMP-PNP (guanyl-5'-imidodiphosphate). These non-hydrolysable analogues of guanosine triphosphate (GTP) enhanced ICa amplitude (+ 10 mV) by 20-40%. Dialysates containing 100 microM-GTP or GDP-beta-S (guanosine 5'-O-(2-thiodiphosphate] were ineffective, and pre-dialysis with GDP-beta-S blocked stimulation by GTP-gamma-S. 3. Non-hydrolysable GTP analogues slowed the inactivation of ICa and shifted the voltage eliciting maximum ICa by 5-10 mV in the negative direction. 4. ICa enhancement by GTP analogues was attributed to the activation of three GTP-binding regulatory (G) proteins (Gi, Gp and Gs). In single-pipette experiments, the inactivation of Gi by pre-treatment with pertussis toxin did not block enhancement, and a Gp-activating regimen (external acetylcholine-internal GTP) was without effect. Thus, it is probable that the effects of GTP analogues on ICa were primarily mediated by Gs activation. 5. PI-MICS dialysates contained phosphorylation-pathway inhibitors and were used to inhibit Ca2+ channel phosphorylation via the adenyl cyclase pathway. These were deemed effective since forskolin (1-5 microM) doubled ICa during control dialysis but was without effect after 8 min PI-MICS dialysis. However, 0.1 microM-isoprenaline increased ICa by 35% in myocytes totally unresponsive to forskolin, suggesting that beta-adrenergic receptor occupation can stimulate ICa even when the phosphorylation pathway is blocked. 6. After prolonged dialysis of myocytes with PI-MICS, ICa was still enhanced by pressure-assisted dialysis of 100 microM-GTP-gamma-S or GMP-PNP. We conclude that activated Gs has a direct effect on cardiac Ca2+ channels.

Action Potentials↗
PubMed1990

Membrane-delimited stimulation of heart cell calcium current by beta-adrenergic signal-transducing Gs protein.

A severalfold increase in calcium current (ICa) is a signal feature of the maximal beta-adrenergic response of the heart. It is generally ascribed to enhanced adenosine 3',5'-cyclic monophosphate (cAMP)-dependent phosphorylation of calcium (Ca) channels after beta-receptor activation of the guanosine nucleotide-binding (G) protein Gs, and Gs activation of the adenylyl cyclase cascade. We blocked phosphorylation pathways in guinea pig cardiomyocytes to unmask other possible ICa-stimulatory modes. In blocked cells, ICa increased by approximately 50% during 1) beta-receptor activation of Gs, 2) intracellular activation of Gs, and 3) intracellular application of preactivated Gs, We conclude that fast, membrane-delimited Gs modulation participates in the physiological regulation of cardiac ICa.

Animals↗
PubMed1990

Arrhythmia after the release of inhibited oxidative phosphorylation.

Automaticities due to delayed afterdepolarizations, elicited upon reoxygenation, are thought to be caused by Ca overload. Since tissue Ca uptake upon reoxygenation has been reported to be closely related to metabolic inhibition during hypoxic perfusion, the relationship between the degree of metabolic inhibition during hypoxia and reoxygenation-induced arrhythmias was investigated in guinea pig papillary muscles. (1) Arrhythmias occurred after 60 min substrate-free hypoxia, but not after 30 min hypoxia. The chance of automaticities was closely related with the increase in resting tension achieved during hypoxic period. The incidence of arrhythmias was, however, lower after 90 or 120 min hypoxia. (2) There were arrhythmias after 20-30 min hypoxia with glycolytic inhibition (20 mM 2-deoxyglucose + 5 mM acetate). On the other hand, 60-min hypoxia in the presence of 5 mM glucose did not elicit arrhythmias on reoxygenation. (3) Stimulation of glycolysis (50 mM glucose) during substrate-free hypoxia prolonged the action potential duration, but did not cause arrhythmias. Washout of cyanide (1 mM) after 60 min perfusion in the presence of oxygen, caused arrhythmias and aftercontractions. These results suggest that the degree of metabolic inhibition during hypoxia is closely related to Ca overload and the resultant arrhythmias upon reoxygenation. The release of inhibited oxidative phosphorylation, rather than the reintroduction of oxygen per se, was thought to be the key mechanism of reoxygenation-induced arrhythmias.

Animals↗
PubMed1989

Acetate-induced depression of electrical and contractile activity in normoxic and hypoxic guinea pig papillary muscle.

The action potential configuration, developed tension, and resting tension were monitored in normoxic and hypoxic guinea pig papillary muscles superfused with solutions containing no substrate, glucose, or acetate (1-10 mM). In normoxic muscle, acetate provoked a concentration-dependent transient depression of the action potential duration and force of contraction, depression was maximal after 10-30 min, and recovery was complete after 90-120 min. In hypoxic muscle, acetate accelerated functional rundown (action potential shortening, decline of developed tension, increase in resting tension). Because rundown in hypoxic muscle was sensitive to factors affecting glycolysis (moderated by external glucose; accentuated by 2-deoxyglucose), the accentuated rundown with acetate may be accounted for by a partial block of glycolysis. However, block of glycolysis cannot explain the acetate-induced transient depression in normoxic muscle, since the depression was enhanced in normoxic muscle with 2-deoxyglucose-blocked glycolysis. We suggest that the transient depression is due to a transient depression of high energy nucleotides with consequent effects on ionic currents.

Acetates↗
PubMed1988

Cell turnover in ciliary epithelium compared to other slow renewing epithelia in the adult mouse.

Adult albino mice received tritiated thymidine either injected subcutaneously (333 microCi) every 6 hours for up to 36 hours, or administered in their drinking water for up to 74 days (about 45 microCi/day). Tissue sections were examined with autoradiography to determine the distribution of the label. Animals receiving subcutaneous injections showed no labeled cells in the choroid plexus epithelium and only one cell of 6600 cells counted in the ciliary epithelium was labeled. Animals exposed to the isotope in their drinking water for 74 days showed considerable uptake of label in hepatocytes (15%) and cortical kidney tubules (17%), whereas ciliary and choroid epithelia showed very low uptake at 0.25% and 0.01%, respectively. The data show that the ciliary and choroid epithelia have a very slow turnover rate compared to other slow renewing tissues, and, under normal conditions, these tissues are not renewed in the animal's adult life span.

Animals↗
PubMed1987

Action potential duration in ventricular muscle during selective metabolic block.

We have examined whether maintenance of the cardiac action potential duration depends exclusively on energy from glycolysis. Oxidative phosphorylation in guinea pig papillary muscles was inhibited by superfusion with hypoxic solutions. After 60 min in 50 mM glucose solution, the action potential duration was 85% of aerobic control, but ATP content was only 25%; after 60 min in 0 mM glucose, both the duration and ATP content had declined to 15% control. When the glucose concentration of hypoxic solution was raised from 0 to 50 mM, there was nearly full recovery of the action potential duration but ATP only increased to about 25% control. We attribute action potential shortening during metabolic inhibition to suppression of calcium current and activation of potassium current; the latter are graded in intensity and expressed only at low ATP. When normoxic muscle was treated with 20 mM 2-deoxy-D-glucose (2-DG) to inhibit glycolysis, there was an early transient shortening of the action potential. This was attributed to ATP consumption related to early rapid 2-DG influx and phosphorylation. After the transient, the action potential duration was maintained for several hours in oxygenated 2-DG solution. The duration was also maintained in oxygenated muscle depleted of glycolytic substrate. Thus we found no evidence of an exclusive relation between action potential duration and glycolysis.

Acetates↗
PubMed1987

Arrhythmic activity in reoxygenated guinea pig papillary muscles and ventricular cells.

Aftercontractions, delayed afterdepolarizations, and automaticity occurred in guinea pig papillary muscles that were reoxygenated after hypoxic conditioning. The emergence of dysfunction was dependent on the severity of hypoxic conditioning and on stimulation during reoxygenation. After 60 minutes of substrate-free hypoxia, reoxygenation induced automaticity in a high proportion of stimulated muscles; the automaticity appeared within 1 minute and lasted for 10-20 minutes. After similar conditioning, muscles reoxygenated for 7-15 minutes were stimulated at various cycle lengths. The incidence of automaticity and the amplitudes of delayed events had W-shaped dependencies on cycle length (200-1,000 msec), whereas coupling intervals had M-shaped dependencies. In ventricular myocytes that displayed automaticity after reoxygenation, extrasystolic upstrokes arose smoothly from delayed afterdepolarizations that reached threshold. In tissue, extrasystolic upstrokes usually rose sharply from delayed afterdepolarizations that were distinctly subthreshold. Thus, threshold was reached elsewhere in the tissue. Further evidence of electrical heterogeneity was obtained from surface mapping of delayed-afterdepolarization amplitude in reoxygenated muscle. There were no detectable aftercontractions, delayed afterdepolarizations, or signs of automaticity in quiescent reoxygenated muscles or in stimulated reoxygenated muscles that were treated with 1 microM ryanodine. We conclude that the dysfunction precipitated by reoxygenation is due to synchronized spontaneous releases of calcium from overloaded sarcoplasmic reticulum.

Animals↗
PubMed1987

Prostaglandin involvement in the responses of the rabbit eye to water-soluble marihuana-derived material.

Both anticoagulants (heparin and streptokinase) and non-steroidal anti-inflammatory compounds (aspirin and indomethacin) were used against a water-soluble derivative of marihuana, MDM. While the anticoagulants had no effect on the ocular effects of MDM, both aspirin and indomethacin altered the time course and effected the MDM-induced reduction of intraocular pressure. The usual initial hypertensive effect of intravenous MDM was eliminated and the later intraocular pressure fall occurred earlier as well as being inhibited by about 35 to 50%. Assay for prostaglandins revealed that intravenous MDM (3.86 micrograms) caused a marked rise in PGE2 concentration of the aqueous humor and iris-ciliary body during the first hour or two after administration of MDM, but normal values occurred at 4, 6, and 8 hours when the intraocular pressure is reduced by up to 60%. Following intravitreal MDM (0.002 microgram), however, the PGE2 levels remained unchanged over 24 hours, despite the induction of a fall in intraocular pressure between 14 and 18 hours which lasts for many hours. Prostaglandin appears to be involved in the hypertensive phase of intraocular pressure change after intravenous MDM injection; and, while the fall in intraocular pressure may contain a component partially mediated by prostaglandins, there is no evidence that intravitreal MDM induces any effect on prostaglandin levels. The involvement of prostaglandins, therefore, in the mediation of MDM-induced ocular hypotensive effects is apparently small.

Animals↗
PubMed1986

Voltage-dependent properties of macroscopic and elementary calcium channel currents in guinea pig ventricular myocytes.

Whole-cell Ca channel currents were recorded from guinea pig ventricular myocytes that were internally perfused with Cs solution and bathed in solutions containing 3.6 mM Ca, 3.6 mM Ba or 90 mM Ba (34 degrees C). Single Ca channel currents were recorded from cell-attached membrane patches of similar myocytes; the patch pipettes contained a 90 mM Ba solution. 1. Although the shape of the whole-cell I-V relation was independent of the bathing solution, this was not the case with the location of the inward current maximum (Vpeak); Vpeak in 90 mM Ba was about 30 mV positive to Vpeak in 3.6 mM Ba. 2. The activation and inactivation of whole-cell currents were voltage dependent. Compared to the voltage dependencies in 3.6 mM Ba, those in 90 mM Ba were shifted by about 30 mV to the right, suggesting a neutralization of surface charges. 3. Observations compatible with the ion permeation model proposed by Hess and Tsien (1984) included (a) a depression of current during Ca/Ba solution exchange, (b) a high divalent to monovalent ion permeability, and (c) rectification of the outward limb of the I-V relation. 4. Estimated current densities at Vpeak were similar for myocytes in 3.6 mM Ca and 3.6 mM Ba, and about 10 times larger in 90 mM Ba. 5. Average currents (I) calculated from ensembles of records of single Ca channel current had voltage-dependent time courses resembling those of whole-cell IBa (90 mM). 6. Single-channel I-V relations were superimposable on whole-cell I-V curves suggesting that voltage-dependent single-channel parameters (probability of opening, elementary current amplitude) can be related to the voltage-dependent macroscopic current parameters (activation, instantaneous I-V relation) when scaled by channel number. 7. The density of Ca channels in myocytes was calculated from whole-cell IBa (90 mM) and average current through single channels. The outcome, 3-5 channels/micron 2, agrees with two other recent estimates (Tsien et al. 1983; Lux and Brown 1984). However, it is difficult to reconcile with the much lower density that one would forecast from the frequency of functional channel observation in myocyte membrane patches (Pelzer et al. 1985c).

Animals↗
PubMed1986

Tetrodotoxin exerts a large frequency-dependent depression of the maximum rate of rise of action potentials in guinea pig ventricular myocytes.

The action potential configuration in guinea pig ventricular myocytes was unaffected by low concentrations (0.3-1 microM) of tetrodotoxin (TTX); high concentrations (10-30 microM) depressed both the overshoot (5-10 mV) and duration (5-10%). Although the control Vmax was unaffected by stimulation rate (0.1-5 Hz), the depression of Vmax by TTX was greatly potentiated at rates above 1 Hz: on dose-response curves, 50% control Vmax occurred at 4.3 microM (5 Hz) versus 22 microM (less than or equal to 1 Hz). The frequency dependent component of the Vmax depression reported here is much larger than the "extra" block of Na channels observed by others in voltage clamp studies on Purkinje strands. This is not a discrepancy; rather it is a consequence of a non-linear relation between Vmax and available Na conductance.

Action Potentials↗
PubMed1986

Effects of water-soluble marihuana-derived material (MDM) on the rabbit ciliary body: light and electron microscopy.

The response of the ciliary processes of the rabbit eye to water-soluble marihuana-derived material (MDM) has been examined with light and electron microscopy. Following intravenous injection of MDM, the processes undergo considerable swelling within 1 hour followed by thrombus formation in the capillaries and extravasation of red cells. Later phases include the formation of cysts between the non-pigmented and pigmented cell layers of the ciliary epithelium. The ciliary process edema coincides with the initial hypertensive phase seen after intravenous MDM, while the hematogenous response coincides with the fall in intraocular pressure. Following intravitreal injection of MDM, a similar pattern of structural changes occurs that accompanies a fall in intraocular pressure that lasts for several days; because the physiological response occurs over a longer time course (14-20 hours) relative to intravenous administration where the intraocular pressure changes occur rapidly, the ciliary process swelling phase does not result in an increase in intraocular pressure. The physiologic changes in the eye caused by MDM appear to be related to the induction of a general inflammatory response in the ciliary processes, with a primary effect on the vascular system.

Animals↗
PubMed1985

Temperature-induced transitory and steady-state changes in the calcium current of guinea pig ventricular myocytes.

ICa was recorded in guinea pig ventricular myocytes using the whole-cell voltage-clamp technique. The shape of the I-V relation was unaffected by temperature (21-37 degrees C) but there were large changes in ICa amplitude and time course. Steady-state responses indicated Q10's of 2.96 +/- 0.14 (amplitude), 2.52 +/- 0.13 (time to peak), and 2.82 +/- 0.28 (T1/2 inactivation) (mean +/- SD, n = 6). Quick changes in temperature (T1/2 less than 30 s) induced pronounced deviations from the steady-state Q10 relations (early depression, compensatory overshoot). Thus, cardiac ICa differs from other currents in having a high amplitude-Q10 and an oscillatory response to rapid temperature changes.

Animals↗
PubMed1985

Ventricular action potentials, ventricular extracellular potentials, and the ECG of guinea pig.

Action potentials were recorded from different regions of the guinea pig ventricle to characterize regional differences in waveform configuration, and to acquire insight into the generation of the T-wave of the electrocardiogram. Isolated tissue preparations were driven at 1 Hz, and microelectrodes were used to map accessible surface regions of the epicardium, endocardium, and septum. There were minimal differences in regional resting potentials (mean -87 mV) and amplitudes (mean 122 mV), but Vmax in the epicardium (mean 110 V/sec) was much smaller than elsewhere (mean 247 V/sec). The action potential duration at the -80 mV repolarization level was longest in the papillary muscles (mean 154 msec), shortest in the septum (mean 126 msec), and generally 10-15 msec longer at the base than at the apex. The characteristics of intramural action potentials were inferred from measurements on enzymatically isolated myocytes, the rationale being that most dissociated myocytes originated from intramural cell layers. The action potentials in about 40% of the myocytes had durations similar to those recorded from the tissue surface (110-170 msec), and the remainder ranged from 170-290 msec long. The existence of longer-than-surface action potentials in the ventricle was also inferred from the body surface electrocardiogram and from bipolar electrograms of isolated left ventricles. In both cases, the Q-T intervals could be accounted for only by action potentials longer than those recorded from the ventricular surface.

Action Potentials↗
PubMed1984

Cat ventricular muscle treated with D600: effects on calcium and potassium currents.

In single sucrose-gap experiments on cat ventricular muscle strands stimulated with 300 ms pulses at 0.33 Hz, 2 microM-D600 reduced the Ca-dependent slow inward current (ICa) by 50% within 5 min and more than 90% in 90-120 min. The late outward current was reduced by up to 30%. During the exposure to D600, Ca channels could be unblocked by hyperpolarizing pulses and blocked again by stimulation with depolarizing pulses. Since the degree of unblocking depended on voltage, and the degree of blocking depended on stimulation pattern, ICa amplitude could be rapidly manipulated to probe the dependence of K conductance on ICa. Under control conditions, an increase in stimulation rate from 0.02 to 1 Hz reduced ICa by 15% and increased the late outward current by a smaller amount. During exposure to D600, a similar intervention provoked a 60% reduction in ICa, but a control-like increase in the late outward current. Two other series of experiments failed to disclose a link between ICa and K conductance: when a block of Ca channels was reimposed following their unblocking, the outward currents were independent of ICa amplitude. Unblock-block experiments also provided information on the extent of steady-state ICa at 0 mV. The fraction of Ca channels not undergoing inactivation appears to be very small. During full D600 block, the inward peak of the current wave form is broad and very much delayed in comparison with pre-drug currents or currents on the first pulse following unblocking. A similar wave form was recorded in D600-treated ventricular myocytes from cat but not guinea-pig. The likely explanation is that D600 unmasks a small transient outward current in cat ventricle.

Action Potentials↗