We studied the effects of thyroid hormone on the action potential and membrane currents recorded from enzymatically dissociated guinea pig ventricular myocytes, by means of the whole-cell recording ...technique. Hypothyroidism was associated with an increase in action potential duration, whereas hyperthyroidism was associated with a decrease in duration. These effects are similar to those reported in multicellular preparations. Hypo- and hyperthyroidism were also associated with a decrease and an increase, respectively, in the slope of the action potential plateau. Resting potential and action potential amplitude were unaffected by the alterations in the thyroid state. The voltage-clamp experiments revealed that as compared with euthyroid myocytes, the peak calcium current was bigger in hyperthyroid myocytes and smaller in hypothyroid myocytes. The potassium outward current (at a membrane potential = 50 mV) was of similar amplitude in hypo- and euthyroid myocytes and bigger in hyperthyroid myocytes. Our major conclusion is that thyroid hormones regulate the amplitude of the calcium current and that this effect may be responsible in part for the modulation of myocardial contractility by thyroid hormones.
We studied the effect of acetylcholine (ACh), 1 x 10(-8) to 5 x 10(-7) M, on electrophysiologic characteristics of the isolated (Langendorf), perfused fetal canine heart. ACh induced ...concentration-dependent decreases in sinoatrial (SA) rate and recovery from overdrive pacing and in atrioventricular (A-V) conduction. These effects of ACh were greater in mid-gestation than late-gestation hearts. The effects of ACh were potentiated by inhibition of acetylcholinesterase by neostigmine, 1 x 10(-7) M, in the late- but not the mid-gestation fetal heart. Decreasing the pH of the perfusion solution from 7.3 to 6.8 potentiated the response to ACh of SA rate and A-V conduction more in mid- than in late-gestation hearts. The response to ACh of the late-gestation fetal canine heart is more sensitive to cholinesterase inhibition whereas the response of the mid-gestation heart is more sensitive to the action of ACh in the presence of acidosis.
CTL, primary effectors in immune responses, deliver a "lethal hit" signal to target cells, causing their destruction. The precise membrane events associated with the lethal hit remain elusive. We ...investigated the signal(s) mediating destruction of tumor target cells (EL4) by perforin-deficient peritoneal exudate CTL (PEL). We utilized patch clamp techniques to record electrophysiological events associated with the cytolytic interaction of PEL and EL4 in isolated conjugates. PEL-EL4 interaction resulted in induction in EL4 cells, of single channels (followed by EL4 destruction), with a mean conductance of 437 pS and a reversal potential of -1.0 mV, suggestive of nonselective pathways. Similar channels were induced in EL4 cells conjugated with perforin-rich PEL blasts (PEB), by perforin, postnuclear extract from PEL (pnPEL) and from other cytotoxic lymphocytes, but not from noncytolytic lymphocytes. As similar channels were induced by pnPEL in EL4 membrane patches, we propose that these channels result from a direct effect of PEL-derived channel-forming substance(s) on the target cell's membrane. Importantly, postnuclear extracts from perforin-devoid cytotoxic PEL-hybridomas induced similar channels, suggesting the presence of a nonperforin, channel-forming activity in PEL and PEL-hybridomas. Based on the present study, we conclude that the delivery of the lethal hit by cytolytic PEL and PEL-hybridoma is associated with induction in the target cell of high-conductance channels, which most likely mediate its destruction. We propose that these channels are related to the Fas pathway of lymphocytotoxicity.
The effect of transdermal scopolamine on performance was tested on 23 naval volunteers. Performance was evaluated by using a battery of professional (naval-related) and cognitive tests. For all tests ...performed there were no significant differences between the scores obtained in placebo and transdermal scopolamine conditions. These results were in close agreement with subjective estimations of performance. Transdermal scopolamine significantly reduced salivary flow, whereas mood state, visual acuity, and eye accommodation for near vision were not affected. We conclude that transdermal scopolamine administration is not accompanied by decrement in performance abilities and can safely be used by naval crews.
Transdermal scopolamine has been reported to provide protection against motion sickness, both while sailing at sea (7-8 h) and under experimental conditions. In this study, we tested the efficacy of ...transdermal scopolamine and evaluated its side effects during a 72-h cruise at sea. We tested 38 male volunteers, 20-25 years old, who were located on a 3000-ton vessel. The presence of seasickness, defined by Graybiel's diagnostic criteria, was used to calculate percent protection. When sickness was considered as malaise II or more, the drug provided 74, 73, and 39% protection during the three sailing days, respectively. There were no significant differences in the magnitude of the side effects reported by experimental and placebo groups. We conclude that transdermal scopolamine's efficacy against seasickness during a 3-day cruise was not associated with significant side effects and, therefore, we find the drug suitable for long-term use by sailing crews.
Previous studies have demonstrated that in different cardiac preparations action potential duration (APD) increases with age. As in various species, thyroid hormone levels increase developmentally, ...and since hyperthyroidism shortens APD while hypothyroidism prolongs it, we hypothesized that developmental changes in APD result from age-related variations in the thyroid state. The hypothesis was tested by analysing ventricular action potentials and total T4 (TT4) levels in guinea-pigs in the age range of 0 days to 3 months (adult), and in hyperthyroid and hypothyroid newborns (0-5 days old). We found that APD50 increased exponentially with age with a time constant of 6.7 days, from 100.6 +/- 3.4 ms in newborns (0-5 days old) to 147.4 +/- 5.2 ms in adults (P less than 0.001). TT4 decreased exponentially with age with a time constant of 4.8 days, from 3.9 +/- 0.4 micrograms/dl in newborns to less than 1.0 microgram/dl in adults. In the age range studied, APD50 and TT4 were linearly correlated: Y = -12.13X + 142, r - 0.865. In contrast to the marked changes in APD, resting potential and action potential amplitude were age-independent, and Vmax only slightly increased with age. Alterations in the thyroid state in newborns affected ventricular action potentials as predicted by the hypothesis. In euthyroid (TT4 = 3.9 +/- 0.4 micrograms/dl), hypothyroid (TT4 = 1.6 +/- 0.4 micrograms/dl) and hyperthyroid (TT4 = 39.8 +/- 10.8 micrograms/dl) newborns, APD50 was: 100.6 +/- 3.4 ms, 117.7 +/- 4.2 ms and 63.7 +/- 7.4 ms, respectively (P less than 0.01).
Chronic alterations in the thyroid state have been shown to induce marked changes in action potential characteristics, the most pronounced being shortening of action potential duration (APD) by ...hyperthyroidism and an increase in duration by hypothyroidism. In the present study our major objectives were to investigate the time course of the effect of thyroid hormone on action potential characteristics, to examine the relationships between thyroid hormone levels and these changes, and to test whether the electrophysiological alterations are induced both by thyroxine (T4) and triiodothyronine (T3). The major findings were that a single dose of either hormone (100 micrograms/kg) caused a marked shortening of APD, while resting potential, action potential amplitude and Vmax were unchanged. APD shortening was observed promptly after ip T4 or T3 administration, with maximal effect occurring within 2 to 3 hrs. Having determined thyroid hormone levels in the guinea-pigs used for the electrophysiological experiments, we found a close temporal association and inverse linear relationships (r = -0.82) between total T4 levels and APD. To determine whether APD shortening is induced due to a direct effect of thyroid hormone on the myocardium, euthyroid papillary muscles were superfused with 10(-6) M T3; within 3 hrs of superfusion with T3, APD was shortened from 148.8 +/- 4.7 ms to 117.7 +/- 6.4 ms (P less than 0.01), an effect blocked by the protein synthesis inhibitor cycloheximide. Our results demonstrate that thyroid hormones affect the duration of the ventricular action potential in a concentration dependent fashion. Furthermore, the study suggests that thyroid hormones affect the myocardium directly via mechanism(s) that are probably associated with thyroid hormone-related protein synthesis.
Speckle tracking echocardiography is a tool for measuring myocardial velocities from echocardiography. Since the measured velocities are noisy, only global measures are obtained. The use of wavelet ...de-noising for filtering the raw velocities, allows processing the high spatial frequency components, and this may reveal new insight into cardiac mechanics. Echocardiography was applied to 27 normal rats, and the myocardial velocities from 3 short axis levels were analyzed by a commercial speckle tracking program and by a wavelet de-noising process. Thereafter, the circumferential and radial strains were calculated for 6 segments. The circumferential strain was heterogeneous at the apical and basal levels (P<;0.001); while it was homogeneous at the mid-ventricular level. The radial strain was heterogeneous at all scan levels (P<;0.01). Wavelet de-noising of the myocardial velocities reveals heterogeneity of the circumferential and radial strains.
The effects of sodium salts of various bile acids on the contractile force and the electrophysiological properties of rat ventricular muscle were studied in vitro. Primary, conjugated, and secondary ...bile acids were studied in a concentration range of 10(-9)-10(-6) mol/l, which corresponds to concentrations found in the plasma of patients with cholestatic jaundice. In general, the bile acid induced a negative inotropic effect which was manifested as a reduction in active tension, maximum rate of tension activation, and maximum rate of tension relaxation. Twitch duration and time to peak tension were unaffected by the bile acids. The negative inotropism was associated with a reduction in ventricular action potential duration. Resting potential, action potential amplitude, and maximum upstroke velocity of phase 0 depolarization were unaffected. Voltage clamp experiments in rat ventricular myocytes demonstrated that sodium taurocholate decreased the slow inward current and slightly increased the outward potassium current. Hence, these effects on the membrane currents are probably responsible for the negative inotropic effect.
