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At least 19 recordsLinked to original sources
PubMed1992

Mechanism of heptanol-induced uncoupling of cardiac gap junctions: a perforated patch-clamp study.

The influence of heptanol on gap junctional and non-junctional membrane currents was studied in cultured neonatal rat heart cells using both the whole cell and perforated patch voltage-clamp method. With both methods, exposure to heptanol produced a dose-dependent decrease in the junctional current (dissociation constant = 0.54 and 1.20 mM for whole cell and perforated patch experiments, respectively). Heptanol-induced uncoupling was reversible. In the same concentration range, heptanol reduced all nonjunctional membrane ionic currents examined. This suggests that heptanol does not act specifically on gap junction channels but rather on the structure of the lipid membrane. This hypothesis is strengthened by the observation that in monolayer cultures of neonatal rat heart cells fluorescence steady-state anisotropy decreased proportional with increasing the heptanol concentration in the bath. Single-channel conductances (gamma j) were identical with both recording methods (21 and 40-45 pS); heptanol did not alter gamma j. Under conditions of reduced junctional coupling induced by heptanol, junctional conductance (gj) displayed voltage sensitivity at values of gj at which no voltage sensitivity could be observed under control conditions. These results suggest that heptanol-dependent uncoupling was caused by a decrease in open probability of the gap junction channels.

Alcohols↗
PubMed1990

Interaction of heptanol and pressure on sodium and chloride transport by toad skin.

We examined the interaction of heptanol and hydrostatic pressure on Na+ and Cl- transport in isolated toad skin. In the presence of Cl-, heptanol decreased short-circuit current (Isc) and total transepithelial resistance (Rt). However, in the absence of Cl- in the mucosal bath, heptanol increased Rt, although it retained the same inhibitory effect on Isc. When transepithelial active Na+ transport was blocked by amiloride, heptanol had no effect on Isc whether or not Cl- was present, whereas it decreased the shunt resistance (Rs) only in the presence of Cl- in the mucosal bath. Moreover, this effect of heptanol on Rs was significantly smaller in the presence of diphenylamine-2-carboxylate (DPC), a known Cl- channel blocker. Pressure also decreased Isc through inhibition of active Na+ transport, but it increased Rs. When heptanol and pressure were applied together, their inhibitory effects on Isc were additive, but their effects on Rs were antagonistic. Furthermore, when a transepithelial Cl- current was produced by reducing the Cl- concentration of the serosal bath, heptanol stimulated this current, which was reversibly inhibited by pressure or DPC addition to the mucosal bath. When the heptanol-stimulated Cl- current was first inhibited by pressure, subsequent DPC addition had less or no effect. These results suggest that one site of an antagonistic interaction of heptanol and pressure in toad skin is an apical membrane Cl- conductance.

Alcohols↗
PubMed1995

Reversible inhibition of gap junctional intercellular communication, synchronous contraction, and synchronism of intracellular Ca2+ fluctuation in cultured neonatal rat cardiac myocytes by heptanol.

We analyzed by Fotonic Sensor, a fiber-optic displacement measurement instrument, the effects of heptanol on synchronized contraction of primary neonatal rat cardiac myocytes cultured at confluent density. We also examined the effect of heptanol on the changes in gap junctional intercellular communication by using the microinjection dye transfer method, and on intercellular Ca2+ fluctuation by confocal laser scanning microscopy of myocytes loaded with the fluorescent Ca2+ indicator fluo 3. In addition, we studied expression, phosphorylation, and localization of the major cardiac gap junction protein connexin 43 (Cx43) using immunofluorescence and Western blotting. At Day 6 of culture, numerous myocytes exhibited spontaneous, synchronous contractions, excellent dye coupling, and synchronized intracellular Ca2+ fluctuations. We treated the cells with 1.5, 2.0, 2.5, and 3.0 mmol/liter heptanol. With 1.5 mmol/liter heptanol, we could not observe significant effects on spontaneous contraction of myocytes. At 3.0 mmol/liter, the highest concentration used in the current experiment, heptanol inhibited synchronous contractions and even after washing out of heptanol, synchronous contraction was not rapidly recovered. On the other hand, at the intermediate concentrations of 2.0 and 2.5 mmol/liter, heptanol reversely inhibited synchronized contraction, gap junctional intercellular communication, and synchronization of intracellular Ca2+ fluctuations in the myocytes without preventing contraction and changes of intracellular Ca2+ in individual cells. Brief exposure (5-20 min) to heptanol (2.0 mmol/liter) did not cause detectable changes in the expression, phosphorylation, or localization of Cx43, despite strong inhibition of gap junctional intercellular communication. These results suggest that gap junctional intercellular communication plays an important role in synchronous intracellular Ca2+ fluctuations, which facilitate synchronized contraction of cardiac myocytes.

Alcohols↗
PubMed1990

Effect of cellular uncoupling by heptanol on conduction in infarcted myocardium.

Experiments were performed in vitro on six normal thin ventricular epicardial tissue strips and 10 strips removed from the infarcted regions of dogs 21-60 days after experimental myocardial infarction. Conduction was evaluated by mapping activation sequences at 40-45 sites over an area of 1 x 2 cm during pacing at a basic cycle length of 2,000 msec. The amplitude and length of recorded electrograms were also determined at each site. After control recordings, heptanol, which increases gap junctional resistance, was added to the tissue bath at concentrations ranging between 0.2 and 1.0 mM. In contrast to its effect on normal tissues, heptanol caused 75 of 260 previously active sites in the infarcted tissues to become inactive. The affected sites were located in areas of very slow conduction and/or adjacent to areas of preexisting conduction block. In addition, heptanol decreased the length and degree of fractionation of electrograms recorded in slowly conducting regions of the infarcted tissues. The magnitude of the decrease in electrogram length following heptanol was related to the degree of electrogram abnormality during control as reflected in the ratio of electrogram length to amplitude. Heptanol shortened electrograms by causing local conduction block, which eliminated some components of the fractionated electrograms. In an additional eight epicardial strips removed from the infarcted region, 0.5 mM heptanol had only a slight effect (10.7% decrease) on the maximum rate of membrane depolarization. Thus, heptanol does not act primarily by way of depressing the fast inward current. We conclude from heptanol's effects on conduction and electrogram characteristics that slow and dissociated conduction in the infarcted region is due to an abnormality in gap junctional distribution between surviving cells and/or an abnormality in individual gap junctional function.

Action Potentials↗
PubMed1991

Differential effects of heptanol, potassium, and tetrodotoxin on reentrant ventricular tachycardia around a fixed obstacle in anisotropic myocardium.

BACKGROUND: The aim of this study was to test the hypothesis that electrical uncoupling and depression of the fast sodium channels have differential effects on propagation of the electrical impulse relative to the fiber orientation. METHODS AND RESULTS: In a model of reentrant ventricular tachycardia (VT) (mean cycle length, 144 +/- 13 msec) around a ring of anisotropic myocardium in 10 Langendorff-perfused rabbit hearts, the effects of extracellular K+ concentration [( K+]o) and heptanol were studied. [K+]o and heptanol each had a dose-dependent effect on VT cycle length. However, high [K+]o slowed the VT mainly by depressing longitudinal conduction, whereas heptanol preferentially depressed transverse conduction. The ratio between longitudinal and transverse conduction velocities progressively decreased with high [K+]o and progressively increased with heptanol. Heptanol terminated VT at a mean concentration of 3.5 +/- 0.5 mM. The cycle length before termination was 446 +/- 120 msec (p less than 0.001). In eight of 10 experiments, termination occurred by failure of conduction during transverse propagation. VT terminated at a mean [K+]o of 11.6 +/- 1.8 mM. The cycle length before termination was 493 +/- 341 msec (p less than 0.01). In seven of 10 cases, termination occurred by failure of conduction during longitudinal propagation. In the remaining five episodes (two with heptanol and three with high [K+]o), termination occurred by collision of the reentrant beat with an antidromic impulse being reflected within the ring. In a separate series of six hearts, tetrodotoxin was administered during VT. Like high [K+]o, tetrodotoxin prolonged the cycle length of the VT by preferentially slowing longitudinal conduction, and VT was terminated by longitudinal block. CONCLUSIONS: During reentrant VT, electrical uncoupling of cells by heptanol or modification of active membrane properties by high [K+]o or tetrodotoxin has a differential depressing effect on propagation of the impulse relative to the fiber orientation.

Alcohols↗
PubMed1991

Effects of the anesthetics heptanol, halothane and isoflurane on gap junction conductance in crayfish septate axons: a calcium- and hydrogen-independent phenomenon potentiated by caffeine and theophylline, and inhibited by 4-aminopyridine.

This study has monitored junctional and nonjunctional resistance, [Ca2+]i and [H+]i, and the effects of various drugs in crayfish septate axons exposed to neutral anesthetics. The uncoupling efficiency of heptanol and halothane is significantly potentiated by caffeine and theophylline. The modest uncoupling effects of isoflurane, described here for the first time, are also enhanced by caffeine. Heptanol causes a decrease in [Ca2+]i and [H+]i both in the presence and absence of either caffeine or theophylline. A similar but transient effect on [Ca2+]i is observed with halothane. 4-Aminopyridine strongly inhibits the uncoupling effects of heptanol. The observed decrease in [Ca2+]i with heptanol and halothane and negative results obtained with different [Ca2+]o, (Ca2+)-channel blockers (nisoldipine and Cd2+) and ryanodine speak against a Ca2+ participation. Negative results obtained with 3-isobutyl-1-methylxanthine, forskolin, CPT-cAMP, 8Br-cGMP, adenosine, phorbol ester and H7, superfused in the presence and absence of caffeine and/or heptanol, indicate that neither the heptanol effects nor their potentiation by caffeine are mediated by cyclic nucleotides, adenosine receptors and kinase C. The data suggest a direct effect of anesthetics, possibly involving both polar and hydrophobic interactions with channel proteins. Xanthines and 4-aminopyridine may participate by influencing polar interactions. The potentiating effect of xanthines on cell-to-cell uncoupling by anesthetics may provide some clues on the nature of cardiac arrhythmias in patients treated with theophylline during halothane anesthesia.

4-Aminopyridine↗
PubMed1993

Heptanol-induced decrease in cardiac gap junctional conductance is mediated by a decrease in the fluidity of membranous cholesterol-rich domains.

To assess whether alterations in membrane fluidity of neonatal rat heart cells modulate gap junctional conductance (gj), we compared the effects of 2 mM 1-heptanol and 20 microM 2-(methoxy-ethoxy)ethyl 8-(cis-2-n-octylcyclopropyl)-octanoate (A2C) in a combined fluorescence anisotropy and electrophysiological study. Both substances decreased fluorescence steady-state anisotropy (rss), as assessed with the fluorescent probe 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH) by 9.6 +/- 1.1% (mean +/- SEM, n = 5) and 9.8 +/- 0.6% (n = 5), respectively, i.e., both substances increased bulk membrane fluidity. Double whole-cell voltage-clamp experiments showed that 2 mM heptanol uncoupled cell pairs completely (n = 6), whereas 20 microM A2C, which increased bulk membrane fluidity to the same extent, did not affect coupling at all (n = 5). Since gap junction channels are embedded in relatively cholesterol-rich domains of the membrane, we specifically assessed the fluidity of the cholesterol-rich domains with dehydroergosterol (DHE). Using DHE, heptanol increased rss by 14.9 +/- 3.0% (n = 5), i.e., decreased cholesterol domain fluidity, whereas A2C had no effect on rss (-0.4 +/- 6.7%, n = 5). Following an increase of cellular "cholesterol" content (by loading the cells with DHE), 2 mM heptanol did not uncouple cell pairs completely: gj decreased by 80 +/- 20% (range 41-95%, n = 5). The decrease in gj was most probably due to a decrease in the open probability of the gap junction channels, because the unitary conductances of the channels were not changed nor was the number of channels comprising the gap junction. The sensitivity of nonjunctional membrane channels to heptanol was unaltered in cholesterol-enriched myocytes. These results indicate that the fluidity of cholesterol-rich domains is of importance to gap junctional coupling, and that heptanol decreases gj by decreasing the fluidity of cholesterol-rich domains, rather than by increasing the bulk membrane fluidity.

Alcohols↗
PubMed1995

Modulation of alpha 1-adrenergic contractility in isolated vascular tissues by heptanol: a functional demonstration of the potential importance of intercellular communication to vascular response generation.

After years of intensive investigation, the mechanism(s) underlying syncytial vascular smooth muscle responses both in vitro and in vivo is still poorly understood. Neither perivascular innervation nor regenerative electrical events appear sufficient to coordinate responses among vascular smooth muscle cells in many blood vessels. The implication of these observations is that another mechanism is required for organizing syncytial vascular responses. Although gap junctions are ubiquitously distributed among vascular wall cells throughout the vascular tree, their contribution to the modulation of vasomotor tone is still considered controversial. Resolution of the long standing debate awaits a clear demonstration that gap junctions modulate contraction or relaxation responses to vascular smooth muscle. Despite the absence of specific gap junctional uncoupling agents, it has still been possible to identify reasonable experimental conditions under which the contribution of gap junctions to contractile responses in isolated vascular tissues could be evaluated. Studies in isolated preparations known to contain gap junctions have indicated that alpha 1-adrenergic receptor-mediated contractile responses of diverse isolated vascular tissues, are significantly modulated by selective disruption of intercellular communication with the well studied lipophilic uncoupling agent heptanol. Interpretation of these pharmacological studies is explicitly dependent on the selectivity of the uncoupling actions of heptanol. Considerable experimental evidence suggests that, at the concentrations used, in the preparations thus far examined, heptanol does indeed have selective uncoupling actions. In fact, recent experiments provide empirical support for an operational definition of the selectivity of heptanol, and a functional role for gap junctions in modulating contractile responses in isolated vascular tissues. The operational definition states only that there exists a narrow, albeit identifiable, concentration range over which it is reasonable to assume that the effects of heptanol are primarily related to its uncoupling actions on gap junctions. The functional role for gap junctions is defined by their requisite contribution to tension development during contraction of isolated tissues. Experimentally, this can be visualized as a significant diminution in the contractile responses of isolated vascular tissues in the presence of selective uncoupling heptanol concentrations. Thus, a cogent interpretation of available data is that they provide compelling indirect evidence for a principle role of gap junctions in modulating the alpha 1-adrenergic contractility of isolated vascular tissues.

Alcohols↗
PubMed1991

Block of sodium current by heptanol in voltage-clamped canine cardiac Purkinje cells.

Heptanol blocks sodium current (INa) in nerve, but its effects on cardiac INa have not been well characterized. Block of INa by heptanol was studied in 16 internally perfused voltage-clamped cardiac Purkinje cells at reduced Na+ (45 mM outside, 0 mM inside). Heptanol block of peak sodium conductance was well described by a single-site binding curve with half block at 1.3 mM (20 degrees C) and showed no "use dependence." With 1.5 mM heptanol, block increased slightly by 0.7%/degrees C from 10 degrees C to 27 degrees C. With 3.0 mM heptanol, steady-state availability shifted by 9.4 +/- 1.3 mV (n = 6) in the hyperpolarizing direction, and steady-state activation shifted by 8.3 +/- 2.2 mV (n = 5) in the depolarizing direction, thus closing off the INa "window current." Heptanol also decreased the time to peak and accelerated the decay of INa. Similar results were found with octanol at lower concentrations. These alcohols have important effects on cardiac INa at concentrations used in studies for cellular uncoupling in heart.

Alcohols↗
PubMed1990

Heptanol effects on protected livers.

Heptanol, an agent known for inducing closure of gap junctions in a variety of organs, was used to evaluate the influence of uncoupling on the electrical impedance of livers during ischemia. Heptanol was added to a modified HTK solution or to Belzer's UW-CSS solution. Livers of swine were then perfused for 8 min with either one of the solutions containing heptanol or a solution devoid of this additive. During the following ischemia the phase angle of impedance at 5 kHz, pH and different biochemical parameters were determined. Heptanol fundamentally changed the time course of impedance and made the otherwise characteristic fast increase of the phase angle of impedance disappear. Already early during ischemia the phase angle was raised in a dose-dependent manner up to even highest values at the beginning of the whole observation period in case of a fully developed effect. Heptanol also stimulated anaerobic energy turnover. The results suggest that, besides unspecific effects, heptanol induces uncoupling which is detectable by electrical impedance measurement.

Alcohols↗
PubMed1995

Rapid onset and calcium independence of the gap junction uncoupling induced by heptanol in cultured heart cells.

The kinetics of the reversible interruption of gap junction communication by the aliphatic alcohol heptanol and the possible mediation of an increase of the cytosolic Ca2+ concentration have been investigated in pairs of myocytes dissociated from neonatal rat ventricles and cultured for 2-3 days. Junctional communication was estimated by measuring either the cell-to-cell electrical conductance with a double whole-cell voltage-clamp method, or the rate constant of dye diffusion with the fluorescence recovery after photo-bleaching (gap FRAP) technique. Electrical coupling was seen to be abruptly interrupted (in less than 0.5 s) by heptanol (1-3 mM). The cytosolic Ca2+ concentration was not affected, even at a saturating heptanol concentration. Heptanol removal allowed a gradual re-opening of gap junctional channels, as shown by the recovery curve of the cell-to-cell conductance, which is 90% complete within 90 s. These data are consistent with a direct interaction of heptanol with channel proteins or with their lipid environment.

4-Aminopyridine↗
PubMed1991

Regeneration of the rat corneal epithelium after injury. A cell kinetic study comparing the reaction after abrasions made mechanically and with n-heptanol.

Central corneal epithelial defects with diameter 3.5 mm were made with n-heptanol in the right eyes of rats. Erosions of the same size were made by mechanical scraping in the left eyes of the same animals. All the erosions were covered by epithelium after one day. After one day the mitotic rate and the labelling index were higher in the n-heptanol treated corneas compared to the mechanically abraded ones. Both methods produced similar mitotic rates and labelling indexes after 3 and 12 days. The results from wound healing studies using n-heptanol or mechanical scraping are therefore not entirely comparable because of the different regenerative responses after one day. However, the n-heptanol method is easier to perform and to standardize, and is therefore preferable.

Alcohols↗
PubMed1984

Reversible effects of heptanol on gap junction structure and cell-to-cell electrical coupling.

It has been shown that certain alkanols such as heptanol and octanol reversibly uncouple crayfish axons. We have studied the effects of heptanol on the electrical coupling in Xenopus embryo cells and on the gap junction particle distribution of stomach and pancreas epithelia. Cell-to-cell electrical communication in Xenopus embryos reversibly decreases 10-15 min after the beginning of heptanol superfusion to reach values of coupling ratio lower than 0.05. Particle density of rat stomach and pancreas gap junction reversibly increases after exposure to heptanol-Tyrode's solutions. In stomach, gap junction particles from isles with hexagonal patterns after 10 to 15 min; in pancreas crystallization occurs after 20 to 30 min. Optical diffractions are used to average particle spacings in treated and control junctions of pancreas.

Alcohols↗
PubMed1991

Tear plasminogen activators--indicators of epithelial cell destruction. The effect of scraping, n-heptanol debridement, and alkali burn of the cornea on the plasminogen activator activity of rabbit tears.

Plasminogen activator (uPA) activities were determined in the tears of rabbits following mechanical (scraping) or chemical (n-heptanol) debridement and alkali burn of the central part of the corneal epithelium. All three types of injury enhanced the plasminogen activator activities in the tears. The increase in uPA activity was highest in alkali burn, lowest for n-heptanol debridement. Scraping yielded an intermediate increase in uPA activity. The maximum value in activator activity was reached at 5 hours for mechanical injury and at 24 hours for chemical injuries. uPA activity values returned to the normal range by the time of re-epithelialization for mechanical scraping and 1-3 days following re-epithelialization for heptanol debridement and alkali burn. A trend was observed between uPA activity level and the size of the wound but the correlation was not pronounced (R = 0.538).

Alcohols↗
PubMed1994

Lethality, teratogenicity and growth inhibition of heptanol in Xenopus assayed by a modified frog embryo teratogenesis assay-Xenopus (FETAX) procedure.

The frog embryo teratogenesis assay-Xenopus (FETAX), a powerful test for the presence of developmental toxicants, has been modified mainly by performing an in vitro fertilization and increasing the exposure time to 112 h. The modified assay (modFETAX) that presents several advantages over the original FETAX methodology has been validated by the use of ZnSO4, a standard teratogen for FETAX. The modFETAX has been applied to evaluate the 1-heptanol effects on mortality, malformation and growth inhibition. The results indicate that heptanol causes a significant growth inhibition of Xenopus tadpoles and that LC50 and TC50 at 120 h are, respectively, 1.49 and 0.37 mM; the resulting teratogenic index (TI50) of 4.03 suggests that heptanol is a strong teratogen.

Alcohols↗
PubMed1992

Effect of coronary perfusion of heptanol or potassium on conduction and ventricular arrhythmias.

Abnormalities in cellular coupling, modulated in part by intracellular gap junctions, have an important role in the genesis of reentrant arrhythmias in the setting of chronic myocardial infarction. The effects of heptanol, which has a relatively selective action on gap junctional resistance at low concentrations, and potassium, which primarily affects active membrane properties, were assessed using a localized intracoronary infusion system in 11 normal dogs in vivo. Both agents caused a dose-related slowing of conduction. Programmed stimulation during potassium infusion resulted in ventricular fibrillation in two of six animals treated with a low dose (5.0-5.5 meq/l) and five of six animals treated with a high dose (7.0-7.5 meq/l). During the infusion of 1.0 mM heptanol, uniform ventricular tachycardia was induced in four of eight animals. Infusion of heptanol, but not potassium, increased the susceptibility to presumably reentrant ventricular tachycardia in normal myocardium. This suggests that agents that affect cellular coupling may have markedly different arrhythmogenic consequences than agents that primarily alter active membrane properties.

Alcohols↗
PubMed1989

Electrical properties of gap junction channels in guinea-pig ventricular cell pairs revealed by exposure to heptanol.

Cell pairs were isolated from adult guinea pig ventricles to study the electrical properties of gap junction channels. The experiments involved a double voltage-clamp approach and whole-cell, tight-seal recording. Heptanol decreased the intracellular current, In, in a dose-dependent fashion. Before complete uncoupling, In showed fluctuations suggesting the operation of gated channels. In the presence of 3 mM heptanol, In showed quantal steps arising from spontaneous opening and closing of single channels. The IV-relationship of the channels was linear (range: +/- 95 mV). Analysis of current records revealed the following single-channel conductances, gamma n: Mean value = 37 pS; median value = 33 pS. gamma n was insensitive to the non-junctional membrane potential (range: -90 to +10 mV). 3 mM ATP4- in the pipette solution had no effects on gamma n, 6 mM ATP4- produced a small decrease, and 6 mM ATP + 0.1 mM cAMP- an increase in gamma n. Channel transitions from closed to open state were variable (range of apparent time constants: 2.5-32 ms; mean: 11 ms).

Alcohols↗
PubMed1993

Reentrant circuits and the effects of heptanol in a rabbit model of infarction with a uniform anisotropic epicardial border zone.

INTRODUCTION: The purpose was to study reentry in a rabbit model of infarction. METHODS AND RESULTS: A model of an infarct epicardial border zone was produced in Langendorff perfused rabbit hearts by freezing the inner two thirds of the left ventricular wall, allowing only a thin epicardial muscle layer to survive. Reentrant circuits causing stable ventricular tachycardia occurred in the surviving rim of epicardial muscle as shown by mapping impulse propagation with a 196-electrode array. The circuits were functional, and reentry did not occur around an anatomical obstacle. Slow conduction in the circuits was caused by the anisotropic properties of the epicardial muscle. Activation in the circuits was slow transverse to the long axis of the fiber bundles and rapid parallel to the long axis. Other features of the circuits, including orientation of the central functional line of block parallel to the fiber long axis, and an oval shape are also characteristic of anisotropic reentry. Since the slow conduction causing reentry is a result of poor transverse intercellular coupling, we determined whether the "uncoupler" heptanol would cause block in the circuits and terminate tachycardia. Heptanol in concentrations up to 1.2 mM slowed conduction in the transverse and longitudinal directions in the circuits and sometimes extended the central line of functional block. It did not, however, stop reentry because the reentrant impulse was still able to conduct around the ends of the block line. CONCLUSION: Drugs that decrease intercellular coupling may not be effective antiarrhythmic agents when uniform anisotropy causes functional reentry.

Alcohols↗