Hormonal and neurotransmitter regulation of Ca++ influx through voltage-dependent slow channels in cardiac muscle membrane.

The voltage- and time-dependent slow channels in the myocardial cell membrane are the major pathway by which Ca++ ions enter the cell during excitation for initiation and regulation of the force of contraction of cardiac muscle. These slow channels behave kinetically as if their gates open, close, and recover more slowly than those of the fast Na+ channels; in addition, the slow channel gates operate over a less negative (more depolarized) voltage range. Tetrodotoxin does not block the slow channels, whereas the calcium antagonistic drugs, Mn++, Co++, and La ions do.

Age-dependent changes in electrophysiologic characteristics of fast and slow action potentials in rat papillary muscle.

Isolated papillary muscles from juvenile (about 2 months old, average weight of 250 g) and young adult rats (about 4 months old, average weight 485 g) were studied for age-dependent differences in the characteristics of fast and slow action potentials (APs). The fast and slow APs were recorded in 5.4 mM and 25 mM K+-Tyrode solutions, respectively (stimulation rate of 1 Hz).

Effect of Na+- or Ca2+-filled liposomes on electrical activity of cultured heart cells.

Phosphatidylcholine (PC) liposomes were used to deliver their entrapped ions into spontaneously contracting cultured heart cells (reaggregates) prepared from 15-day embryonic chick ventricles (superfused at 8 ml/min). With slowly rising action potentials (AP) (+Vmax less than 30 V/s), when Na+ liposomes were added (13.2% vol/vol), there was a progressive decrease in slope of the pacemaker potential and in firing frequency.

Ca2+-dependent slow action potentials in normal and dystrophic mouse skeletal muscle.

Slowly rising action potentials (APs), previously described in amphibian skeletal muscle, were examined in skeletal muscle of normal and dystrophic mice (129/ReJ strain). A standard two-microelectrode recording technique was used. Muscles were bathed in a solution that was Cl- free (methanesulfonate substituted), high in K+ (20 mM), and contained 15 mM tetraethylammonium.

Calcium antagonistic drugs differ in ability to block the slow Na+ channels of young embryonic chick hearts.

Young (3-day-old) embryonic chick hearts have slowly rising action potentials (APs) dependent on slow Na+ channels, and these slow APs are blocked by verapamil, but not by Mn2+ (1 mM). In contrast, old embryonic hearts possess slow Ca2+-Na+ channels which can be blocked by both verapamil and Mn2+. In the present experiments, we compared the effects of a number of Ca antagonistic drugs on the spontaneous APs recorded from intact 3-day-old embryonic chick hearts (ventricles).

Effects of pH on membrane resistance in normal and dystrophic mouse skeletal muscle fibers.

Membrane cable properties of skeletal muscle fibers of dystrophic mice (Rej-129) and their littermate controls were examined using a conventional two-microelectrode recording technique. Fibers from dystrophic mice had a decreased membrane resistivity (Rm) compared with those from normal mice (517 +/- 27 vs 642 +/- 34 omega - cm2), while the internal resistivities (Ri) did not differ significantly. The increase in membrane specific conductance was due to an increased Cl- conductance (gCl) (2304 vs 1346 microseconds/cm2 for normal fibers), although the K+ conductance (gK) was actually decreased (234 vs 369 microseconds/cm2 for normal fibers).

Protection by oral pretreatment with taurine against the negative inotropic effects of low-calcium medium on isolated perfused chick heart.

Chicks were given taurine by mouth using a cannula pushed down into the oesophagus. This treatment had protected the heart, when subsequently removed, against the decline of contractile force in the perfused heart brought about by low-calcium media. A small but statistically significant increase in taurine concentration occurred in the ventricular tissue of such pretreated hearts.

Calcium antagonist blockade of slow action potentials in cultured chick heart cells.

The effects of four Ca antagonists, bepridil, diltiazem, nifedipine, and verapamil, on slow channels were studied in cultured cell reaggregates prepared from 14-day-old chick embryonic hearts. The cell membrane was partially depolarized to about -45 mV by using 22 mM KCl to inactivate the fast Na+ channels. Slow action potentials were induced by 10(-6) M isoproterenol with electrical stimulation.

Comparison of the effects of several calcium antagonistic drugs on the electrical activity of guinea pig Purkinje fibers.

The effects of several slow channel blockers were compared on the normal fast action potentials (APs) and the slow APs of guinea pig Purkinje fibers. In spontaneously-firing Purkinje fibers perfused with normal Tyrode solution, mesudipine (analog of nifedipine) at 10(-7) and 10(-6) M, had no significant effect on the fast AP parameters (at 5 X 10(-6) M, excitability was abolished due to depolarization to about -45 mV). Washout of the drug rapidly (within 3 min) repolarized the preparations and restored automatic activity.

Nifedipine, diltiazem, bepridil and verapamil uptakes into cardiac and smooth muscles.

Vogel et al. (1979; J. Pharmacol.

Characterization of phospholipase A2 activity in rat aorta smooth muscle cells.

Phospholipase A activity was measured in homogenates and acid extracts of smooth muscle cells from rat aorta and mesenteric artery using [1-14 C]oleate-labeled autoclaved Escherichia coli and 1-[1-14C]stearyl-2-acyl-3-sn-glycerophosphorylethanolamine as substrates. The results demonstrate the presence of neutral-active phospholipase(s) A that exclusively catalyze the release of fatty acid from the 2-position of phospholipids. Optimal activity was at pH 7.

Depression of contractions of rabbit aorta and guinea pig vena cava by mesudipine and other slow channel blockers.

The effects of several drugs having Ca++-antagonistic and vasodilating properties were compared in arterial and venous smooth muscles. Developed force (phasic component) was recorded from isolated rings (about 2 mm wide) of blood vessel wall taken from rabbit aorta or guinea pig inferior vena cava. The vascular smooth muscle (VSM) was stimulated to contract for a sustained period by elevating the extracellular K+ concentration ([K]o) to 100 mM or by exposure to norepinephrine (NE).

Membrane alterations in skeletal muscle fibers of dystrophic mice.

Skeletal muscle fibers from dystrophic mice and littermate controls (ReJ-129) were characterized electrically and then injected with an intracellular marker. In this way they could be identified for examination with an electron microscope to correlate the relative time course of electrical and ultrastructural alterations resulting from the dystrophic process. On the average, dystrophic muscle fibers displayed decreased membrane potentials (-59 +/- 1.

Concentration-dependent effect of trapidil on slow action potentials in cardiac muscle.

Trapidil, a coronary vasodilator and positive inotropic agent, was tested for its ability to affect the normal "fast" action potentials and the "slow" action potentials and contractions of isolated perfused chick hearts, and to affect the tissue cyclic AMP level. At 5 X 10(-3) M, trapidil completely blocked the fast Na+ channels in hearts perfused with normal Tyrode solution, since this dose abolished the action potential when verapamil (2 X 10(-6) M) was present to eliminate the inward slow current. To study effects on the slow channels, the fast Na+ channels were voltage-inactivated by partial depolarization to about -40 mV with an elevated (25 mM) K+-Tyrode solution, resulting in loss of excitability.

Stimulation of slow action potentials in guinea pig papillary muscle cells by intracellular injection of cAMP, Gpp(NH)p, and cholera toxin.

To test the hypothesis that intracellular cAMP has a regulatory role in cardiac slow channel function, intracellular pressure injections of cAMP and adenylate cyclase activators, Gpp(NH)p and cholera toxin, were carried out. Guinea pig papillary muscles were depolarized to about -45 mV by superfusion with 22 mM K+-Tyrode's solution to inactivate the fast Na+ channels. Induction of slow action potentials or enhancement of ongoing slow action potentials was observed in about 70% of all cells in which a successful intracellular injection of the testing compounds was obtained.

Veratridine stimulation of calcium uptake by chick embryonic heart cells in culture.

Veratridine (2 X 10(-5) to 1 X 10(-4)M) stimulated Ca uptake into monolayer cultures of chick embryonic heart cells in a dose-dependent manner. The stimulation of veratridine was independent of the age of the chick embryos from which the heart cells were taken, and was inhibited by tetrodotoxin (3 microM). The half-maximal effect of veratridine was 37 microM.

Effect of ion channel inhibitors on the cytopathogenicity of Entamoeba histolytica.

Entamoeba histolytica (axenic strain HM1-IMSS), a cytolytic enteric pathogen, kills target Chinese hamster ovary cells in two discrete steps: (1) carbohydrate-specific adherence of amoebae to target cells, followed by (2) cytolysis of adherent target cells. Both steps require intact amoebic microfilament function. The effects of the fast Na+ channel blocker tetrodotoxin and the slow Na+-Ca++ channel blockers verapamil (10(-5) M) and bepridil (10(-5) M) on amoebic killing were evaluated.

Comparison of [3H]bepridil and [3H]verapamil uptake into rabbit aortic rings.

The efflux and uptake of [3H]Ca antagonists were studied in isolated rings of rabbit aorta. The efflux of [3H]bepridil occurred from two compartments. The faster (T1/2 = 0.