Na-Ca Exchange Mechanism Research Articles

771-4 Enhancement of Delayed Afterdepolarlzatlons (DADs) and Triggered Activity by E-4031 and Dofetilide In a Cardiac Glycoside Model of Cell Ca 2+ Overload

Several new class III antiarrhythmic drugs, including E-4031 and Dofetilide. are reported to selectively block the rapidly activating delayed rectifier current (iKR). These drugs increase action potential duration (APD) which should load cells with Ca2+ via the Na-Ca exchange mechanism and Ca2+ channels. Thus DADs, which occur in Ca2+ loaded cells, should be enhanced by these drugs. Action potentials were recorded from sheep Purkinje fibers at pacing cycle lengths (CL) of 990 and 690 ms. Ca2+ overload with DADs were induced by exposing fibers to acetylstrophanthidin (AS, 0.15 μM) for 30 min. Fibers were then exposed to AS-free Tyrode's containing E-4031 (E, 5.0 μM; Group 1, n = 5), or Dofetilide (D, 0.5 μM; Group 2, n = 5), or no drug (Group 3, n = 5) for 30 min. 1) Both E and 0 enhanced DAD amplitude. With AS exposure for 30 min. mean DAD amplitude reached 5.6 ± 1.3 and 4.4 ± 0.7 mV for Groups 1–2, respectively (CL 990 ms). After 10 min exposure to E or D, DAD amplitude increased to 6.6 ± 1.3 and 6.5 ± 1.0 mV, respectively (p < 0.05). In Group 3, after switching from AS to no drug for 10 min, DAD amplitude was decreased by 2.2 ± 0.5 mV (p < 0.05). Similar findings were obtained at the 690 ms CL. 2) E and D exerted a biphasic effect on APD, initially shortening it at 10 min of exposure (p < 0.05) before it lengthened. 3) E and D prolonged DAD disappearance time (36.0 ± 2.4, 34.0 ± 8.7, and 16.0 ± 2.4 min in Groups 1–3, respectively). 4) E and D occasionally induced triggered action potentials. Lowering [K]&z.omicr; (5.4 to 4.0 mM) worsened these effects. 5) Without prior AS exposure, E caused only prolongation of APD and occasionally the induction of early afterdepolarizations. E and D enhanced DADs and triggered activity. In the presence of AS induced Ca2+ overload, E and D caused shortening of APD. These effects can not be explained solely by selective block of iKR by E and D. Additional drug effects, resembling enhancement of cardiac glycoside toxicity, exist.

Lithium-induced inhibition of Na-K ATPase and Ca ATPase activities in rat brain synaptosome.

To explore the action mechanism of lithium in the brain, the author investigated the effects of lithium on Na-K ATPase and Ca ATPase in rat brain synaptosomes prepared from forebrains by the method of Booth and Clark. The activities of Na-K ATPase and Ca ATPase were assayed by the level of inorganic phosphate liberated from the hydrolysis of ATP. Lithium at the optimum therapeutic concentration of 1 mM decreased the activity of Na-K ATPase from the control value of 19.08 +/- 0.29 to 18.27 +/- 0.10 micromoles Pi/mg protein/h and also reduced the activity of Ca ATPase from 6.38 +/- 0.12 to 5.64 +/- 0.12 micromoles Pi/mg protein/h. The decreased activity of Na-K ATPase will decrease the rate of Ca2+ efflux, probably via an Na-Ca exchange mechanism and will increase the rate of Ca2+ entry by the depolarization of nerve terminals. The reduced activity of Ca ATPase will result in the decreased efflux of Ca2+. As a Conclusion, it can be speculated that lithium elevates the intrasynaptosomal Ca2+ concentration via inhibition of the activities of Na-K ATPase and Ca ATPase, and this increased [Ca2+]i will cause the release of neurotransmitters and neurological effects of lithium.

Contractile activation in the retractor unguis muscle of the cockroach Periplaneta americana

1. The K + -induced contracture consists of a phasic and a sustained component. Both were eliminated in Ca 2+ -free saline, but the sustained component recovered on the addition of Ca 2+ to the muscle. 2. Procaine mainly inhibited the phasic component. 3. Unlike the sustained component, the phasic component was inhibited by nifedipine in a concentration dependent manner. 4. Divalent cations such as Mn 2+ , Co 2+ and Ni 2+ markedly increased the sustained component at low concentrations, but decreased it at high concentrations. The cations also modified the phasic component differentially, but to a lesser extent. High concentration abolished the phasic component. 5. Ouabain markedly enhanced the sustained component. 6. Caffeine contracture was a phasic type. Its duration and amplitude were augmented by pre-soaking the muscle in Na + -reduced salines. Immediate pre-treatment with caffeine eliminated the phasic component of the 160mM K + -induced contracture. 7. These results suggest that a Na-Ca exchange mechanism may play a role in excitation-contraction coupling in insect muscle. Calcium ions flowing into the cell upon membrane depolarization may specifically activate the phasic component by way of a calcium-induced calcium releasing mechanism.

Sodium-calcium exchange-mediated contractions in feline ventricular myocytes.

The hypothesis that Ca entry by the sarcolemmal Na-Ca exchange mechanism induces sarcoplasmic reticulum (SR) Ca release, loads the SR with Ca, and/or directly induces contractions by elevating cytosolic free Ca was tested in voltage-clamped feline ventricular myocytes. Intracellular Na concentration was increased by cellular dialysis to enhance Ca influx via "reverse-mode" Na-Ca exchange at positive membrane potentials, at which the "L-type" Ca current (ICa) should be small. Contractions were induced in the presence of Ca channel antagonists by depolarization to these potentials, suggesting that Ca influx via reverse-mode Na-Ca exchange was involved. These contractions had both phasic (SR related) and tonic components of shortening. They were smaller and began with more delay after depolarization than contractions which involved ICa. The magnitude of shortening was graded by the amount and duration of depolarization, suggesting that Ca influx via reverse-mode Na-Ca exchange has the capacity to induce and grade SR Ca release. Small slow contractions could be evoked in the presence of ryanodine (to impair SR function) and verapamil (to block ICa), supporting the idea that Ca influx via Na-Ca exchange is sufficient to directly activate the contractile proteins. Contractions induced by voltage steps to +10 mV, which were usually small when ICa was blocked, were potentiated if preceded by a voltage step to strongly positive potentials. This potentiation was inhibited by ryanodine, suggesting that Ca entry that occurs by Na-Ca exchange may be important for normal SR Ca loading.(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetics, stoichiometry and role of the Na–Ca exchange mechanism in isolated cardiac myocytes

Compelling evidence has existed for more than a decade for a sodium/calcium (Na-Ca) exchange mechanism in the surface membrane of mammalian heart muscle cells which exchanges about three sodium ions for each calcium ion. Although it is known that cardiac muscle contraction is regulated by a transient increase in intracellular calcium ([Ca2+]i) triggered by the action potential, the contribution of the Na-Ca exchanger to the [Ca2+]i transient and to calcium extrusion during rest is unclear. To clarify these questions, changes in [Ca2+]i were measured with indo-1 in single cardiac myocytes which were voltage clamped and dialysed with a physiological level of sodium. We find that Ca entry through the Na-Ca exchanger is too slow to affect markedly the rate of rise of the normal [Ca2+]i transient. On repolarization, Ca extrusion by the exchanger causes [Ca2+]i to decline with a time constant of 0.5 s at -80 mV. The rate of decline can be slowed e-fold with a 77-mV depolarization. Calcium extrusion by the exchanger can account for about 15% of the rate of decline of the [Ca2+]i transient (the remainder being calcium resequestration by the sarcoplasmic reticulum (SR]. The ability of the cell to extrude calcium was greatly reduced on inhibiting the exchanger by removing external sodium, which itself led to an increase in resting [Ca2+]i. This finding is in contrast to the suggestion that calcium extrusion at rest is mediated mainly by a sarcolemmal Ca-ATPase.(ABSTRACT TRUNCATED AT 250 WORDS)

Membrane transport of sodium ions in erythrocytes of the american black bear, Ursus americanus

1. 1. Membrane transport of Na ions was investigated in red blood cells of bears by methods of measurement of unidirectional isotopic fluxes. 2. 2. Like red blood cells of dogs, bear red cells contain a high Na concentration and low concentrations of K and ATP. 3. 3. As in dog red cells, Na efflux from bear cells was not inhibited by ouabain but was activated by the presence of Ca in the medium, possibly indicating the presence of a Na-Ca exchange mechanism. 4. 4. ATP depletion of cells was accelerated by Ca in the medium, consistent with the presence of a strong ATP-dependent Ca pump. 5. 5. As in other carnivore red cells, Na influx into bear cells was strongly activated by shrinkage and inhibited by swelling. Shrinkage-activated influx was blocked by amiloride. 6. 6. Amiloride-sensitive influx was activated by cytoplasmic Ca and also correlated with the presence of a Na-dependent, amiloride-sensitive H loss. 7. 7. Amiloride-sensitive Na influx exhibited a strong seasonal cycle with a minimum in the middle of the hibernation period, suggesting a possible avenue of cellular energy conservation.

Effect of palytoxin on the calcium current and the mechanical activity of frog heart muscle.

1. The effect of palytoxin (PTX) on the Ca current (ICa) and the mechanical activity of frog atrial fibres was studied by use of the double sucrose gap voltage clamp technique. 2. In normal Ringer solution, PTX transiently increased the electrically-evoked peak tension which then decreased while a major contracture developed. PTX slowed the time course of the relaxation phase of the evoked tension. 3. Evidence is presented which suggests that the toxin also increased the entry of Ca and Sr via the Na-Ca exchange mechanism. It also induced the development of a Ca-dependent outward current which was inhibited by Sr. 4. In Na-free solution, PTX increased ICa and shifted the reversal potential for Ca towards more negative membrane potentials, thus suggesting that the internal Ca concentration had increased. Current-voltage, tension-voltage, time to peak-voltage and inactivation time constant-membrane potential curves were all shifted towards more negative membrane potentials in the presence of PTX. 5. These effects of PTX are similar to those caused by the increase in internal Ca concentration induced by Na ionophores by way of voltage-dependent Ca influx of the Na-Ca exchange mechanism.

Excitation-contraction coupling in heart muscle

We have investigated the links between electrical excitation and contraction in mammalian heart muscle. Using isolated single cells from adult rat ventricle, a whole-cell voltage-clamp technique and quantitative fluorescence microscopy, we have measured simultaneously calcium current (ICa) and [Ca2+]i (with fura-2). We find that the voltage-dependence of ICa and the [Ca2+]i-transient and the dependence of [Ca2+]i-transient on depolarization-duration cannot both be readily explained by a simple calcium-induced Ca-release ('CICR') mechanism. Additionally, we find that when [Ca2+]i and [Na+]i are at their diastolic levels, activation of the Na-Ca exchange mechanism by depolarization does not measurably trigger the release of Ca2+i. Finally, measuring ICa in adult and neonatal rat heart cells and using the alkaloid ryanodine, we have carried out complementary experiments. These experiments show that there may be an action of ryanodine on ICa that is independent of [Ca2+]i and independent of a direct action of the alkaloid on the calcium channel itself. Along with experiments of others showing that ryanodine binds to the sarcoplasmic reticulum calcium-release channel/spanning protein complex, our data suggests a model to explain our findings. The model links the calcium channels responsible for ICa to the sarcoplasmic reticulum by means of one or more of the spanning protein(s). Information from the calcium channel can be communitated to the sarcoplasmic reticulum by this route and, presumably, information can move in the opposite direction from the sarcoplasmic reticulum to the calcium channel.

Sodium-calcium exchange in guinea-pig cardiac cells: exchange current and changes in intracellular Ca2+.

1. Membrane currents and changes in [Ca2+]i attributable to the operation of an electrogenic Na-Ca exchange mechanism were recorded in single isolated guinea-pig ventricular myocytes under voltage clamp and internal perfusion with the Ca2+ indicator Fura-2. 2. Ionic currents that interfere with the measurement of Na-Ca exchange current were blocked through the use of caesium (Cs+), verapamil and tetrodotoxin (TTX). Entry of Ca2+ through surface membrane Ca2+ channels and release of Ca2+ from sarcoplasmic reticulum were blocked with verapamil and ryanodine, respectively. 3. In the presence of the blockers listed above, depolarization to positive membrane potentials elicited slow increases in [Ca2+]i and, after an instantaneous increase, a declining outward current. Repolarization elicited a decline in [Ca2+]i and, after an instantaneous increase, a declining inward current. The changes in [Ca2+]i and a major component of the current were abolished by nickel ions (Ni2+; 5 mM). 4. The reversal potential of the current abolished by Ni2+ (Ni2+-sensitive current) was determined at different levels of [Ca2+]i by ramp repolarizations from +80 to -80 mV (1-5 mV/ms). The reversal potential of the current increased linearly with log [Ca2+]i. As a result of the foregoing and other data, the Ni2+-sensitive current was taken to be Na-Ca exchange current (INaCa). 5. The relation between INaCa and [Ca2+]i (less than 1 microM) at constant voltage over the range of -80 to +60 mV was approximately linear. No evidence of saturation could be found; small deviations from linearity at high [Ca2+]i were in the direction expected for a minor contribution from Ca2+-activated non-specific cation current (Ehara, Noma & Ono, 1988). 6. When measured at the same [Ca2+]i, the peak INaCa upon repolarization to -80 to -140 mV seemed to approach a limiting value at very negative potentials. 7. Over the range of +40 to +160 mV INaCa (measured soon after depolarization and thus at the same [Ca2+]i) increased exponentially with clamp-pulse potential. These pulses (to potentials up to +160 mV) elicited a slow rise in [Ca2+]i with the peak at the end of the pulse also increasing exponentially with pulse potential. 8. Inward membrane currents with properties similar to those described above were also recorded in association with physiological [Ca2+]i transients, when Ca2+ channels and the sarcoplasmic reticulum were not blocked. 9. Some of the results are not consistent with certain predictions of a sequential step model, or with those of a simultaneous step model in which the internal binding site for Ca2+ is saturated, or with those of a model based only on thermodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet free calcium concentrations measured with fura-2 are influenced by the transmembrane sodium gradient

The influence of the transmembrane Na + gradient on the intracellular free calcium concentration, [Ca 2+] i, was studied in Sepharose gel-filtered platelets from healthy human subjects, using the Ca-sensitive fluorescent dye, fura-2. Raising the internal Na + concentration, [Na +] i, by Na + pump inhibition with 0.05 mM ouabain, without changing external Na + did not cause a significant increase in [Ca 2+] i. Substitution of extracellular Na + by iso-osmolar sucrose induced a rapid (half-time about 2 min) and significant rise in [Ca 2+] i; this effect was ampilfied in Na-loaded platelets. Partial restitution of external Na + in these cells with increased [Ca 2+] i promoted a significant and rapid Na + concentration-dependent fall in [Ca 2+] i; little decline in [Ca 2+] i was observed if K + was used instead of Na +. These observations represent in vitro evidence for the existence of a Na Ca exchange mechanism in human platelets that may, in vivo, participate in the control of [Ca 2+] i.

Effects of Na-Ca Exchange Mechanism on the Action Potential and Membrane Currents in the Single Cells of the Guinea-Pig and the Rabbit Heart

Effects of Na-Ca Exchange Mechanism on the Action Potential and Membrane Currents in the Single Cells of the Guinea-Pig and the Rabbit Heart

Effect of tetrodotoxin, lidocaine, and quinidine on the transient inward current of sheep Purkinje fibres.

The effect of tetrodotoxin (TTX), lidocaine, and quinidine on the transient inward current (TI) was studied in voltage-clamped sheep cardiac Purkinje fibres. The TI was induced by elevation of extracellular Ca or addition of strophanthidin. Reduction of external Na had a biphasic effect on the steady state TI magnitude; a moderate (less than 50%) reduction of external Na had an enhancing effect on the TI; a further decrease of extracellular Na was accompanied by a decline of TI amplitude. The TI could not be induced in Na-free medium (external Ca less than or equal to 9.0 mM). TTX, lidocaine, and quinidine reduced the magnitude of the TI in a dose-dependent way. The blocking effect of these agents could be compensated for by a moderate (less than 50%) reduction of external Na or an elevation of extracellular Ca. It is suggested that the blocking effect of TTX, lidocaine, and quinidine on the TI is due to a reduction of intracellular Na, which causes a decay of intracellular Ca via the Na-Ca exchange mechanism.

3H]noradrenaline release from rabbit pulmonary artery: sodium‐pump‐dependent sodium‐calcium exchange.

1. The release of [3H]noradrenaline ([3H]NA) from the isolated main pulmonary artery of the rabbit has been measured in the presence of neuronal (cocaine, 3 X 10(-5) M) and extraneuronal (corticosterone, 5 X 10(-5) M) uptake blockers. 2. K+ removal from the external medium increased the release of [3H]NA, an action transiently inhibited by Ca2+-free (+1 mM-EGTA) solution, i.e. after Ca2+ removal transmitter release was first abolished and then started to increase again after a delay lasting about 90-120 min. 3. Ca2+ readmission to arteries which had been kept in Ca2+- and 'K+-free' solution, markedly increased the [3H]NA release. The rate of transmitter release was dependent on the preceding perfusion period with 'K+-free' solution, being greater for longer exposure times. 4. When Ca2+ and K+ were readmitted together to K+-depleted and Na+-enriched preparations, the release of [3H]NA transiently increased. 5. If K+ was readmitted first, the subsequently applied Ca2+ was ineffective in producing transmitter release. 6. Different alkali metal ions (Rb+, Cs+ or Li+) were also readmitted as K+ substitutes together with Ca2+. In all cases the release of neurotransmitter transiently increased; however, the rate of release was dependent on the monovalent cation used. Thus, Rb+ ions were as effective as, Cs+ about one-third as effective as, and Li+ about one-fifth as effective as K+ in activating the Na+ pump. 7. It is concluded that in the absence of external Ca2+, and in response to Na+-pump inhibition, the release of Ca2+ from internal stores is responsible for the NA release observed. On readmission of Ca2+ the rate of transmitter release is dependent on the Na+ previously gained inside. Furthermore, the activity of the Na+ pump determines the rate of transmitter release through the Na-Ca exchange mechanism.

Electrophysiological effects of Ca antagonists, tetrodotoxin, [Ca]o and [Na]o on myocardium of hibernating chipmunks: possible involvement of Na-Ca exchange mechanism.

The electrophysiological performance of myocardium of hibernating chipmunks was investigated in the presence of Ca antagonists and tetrodotoxin, and the effects of high [Ca]o and low [Na]o were examined. The action potential of the preparations was characterized by the low amplitude of the plateau phase (APp). Ca antagonists, nifedipine (10(-6) M) and nitrendipine (2 X 10(-6) M), did not significantly inhibit this APp or the contraction. These nifedipine-insensitive electromechanical responses were completely abolished by an internal Ca release inhibitor, ryanodine. Both increasing [Ca]o and lowering [Na]o, by replacing Na by lithium or choline, also inhibited APp. Tetrodotoxin (10(-5) M) which markedly inhibited the initial rapid phase of the action potential slightly affected APp. These results suggest that the plateau potential of the present preparations is controlled by a process linked to Ca release from internal stores, most likely the Na-Ca exchange mechanism.

Effects of Nicorandil on Electromechanical Activity of Frog Atrial Muscle

The effects of the antianginal drug nicorandil on electrical and mechanical activity of bullfrog atria were examined. The application of nicorandil at concentrations from 0.3 to 10 mM caused a negative inotropic effect without any appreciable change in the resting membrane potential. The amplitude of action potentials was attenuated. In the voltage clamp experiments, the slow inward current was slightly inhibited, but the background inward current and delayed outward current were not affected in the presence of nicorandil. The inward rectifying properties of time-independent outward current were slightly inhibited by 10 mM nicorandil. Nicorandil inhibited the caffeine-induced contractures elicited in the depolarized preparation, but had no effect on the contracture mediated through the Na-Ca exchange mechanism. These results suggest that the negative inotropic action of nicorandil is caused by inhibition of Ca influx and intracellular mobilization of Ca. Nicorandil had little effect on the potassium conductance in this preparation.

Lack of Effects of Carbachol on the Na-Ca Exchange Mechanism in Frog Atrial Muscle Treated with Goniopora Toxin

Lack of Effects of Carbachol on the Na-Ca Exchange Mechanism in Frog Atrial Muscle Treated with Goniopora Toxin

Lack of effects of carbachol on the Na-Ca exchange mechanism in frog atrial muscle treated with goniopora toxin.

Carbachol (CCh) at a concentration of 10(-7) M completely inhibited the twitch contraction of frog atrial muscle. However, when the preparation was treated with goniopora toxin (GPT), a selective inhibitor of Na channel inactivation, and the twitch contraction was augmented through the activation of Na-Ca exchange by this toxin, the reduction in contractile amplitude by CCh was only about 30% even at higher concentrations. The maximum rate of rise of the twitch contraction was not affected by CCh in GPT-treated preparations. The time course of configuration change of the twitch contraction after application of CCh in GPT-treated muscle indicated that the attenuation of amplitude preceded the shortening of duration. The residual contraction under the combined treatments with GPT and CCh was abolished by removal of external Ca++ or addition of TTX. CCh only moderately shortened the action potential which was prolonged by GPT, and further addition of TTX abolished the action potential. From these results, we suggest that CCh does not influence the twitch contraction which is augmented via the activation of the Na-Ca exchange mechanism in frog atrial muscle.

Calcium channels and excitation-contraction coupling of crustacean skeletal muscle fiber

1. 1. The simultaneous recordings of membrane potential, E m, and contraction produced by a sudden increase in the external K concentration show, in presence of TEA, two phases in the contraction and an overshoot in E m, the overshoot appearing only when Ca 2+ ions were present in extracellular solution. 2. 2. Time course of E m and contraction were not changed when Na + ions were replaced by Li + ions; only the amplitude of the contractions was reduced by a factor of about 0.5. This reduction probably corresponded to a blockage of the Na-Ca exchange mechanism. 3. 3. In the presence of Mn 2+ ions (10 mM) and Li + ions, known to block the inward Ca current and Na-Ca exchange respectively, the second component of contraction persisted. It was associated with the overshoot which was somewhat reduced but longer than in normal conditions. The same was obtained in Mn-free solution containing Sr 2+ ions instead of Ca 2+ ions. 4. 4. Results suggest that the diphasic contraction could be dependent on two Ca inward currents (fast current, I Ca1 and slow current, I Ca2); these two inward currents flowing by two kinds of Ca channels in crustacean muscle fibre (Zahradnik and Zachar, 1982, Gen. Physiol. Biophys. 1, 457–461; Jdaïâa and Guilbault, 1986, Gen. Physiol. Biophys. 5, 3–16). 5. 5. In the presence of Sr 2+ ions and in the absence of Ca 2+ ions or in the presence of Mn 2+ ions and Ca 2+ ions, as Ica ca1, the first component of contraction was lost, which suggests that the fast Ca channel is more selective to Ca 2+ ions than the slow Ca channel. 6. 6. To conclude, in crab muscle fibre, the contraction recorded in our normal conditions i.e. in the presence of Na + ions and Ca 2+ ions, could correspond to three components elicited by three Ca movements: two movements of Ca corresponding to I Ca1 and I Ca2 and the last corresponding to Na-Ca exchange.

The role of Na-Ca exchange mechanism in controlling intestinal motility: Utilization of harmaline

THE ROLE OF Na-Ca EXCHANGE MECHANISM IN CONTROLLING INTESTINAL MOTILITY: UTILIZATION OF HARMALINE. M.S. Suleiman, Biology Dept., An-Najah University, Nablus, West Bank, via Israel. The existence of the Na-Ca exchanger in ileal smooth m'uscle has been demonstrated for both the guinea pig and the rabbit, and by utilizing harmaline as a probe (Biosci. Rep. 5:667, 1985, Molec. Cel. Bioch. 67:145, 1985). The role of the exchanger in the physiology of intestinal motility has not been clarified. However, an early suggestion was made indicating the exchanger can be considered as an effector molecule, activated by various agonists and by changes in ionic gradient across the membrane of smooth muscle cells. Evidence for such a possibility has not been provided yet, however, work with acetylcholine and ouabain has provided support for this idea (Europ. J. Pharmacol, 70:429 & 71:87, 1981). The electrogenicity of the exchanger was also predicted. Harmaline was found to inhibit the spontaneous contractile activity of the rabbit ileum in a dose-dependent manner. The range of harmaline concentration was found to be comparable to that reported for inhibiting the Na-Ca exchanger in ileal smooth muscle. These observations indicate that the Na-Ca exchanger is probably responsible for producing the spontaneous contractions. Furthermore, it would appear that changing the activity of the exchanger by various agonists results in a physiological response. Harmaline's inhibitory effect is not mediated via the adrenergic receptor, since adrenergic blockers failed to alter harmaline's inhibitory action on the rabbit ileum. Furthermore, work with cardiac sarcolemma1 vesicles has shown that harmaline inhibits the Na-Ca exchanger in a dose-dependent manner.

P-211 - Does carbachol affect the Na-Ca exchange mechanism in frog atrial muscle?

P-211 - Does carbachol affect the Na-Ca exchange mechanism in frog atrial muscle?