Inhibition Of Cardiac Na Research Articles

Increased susceptibility to ventricular arrhythmia at low-normal and moderately low levels of extracellular potassium in catecholaminergic polymorphic ventricular tachycardia.

Recent studies have shown that the predominant arrhythmogenic mechanism in hypokalemia is through inhibition of cardiac Na+/K+ ATPase [Figure 1A(1)]. This results in accumulation of intracellular Na+, which reduces the concentration gradient across the sodium/calcium exchanger [Figure 1A(2)]. The resultant Ca2+ buildup activates CaMKII, an enzyme that facilitates further Na+ and Ca2+ accumulation by activating cardiac ryanodine receptors (RyR2), L-type Ca2+ channels, phospholamban, and the late sodium current [Figure 1A(3)].

Effect of N6-Cyclopentyladenosine on Ouabain-Induced Toxicity in Isolated Guinea Pig Atria

ABSTRACTThe effect of N6-cyclopentyladenosine (CPA), an A1-selective adenosine agonist, was studied on ouabain-induced toxicity in spontaneously beating isolated guinea pig atria. CPA (2–16 nM) produced a dose-dependent decrease in the force of contractions (34%–51%) and in the rate of contractions (22%–48%). CPA significantly increased the time of onset of arrhythmia (toxicity) induced by ouabain (1.2 μM) when it was administered 10 min before ouabain was added in organ bath. Ouabain (1.2 μM) alone produced arrhythmia at 7 min and either asystole or standstill at 22 min. CPA (8 nM) increased the time required to produce arrhythmia to 27.5 min and prolonged beating atria to more than 63 min and prevented the occurrence of asystole. These findings indicated that CPA produces direct cardiac action, probably due the inhibition of cardiac Na+ and Ca2+ channels. Moreover, our results suggest that CPA may reduce the membrane conduction through inhibition of ionic channels, which decrease ouabain-induced toxicity.

Inhibition of cardiac Na+ current by primaquine.

The electrophysiological effects of the anti-malarial drug primaquine on cardiac Na(+) channels were examined in isolated rat ventricular muscle and myocytes. In isolated ventricular muscle, primaquine produced a dose-dependent and reversible depression of dV/dt during the upstroke of the action potential. In ventricular myocytes, primaquine blocked I(Na)(+) in a dose-dependent manner, with a K(d) of 8.2 microM. Primaquine (i) increased the time to peak current, (ii) depressed the slow time constant of I(Na)(+) inactivation, and (iii) slowed the fast component for recovery of I(Na)(+) from inactivation. Primaquine had no effect on: (i) the shape of the I - V curve, (ii) the reversal potential for Na(+), (iii) the steady-state inactivation and g(Na)(+) curves, (iv) the fast time constant of inactivation of I(Na)(+), and (v) the slow component of recovery from inactivation. Block of I(Na)(+) by primaquine was use-dependent. Data obtained using a post-rest stimulation protocol suggested that there was no closed channel block of Na(+) channels by primaquine. These results suggest that primaquine blocks cardiac Na(+) channels by binding to open channels and unbinding either when channels move between inactivated states or from an inactivated state to a closed state. Cardiotoxicity observed in patients undergoing malaria therapy with aminoquinolines may therefore be due to block of Na(+) channels, with subsequent disturbances of impulse conductance and contractility.

Erythropoietin modified the cardiac action of ouabain in chronically anaemic-uraemic rats.

The results of the studies reported here demonstrate the cardiac non-haematopoietic effect of erythropoietin, providing a new physiological function of the hormone. We demonstrate that myocardium from rat with chronic renal failure (CRF) showed an abnormal response to ouabain associated with an inhibition of cardiac Na+/K+/ATPase activity and with a decrease in the high affinity 3H-ouabain binding sites. The extent to which both actions were improved with the recombinant human erythropoietin (rHuEpo) treatment suggests that the lack of the hormone is responsible for this phenomenon. The fact is that neither contractile nor enzymatic action of rHuEpo was accompanied with the improvement of the functional renal and haematologic parameters, indicating a primary effect on myocardial contractile function of rHuEpo, independent of the anaemic and uraemic state of the animal. The reason why erythropoietin is able to modulate directly the cardiac Na+/K+ pump makes it possible to conclude that the lack of erythropoietin in CRF may be at least in part responsible for the inhibition of cardiac enzymes, altering the contractile behaviour of the heart.

Inhibition of cardiac Na+ currents by isoproterenol

The mechanism by which the beta-adrenergic agonist isoproterenol (ISO) modulates voltage-dependent cardiac Na+ currents (INa) was studied in single ventricular myocytes of neonatal rat using the gigaseal patch-clamp technique. ISO inhibited INa reversibly, making the effect readily distinguishable from the monotonic decrease of INa caused by the shift in gating that customarily occurs during whole cell patch-clamp experiments (E. Fenwick, A. Marty, and E. Neher, J. Physiol. Lond. 331: 599-635, 1982; and J. M. Fernandez, A. P. Fox, and S. Krasne, J. Physiol. Lond. 356: 565-585, 1984). The inhibition was biphasic, having fast and slow components, and was voltage-dependent, being more pronounced at depolarized potentials. In whole cell experiments the membrane-permeable adenosine 3',5'-cyclic monophosphate (cAMP) congener 8-bromo-cAMP reduced INa. In cell-free inside-out patches with ISO present in the pipette, guanosine 5'-triphosphate (GTP) applied to the inner side of the membrane patch inhibited single Na+ channel activity. This inhibition could be partly reversed by hyperpolarizing prepulses. The nonhydrolyzable GTP analogue guanosine-5'-O-(3-thiotriphosphate) greatly reduced the probability of single Na+ channel currents in a Mg2(+)-dependent manner. We propose that ISO inhibits cardiac Na+ channels via the guanine nucleotide binding, signal-transducing G protein that acts through both direct (membrane delimited) and indirect (cytoplasmic) pathways.

Inhibition of cardiac Na +, K +-ATPase activity by dynorphin-A and ethylketocyclazocine

The effect of various opioids on Na +, K +-ATPase partially purified from rat heart was examined. Dynorphin-A(1–13), dynorphin-A(1–17) and ethylketocyclazocine (EKC), which are κ-type opiate agonists, markedly inhibited the enzyme activity in a dose-dependent manner; IC 50 values were 12 μM, 21 μM and 0.38 mM, respectively. Morphine (μ-type agonist), methionine- and leucine-enkephalin (δ-type agonist) at the concentration of 1 mM did not affect the enzyme activity. The effect of dynorphin-A(1–13) and EKC was not antagonized by naloxone. Dynorphin-A(1–13) mainly decreased Vmax value without the change of Km value in the activation of Na +, K +-ATPase by ATP, Na + and K +. Dynorphin-A(1–13) inhibited the partial reactions of Na +, K +-ATPase at the different degree of the potency; the inhibition of K +-stimulated phosphatase was greater than that of Na +-dependent phosphorylation. The present study suggests that dynorphin-A and EKC have an effect on cardiovascular system which is mediated by the inhibition of Na +, K +-ATPase in the heart.

Chronic digoxin treatment on canine myocardial Na+, K+ -ATPase.

In order to determine whether a prolonged inhibition of cardiac Na+, K+-ATPase causes a compensatory or adaptive change in this enzyme, the relationships among serum digoxin concentration, binding of digoxin to the enzyme and cardiac Na+, K+-ATPase and sodium pump activity were studied in dogs chronically treated with digoxin. Digoxin was injected intravenously twice daily up to 4 weeks. Two hours after the injection of a single non-toxic dose of digoxin, Na+, K+-ATPase and sodium pump activities were inhibited quantitatively in a manner corresponding to the binding of digoxin to the enzyme. The magnitude of sodium pump inhibition was reduced 12 h after the digoxin injection, with simultaneous decreases in serum digoxin concentration and the binding of digoxin to the enzyme. After 1 or 4 weeks of digoxin treatment with non-toxic doses, the relationships among serum digoxin concentration, binding of digoxin to cardiac Na+, K+-ATPase and the degree of cardiac Na+, K+-ATPase or sodium pump inhibition remained unchanged. The magnitude of the inhibition was related to serum digoxin concentrations and digoxin binding to cardiac Na+, K+-ATPase, in a manner similar to that observed after a single digoxin injection. After 4 weeks of digoxin treatment with toxic doses, these relationships were also unaffected. It was concluded that prolonged digoxin treatment fails to alter the inhibition of myocardial Na+, K+-ATPase by this agent.