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1The electrical activity of sinoatrial node cells is heterogeneous. To understand the reasons for this, the density of the delayed‐rectifier K+current and its two components, iK,rand iK,s, as a function of the size (as measured by cell capacitance) of rabbit sinoatrial node cells was investigated using the whole‐cell voltage‐clamp technique at 35 °C.2iK,rand iK,swere isolated using E‐4031 and 293B. Features of the E‐4031‐sensitive and 293B‐insensitive currents corresponded well to those of iK,r, while features of the E‐4031‐insensitive and 293B‐sensitive currents corresponded well to those of iK,s.3The densities of the outward current under control conditions and the drug‐sensitive and ‐insensitive currents were significantly (P< 0.01)correlated with cell capacitance, with current densities being greater in larger cells.4The effects of partial blockade of iK,rby 0.1 μmE‐4031 on spontaneous action potentials were greater in smaller cells.5It is concluded that there are cell size‐dependent differences in the density of the iK,rand iK,scomponents, and these may be involved in the heterogeneity of the electrical activity of single sinoatrial node cells as well as that of the intact sinoatrial node.

This study compares the effects of long-term hormone replacement therapy on the lipid profile of postmenopausal women with or without hypercholesterolemia, with a comparison of 2 different regimens over a 3-year period. A total of 209 women were enrolled in this prospective, nonrandomized trial. They were classified into 2 groups according to baseline serum levels of total cholesterol and low-density lipoprotein (LDL) cholesterol. The hypercholesterolemic group consisted of 83 subjects with a total cholesterol level of 220 mg/dL or higher and LDL cholesterol 140 mg/dL or higher. The normocholesterolemic group consisted of 126 subjects with normal total and LDL cholesterol levels. Therapy was assigned as follows: 44 subjects in the hypercholesterolemic group and 67 in the normal cholesterol group with a total hysterectomy received conjugated equine estrogen (CEE) 0.625 mg/d, while 39 subjects in the hypercholesterolemic group and 59 in the normal cholesterol group with a physiological menopause received CEE 0.625 mg/d plus medroxyprogesterone acetate 2.5 mg/d. Fasting blood samples were monitored periodically for 3 years. Nine women withdrew from the study. Hormone replacement therapy had a more favorable effect in the hypercholesterolemic group versus the normal cholesterol group by decreasing total and LDL cholesterol, 7.0% and 16.6%, versus the normal cholesterol group, 0.8% and 3.9%. Serum levels of high-density lipoprotein (HDL) cholesterol were increased in both groups (hypercholesterolemic, 14.4%; normal cholesterol group, 26.5%), with the increase being larger in the normal cholesterol group. These changes were similar with both treatments and were maintained over 3 years. Serum levels of triglyceride were also increased in both groups, with the increase being statistically significant only in the group with normal cholesterol levels at baseline. There were no consistently reported side effects of therapy. The effects of postmenopausal hormone replacement therapy, estrogen with or without progestin, on the lipid profile appear to be related to the subject's baseline lipid values. Thus, such therapy may have a more favorable effect on LDL cholesterol in postmenopausal women with hypercholesterolemia, with the beneficial effect being maintained over 3 years.

Okadaic acid is a monocarboxylic acid with a unique molecular structure of C44H66O13. Okadaic acid, at concentrations above 10(‐5) M, caused a dose‐dependent increase of contractile force in guinea‐pig isolated ventricular muscles. The increase of contractile force by okadaic acid (1‐4 X 10(‐5) M) was accompanied by a prolongation of action potential duration (a.p.d.), while a.p.d. was shortened by okadaic acid at above 10(‐4) M. The okadaic‐acid‐induced changes in contractile force and a.p.d. were abolished by pre‐treatment with verapamil (2 X 10(‐6 M) or nifedipine (10(‐6) M). In a low‐Ca2+ medium (0.12 mM), the contractile response to okadaic acid (4 X 10(‐5) M) was inhibited, whereas the a.p.d. was more prolonged by the drug than in a control medium (containing 1.2 mM‐Ca2+). In a low‐Na+ (70 mM) medium or in a low‐Na+ (70 mM) and low‐Ca2+ (0.12 mM) medium both the contractile force and a.p.d. were unaffected by okadaic acid (4 X 10(‐5) M). The positive inotropic effect of okadaic acid (4 X 10(‐5) M) was not inhibited by treatment with tetrodotoxin (TTX, 2 X 10(‐6) M) or with ryanodine (2 X 10(‐6) M). In voltage‐clamp experiments using a single sucrose‐gap technique, okadaic acid (4 X 10(‐5) M), caused a significant increase of slow inward current, while it did not affect the net outward current. These findings suggest that okadaic acid has a positive inotropic effect on the heart, probably due to the enhancement of slow Ca2+ and/or Na+ inward current through the cell membrane.

The effects of 5-(N,N-dimethyl)amiloride, a potent and specific Na^+-H^+ exchange inhibitor, were investigated in isolated perfused rabbit hearts subjected to ischemia and reperfusion. Phosphorus 31-nuclear magnetic resonance spectroscopy was used to monitor intracellular pH, creatine phosphate, @b-adenosine triphosphate, and inorganic phosphate. After cardioplegic arrest with St. Thomas' Hospital solution, normothermic (37@? C) global ischemia was induced for 45 minutes, and the hearts were reperfused for 50 minutes. Dimethyl amiloride at 10 @mmol/L, which has minimal inotropic and chronotropic effects on the nonischemic heart, was added to the cardioplegic solution. Treatment with dimethyl amiloride reduced the elevation of left ventricular end-diastolic pressure during and after the ischemia and improved the postischemic recovery of developed pressure from 76% +/- 3.2% at 30 minutes of reperfusion in control hearts ( n = 6) up to 99% +/- 1.9% in hearts treated with dimethyl amiloride ( n = 8). Dimethyl amiloride did not affect the decline in intracellular pH during ischemia for up to 30 minutes but enhanced the intracellular acidosis thereafter. The intracellular pH at the end of ischemia was 6.21 +/- 0.05 in control hearts compared with 5.24 +/- 0.17 in hearts treated with dimethyl amiloride ( p < 0.05). During reperfusion, intracellular pH of hearts treated with dimethyl amiloride was less than control for 5 minutes, but subsequent recovery of intracellular pH was similar to control. Treatment with dimethyl amiloride did not affect creatine phosphate breakdown, inorganic phosphate accumulation, and @b-adenosine triphosphate depletion during 45 minutes of ischemia. The creatine phosphate resynthesis and inorganic phosphate reduction during reperfusion were also unaffected. These findings suggest that Na^+-H^+ exchange plays an important role not only during reperfusion but also during ischemia for the development of postischemic cardiac dysfunction most likely by inducing primary Na^+ and secondary Ca^2^+ overload. Specific Na^+-H^+ exchange inhibitors like dimethyl amiloride would have a potential therapeutic profile in cardiac surgery, especially if added before ischemia. (J THORAC CARDIOVASC SURG 1996;112:765-75)

Effects of KT-362 (5-[3[2-3, 4-dimethoxyphenyl) ethyl]amino]-1-oxopropyl]-2,3,4,5- tetrahydro-1,5-benzothiazepine fumarate; 3-100 microM) on the twitch contraction of isolated rabbit left atria were examined to elucidate the influence of this substance on the intracellular calcium mobilization of cardiac muscles. A 30-sec rest period interrupting the conditioning stimulation at rates greater than 0.5 Hz caused positive inotropy of the first postrest (B1) contraction (rest potentiation). The potentiated B1 contraction was much more resistant to the negative inotropic effect of nifedipine (1 and 3 microM) than the steady-state contraction. The nifedipine-resistant B1 contraction was abolished by ryanodine (30 nM) or caffeine (5 mM). Single treatment of the muscle with KT-362 much greater than or equal to 10 microM resulted in a concentration-dependent decrease in the steady state beat as well as in B1 contraction. In preparations pretreated with 1 microM nifedipine, KT-362 had greater inhibitory action against B1 contraction (IC50 = 7.8 microM). KT-362 (3 and 10 microM) reduced the late plateau amplitude of transmembrane action potential associated with the B1 contraction. Tetrodotoxin (1 and 3 microM) and quinidine (3 and 10 microM) caused a rightward shift of the force-frequency relationship for the B1 contraction but, unlike KT-362, they caused no or minimal reduction of the maximal B1 values. In the presence of 1 microM nifedipine, B1 contraction showed biphasic response to a prolongation of the preceding rest period, an initial rapid increase up to 30 sec was followed by a gradual decrease.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrotonic interaction between the sinoatrial (SA) node and surrounding atrial muscle was investigated in a computer simulation using a modified Oxsoft HEART model (Oxsoft, Oxford, UK). When an SA node cell model was coupled to a passive atrial membrane model (RC circuit) with various coupling conductances (G"c), there was a G"c-dependent prolongation of spontaneous cycle length (SCL). At a sufficiently high value of G"c, the spontaneous activity was finally stopped. A nonlinear relationship between G"c and SCL was obtained, similar to that observed in experiments on rabbit SA node cells. When the muscarinic potassium current (i"K","A"C"h) was activated in the SA node cell model, the coupling-induced inhibition of pacemaker activity was potentiated. Although coupling current and i"K","A"C"h were additive, their effects on SCL were more than additive because of the nonlinear dependence of SCL on net current. A decrease in the input resistance of the atrial membrane model to simulate the activation of i"K","A"C"h in atrial muscle was also shown to potentiate the coupling-induced inhibition of SA node spontaneous activity.

An interaction between aprindine and lidocaine on cardiac fast sodium channels was investigated in isolated guinea pig ventricular muscles. A conditioning clamp pulse was applied from -90 to 0 mV through the single sucrose gap voltage clamp, and the maximum upstroke velocity (Vmax) of action potential elicited after the clamp pulse was measured as an index of sodium channel availability. In the presence of aprindine (2 and 5 microM) or lidocaine (20 and 40 microM), Vmax of test action potential 100 msec after the clamp pulse was decreased progressively as the clamp pulse duration was prolonged. The time constant of this inactivated channel block by aprindine was much slower than by lidocaine. Vmax after a 1000 msec clamp pulse recovered exponentially with a time constant of 4.75 to 4.81 sec for aprindine and 254 to 260 msec for lidocaine. In the presence of both aprindine and lidocaine, Vmax recovered in dual exponential function, where the short and the long time constant corresponded to the values for single treatment with each drug. In preparations treated with aprindine alone the use-dependent decrease of Vmax was observed during stimulation trains at rates higher than 0.1 Hz. This use-dependent block was attenuated significantly after additional application of lidocaine resulted in a net increase in Vmax at 0.5 to 1.0 Hz. These findings suggest that aprindine and lidocaine may block the sodium channels by binding to a common receptor site with different kinetics, leading to a competitive displacement with each other at their high concentrations.

The effects of dimethylpropranolol (UM-272) on transmembrane action potentials were examined in isolated right ventricular papillary muscles of the guinea pig. UM-272 (10(-5) to 3 X 10(-4) M) caused a dose-dependent decrease in the Vmax of the action potential. At 3 X 10(-4) M, a slight decrease in the amplitude of action potential was also observed. The resting potential and the action potential duration were not affected by the drug. In the presence of UM-272, trains of stimuli at rates higher than 0.1 Hz led to an exponential decline in Vmax (onset rate, 0.13-0.28 per action potential) to a new plateau level. This use-dependent block was augmented at the higher stimulation frequency. The time constant for the recovery of Vmax from the use-dependent block (offset) was 7.1 to 7.3 sec. In depolarized papillary muscles with 8 or 10 Mm [K+]0, the inhibitory action of UM-272 on Vmax of the first action potential after a long quiescent period (tonic block) was augmented markedly, but the rates of onset and offset of the use-dependent block were similar to those in normally polarized preparations under 5 mM [K+]0. The curves relating membrane potential and Vmax in preparations stimulated infrequently were shifted by 7.2 mV with UM-272 at 10(-4) M in the direction of more negative potentials. These findings suggest that UM-272 has kinetically similar use-dependent inhibitory action of the fast sodium channels of cardiac muscles as other Class Ia antiarrhythmic drugs like quinidine or procainamide.(ABSTRACT TRUNCATED AT 250 WORDS)