Lactate activates ATP-sensitive potassium channels in guinea pig ventricular myocytes.

The functional significance of cardiac ATP-sensitive potassium channels remains controversial because of the discrepancy between the low levels of ATP at which activation of the channels occurs and the much higher levels of ATP maintained during myocardial ischemia. We studied the effects of (+)-lactate, which accumulates in large quantity as a result of increased glycolysis during ischemia, on ATP-sensitive potassium channels in adult guinea pig ventricular myocytes using the whole-cell patch-clamp technique. Lactate at 20-40 mM in the internal solution activated ATP-sensitive potassium channels and shortened action potential duration. Activation of the channels occurred even in the presence of 2-5 mM ATP in the internal solution and was dependent on intracellular free magnesium levels. Our results suggest that intracellular lactate may play a significant role in activating cardiac ATP-sensitive potassium channels and shortening action potential duration even at ATP levels similar to those resulting from moderate to severe myocardial ischemia.

Complex regulation of calcium current in cardiac cells. Dependence on a pertussis toxin-sensitive substrate, adenosine triphosphate, and an alpha 1-adrenoceptor.

We investigated regulation of the cardiac L-type calcium channel by intracellular ATP and by alpha 1-adrenergic agonism using single adult guinea pig ventricular cells and the whole-cell patch clamp method. Inclusion of 5 mM ATP in the patch clamp pipette prevented calcium current rundown but did not increase the maximal magnitude of the slow inward calcium current (ICa). During beta 1-adrenergic blockade with 10 microM (-)-propranolol, cells preincubated with 1 microgram/ml pertussis toxin for 2-5 h exhibited a rapid twofold increase in ICa after rupture of the membrane patch when 5 mM ATP was present in the patch clamp pipette. In the absence of ATP, the increase in ICa did not occur. In pertussis toxin-treated cells, 100 microM (-)-phenylephrine inhibited the augmentation of ICa. This inhibitory effect was blocked by 100 nM terazosin, a selective alpha 1-antagonist. The inhibitory effect of alpha 1-adrenergic agonism was not mediated by cAMP-dependent phosphodiesterase since incubation with 100 microM (-)-phenylephrine did not augment the activity of this enzyme. We conclude that regulation of the L-type calcium channel in cardiac cells is complex, and is dependent on a pertussis toxin-sensitive substrate, ATP, and an alpha 1-adrenergic receptor. The marked increase in ICa after pertussis toxin treatment in the presence of ATP indicates significant inhibition of ICa by a pertussis toxin substrate, presumably the guanine nucleotide inhibitory protein (Gi) in the basal state. The inhibitory action of (-)-phenylephrine in pertussis toxin-treated cells is consistent with modulation of ICa by an alpha 1-adrenergic receptor not coupled to Gi.

Effects of beta-adrenergic blockade on verapamil-responsive and verapamil-irresponsive sustained ventricular tachycardias.

To assess effects of beta-adrenergic blockade on ventricular tachycardia (VT) of various mechanisms, electrophysiology studies were performed before and after intravenous infusion of propranolol (0.2 mg/kg) in 33 patients with chronic recurrent VT, who had previously been tested with intravenous verapamil (0.15 mg/kg followed by 0.005 mg/kg/min infusion). In the verapamil-irresponsive group, 10 patients (group IA) had VT that could be initiated by programmed ventricular extrastimulation and terminated by overdrive ventricular pacing, and 11 patients (group IB) had VT that could be provoked by isoproterenol infusion (3-8 micrograms/min) but not by programmed electrical stimulation, and that could not be converted to a sustained sinus rhythm by overdrive ventricular pacing. Notably, in the group IA patients, all 10 patients had structural heart disease (coronary arteriosclerosis or idiopathic cardiomyopathy); beta-adrenergic blockade accelerated the VT rate in one patient but exerted no effects on the VT rate in the remaining 9 patients, and VT remained inducible in all 10 patients. By contrast, in the group IB patients, 7 of the 11 patients had no apparent structural heart disease; beta-adrenergic blockade completely suppressed the VT inducibility during isoproterenol infusion in all 11 patients. There were 12 patients with verapamil-responsive VT (group II). 11 of the 12 patients had no apparent structural heart disease. In these patients, the initiation of VT was related to attaining a critical range of cycle lengths during sinus, atrial-paced or ventricular-paced rhythm; beta-adrenergic blockade could only slow the VT rate without suppressing its inducibility. Of note, 14 of the total 33 patients had exercise provocable VT: two in group IA, five in group IB, and seven in group II. Thus, mechanisms of VT vary among patients, and so do their pharmacologic responses. Although reentry, catecholamine-sensitive automaticity, and triggered activity related to delayed afterdepolarizations are merely speculative, results of this study indicate that beta-adrenergic blockade is only specifically effective in a subset group (group IB) of patients with VT suggestive of catecholamine-sensitive automaticity.

L-type cardiac calcium channels in doxorubicin cardiomyopathy in rats morphological, biochemical, and functional correlations.

Doxorubicin (DXR) is an effective antitumor agent in a wide spectrum of neoplasms. Chronic treatment is associated with cardiomyopathy and characteristic myocardial ultrastructural changes, which include swelling of the t tubules. Accordingly, we investigated excitation-contraction coupling in cardiomyopathic rat heart resulting from chronic DXR treatment. Using the whole-cell patch clamp technique, we studied the L-type calcium channel in single cells enzymatically isolated from normal (CTRL) and DXR rat hearts. Despite similar cell dimensions, the total membrane capacitance was significantly smaller in the DXR cells (138 +/- 9 pF) than in the CTRL cells (169 +/- 11 pF) (mean +/- SEM, n = 9, P less than 0.05). The mean current and the current density-voltage relationships of the CTRL and the DXR cells were significantly different (n = 9, P less than 0.001) with the maximal peak L-type calcium current (ICa) density increased from 6.4 +/- 0.9 in CTRL cells to 10.5 +/- 2.4 microA/cm2 in the DXR cells (P less than 0.05). There was no shift either in the current-voltage relationship or the steady-state inactivation curve in the two cell groups. However, the fast time constant of inactivation was increased at a membrane voltage of -10 to 10 mV. Calcium channel antagonist equilibrium binding assays using [3H]-PN200-110 revealed no difference in the maximal receptor binding capacity (CTRL, 194 +/- 27 and DXR 211 +/- 24 fmol/mg protein; P greater than 0.05, n = 6) and in receptor affinity (CTRL, 0.15 +/- 0.05 and DXR 0.13 +/- 0.03 nM; P less than 0.05). These data suggest that a decrease in effective capacitance might be associated with t-tubular damage. Despite this decrease, ICa was increased in the DXR cells. Such an increase may result from an alteration in the properties of the calcium channels and/or recruitment of "hibernating" channels in the remaining surface and t-tubular membranes.

Electrophysiologic demonstration of concealed conduction in anomalous atrioventricular bypass tracts.

To demonstrate the occurrence of concealed conduction in anomalous atrioventricular (AV) bypass tracts, 11 patients were selected for study. Two had a right-sided and nine had a left-sided bypass tract. Electrode catheters were placed in the right atrium, coronary sinus, AV junction and right ventricle. After every eighth atrial or ventricular driving beat (A1 or V1) at a constant cycle length, two successive atrial or ventricular premature beats (A2 and A3 or V2 and V3) were delivered. The A1A2 or V1V2 interval was fixed at 30 ms greater than the effective refractory period of the atrium or right ventricle, but less than the effective refractory period of the bypass tract in the anterograde or retrograde direction. This allows A2 or V2 to capture the atrium or ventricle, but not conduct in the bypass tract. The A3 or V3 was delivered from late diastole with a progressively shorter A2A3 or V2V3 interval until atrial or ventricular refractoriness was encountered. In the anterograde direction, the presence of A2 prevented A3 conduction in the bypass tract despite A1A3 intervals being longer than the anterograde effective refractory period of the bypass tract in 8 of the 11 patients. In the retrograde direction, the presence of V2 prevented V3 conduction in the bypass tract despite V1V3 intervals being longer than the retrograde effective refractory period of the bypass tract in 3 of the 11 patients. Thus, using the technique of programmed electrical stimulation, concealed conduction in anomalous AV bypass tracts can be demonstrated in both anterograde and retrograde directions.

Transmembrane action potentials and the electrocardiogram in rats with renal hypertension.

The results of previous studies of the relation between the surface electrocardiogram and cellular transmembrane potentials have suggested that the T wave configuration of the ECG is the result of a difference in the duration of endocardial and epicardial action potentials. Ventricular hypertrophy induced by renal hypertension in rats is associated with lengthening of action potential duration and a reproducible decrease in T wave magnitude. Therefore, this model was used to study the relation between the surface T wave configuration and regional differences in action potential duration. ECGs were recorded from hypertensive (HBP) and sham-operated (SHAM) rats. The hearts from these animals were removed and transmembrane action potentials were recorded by standard microelectrode techniques from endocardial and epicardial preparations. We found that the normally peaked T waves seen in the ECG of SHAM rats was reduced by 35% in the ECG of HBP rats. This reduction of T wave magnitude was associated with similar duration of epicardial and endocardial action potentials in HBP rats. However, peaked T wave in SHAM ECG was not accompanied by a significant disparity in the duration of the epicardial and endocardial action potentials. Thus, there is no simple, consistent correlation between surface T wave configuration and regional differences in intracellular action potential duration in rats.

Role of intravenous isoproterenol in the electrophysiologic induction of atrioventricular node reentrant tachycardia in patients with dual atrioventricular node pathways.

To assess the role of intravenous isoproterenol for the facilitation of electrophysiologic induction of atrioventricular (AV) node reentrant tachycardia, 20 patients with dual AV node pathways who lacked inducible AV node reentrant tachycardia at control study had a constant isoproterenol infusion administered and underwent repeat study. Six (30%) of 20 patients (group I) had inducible AV node reentrant tachycardia during isoproterenol infusion whereas the other 14 (70%) patients (group II) did not. Paroxysmal supraventricular tachycardia was clinically documented in all 6 group I patients compared to 3 (21%) of 14 group II patients (p = 0.002). The sensitivity and specificity of isoproterenol-facilitated induction of AV node reentrant tachycardia were 67 and 100%, respectively. The isoproterenol-facilitated induction of sustained AV node reentry was mediated by resolution of the weak link in anterograde slow pathway in 2 (33%) patients, in retrograde fast pathway in 3 (50%) and in both anterograde slow and retrograde fast pathways in 1 (17%) patient. Four group I patients were given intravenous propranolol, 0.2 mg/kg body weight, and had complete suppression of isoproterenol-facilitated induction of AV node reentry. Thus, intravenous isoproterenol is a rather sensitive and highly specific adjunct to electrophysiologic induction of AV node reentrant tachycardia in patients with dual AV node pathways but without inducible sustained AV node reentry.

Effects of beta-adrenergic stimulation on atrial latency and atrial vulnerability in patients with paroxysmal supraventricular tachycardia.

To assess the effects of beta-adrenergic stimulation on atrial latency and atrial vulnerability, the electrophysiologic properties of the atrium were studied before and during intravenous infusion of isoproterenol at 2 to 5 micrograms/min in 11 patients with paroxysmal supraventricular tachycardia exhibiting atrial latency during programmed atrial extrastimulation. In all patients, the isoproterenol infusion reduced the extent of maximum atrial latency (from 86 +/- 19 to 62 +/- 16 ms, p less than 0.001). This was accompanied by a significant shortening of both effective and functional refractory periods of the atrium (from 213 +/- 31 to 174 +/- 40 ms, p less than 0.005 and from 259 +/- 31 to 215 +/- 29 ms, p less than 0.001, respectively). The intra-atrial and interatrial conduction times were also significantly reduced (from 24 +/- 15 and 63 +/- 17 to 15 +/- 10 and 48 +/- 15 ms, p less than 0.005, respectively). In 3 patients with demonstrable atrial vulnerability, the isoproterenol infusion abolished the inducibility of repetitive atrial responses or atrial flutter, or both. Although the clinical significance of the suppressive action of beta-adrenergic stimulation on atrial vulnerability remains to be determined, the present study has demonstrated that beta-adrenergic stimulation significantly reduces atrial latency.

Electrophysiologic manifestations of the excitable gap of orthodromic atrioventricular reciprocating tachycardia demonstrated by single extrastimulation.

To assess the electrophysiologic characteristics of the excitable gap, 12 patients with orthodromic atrioventricular (AV) reciprocating tachycardia were studied. During tachycardia, 8 patients used a left-sided and 4 patients a right-sided anomalous bypass tract for retrograde conduction. QRS complex-synchronized single extrastimuli were delivered from high right atrium, right ventricular apex and coronary sinus, respectively, scanning the whole cycle length of tachycardia. An excitable gap was determined to be present if tachycardia resetting or tachycardia termination occurred. The duration of the excitable gap varied among different pacing sites and occupied 0 to 48% (mean 17 +/- 16) of basic tachycardia cycle length (240 to 480 ms, mean 327 +/- 70). Three patterns of tachycardia resetting were observed: the sum of coupling interval and return cycle being (1) less than a fully compensatory pause in 12 of 12 patients, (2) more than a fully compensatory pause in 5 of 12 patients and (3) equal to a fully compensatory pause in 2 of 12 patients, depending on extent of AV nodal conduction delay exhibited in return cycle. Tachycardia termination was possible when extrastimuli were delivered from right ventricular apex and coronary sinus but not from high right atrium, and only when basic tachycardia cycle length was greater than or equal to 290 ms in 7 of 12 patients. Tachycardia termination was accounted for by development of orthodromic conduction block in AV node in 7 of 7 patients and in bypass tract in 2 of 7 patients. Therefore, site of extra-stimulation and basic tachycardia cycle length affect electrophysiologic manifestations of excitable gap. Further, functional properties of the AV node influence patterns of tachycardia resetting and are primarily responsible for tachycardia termination during programmed single extrastimulation.

Radio frequency heating of chronic ovine infarct leads to sustained infarct area and ventricular volume reduction.

OBJECTIVE: Myocardial infarct expansion and subsequent left ventricular remodeling are associated with increased incidence of congestive failure and mortality. Collagen is known to denature and contract when heated above 65 degrees C. We therefore tested the hypothesis that radio frequency heating of myocardial infarct tissue with application of a restraining patch causes a sustained reduction in myocardial infarct area and left ventricular volume. METHODS: Thirteen male Dorset sheep underwent surgical coronary artery ligation. At least 14 weeks later, animals were randomized to either radio frequency infarct heating (95 degrees C) with application of a restraining patch or a sham operation. Before treatment, after treatment, and 10 weeks later, left ventricular volume was measured with transdiaphragmatic echocardiography and myocardial infarct area was measured with an array of sonomicrometry crystals. RESULTS: Radio frequency infarct heating causes an acute decrease of 34% (-215 +/- 82 mm(2); P =.0002) in infarct area at end-diastole that is maintained at 10 weeks (-144 +/- 79 mm(2); P =.0002). Radio frequency infarct heating causes a downward trend in end-diastolic left ventricular volume measured by echocardiography of 20% (-15.7 +/- 6.3 mL; P = no significant difference) and end-systolic left ventricular volume of 32% (-17.1 +/- 9.8 mL; P =.09), which are significantly decreased at 10 weeks (-13.6 +/- 22.3 mL; P =.007 and -15.3 +/- 21.9 mL; P =.008, respectively). Radio frequency infarct heating causes an acute improvement in systolic function (P <.001), a sustained increase in left ventricular ejection fraction (+0.11%; P =.06), and preserved stroke volume. CONCLUSION: Radio frequency heating of chronic left ventricular myocardial infarct causes a sustained reduction in infarct area and left ventricular volume. This technique may beneficially reverse infarct expansion and left ventricular remodeling after myocardial infarction.

Arrhythmias in single-chamber pacemakers.

Arrhythmias mediated by normal pacemaker functions and induced by pacemaker malfunctions are listed in Tables 1 and 2. Frequently, a careful review of the performance specifications in the technical or physician manual of the pacemaker model in question will provide a better understanding of pacemaker-related arrhythmias. By reprogramming selected parameters, the physician may eliminate the arrhythmia and avoid replacement of a normally functioning pulse generator.

Calcium current is increased in isolated adult myocytes from hypertrophied rat myocardium.

To study the effects of myocardial hypertrophy resulting from chronic pressure overload on excitation-contraction coupling, the cardiac transmembrane L-type calcium current (ICa) was investigated in the Goldblatt renovascular hypertensive (HBP) rat. ICa was measured in single myocytes enzymatically isolated from control (CTRL) and HBP rat hearts using the whole-cell, patch-clamp method. The peak ICa and ICa density (obtained by normalizing ICa to the average cell capacitative surface area) were larger in HBP cells (n = 15) than in CTRL cells (n = 10) at membrane potentials of -20 to 50 mV (p less than 0.01). The maximal peak ICa increased from 0.9 +/- 0.5 nA (mean +/- SD) in CTRL cells to 2.8 +/- 1.0 nA in HBP cells (p less than 0.001). The corresponding ICa density increased from 5.3 +/- 2.7 to 16.2 +/- 6.0 microA/cm2 (p less than 0.001). There was no shift in the current-voltage relation between CTRL and HBP cells. The time course of decay of HBP ICa in response to clamp steps to the plateau range of the action potential (membrane potential, Vm = -10 to 30 mV) was delayed when compared with that of CTRL ICa. The inactivation time constants (biexponential) for the maximal ICa were 6.9 +/- 1.9 and 36.0 +/- 9.3 msec for CTRL cells and 6.7 +/- 1.4 and 49.5 +/- 12.9 msec for HBP cells (p less than 0.05 for the slower component of the maximal ICa). There was no difference in the steady-state inactivation of ICa (f infinity) for the CTRL and HBP cells. From the maximal peak ICa, cytoplasmic free Ca2+ was estimated to reach a pCa of 6.95 +/- 0.07 for CTRL cells and 6.64 +/- 0.13 for HBP cells. It is concluded that ICa is increased with myocardial hypertrophy. The lengthening of the action potential in hypertrophied rat myocardium is due to an increase in peak current density and to the slower inactivation of the maximal ICa. The increased transmembrane flux of Ca2+ via ICa in HBP cells is inadequate to achieve a myoplasmic free Ca2+ level sufficient for direct partial activation of the contractile myofilaments. However, in the scheme of the calcium-triggered calcium release hypothesis such an increase could provide an increased amount of activator calcium and/or serve to amplify the release of Ca2+ from sarcoplasmic reticulum, thereby contributing to preserved peak developed tension in hypertrophied rat myocardium.

Non-uniform electrophysiological properties and electrotonic interaction in hypertrophied rat myocardium.

We studied the distribution and nature of the electrical changes associated with myocardial hypertrophy induced by renal hypertension in rats. Standard microelectrode techniques were used to study transmembrane action potentials recorded from endocardial, papillary muscle, and epicardial stimulation from hypertrophied (HBP) and normal (SHAM) hearts. We also determined the effects of stimulation frequency on the action potentials recorded from these preparations. To assess whether altered intercellular electrical connections contribute to the electrophysiological changes associated with hypertrophy, we analyzed the spatial steady state voltage decrement produced by passing intracellular constant current pulses and determined the effective input resistance (Rin) of endocardial HBP and SHAM preparations. Our results show that the action potential prolongation that accompanies hypertrophy is not uniform. Thus, the entire course of repolarization is prolonged in epicardial and papillary muscle fibers, but only the latter half of repolarization is prolonged in epicardial fibers. Endocardial action potentials is general, and HBP action potentials in particular, have a distinctive steep relation between duration and stimulation frequency which may be due to a difference in the rate dependence of a membrane conductance(s), although relatively greater accumulation of extracellular potassium or altered activity of the Na+-K+ pump cannot be excluded as contributing factors. In addition, the similarity in the profile of spatial voltage decrement and the values for Rin in HBP and SHAM preparations indicates that alterations in electrotonic coupling between cells are unlikely to account for the prolonged action potentials of hypertrophied myocardium.

Effects of myocardial hypertrophy on transient outward current.

In the one-clip, two-kidney model of hypertensive rat, a gradual chronic pressure overload is imposed on the heart. Myocardial hypertrophy resulting from such pressure overload is associated with an increased but slower inactivating L-type calcium current and prolongation of action potential duration. Voltage clamp experiments in a variety of excitable tissues indicate that a 4-aminopyridine-sensitive transient outward current (Ito) plays an important role in regulating the action potential duration. Accordingly, we studied Ito in single adult cardiac myocytes enzymatically isolated from hypertrophied left ventricles of the renovascular hypertensive (HBP) rat hearts using the whole cell patch-clamp method. The current densities (normalized to cell capacitative surface area) measured at the early transient peak Ito, at the steady state, and as the difference between the transient peak and the steady state were larger in HBP cells (n = 23) than in control (Ctrl) cells (n = 20) (P < 0.05). There was no difference in the Ito reversal potential between Ctrl (-60.9 +/- 1.9 mV, mean +/- SE; n = 16) and HBP (-63.7 +/- 2.6 mV; n = 19) cells. The observed increase in Ito amplitude was not due to an increase in the number of channels available for activation or in the fraction of channels activated because there were no statistical differences in the membrane potential at which one-half of the Ito channels are activated (V0.5) for the steady-state activation and inactivation curves between Ctrl and HBP cells. The time course of inactivation of Ito was described by a double-exponential function.(ABSTRACT TRUNCATED AT 250 WORDS)

Passive electrical properties of normal and hypertrophied rat myocardium.

We determined the electrical constants of epicardial and endocardial preparations from both normal and hypertrophied rat hearts. This was done by comparative analysis of the spatial decay of steady-state electronic voltage deflection produced by injection of a hyperpolarizing constant-current pulse. We used a two-dimensional finite disk model to obtain the apparent membrane resistance, (Rm)app, and internal longitudinal resistivity (Ri), (Rm)app was significantly larger in epicardial (565 +/- 222 omega . cm2) than endocardial (375 +/- 137) preparations from normal hearts. This regional difference disappeared in hypertrophied hearts (epicardium 421 +/- 138, endocardium 383 +/- 121 omega . cm2). Ri was similar for normal endocardial (272 +/- 169 omega . cm) and epicardial (326 +/- 152) preparations, as well as for hypertrophied endocardial (251 +/- 108) and epicardial (312 +/- 59) preparations. We determined the effective membrane capacity (Ceff) by measuring the ratio of applied charge to the displacement of membrane potential. Ceff was larger for normal hearts (epicardium 9.7 +/- 2.5 micro F/cm2, endocardium 7.5 +/- 3.0) than for hypertrophied hearts (epicardium 4.1 +/- 1.4, endocardium 4.7 +/- 1.2). From the values for Ceff we calculated the effective membrane resistance, (Rm)eff. (Rm)eff was larger for normal (epicardium 5,392 +/- 2,613 omega . cm2, endocardium 3,013 +/- 2,096) than for hypertrophied (epicardium 1,552 +/- 633, endocardium 1,838 +/- 826) preparations. Our results show that the amount of electrically effective membrane area is decreased in hypertrophied myocardium, despite the increased total area per hypertrophied cell. One functional implication of this finding is that activation of contraction by spread of surface electrical depolarization into the T-tubules may be impaired in hypertrophied cardiac muscle.

Effects of combined dopamine and nitroprusside therapy in patients with severe pump failure and hypotension complicating acute myocardial infarction.

In severe pump failure with hypotension complicating acute myocardial infarction, dopamine has been useful in raising arterial pressure by increasing myocardial performance and augmenting peripheral resistance. Once adequate blood pressure are obtained, vasodilators may be used to reduce peripheral resistance and thus enhance pump performance. Accordingly, the hemodynamic effects of dopamine and nitroprusside administration were monitored in eight patients who developed hypotension following an acute myocardial infarction. With dopamine therapy alone, mean arterial pressure averaged 84 +/- 3.6 mm Hg and mean left ventricular filling pressure 32 +/-7.9 mm Hg. The addition of nitroprusside, at doses ranging from 0.5 to 1.6 micrograms/kg/min, resulted in a decrease in arterial pressure to 75 +/- 2.4 mm Hg (p less than 0.01) and in left ventricular filling pressure to 23 +/- 7.2 mm Hg (p less than 0.001). Cardiac index increased modestly from 1.81 +/- 0.61 to 2.01 +/- 0.60 liters/min/m2 (p less than 0.05), while systemic vascular resistance fell from 1,967 +/- 707 to 1,586 +/- 634 dynes-sec-cm-5 (p less than 0.01). Heart rate did not change significantly. Seven of eight patients died in the hospital within 4 days of admission. It appears that despite a beneficial hemodynamic response effected by combined dopamine-nitroprusside administration, the prognosis of this group of patients may not be favorably altered because of the extensive destruction of myocardium.

Ca2+ regulates the kinetics of tension development in intact cardiac muscle.

The goal of this study was to determine whether Ca2+ plays a role in regulating tension development kinetics in intact cardiac muscle. In cardiac muscle, this fundamental issue of Ca2+ regulation has been controversial. The approach was to induce steady-state tetanic contractions of intact right ventricular trabeculae from rat hearts at varying external Ca2+ concentrations ([Ca2+]) at 22 degreesC. During tetani, cross bridges were mechanically disrupted and the kinetics of tension redevelopment were assessed from the rate constant of exponential tension redevelopment (ktr). There was a relationship between ktr and external [Ca2+] that was similar in form to the relationship between tension and [Ca2+]. Thus a close relationship also existed between ktr and tension (r = 0.88; P < 0. 001); whereas at maximal tetanic tension (saturating cytosolic [Ca2+]), ktr was 16.4 +/- 2.2 s-1 (mean +/- SE, n = 7), at zero tension (low cytosolic [Ca2+]), ktr extrapolated to 20% of maximum (3.3 +/- 0.7 s-1). Qualitatively similar results were obtained using different mechanical protocols to disrupt cross bridges. These data demonstrate that tension redevelopment kinetics in intact cardiac muscle are influenced by the level of Ca2+ activation. These findings contrast with the findings of one previous study of intact cardiac muscle. Activation dependence of tension development kinetics may play an important role in determining the rate and extent of myocardial tension rise during the cardiac cycle in vivo.

MK-801 reduces uptake and stimulates efflux of excitatory amino acids via membrane depolarization.

MK-801 and related compounds reduce excitotoxic neuronal injury by blocking N-methyl-D-aspartate (NMDA) receptorgated ion channels. These agents also cause neuronal vacuolization and block glutamate-induced astrocyte swelling, effects that may be unrelated to actions at the NMDA receptor. In the present study, high concentrations of MK-801 (100-1,000 microM) caused uncompetitive inhibition of glutamate uptake in astrocyte and neuronal cultures and stimulated D-aspartate efflux from astrocytes. MK-801 (500 microM) reduced the maximal velocity for glutamate uptake in astrocytes from 31 to 17 nmol.mg protein-1.min-1, whereas competitive NMDA receptor antagonists did not affect glutamate uptake. MK-801 also inhibited uptake of gamma-aminobutyric acid (GABA). Because both GABA uptake and glutamate uptake are electrogenic, one mechanism by which MK-801 could inhibit uptake is by membrane depolarization. Whole cell patch-clamp recording confirmed that MK-801 in the range of 100-1,000 microM caused dose-dependent and reversible depolarization. These concentrations are far higher than necessary to block NMDA receptors, and the findings suggest that actions at sites other than NMDA receptors could contribute to the effects of high doses of MK-801 in some experimental and clinical settings.

Dobutamine therapy in acute myocardial infarction.

The short-term response of combined dopamine hydrochloride-sodium nitroprusside therapy was compared with administration of dobutamine in eight patients with acute myocardial infarction complicated by hypotension and severe left ventricular dysfunction. All patients were receiving dopamine before the study began. The addition of sodium nitroprusside increased cardiac index (Cl) from 1.94 +/- 0.490 to 2.22 +/- 0.48 L/min/sq m; decreased left ventricular filling pressure (LVFP) from 28.9 +/- 3.5 to 19.9 +/- 3.3 mm Hg and mean systemic arterial pressure (MAP) from 82.1 +/- 5.1 to 71.5 +/- 6.0 mm Hg. During dobutamine infusion, Cl, LVFP, and MAP were 2.33 +/- 0.31 L/min/sq m, 20.8 +/- 4.8 mm Hg, and 74.1 +/- 8.1 mm Hg, respectively. There was no statistical difference between short-term hemodynamic benefits produced by dobutamine or combined dopamine-sodium nitroprusside therapy. Dobutamine, a synthetic cathecholamine, provides a substitute for dopamine-sodium nitroprusside therapy in acute myocardial infarction. Dobutamine has the advantage of being a single agent and is therefore easier to administer.