Guinea Pig Ventricular Muscle Research Articles

Contribution of ATP-Mediated Positive Feedback to Sympathetic Nerve-Induced Positive Inotropy in Guinea Pig Ventricular Myocardium.

The functional role of ATP released from sympathetic nerve terminals was examined in isolated guinea pig ventricular papillary muscles. The contractile force of papillary muscles was increased by field electrical stimulation of sympathetic nerve endings. This increase was attenuated by pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) or suramin, blockers of the P2X receptor, and was abolished by propranolol and prazosin. PPADS, suramin, and ATP affected neither the basal contractile force nor the positive inotropic effect of noradrenaline. These results provide functional evidence that ATP released from sympathetic nerve terminals enhances noradrenaline release and contributes to sympathetic nerve-induced inotropy.

Nonclinical Cardiovascular Studies of Prucalopride, a Highly Selective 5-Hydroxytryptamine 4 Receptor Agonist.

Patients with chronic constipation benefit from treatment with 5-hydroxytryptamine 4 (5-HT4) receptor agonists. However, the first-generation 5-HT4 receptor agonists cisapride and tegaserod were withdrawn from the market owing to rare cardiovascular adverse events that were not 5-HT4-receptor-related but due to the lack of selectivity of these drugs. Here we report the nonclinical cardiovascular profile of the selective 5-HT4 receptor agonist prucalopride. To assess its non-5-HT4 receptor-mediated effects on cardiovascular electrophysiological parameters, in vitro studies were performed in human ether-à-go-go-related gene-transfected cells, guinea pig ventricular myocytes and papillary muscle preparations, rabbit and dog Purkinje fibers, and the Langendorff rabbit heart. In vivo experiments were performed in a rabbit model for drug-induced proarrhythmogenesis, in anesthetized guinea pigs, and anesthetized and conscious dogs. In addition, human platelet aggregation and coronary artery contraction were studied to exclude interactions that have been suggested to mediate the cardiovascular effects of tegaserod. Effects at 5-HT4 receptors were evaluated in piglet and human atrial myocardium, and in anesthetized pigs. Finally, cardiovascular endpoints were investigated in chronic, repeated-dose toxicology studies at very high prucalopride doses in rats and dogs. No relevant effects were observed in any of the cardiovascular studies at concentrations at least 50 times the therapeutic plasma level. Only in pigs were minor and transient increases in heart rate and blood pressure noted upon first exposure to prucalopride, at plasma levels at least 10 times higher than human therapeutic plasma levels. Prucalopride may thus provide therapeutic benefit without the cardiovascular risks reported for other 5-HT4 receptor agonists.

166 Changes in e-c coupling proteins and transverse and axial tubular structures in guinea pig ventricular muscle during pre- and post-natal development to adulthood

Transverse tubules (TT), plasmalemma invaginations perpendicular to the long axis of the cardiomyocyte, facilitate rapid action potential transmission to the cell interior and efficient cardiac excitation-contraction coupling (ECC). Tubule alteration...

Rate-dependent activation failure in isolated cardiac cells and tissue due to Na+ channel block.

While it is well established that class-I antiarrhythmics block cardiac sodium channels, the mechanism of action of therapeutic levels of these drugs is not well understood. Using a combination of mathematical modeling and in vitro experiments, we studied the failure of activation of action potentials in single ventricular cells and in tissue caused by Na(+) channel block. Our computations of block and unblock of sodium channels by a theoretical class-Ib antiarrhythmic agent predict differences in the concentrations required to cause activation failure in single cells as opposed to multicellular preparations. We tested and confirmed these in silico predictions with in vitro experiments on isolated guinea-pig ventricular cells and papillary muscles stimulated at various rates (2-6.67 Hz) and exposed to various concentrations (5 × 10(-6) to 500 × 10(-6) mol/l) of lidocaine. The most salient result was that whereas large doses (5 × 10(-4) mol/l or higher) of lidocaine were required to inhibit action potentials temporarily in single cells, much lower doses (5 × 10(-6) mol/l), i.e., therapeutic levels, were sufficient to have the same effect in papillary muscles: a hundredfold difference. Our experimental results and mathematical analysis indicate that the syncytial nature of cardiac tissue explains the effects of clinically relevant doses of Na(+) channel blockers.

The differential effects of a selective kappa-opioid receptor agonist, U50488, in guinea pig heart tissues.

The differential effects of a selective kappa- (κ-) opioid receptor agonist, U50488, were elucidated by monitoring the contraction of isolated guinea pig atrial and ventricular muscles. In electrically driven left atria, U50488 in nanomolar concentration range decreased the contractile force. Norbinaltorphimine (norBNI), a selective κ-receptor antagonist, and pertussis toxin (PTX) abolished the negative inotropic effect of U50488. In contrast, the inhibitory effect was not affected by the pretreatment of atropine or propranolol. Even though U50488 exerted a negative inotropic effect in the left atrium, it did not affect the contractile force of the right atrium and ventricles paced at 2 Hz. Similarly, the beating rate of the spontaneously beating right atrium was also unaffected by U50488. These results indicate that the activation of κ-opioid receptors can only produce negative inotropic effect in left atria via activation of PTX-sensitive G protein in guinea pigs. The absence of negative inotropic effects in right atria and ventricles suggests that there may be a greater distribution of functional κ-opioid receptors in guinea pig left atria than in right atria and ventricles, and the distribution of the receptors may be species-specific.

Myocardial Depressant Effects of Desflurane

The authors determined whether desflurane altered myocardial excitation-contraction coupling and electrophysiologic behavior in the same manner as isoflurane and sevoflurane. The effects of desflurane on isometric force in guinea pig ventricular papillary muscles were studied in modified standard and in 26 mM K(+) Tyrode solution with 0.1 microm isoproterenol. Desflurane effects on sarcoplasmic reticulum Ca(2+) release were also determined by examining its actions on rat papillary muscles, guinea pig papillary muscles in low-Na(+) Tyrode solution, and rapid cooling contractures. Normal and slow action potentials were recorded using a conventional microelectrode technique. Ca(2+) and K(+) currents of guinea pig ventricular myocytes were examined. Desflurane (5.3% and 11.6%) decreased peak force to approximately 70% and 40% of the baseline, respectively, similar to the effects of equianesthetic isoflurane concentrations. With isoproterenol in 26 mM K(+) Tyrode solution, desflurane markedly depressed late peaking force and modestly depressed early peak force. The rested state contractions of rat myocardium or guinea pig myocardium in low-Na(+) Tyrode solution were modestly depressed, whereas rapid cooling contractures were virtually abolished after desflurane administration. Desflurane significantly prolonged the action potential duration. Desflurane reduced L-type Ca(2+) current and the delayed outward K(+) current but did not alter the inward rectifier K(+) current. Myocardial depression by desflurane is due to decreased Ca(2+) influx, whereas depolarization-activated sarcoplasmic reticulum Ca(2+) release is modestly depressed, similar to the actions of isoflurane and sevoflurane. Desflurane depressed the delayed outward K(+) current associated with significant lengthening of cardiac action potentials.

Bepridil, an Antiarrhythmic Drug, Opens Mitochondrial KATPChannels, Blocks Sarcolemmal KATPChannels, and Confers Cardioprotection

Bepridil, which is clinically useful in the treatment of arrhythmias, has been reported to inhibit sarcolemmal ATP-sensitive K(+) (sarcK(ATP)) channels. However, the effect of bepridil on mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels remains unclear. The objective of the present study was to determine whether bepridil activates mitoK(ATP) channels and confers cardioprotection. SarcK(ATP) channels composed of Kir6.2+SUR2A in human embryonic kidney (HEK) 293 cells were examined using the patch-clamp technique. Flavoprotein fluorescence in guinea pig ventricular cells and matrix volume in isolated rat heart mitochondria were measured to assay mitoK(ATP) channel activity. Mitochondrial Ca(2+) concentration ([Ca(2+)](m)) was measured by loading cells with rhod-2 fluorescence. Coronary-perfused guinea pig ventricular muscles were subjected to 35-min no-flow ischemia followed by 60-min reperfusion. Bepridil (10 microM) completely inhibited the pinacidil-induced Kir6.2+SUR2A channel current expressed in HEK 293 cells. Bepridil reversibly oxidized the flavoprotein and increased mitochondrial matrix volume in a concentration-dependent manner. Furthermore, bepridil significantly attenuated the ouabain-induced increase of [Ca(2+)](m). Pretreatment with bepridil for 5 min before ischemia improved the recovery of developed tension measured after 60 min of reperfusion. These effects of bepridil were abolished by the mitoK(ATP) channel blocker 5-hydroxydecanoate (500 microM) and by the nonselective K(ATP) channel blocker glisoxepide (10 microM). Our results indicate that bepridil is an opener of mitoK(ATP) channels but an inhibitor of sarcK(ATP) channels and exerts a direct cardioprotective effect on native cardiac myocytes. This is the first report of a unique modulator of K(ATP) channels; bepridil would be expected to mitigate ischemic injury while blunting arrhythmias.

Behavior of Ca(2+) waves in multicellular preparations from guinea pig ventricle.

Ca(+) waves have been implicated in Ca(2+) overload-induced cardiac arrhythmias. To deepen understanding of the behavior of Ca(2+) waves in a multicellular system, consecutive two-dimensional Ca(2+) images were obtained with a confocal microscope from surface cells of guinea pig ventricular papillary muscles loaded with fluo 3 or rhod 2. In intact muscles, no Ca(2+) waves were detected under the resting condition, whereas they were frequently observed during the rest immediately after high-frequency stimulations where cytoplasmic Ca(2+) concentration and Ca(2+) stored in the sarcoplasmic reticulum (SR) were gradually decreasing. The intervals of Ca(2+) waves increased as they occurred later, their amplitudes and velocities remaining unchanged. A SERCA inhibitor reversibly prolonged the wave intervals. In Na(+)-free/Ca(2+)-free medium where neither Ca(2+) influx nor Na(+)/Ca(2+) exchange took place, recurrent Ca(2+) waves emerged at constant intervals in each cell. These results are consistent with the conclusion that the loading level of the SR is critical for induction of Ca(2+) waves. Each cell independently exhibited its own regular rhythm of Ca(2+) wave with a distinct interval. These waves propagated in either direction along the longitudinal axis within a muscle cell, but seldom beyond the cell boundary. In contrast, in partially damaged muscles that showed spontaneous Ca(2+) waves at rest in normal Krebs solution, their propagation often was unidirectional, decreasing in frequency. In these cases, however, Ca(2+) waves rarely moved beyond the cellular boundary. The gradient of the cytoplasmic Ca(2+) concentration was suggested to be the cause of the one-way propagation.

Direct Myocardial Depressant Effect of Desflurane: Mechanical and Electrophysiological Actions in Vitro

Background: Desflurane actions on myocardial contractility and cellular electrophysiologic behavior were studied in isolated guinea pig and rat right ventricular papillary muscles. Methods: The isometric force of isolated guinea pig ventricular papillary muscles was studied in normal and 26 mM Tyrode's solution at various stimulation rates. Experiments using rat papillary muscles under normal Tyrode's solution at the rested-state (RS) and using guinea pig papillary muscles under low Tyrode's solution (25 mM) were performed to evaluate the effect of release from the sarcoplasmic reticulum (SR). Effects of desflurane on SR function in situ were examined by its effect on rapid cooling contractures (RCCs). Normal and slow action potentials (APs) were evaluated by using a conventional microelectrode technique. Finally, currents of isolated guinea pig ventricular myocytes were examined using the whole cell patch clamp technique. Results: 1 MAC (minimum alveolar concentration: 6%) and 2 MAC desflurane were applied. 1 MAC and 2 MAC desflurane depressed guinea pig myocardial contractions by 30% and 60%, respectively, from RS to 3 Hz stimulation rates. 1 MAC (1.15%) and 2 MAC isoflurane depressed peak force by 25% and 45%, respectively. Contractile force after rest in rat and guinea pig myocardium under low Tyrode's solution showed modest depression. In the partially depolarized, adrenergically stimulated myocardium, 1 MAC and 2 MAC desflurane caused a marked depression of the late peak force (1 MAC:60%, 2 MAC:80%) with moderate changes of the early peak force (1 MAC: 20%, 2 MAC: 40%). RCCs were abolished at 1 MAC desflurane. Desflurane did not alter the peak amplitude or maximum depolarization rate of normal and slow APs, however, AP duration was significantly prolonged. In isolated guinea pig myocytes at room temperature, 1 MAC and 2 MAC desflurane caused a 28% and 55% decrease in currents, respectively. Conclusions: These results indicate that desflurane causes a dose-dependent depression of contractile force in isolated myocardium, which is comparable to that of isoflurane. The depression seems to be related, at least in part, to its ability to reduce inward currents through the cardiac membrane. Therefore, it is likely that various methods employed to enhance inward current may improve the hemodynamic depression induced by desflurane.

Cardiac electrophysiological modulation by NS-7, a novel neuroprotective drug, of guinea pig ventricular muscles

Effects of NS-7 (1 to 100 μM), a novel neuroprotective drug, on the action potentials in guinea pig ventricular muscles were investigated at different stimulation frequencies, different extracellular Ca 2+ concentrations ([Ca] o) and in the presence of inhibitors for selective delayed rectifier K + channels. A conventional microelectrode technique was carried out. NS-7 caused inhibitory actions on the action potential configuration in a concentration-dependent manner. NS-7 at less concentrations than 30 μM did not affect, but at 100 μM decreased the action potential amplitude (APA) and the maximum rate of depolarization (V max) by 11.1 ± 2.3% (n = 14, P < 0.05) and by 24.3 ± 2.6% (n = 14, P < 0.01), respectively. NS-7 at 100 μM also prolonged the 75 and 90% repolarizations of action potential duration (APD 75 and APD 90) by 14.5 ± 2.2% (n = 14, P < 0.05) and 20.2 ± 2.4% (n = 14, P < 0.01), respectively, but it at any concentrations failed to affect the 50% repolarization of action potential duration (APD 50). The resting potential was unaffected. These responses were almost reversible after 10-to 20-min washout. The stronger inhibition was caused at higher frequencies of stimulation. NS-7 prolonged the APD at lower [Ca] o than 3.6 mM. In the presence of 5 μM E-4031 or 30 μM 293B, NS-7 increased further the APD. These results indicate that NS-7 at relatively higher concentrations produced inhibitory actions on the cardiac muscles, and that the APD prolongation and the V max inhibition induced by NS-7 are dependent on stimulation frequencies, but are independent of [Ca] o levels, resulting in exhibition of its cardioprotective action.

A review of HNS-32: a novel azulene-1-carboxamidine derivative with multiple cardiovascular protective actions.

HNS-32 [N(1),N(1)-dimethyl-N(2)-(2-pyridylmethyl)-5-isopropyl-3,8-dimethylazulene-1- carboxamidine] (CAS Registry Number: 186086-10-2) is a newly synthesized azulene derivative. Computer simulation showed that its three dimensional structure is similar to that of the class Ib antiarrhythmic drugs, e.g., lidocaine or mexiletine. HNS-32 potently suppressed ventricular arrhythmias induced by ischemia due to coronary ligation and/or ischemia-reperfusion in dogs and rats. In the isolated dog and guinea pig cardiac tissues, HNS-32 had negative inotropic and chronotropic actions, prolonged atrial-His and His-ventricular conduction time and increased coronary blood flow. In the isolated guinea pig ventricular papillary muscle, HNS-32 decreased maximal rate of action potential upstroke (Vmax) and shortened action potential duration (APD). These findings suggest that HNS-32 inhibits inward Na+ and Ca2+ channel currents. In the isolated pig coronary and rabbit conduit arteries, HNS-32 inhibited both Ca2+ channel-dependent and -independent contractions induced by a wide variety of chemical stimuli. HNS-32 is a potent inhibitor of protein kinase C (PKC)-mediated constriction of cerebral arteries. It is likely to block both, Na+ and Ca2+ channels expressed in cardiac and vascular smooth muscles. These multiple ion channel blocking effects are largely responsible for the antiarrhythmic and vasorelaxant actions of HNS-32. This drug may represent a novel approach to the treatment of arrhythmias.

Dual Signaling via Protein Kinase C and Phosphatidylinositol 3′-Kinase/Akt Contributes to Bradykinin B2Receptor-induced Cardioprotection in Guinea Pig Hearts

We investigated the role of protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3-K) in the signaling mechanism of cardioprotection afforded by bradykinin (BK). Coronary-perfused guinea pig ventricular muscles were subjected to 20-min no-flow ischemia and 60-min reperfusion. Pretreatment for 5 min with BK (1 μ m) significantly improved the recovery of developed tension measured after 60 min of reperfusion (86.8±2.6%v 34.8±4.1% in control). Prior treatment with B2receptor antagonist HOE 140 completely abolished the protective effect of BK (37.0±7.6%). The protection was reduced by either PKC inhibitor chelerythrine (CH, 58.9±2.2%) or PI3-K inhibitor wortmannin (WM, 59.4±2.5%); however, the recovery of contractility was intermediate between the BK and control groups. Nevertheless, pretreatment with CH and WM together completely eliminated the protective effect of BK (38.9±4.2%). The mitochondrial ATP-sensitive K+(mitoKATP) channel blocker 5-hydroxydecanoate (5HD) significantly but partially inhibited the effect of BK (59.0±2.2%). Pretreatment with 5HD and CH together could not generate further inhibition (61.1±3.3%), while pretreatment with 5HD and WM together totally eliminated the protection (34.9±2.9%). We conclude that BK B2receptors can precondition guinea pig hearts via the dual activation of PKC and PI3-K. The mitoKATPchannels act as downstream targets of PKC, whereas PI3-K is not associated with mitoKATPchannels.

JTV-519, a novel cardioprotective agent, improves the contractile recovery after ischaemia-reperfusion in coronary perfused guinea-pig ventricular muscles.

A newly synthesized benzothiazepine derivative, JTV-519 (JT) has been reported to be cardioprotective. However, the precise mechanism underlying the cardioprotective effect of this drug is unknown. Coronary-perfused guinea-pig ventricular muscles were subjected to 20-min no-flow ischaemia followed by 60-min reperfusion (I/R). I/R significantly decreased the contraction in untreated preparations (control group, 34+/-4% of baseline value, n=6). Brief administration of JT (1.0 microM) prior to ischaemia significantly improved the postischaemic contractile recovery (63+/-5% of baseline value, n=4), as compared to the control group. JT (1.0 microM) slightly prolonged action potential duration before ischaemia and induced conduction disturbance (2 : 1 block) after the initiation of ischaemia. The cardioprotective effect of JT was antagonized by chelerythrine (CH, 5.0 microM), an inhibitor of protein kinase C (PKC) or by 5-hydroxydecanoic acid (5-HD, 400 microM), an inhibitor of mitochondrial ATP-sensitive K(+) (K(ATP)) channels. These results suggest that the protective effect of JT is due to the opening of mitochondrial K(ATP) channels, which, in turn, is linked to PKC activation.

Extracellular ATP induced increase in intracellular Cl- concentrations and its role on spontaneous electrical activities in guinea pig ventricular muscle

Extracellular ATP induced increase in intracellular Cl- concentrations and its role on spontaneous electrical activities in guinea pig ventricular muscle

Cardiac electrophysiological effects of citalopram in guinea pig papillary muscle Comparison with clomipramine

The effect of citalopram, a selective serotonin reuptake inhibitor (SSRI) antidepressant, was studied on cardiac action potential configuration and compared with that of the tricyclic antidepressant (TCA) clomipramine. Conventional microelectrode techniques were used in right ventricular papillary muscle preparations of the guinea pig. Citalopram caused a concentration-dependent (10–100 μM) shortening of action potential duration (APD), depression of plateau and overshoot potential, and reduction of maximum velocity of depolarization ( V max). No significant changes in resting membrane potential were observed. Similar results were obtained with clomipramine; however, reduction of V max and overshoot was more pronounced with clomipramine, whereas citalopram caused relatively greater shortening of APD. Effects of both drugs were partly reversible. The results indicate that the SSRI antidepressant citalopram, similarly to TCA compounds, alters cardiac action potential configuration in guinea pig ventricular muscle, probably owing to inhibition of cardiac Na + and Ca 2+ channels. Differences in cardiac side effects of the two drugs may be related to their different actions on cardiac action potential configuration.

Enhancement of Intracellular Cl Concentrations Induced by Extracellular ATP in Guinea Pig Ventricular Muscle

We investigated effects of extracellular ATP on intracellular chloride activities ([Cl−]i and possible contribution of the Cl−-HCO3− exchange to this increase in [Cl−]i in isolated guinea pig ventricular muscles. The [Cl−]i and intracellular pH (pHO were recorded in quiescent ventricular muscles using double-barreled ion-selective microelectrode techniques. Mg ATP at a concentration higher than 0.1 mM, induced an increase in [Cl−]i, and this increase in [Cl−]i was dependent on the concentration of ATP but not on the concentration of magnesium ions present in the perfusion solution. NaADP, but not NaAMP, at a concentration of 0.5 mM induced a similar increase in [Cl−]i as that induced by MgATP. However, the NaADP-induced increase in [Cl−]i was transient and gradually returned to the control level even though NaADP was continuously present. Furthermore, ATP also triggered a transient acidification of pHi, and both increases in [Cl−]i and intracellular H+ induced by ATP were prevented when preparations were pretreated with stilbene derivatives, SITS and DIDS, or perfused with a Cl−-free solution. Our findings showed that the increased extracellular ATP concentrations might trigger an increase in [Cl−]i in ventricular muscles. In light of previous studies showing that cardiac ischemia induced increases in extracellular nucleotide concentrations and [Cl−]i in ventricular muscles, we propose that ischemia-induced accumulation of ATP concentration in the extracellular space may be an important factor to trigger increment of [Cl−]i during ischemic conditions.

Sodium-pump potentials and currents in guinea-pig ventricular muscles and myocytes

When guinea-pig papillary muscles were depolarized to ca. -30 mV by superfusion with K+-free Tyrode's solution supplemented with Ba2+, Ni2+, and D600, addition of Cs+ transiently hyperpolarized the membrane in a reproducible manner. The size of the hyperpolarization (pump potential) depended on the duration of the preceding K+-free exposure; peak amplitudes (Epmax) elicited by 10 mM Cs+ after 5-, 10-, and 15-min K+-free exposures were 12.9, 17.7, and 23.2 mV, respectively. Pump potentials were unaffected by external Cl- but suppressed by cardiac glycosides, hyperosmotic conditions, and low-Na+ solution. Using Epmax as an indicator of Na+ pump activation, the half-maximal concentration for activation by Cs+ was 12-16.3 mM. At 6 mM, Cs+ was three times less potent than Rb+ or K+ and five times more potent than Li+. From these findings, and correlative voltage-clamp data from myocytes, we calculate that (i) a pump current of 7.8 nA/cm2 generates an Epmax of 1 mV and (ii) resting pump current in normally polarized muscle (approximately 0.16 microA/cm2) is five times smaller than previously estimated.

Inhibition of Na+-K+Pump Alleviates the Shortening of Action Potential Duration caused by Metabolic Inhibition via Blockade of KATPChannels in Coronary Perfused Ventricular Muscles of Guinea-pigs

The Na+-K+pump is a consumer of intracellular ATP. We therefore examined whether blockade of the Na+-K+pump by cardiac glycosides could inhibit ATP-sensitive K+(KATP) channels and prolong the action potential duration (APD) of the guinea-pig ventricular muscles perfused with Tyrode's solution via the coronary artery and stimulated at 3 Hz. The metabolic inhibition (MI) achieved by application of 0.1μm carbonyl cyanidep-(trifluoromethoxy) phenylhydrazone (a mitochondrial uncoupler) shortened the APD in a time-dependent manner. When dihydroouabain (DHO, 5μm) was introduced 5 min but not 10 min after introduction of MI, the APD shortening was significantly attenuated. Application of glibenclamide (1μm), a blocker of KATPchannels, introduced both 5 and 10 min after MI also alleviated the APD shortening; DHO did not alleviate the APD shortening effect produced by cromakalim (5μm), a KATP-channel opener. In separate experiments using whole-cell patch-clamp techniques, we found that this concentration of DHO (5μm) depressed the Na+-K+pump current of the guinea-pig ventricular myocytes from 210 to 100 pA (at 0 mV) or by 49.5%. We conclude that, during early phase (5 min) of MI, the APD shortening mostly results from the activation of KATPchannels, and that even a 50% inhibition of the Na+-K+pump by DHO leads to the blockade of KATPchannels and eventual lengthening of the APD

The relation between the action potential duration, the increase in resting tension, and ATP content during metabolic inhibition in guinea pig ventricular muscles.

To investigate whether the action potential duration (APD) or resting tension was dependent on global ATP content, and whether they were preferentially dependent on glycolytic ATP, APD and resting tension were measured under various metabolic inhibition with corresponding measurement of ATP content in guinea pig ventricular muscles. Oxidative phosphorylation was inhibited by either hypoxic perfusion, the perfusion of sodium cyanide, or 2,4-dinitrophenol. Glycolysis was blocked by the perfusion of iodoacetic acid, and hypoxia with variable glycolytic activities was achieved by hypoxic perfusion in the presence of glucose (5, 10, and 50 mM). APD began to decrease when ATP content decreased to less than 3 mM/kg w.w. from the control level of 4.35 mM/kg w.w. APD shortened significantly and resting tension increased steeply, when ATP content decreased below 1 mM/kg w.w. The dependence of APD and the increase in resting tension on ATP content was not affected by the mode of metabolic block, that is, the inhibition of glycolysis and/or oxidative phosphorylation. Though other factors can affect APD and resting tension, we found no evidence of functional ATP compartmentation, with respect to APD and the increase in resting tension during metabolic inhibition.

Sodium-pump potentials and currents in guinea-pig ventricular muscles and myocytes

Sodium-pump potentials and currents in guinea-pig ventricular muscles and myocytes