Rat Left Ventricular Papillary Muscles Research Articles

Inorganic phosphate accelerates cardiac myofilament relaxation in response to lengthening.

Myocardial relaxation in late systole is enhanced by increasing velocities of lengthening. Given that inorganic phosphate (Pi) can rebind to the force-producing myosin enzyme prior to MgADP release and hasten crossbridge detachment, we hypothesized that myocardial relaxation in late systole would be further enhanced by lengthening in the presence of Pi. Wistar rat left ventricular papillary muscles were attached to platinum clips, placed between a force transducer and a length motor at room temperature, and bathed in Krebs solution with 1.8 mM Ca2+ and varying Pi of 0, 1, 2, and 5 mM. Tension transients were elicited by electrical stimulation at 1 Hz. Peak tension was significantly enhanced by Pi: 0.593 ± 0.088 mN mm−2 at 0 mM Pi and 0.817 ± 0.159 mN mm−2 at 5 mM Pi (mean ± SEM, p < 0.01 by ANCOVA). All temporal characteristics of the force transient were significantly shortened with increasing Pi, e.g., time-to-50% recovery was shortened from 305 ± 14 ms at 0 mM Pi to 256 ± 10 ms at 5 mM Pi (p < 0.01). A 1% lengthening stretch with varying duration of 10–200 ms was applied at time-to-50% recovery during the descending phase of the force transient. Matching lengthening stretches were also applied when the muscle was not stimulated, thus providing a control for the passive viscoelastic response. After subtracting the passive from the active force response, the resulting myofilament response demonstrated features of faster myofilament relaxation in response to the stretch. For example, time-to-70% relaxation with 100 ms lengthening duration was shortened by 8.8 ± 6.8 ms at 0 Pi, 19.6 ± 4.8* ms at 1 mM Pi, 31.0 ± 5.6* ms at 2 Pi, and 25.6 ± 5.3* ms at 5 mM Pi (*p < 0.01 compared to no change). Using skinned myocardium, half maximally calcium-activated myofilaments underwent a 1% quick stretch, and the tension response was subjected to analysis for sensitivity of myosin detachment rate to stretch, g 1, at various Pi concentrations. The parameter g 1 was enhanced from 15.39 ± 0.35 at 0 Pi to 22.74 ± 1.31 s−1/nm at 8 Pi (p < 0.01). Our findings suggest that increasing Pi at the myofilaments enhances lengthening-induced relaxation by elevating the sensitivity of myosin crossbridge detachment due to lengthening and thus speed the transition from late-systole to early-diastole.

Description of the Mechanism of Positive Inotropic Action of the Isoquinoline Alkaloid F-18

This study evaluated the mechanism of inotropic effect of an isoquinoline alkaloid derivative, 1-(2´-bromine-4´,5´-dimethoxyphenyl)-6,7-dimethoxy-1,2,3,4- tetrahydroisoquinoline (F-18) using electrically stimulated rat left ventricular papillary muscle of rat. The F-18 alkaloid have been shown to have positive inotropic effect on papillary muscle contraction activity, IC50 value -14,6 µM. Са2+L-channel blocker - nifedipine was used in experiments. Inotropic effects of F-18 isoquinoline alkaloid on cardiomyocytes were suggested, based on results obtained in experiments carried in cardiomyocytes SR Ca2+- transport systems modulation.

Description of the Mechanism of Positive Inotropic Action of the Isoquinoline Alkaloid F-18

This study evaluated the mechanism of inotropic effect of an isoquinoline alkaloid derivative, 1-(2´-bromine-4´,5´-dimethoxyphenyl)-6,7- dimethoxy-1,2,3,4- tetrahydroisoquinoline (F-18) using electrically stimulated rat left ventricular papillary muscle of rat. The F-18 alkaloid have been shown to have positive inotropic effect on papillary muscle contraction activity, IC50 value -14,6 μM. Са2+L-channel blocker - nifedipine was used in experiments. Inotropic effects of F-18 isoquinoline alkaloid on cardiomyocytes were suggested, based on results obtained in experiments carried in cardiomyocytes SR Ca2+- transport systems modulation.

Interaction of Metabolic and Respiratory Acidosis with α and β-adrenoceptor Stimulation in Rat Myocardium

The effects of acute respiratory versus metabolic acidosis on the myocardium and their consequences on adrenoceptor stimulation remain poorly described. We compared the effects of metabolic and respiratory acidosis on inotropy and lusitropy in rat myocardium and their effects on the responses to α- and β-adrenoceptor stimulations. The effects of acute respiratory and metabolic acidosis (pH 7.10) and their interactions with α and β-adrenoceptor stimulations were studied in isolated rat left ventricular papillary muscle (n=8 per group). Intracellular pH was measured using confocal microscopy and a pH-sensitive fluorophore in isolated rat cardiomyocytes. Data are mean percentages of baseline±SD. Respiratory acidosis induced more pronounced negative inotropic effects than metabolic acidosis did both in isotonic (45±3 versus 63±6%, P<0.001) and isometric (44±5 versus 64±3%, P<0.001) conditions concomitant with a greater decrease in intracellular pH (6.85±0.07 versus 7.12±0.07, P<0.001). The response to α-adrenergic stimulation was not modified by respiratory or metabolic acidosis. The inotropic response to β-adrenergic stimulation was impaired only in metabolic acidosis (137±12 versus 200±33%, P<0.001), but this effect was not observed with administration of forskolin or dibutiryl-cyclic adenosine monophosphate. This effect might be explained by a change in transmembrane pH gradient only observed with metabolic acidosis. The lusitropic response to β-adrenergic stimulation was not modified by respiratory or metabolic acidosis. Acute metabolic and respiratory acidosis induce different myocardial effects related to different decreases in intracellular pH. Only metabolic acidosis impairs the positive inotropic effect of β-adrenergic stimulation.

Intermedin elicits a negative inotropic effect in rat papillary muscles mediated by endothelial-derived nitric oxide

Intermedin (IMD) is a novel vasoactive peptide from the calcitonin gene-related peptide (CGRP) implicated in cardiac regulation, yet the contractile effects of IMD remain controversial, since previous studies in vivo and isolated cardiomyocytes documented contradictory results. We hypothesized cardiac endothelial cells involvement in IMD modulation of cardiac function as an explanation for these opposing observations. With this in mind, we investigated the direct action of increasing concentrations of IMD (10(-8) to 10(-6)M) on myocardial performance parameters in rat left ventricular (LV) papillary muscles with and without endocardial endothelium (EE) and in presence of receptor antagonists and intracellular pathways inhibitors. In LV papillary muscles with intact EE, IMD induced a concentration-dependent negative inotropic action (%decrease relative to baseline, at IMD concentration of 10(-6)M, active tension of 14 ± 4%, and maximum velocity of tension rise of 10 ± 4%). These effects were blunted by EE removal, AM receptor antagonist (AM(22-52)), and CGRP receptor antagonist (CGRP(8-37)). Additionally, nitric oxide (NO) synthase inhibition with N(G)-nitro-l-arginine (l-NAME) in muscles with and without EE and guanylyl cyclase inhibition with {1H-[1,2,4]oxadiazole-[4,4-a]-quinoxalin-1-one} not only blunted the negative inotropic action of IMD but also unmasked IMD-positive inotropic effect dependent on CGRP receptor PKA activation. Western blot quantification of phosphorylated cardiac troponin I (P-cTnI) in IMD-treated papillary muscles revealed a significant increase in P-cTnI when compared with untreated muscles, while in l-NAME-pretreated papillary muscles IMD failed to increase P-cTnI. Finally, we found that stimulation of both EE and microvascular endothelial cells with IMD significantly increased NO production by 40 ± 3 and 38 ± 3%, respectively, suggesting the role of cardiac endothelial cells in NO production upon IMD stimulation. Our findings establish IMD negative inotropic effect in isolated myocardium due to NO/cGMP pathway activation with concomitant thin myofilament desensitization by increase in cTnI phosphorylation and provide a coherent explanation for the previously reported contradictory results.

Pharmacological evidence for Orai channel activation as a source of cardiac abnormal automaticity

Calcium transport through plasma membrane voltage-independent calcium channels is vital for signaling events in non-excitable and excitable cells. Following up on our earlier work, we tested the hypothesis that this type of calcium transport can disrupt myocardial electromechanical stability. Our Western and immunofluorescence analyses show that left atrial and ventricular myocytes express the Orai1 and the Orai3 calcium channels. Adding the Orai activator 2-aminoethoxydiphenyl borate (2-APB) to the superfusate of rat left atria causes these non-automatic muscles to contract spontaneously and persistently at rates of up to 10Hz, and to produce normal action potentials from normal resting potentials, all in the absence of external stimulation. 2-APB likewise induces such automatic activity in superfused rat left ventricular papillary muscles, and the EC50s at which 2-APB induces this activity in both muscles are similar to the concentrations which activate Orais. Importantly, the voltage-independent calcium channel inhibitor 1-[2-(4-methoxyphenyl)-2-[3-(4-methoxyphenyl) propoxy]ethyl-1H-imidazole (SKF-96365) suppresses this automaticity with an IC50 of 11±0.6μM in left atria and 6±1.6μM in papillary muscles. 1-(5-Iodonaphthalene-1-sulfonyl)-hexahydro-1,4-diazepine (ML-7), a second voltage-independent calcium channel inhibitor, and two calmodulin inhibitors also prevent 2-APB automaticity while two calmodulin-dependent protein kinase II inhibitors do not. Thus an activator of the Orai calcium channels provokes a novel type of high frequency automaticity in non-automatic heart muscle.

Abstract 271: Ca 2+ /Calmodulin-Dependent Kinase Kinase β (CaMKKβ) Contributes to AMPK Activation in the Heart during Hypoxia

AMP-activated protein kinase (AMPK) is a stress signaling enzyme that regulates important cellular responses to ischemic stress in the heart. AMPK stimulates glucose uptake and utilization during myocardial ischemia and limits cardiac apoptosis and contractile dysfunction associated with ischemia/reperfusion injury. Activation of AMPK involves allosteric regulation by AMP/ATP ratio as well as phosphorylation by upstream AMPK kinases (AMPKKs) including LKB1 and CaMKKβ. The identity of the AMPKKs involved in the activation of AMPK during myocardial ischemia is not fully defined. The aims of this study were to determine whether CaMKKβ is expressed in the heart and in cardiomyocytes CaMKKβ is activated during ischemia and CaMKKβ contributes to AMPK activation during ischemia. CaMKKβ mRNA and protein were found to be expressed in mouse and rat hearts and isolated rat cardiomyocytes. To determine whether myocardial ischemia stimulates CaMKKβ activity in vivo , mouse hearts were subjected to regional ischemia by LAD occlusion, and assessed for phosphorylation of CaMKI (Thr 177 ), a direct downstream substrate of CaMKKβ. There was a 4-fold increase in CaMKI phosphorylation on its activating Thr 177 site within 2–5 min of ischemia (p&lt;0.05 vs. control). CaMKKβ signaling was transiently activated and correlated with the initial rise in AMPK phosphorylation during the early phase of myocardial ischemia. To further determine whether CaMKKβ participates in ischemia-induced heart AMPK activation and glucose uptake, isolated rat left ventricular papillary muscles were subjected to hypoxia in the presence of a specific CaMKKβ inhibitor, STO-609 (2 μM). CaMKKβ inhibition resulted in a 60% reduction in hypoxia-induced AMPK activation (p&lt;0.01 vs. hypoxia). In addition, inhibition of CaMKKβ yielded an 85% and 30% reduction in hypoxia-induced ACC phosphorylation and glucose uptake, respectively (p&lt;0.05 vs. hypoxia), two well-known downstream consequences of AMPK activation. CONCLUSION: Myocardial ischemia leads to an early, transient stimulation of the CaMKKβ pathway which correlates with the initial activation of AMPK during ischemic stress. CaMKKβ partially mediates hypoxia-induced activation of AMPK pathway in the heart.

Comparison of the effects of mepivacaine and lidocaine on rat myocardium

To compare the inotropic and lusitropic effect of lidocaine and mepivacaine on rat papillary muscle. Effects of lidocaine and mepivacaine (10-8-10-3 M) were studied in rat left ventricular papillary muscles in vitro at a calcium concentration of 1 mmol, under low (isotony) and high (isometric) loads. Lidocaine induced a significant negative inotropic effect in isotonic and isometric conditions whereas mepivacaine did not. Mepivacaine only induced a negative inotropic effect when added as a bolus for the highest concentration and this effect was significantly more pronounced with lidocaine than with mepivacaine (active force at 10-3 M: 63 +/- 10 vs. 84 +/- 10% of baseline, P < 0.05). Increasing calcium concentration resulted in a greater positive inotropic effect in the control (199 +/- 11% of baseline) and mepivacaine groups (197 +/- 22% of baseline) when compared to the lidocaine group (163 +/- 19% of baseline, P < 0.05 vs. lidocaine and control groups), suggesting an impairment on intracellular Ca2+ handling by lidocaine. A negative lusitropic effect under low load was observed only for mepivacaine and suggested an impairment of sarcoplasmic reticulum function. Lidocaine and mepivacaine did not modify post-rest potentiation but significantly depressed the force-frequency relationship. The negative inotropic and lusitropic effects induced by lidocaine were more important than that of mepivacaine and may involve an impairment of intracellular Ca2+ handling.

Nifedipine enhances cGMP production through the activation of soluble guanylyl cyclase in rat ventricular papillary muscle

It is known that nifedipine, an L-type calcium channel blocker, increases cGMP production, which partially contributes to the relaxation of vascular smooth muscle. The aim of our investigation was to clarify whether or not nifedipine regulates cGMP production, which has a physiological role in cardiac muscle. To measure contractile responses and tissue cGMP levels, left ventricular papillary muscles prepared from male Wistar rats (350-400 g) were mounted in the isolated organ chamber under isometric conditions and electrically paced by means of platinum punctate electrodes (1 Hz, 1 ms duration). In papillary muscle preparation, the negative inotropic effect induced by nifedipine (30 to 300 nM) was significantly inhibited in the presence of ODQ(1H-[1,2,4]oxidazolo[4,3-a]quinoxaline1-one; 10 microM), a soluble guanylyl cyclase inhibitor. Furthermore, nifedipine (100 nM) strongly increased the tissue cGMP level, which was significantly decreased in the presence of ODQ. On the other hand,N(G)-monomethyl-(L)-arginine (100 microM), a nitric oxide synthase inhibitor, did not inhibit either the negative inotropic effect or cGMP production induced by nifedipine. These results indicate that in rat left ventricular papillary muscle, nifedipine augments its negative inotropic effect at least partly through direct activation of cardiac soluble guanylyl cyclase but not nitric oxide synthase.

Effects of Eugenol, an Essential Oil, on the Mechanical and Electrical Activities of Cardiac Muscle

Eugenol (EUG) acts as a calcium antagonist but effects on the contractile proteins could also occur. We investigated inotropic effects of EUG in rat left ventricular papillary muscles, measuring isometric force, time variables, and post rest potentiation and EUG actions on the effects of Ca2+ (0.62 to 2.5 mM) and isoproterenol (5 ng/ml), on myosin ATPase activity and on the calcium currents in single ventricular myocytes. EUG reduced tension and time variables without altering the sarcoplasmic reticulum activity increasing post-pause relative potentiation. Isoproterenol and Ca2+ counteract these negative inotropic effects. Tetanic tension diminished, but not the myosin ATPase activity suggesting an isolated sarcolemmal effect. EUG 0.1 mM decreased the Ca2+ current amplitude in the entire potential range tested and 0.5 mM almost completely blocked this inward current. Results suggested that EUG depresses force without affecting the contractile machinery and its action is the only dependent blockade of the calcium inward current.

Cellular distribution of GPR14 and the positive inotropic role of urotensin II in the myocardium in adult rat.

Urotensin II is a cyclic neuropeptide recently shown to play a role via its receptor GPR14 in regulating vascular tone in the mammalian cardiovascular system. The existence of GPR14 in rat heart has been validated by ligand binding assay and RT-PCR. In the present study, we investigated the cellular distribution of GPR14 protein in rat heart by using immunohistochemistry and confocal microscopic immunofluorescence double staining with antipeptide polyclonal antibodies against GPR14 and cell type markers for myocytes and endothelial cells. The direct effect of urotensin II on left ventricular contractility was further evaluated in isolated left ventricular papillary muscles of the rat. In paraffin-embedded heart sections, positive immunohistochemical staining was observed in the left ventricle but not in the right ventricle and atria. Immunofluorescence double staining revealed the cardiac myocyte as the only cell type expressing GPR14 protein in frozen heart sections as well as in isolated cardiac myocytes. There was no visible signal for GPR14 in intramyocardial coronary arteries and capillaries. The existence of GPR14 protein in rat heart was further validated by immunoprecipitation and Western blot analysis. In isolated rat left ventricular papillary muscle preparations, urotensin II induced an increase in active contractile force. GPR14 mRNA was also detected in rat heart by RT-PCR. These data provide the first direct evidence for the cellular localization of GPR14 receptor protein and a positive inotropic effect of urotensin II in normal rat heart.

Cardiovascular effects of the toxin(s) of the Australian paralysis tick, Ixodes holocyclus, in the rat

An extract of toxin(s) from the Australian paralysis tick, Ixodes holocyclus, produced positive inotropic responses in rat left ventricular papillary muscles and positive contractile responses in rat thoracic aortic rings. There was no measurable chronotropic response in rat right atria, but positive inotropic concentrations in papillary muscles produced arrhythmias in right atria. Positive inotropic responses were attenuated by verapamil, but unaffected by metoprolol, cimetidine, pyrilamine, tetrodotoxin and pinacidil. Microelectrode studies on isolated left ventricular papillary muscles demonstrated that the extract prolonged action potential duration at 20, 50 and 90% of repolarisation and delayed ventricular papillary muscle relaxation. Cardiovascular tissues isolated from rats with experimentally induced tick paralysis showed no myocardial damage as identified by histological and ultrastructural examination. The basal rate and force of contraction of isolated cardiac tissues were lower from tick-paralysed than normal rats. Concentration–response curves to dobutamine and calcium chloride were similar between tissues from tick-paralysed and normal rats. Thus, the Australian paralysis tick, I. holocyclus, produces one or more toxins with direct cardiovascular effects which mimic the effects produced by direct blockade of cardiac and vascular K + channels.

Initial mechanical efficiency of isolated cardiac muscle.

The aim of this study was to determine whether the initial mechanical efficiency (ratio of work output to initial metabolic cost) of isolated cardiac muscle is over 60%, as has been reported previously, or whether it is approximately 30%, as suggested by an estimate based on the well-established net mechanical efficiency (ratio of work output to total, suprabasal energy cost) of 15%. Determination of initial efficiency required separation of the enthalpy output (i.e. heat + work) into initial and recovery components. The former corresponds to energy produced by reactions that use high-energy phosphates and the latter to energy produced in the regeneration of high-energy phosphates. The two components were separated mathematically. Experiments were performed in vitro (30 degrees C) using preparations dissected from rat left ventricular papillary muscles (N=13). Muscle work output and heat production were measured during a series of 40 contractions using a contraction protocol designed to mimic in vivo papillary muscle activity. Net mechanical efficiency was 13.3+/-0.7%. The total enthalpy output was 2.16 times greater than the initial enthalpy output, so that initial mechanical efficiency was 28.1+/-1.2%.

Interaction of protamine with alpha- and beta-adrenoceptor stimulations in rat myocardium.

Protamine alters the inotropic responses to beta-adrenoceptor stimulation, but its mechanism of action is not well-understood. Moreover, its interaction with alpha-adrenoceptor stimulation and the lusitropic (relaxation) response to beta-adrenoceptor stimulation remain unknown. The effects of protamine (10 or 100 microg/ml) on the responses induced by phenylephrine and isoproterenol were studied in rat left ventricular papillary muscles. Inotropic and lusitropic effects were studied under low and high loads. The authors also studied the interaction of protamine with forskolin (50 microm) and dibutyryl 3',5'-cAMP (0.5 mm). Data are mean percentage of baseline active force +/- SD. In control groups, phenylephrine (135 +/- 17%, P < 0.05) and isoproterenol (185 +/- 44%, P < 0.05) induced a positive inotropic effect. Isoproterenol induced positive lusitropic effects under low and high loads. Protamine abolished the inotropic responses to alpha- (102 +/- 23%, not significant) and beta-adrenoceptor stimulations (99 +/- 17%, not significant) but did not modify the lusitropic responses to isoproterenol. Protamine abolished the inotropic responses to forskolin (89 +/- 6 vs. 154 +/- 20%, P < 0.05) and markedly decreased that of dibutyryl 3',5'-cAMP (132 +/- 31 vs. 167 +/- 30%, P < 0.05) but did not modify their lusitropic responses. Protamine abolished the inotropic responses to alpha- and beta-adrenoceptor stimulations but preserved the lusitropic responses to beta-adrenoceptor stimulation. Although protamine may act at several sites on the adrenoceptor stimulation cascade, one of its main sites of action is situated downstream from cAMP-mediated phosphorylation.

Pertussis toxin-sensitive and -insensitive mechanisms of α 1-adrenoceptor-mediated inotropic responses in rat heart

In rat left ventricular papillary muscle, phenylephrine, an α1-adrenoceptor agonist, induced a triphasic inotropic response; an initial transient, small, positive inotropic effect followed by a transient chloroethylclonidine-sensitive negative inotropic effect and a sustained 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB4101)-sensitive positive inotropic effect. Treatment with pertussis toxin for 2 days significantly inhibited only the transient negative inotropic effect without changing the sustained positive inotropic effect. This treatment also prevented the acetylcholine (1 μM)-induced negative inotropic effect. Further, phenylephrine-induced transient negative inotropic effect was attenuated in the presence of ouabain. These results suggest that pertussis toxin-sensitive or-insensitive G-protein may be responsible for α1-adrenoceptor subtype-mediated negative inotropic effect or positive inotropic effect, respectively, in which the transient negative inotropic effect was produced via the stimulation of Na +, K + pump, presumably through pertussis toxin-sensitive G-protein-dependent pathway.

Extracellular calcium modulates the effects of protamine on rat myocardium.

We studied the effects of protamine (10-300 microg. mL(-1)) as well as its interaction with heparin in rat left ventricular papillary muscles in vitro at calcium concentrations of 0.5 and 1 mM under low (isotony) and high (isometry) loads. Protamine induced a negative inotropic effect that was less pronounced at calcium 0.5 mM (active force at protamine 300 microg/mL, 84 +/- 20 vs 57 +/- 15% of baseline, P: < 0.05); whereas at calcium 1 mM there was a marked contracture of the muscle. For the smallest concentrations of protamine and at calcium 0.5 mM, we observed a moderate positive inotropic effect that was suppressed by nifedipine. Protamine induced a negative lusitropic effect under low load and decreased postrest potentiation, suggesting an impairment in the functions of the sarcoplasmic reticulum. Heparin was able to inhibit and reverse the negative inotropic effect of protamine. The negative inotropic effect of protamine is enhanced by an increase in extracellular calcium concentration. This negative inotropic effect is probably related to calcium overload and impairment in sarcoplasmic reticulum functions, and heparin can block these effects. The negative inotropic effect of protamine is enhanced by an increase in extracellular calcium concentration. This negative inotropic effect is probably related to calcium overload and impairment in sarcoplasmic reticulum functions, and heparin can block these effects.

Mechanical and electrophysiological effects of thiopental on rat cardiac left ventricular papillary muscle

Thiopental induces a negative inotropic effect on mammalian heart muscle, where it decreases Ca2+ current and Ca2+ release from the sarcoplasmic reticulum and reduces K+ currents. We analysed the effects of thiopental on the mechanical and electrical activities of rat myocardium, which differ markedly from those of other mammals. The effects of thiopental on mechanical parameters and on the transmembrane resting (RP) and action (AP) potentials of rat left ventricular papillary muscle were investigated. These effects were also studied in the presence of atenolol, a beta-blocking agent, and 4-aminopyridine (4-AP), a blocker of the transient outward K+ current. Thiopental (3.8 x 10(-6), 3.8 x 10(-5) and 1.1 x 10(-4) M) induced a dose-dependent positive inotropic effect. This positive inotropic effect persisted in the presence of atenolol (1 x 10(-6) M) but did not develop in the presence of 1 mM 4-AP; 4-AP had a positive inotropic effect but not in the presence of thiopental. Moreover, thiopental (3.8 x 10(-5) M) lengthened the plateau and the slow repolarizing phase of the AP, while 1 mM 4-AP only prolonged the plateau duration. In rat myocardium, the positive inotropic effect of thiopental in part mimics that of 4-AP, and in part may be explained by the lengthening of the slow repolarizing phase of the AP.

Energetics of rat papillary muscle during contractions with sinusoidal length changes.

The mechanical efficiency of rat cardiac muscle was determined using a contraction protocol involving cyclical, sinusoidal length changes and phasic stimulation at physiological frequencies (1-4 Hz). Experiments were performed in vitro (27 degrees C) using rat left ventricular papillary muscles. Efficiency was determined from measurements of the net work performed and enthalpy produced by muscles during a series of 40 contractions. Net mechanical efficiency was defined as the percentage of the total, suprabasal enthalpy output that appeared as mechanical work. Maximum efficiency was approximately 15% at contraction frequencies between 2 and 2.5 Hz. At lower and higher frequencies, efficiency was approximately 10%. Enthalpy output per cycle was independent of cycle frequency at all but the highest frequency used. The basis of the high efficiency between 2 and 2.5 Hz was that work output was also greatest at these frequencies. At these frequencies, the duration of the applied length change was well matched to the kinetics of force generation, and active force generation occurred throughout the shortening period.

Interaction of halogenated anesthetics with dobutamine in rat myocardium.

Halogenated anesthetics potentiate the positive inotropic effects of alpha- and beta-adrenoceptor stimulations, but their interactions with dobutamine remain unknown. The effects of halothane, isoflurane, sevoflurane, and desflurane (1 and 2 minimum alveolar concentration) on the inotropic responses induced by dobutamine (10(-8)-10(-4) M) were studied in rat left ventricular papillary muscles in vitro. Inotropic effects were studied under low (isotony) and high (isometry) loads. The authors also studied the lusitropic effects in isotonic (R1) and isometric (R2) conditions. Data are the mean percentage of baseline +/- SD. Dobutamine induced a positive inotropic effect (active isometric force: 185+/-36%, P < 0.001) and a positive lusitropic effect under low load (R1: 78+/-9%, P < 0.001), but not under high load (R2: 95+/-21%, not significant). Halothane, isoflurane, and sevoflurane did not modify the positive inotropic effect of dobutamine. Even in the presence of alpha-adrenoceptor blockade, isoflurane did not potentiate the positive inotropic effect of dobutamine. Desflurane significantly enhanced the positive inotropic effect of dobutamine (active isometric force: 239+/-35%, P < 0.001), but this potentiation was abolished by pretreatment with reserpine. In contrast to halothane, isoflurane, sevoflurane, and desflurane did not significantly modify the lusitropic effects of dobutamine. Halogenated anesthetics, except desflurane, did not modify the positive inotropic effects of dobutamine. Desflurane enhanced the positive inotropic effect of dobutamine, but this effect was related to the desflurane-induced release in intramyocardial catecholamine stores.

Modifications of the inotropic responses to alpha- and beta-adrenoceptor stimulation by propofol in rat myocardium.

Propofol induces cardiovascular depression but without significant effect on intrinsic myocardial contractility in many species. However, its interactions with adrenoceptor stimulation are unknown. We studied the effects of propofol (1 and 10 microg/mL) and its solvent on the inotropic response induced by phenylephrine (10(-8)-10(-4) M) or isoproterenol (10(-8)-10(-4) M) in rat left ventricular papillary muscles in vitro (Krebs-Henseleit solution, 29 degrees C, pH 7.40, calcium 0.5 mM, stimulation frequency 12 pulses/min). We also studied the lusitropic effects in isotonic and isometric conditions. In control groups, phenylephrine (127% +/- 3% of baseline; P < 0.05) and isoproterenol (169% +/- 11% of baseline; P < 0.05) induced a positive inotropic effect. Propofol (10 microg/mL) completely abolished the positive inotropic effect of phenylephrine (100% +/- 3% of baseline; P = not significant). In contrast, at the lowest concentration (1 microg/mL), propofol did not modify the positive inotropic effect of phenylephrine. Propofol did not modify the inotropic effect of isoproterenol. Propofol (10 microg/mL) enhanced the positive lusitropic effect of isoproterenol under low-load (P < 0.05) but not under high-load conditions. A high concentration of propofol abolished the positive inotropic effect of alpha- but not beta-adrenoceptor stimulation and enhanced the positive lusitropic effect of beta-adrenoceptor stimulation.