The transgenic expression of highly inhibitory monomeric forms of phospholamban in mouse heart impairs cardiac contractility

Transgenic mice were generated with cardiac-specific overexpression of the monomeric, dominant-acting, superinhibitory L37A and I40A mutant forms of phospholamban (PLN), and their phenotypes were compared with wild-type (wt) mice or 2-fold overexpressors of wt PLN (wtOE). The level of PLN monomer in cardiac microsomes was increased 11-13-fold, and the apparent affinity of the sarco(endo)plasmic reticulum Ca(2+)-ATPase for Ca(2+) was decreased from pCa 6.22 in wt or 6.12 in wtOE to 5.81 in L37A and 5.72 in I40A. Basal physiological parameters, measured in isolated myocytes, indicated a significant reduction in the rates of shortening (+dL/dt) and relengthening (-dL/dt). Hemodynamic measurements indicated that peak systolic pressure was unaffected but that pressure changes (+dP/dt and -dP/dt) were lowered significantly in both mutant lines, and relaxation time (tau) was also lengthened significantly. Echocardiography for both mutants showed depressed systolic function and an increase in left ventricular mass of over 1.4-fold. Significant decreases in left ventricular shortening fraction and velocity of circumferential shortening and increases in ejection time were corrected by isoproterenol. The use of antibodies specific against Ser(16)- and Thr(17)-PLN peptides showed that phosphorylation of both pentameric and monomeric PLN were increased between 1.2- and 2.4-fold in both the L37A and I40A lines but not in the wtOE line. These observations show that overexpression of superinhibitory mutant forms of PLN causes depression of contractile parameters with induction of cardiac hypertrophy, as assessed with echocardiography.     

The Effects of Temperature upon Contraction and Ionic Exchange in Rabbit Ventricular Myocardium : Relation to control of active state

The mechanical responses (active and resting tension, dP/dt, TPT) and ionic exchange characteristics (Ca⁺⁺, K⁺, Na⁺) which follow upon a variation in temperature, rate, and [K⁺]₀ were studied in the rabbit papillary muscle and arterially perfused rabbit interventricular setpum. Abrupt changes in temperature provided a means of separating the contributions of rate of development (intensity) of active state and duration of active state to total active tension development (approximated by isometric tension). Threefold changes in duration of active state with proportional changes in active tension can be induced without evidence for alteration of Ca⁺⁺, K⁺, or Na⁺ exchange. Abrupt cooling produced a moderate (~15%) increase of dP/dt which suggests an augmentation of active state intensity. Evidence is presented to suggest that this increase of dP/dt is based upon an increase in membrane Ca⁺⁺ concentration which occurs secondary to inhibition of active Na⁺ transport. The alterations in ionic exchange and active state produced by variation of temperature are discussed in terms of a five-component control system.     

Gender differences on the effects of aging on cardiac and peripheral adrenergic stimulation in old conscious monkeys

We examined the effects of gender and aging on cardiac and peripheral hemodynamic responses to beta-adrenergic receptor (beta-AR) stimulation in young (male = 5.9 +/- 0.4 yr old and female = 6.5 +/- 0.7 yr old) and old (male = 19.8 +/- 0.7 yr old and female = 21.2 +/- 0.2 yr old) conscious monkeys (Macaca fascicularis), chronically instrumented for measurements of left ventricular (LV) and arterial pressures as well as cardiac output. Baseline LV pressure, the first derivative of LV pressure (LV dP/dt), cardiac index, mean arterial pressure, total peripheral resistance (TPR), and heart rate in conscious monkeys were not different among the four groups. Increases in LV dP/dt in response to 0.1 microg/kg isoproterenol (Iso) were diminished (P < 0.05) in old males (+99 +/- 11%) compared with young males (+194 +/- 18%). In addition, the inotropic responses to norepinephrine (NE) and forskolin (FSK) were significantly depressed (P < 0.05) in old males. Iso-induced reductions of TPR were less (P < 0.05) in old males (-28 +/- 2%) than in young males (-49 +/- 2%). The changes of TPR in response to NE and FSK were also significantly attenuated (P < 0.05) in old males. However, the LV dP/dt responses to BAY y 5959 (15 microg. kg-1. min-1), a Ca2+ channel promotor independent of beta-AR signaling, were not significantly different between old and young males. In contrast to results in male monkeys, LV dP/dt and TPR responses to Iso, NE, and FSK in old females were similar to those observed in young females. Thus both cardiac contractile and peripheral vascular dynamic responses to beta-AR stimulation are preserved in old female but not old male monkeys. This may explain, in part, the reduced cardiovascular risk in the older female population.     

Depression of posttetanic twitch potentiation by low calcium and calcium channel antagonists

The purpose of this investigation was to determine if antagonizing extracellular calcium influx altered posttetanic twitch potentiation (PTP). Whole muscles and muscle fiber bundles (less than or equal to 25 fibers) dissected from frog sartorius and semitendinosus muscles were mounted at optimal length in a normal Ringer solution (NR). To determine PTP, isometric twitches were evoked every 10 s (0.1 Hz) before and after a 2.5-s tetanic contraction (80 Hz). To antagonize calcium influx, low-calcium Ringer [LCR, calcium replaced by 3 mM magnesium and 1 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid], NR plus diltiazem (Dilt, 30 microM), NR plus nifedipine (Nif, 10 microM), and NR plus D 600 (30 microM) were also used (n = 8 for each condition). These conditions altered pretetanic twitch tension by only -1.2 +/- 2.4, 4.2 +/- 2.3, 4.7 +/- 3.7, and 1.6 +/- 3.7% (SE), (LCR, Dilt, Nif, and D 600, P greater than 0.05) but caused a noticeable decrease in tension at the end of the tetanus. Under NR conditions, twitches evoked immediately after the tetanus were potentiated by 49.5 +/- 0.4% with the peak rate of tension development (dP/dt) increased by 44.9 +/- 0.5% (P less than 0.05). Antagonizing calcium influx depressed the PTP response by 59.8 +/- 6.2, 55.9 +/- 10.1, 73.2 +/- 6.8, and 29.8 +/- 3.6% (P less than 0.05) and increased dP/dt by 65.8 +/- 11.1, 45.7 +/- 8.6, 55.6 +/- 4.4% and 49.0 +/- 10.5% (P less than 0.05). Addition of drugs immediately after the tetanus only slightly reduced PTP but accelerated recovery of the twitch.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of milrinone on left ventricular relaxation and Ca(2+) uptake function of cardiac sarcoplasmic reticulum

Milrinone, a phosphodiesterase 3 (PDE3) inhibitor, is known to enhance left ventricular (LV) contractility by an inhibition of the breakdown of cAMP through the mechanism inhibiting PDE3. However, it is unclear whether milrinone also exerts positive lusitropy, like dobutamine. Here, we assessed the effects of milrinone on in vivo LV relaxation, as well as the Ca(2+)-ATPase activity and the Ca(2+) uptake function of the cardiac sarcoplasmic reticulum (SR), compared with the effect of dobutamine on those functions. After dobutamine (3 microg x kg(-1) x min(-1)) was administered, the peak value of the first derivative of LV pressure (+dP/dt) increased by 46%, whereas the time constant (tau) of LV pressure decay decreased by 6.9%, respectively. After milrinone (10 microg/kg) was administered, the peak +dP/dt increased to a similar extent as dobutamine (46%), whereas tau decreased much more than dobutamine (19.9%; P < 0.05). In LV crude homogenate, the thapsigargin-sensitive, Ca(2+)-ATPase activity-cAMP relationships was significantly less increased by milrinone compared with dobutamine (P < 0.05), indicating the higher sensitivity of the SR Ca(2+)-ATPase activity on cAMP by milrinone than by dobutamine. In the SR vesicles purified from LV muscles, the addition of cAMP increased the SR Ca(2+) uptake in a dose-dependent fashion, and the PDE3 inhibitors (milrinone and cGMP) significantly augmented this response (P < 0.05). Hence, milrinone substantially improved LV relaxation in association with an acceleration of the SR Ca(2+)-ATPase activity and the SR Ca(2+) uptake. This acceleration might be due to an inhibition of the membrane-bound PDE3 in the SR, leading to a local elevation of cAMP.     

Modeling of summation of individual twitches into unfused tetanus for various types of rat motor units.

Repeated stimulation of motor units (MUs) causes an increase of the force output that cannot be explained by linear summation of equal twitches evoked by the same stimulation pattern. To explain this phenomenon, an algorithm for reconstructing the individual twitches, that summate into an unfused tetanus is described in the paper. The algorithm is based on an analytical function for the twitch course modeling. The input parameters of this twitch model are lead time, contraction and half-relaxation times and maximal force. The measured individual twitches and unfused tetani at 10, 20, 30 and 40 Hz stimulation frequency of three rat motor units (slow, fast resistant to fatigue and fast fatigable) are processed. It is concluded that: (1) the analytical function describes precisely the course of individual twitches; (2) the summation of equal twitches does not follow the results from the experimentally measured unfused tetani, the differences depend on the type of the MU and are bigger for higher values of stimulation frequency and fusion index; (3) the reconstruction of individual twitches from experimental tetanic records can be successful if the tetanus is feebly fused (fusion index up to 0.7); (4) both the maximal forces and time parameters of individual twitches subtracted from unfused tetani change and influence the course of each tetanus. A discrepancy with respect to the relaxation phase was observed between experimental results and model prediction for tetani with fusion index exceeding 0.7. This phase was predicted longer than the experimental one for better fused tetani. Therefore, a separate series of physiological experiments and then, more complex model are necessary for explanation of this distinction.     

Short-term exercise improves myocardial tolerance to in vivo ischemia-reperfusion in the rat.

These experiments examined the independent effects of short-term exercise and heat stress on myocardial responses during in vivo ischemia-reperfusion (I/R). Female Sprague-Dawley rats (4 mo old) were randomly assigned to one of four experimental groups: 1) control, 2) 3 consecutive days of treadmill exercise [60 min/day at 60-70% maximal O2 uptake (VO2 max)], 3) 5 consecutive days of treadmill exercise (60 min/day at 60-70% VO2 max), and 4) whole body heat stress (15 min at 42 degrees C). Twenty-four hours after heat stress or exercise, animals were anesthetized and mechanically ventilated, and the chest was opened by thoracotomy. Coronary occlusion was maintained for 30-min followed by a 30-min period of reperfusion. Compared with control, both heat-stressed animals and exercised animals (3 and 5 days) maintained higher (P < 0.05) left ventricular developed pressure (LVDP), maximum rate of left ventricular pressure development (+dP/dt), and maximum rate of left ventricular pressure decline (-dP/dt) at all measurement periods during both ischemia and reperfusion. No differences existed between heat-stressed and exercise groups in LVDP, +dP/dt, and -dP/dt at any time during ischemia or reperfusion. Both heat stress and exercise resulted in an increase (P < 0.05) in the relative levels of left ventricular heat shock protein 72 (HSP72). Furthermore, exercise (3 and 5 days) increased (P < 0.05) myocardial glutathione levels and manganese superoxide dismutase activity. These data indicate that 3-5 consecutive days of exercise improves myocardial contractile performance during in vivo I/R and that this exercise-induced myocardial protection is associated with an increase in both myocardial HSP72 and cardiac antioxidant defenses.     

Effects of naloxone on systemic and regional hemodynamic responses to exercise in dogs

To determine whether endogenous opiates have a role in circulatory regulation during mild to moderate exercise, 11 chronically instrumented dogs were exercised on a treadmill up a 6% incline at 2.5 and 5.0 mph, each for 20 min, after treatment with either the opiate receptor antagonist naloxone (1 mg/kg bolus and 20 micrograms.kg-1.min-1 infusion) or normal saline. Naloxone increased plasma beta-endorphin and adrenocorticotropic hormone at rest but had no effect on resting heart rate, aortic pressure, cardiac output, left ventricular time derivative of pressure (dP/dt) and ratio of dP/dt at a developed pressure of 50 mmHg and the developed pressure (dP/dt/P), or plasma catecholamines. Plasma beta-endorphin and adrenocorticotropic hormone increased during exercise. In addition, graded treadmill exercise produced proportional increases in heart rate, cardiac output, aortic pressure, left ventricular dP/dt and dP/dt/P, and blood flow to exercising muscles, right and left ventricular myocardium, and adrenal glands. However, there were no differences in the circulatory responses to exercise between animals receiving naloxone and normal saline. Thus the endogenous opiate system probably does not play an important role in regulating the systemic hemodynamic and blood flow responses to mild and moderate exercise.     

Continuum rheology of muscle contraction and its application to cardiac contractility.

A set of constitutive equations is proposed to describe the mechanics of contraction of skeletal and heart muscle. Fiber tension is assumed to depend on the degree of chemical activation, the stretch ratio, and the rate of stretching of the fibers. The time rate of change of activation is governed by a differential equation. The proposed constitutive equations are used to model the time courses of isotonic and isometric twitches during contraction and relaxation phases of the muscle response to stimulation. Various contractility indices of the left ventricle are considered next by using the proposed constitutive equations. The present analysis introduces a new interpretation of the index of contractility (dP/dt)/P used in cardiac literature. It is shown that this index may not be related at all to the maximum speed of shortening and that it may be dependent on both preload and afterload. The development of pressure during isovolumetric contraction of the left ventricle is shown to be governed by a differential equation describing the time rate of change of tension during isometric contraction of myocardium fibers.     

Cardiac responsiveness to beta-adrenergic stimulation in experimental anemia.

Cardiac reactivity of beta-adrenergic stimulation was assessed by isoproterenol dose-reponse curves (dose range 0.025-0.4 mug/kg) before and 1 h after the rapid induction of anemia in dogs anesthetized with halothane:N2O:O2. Anemai (hematocrit = 16 +/- 4%) was induced by an isovolumic exchange transfusion with Dextran 70, and was followed by significant increments in cardiac output (+57 +/- 9%), max dP/dt of the left ventricle (+37 +/- 7%), and in peak acceleration of blood flow in the ascending aorta (+46 +/- 13%). Anemia was associated with a significant reduction of the chronotropic responses to all but the lowest dose of isoproterenol. The simultaneously determined inotropic responses (max dP/dt) where the same before and after the induction of anemia. The responses in terms of peak acceleration of aortic blood flow tended to be greater in the anemic than in the control phase, at all dose levels used. These findings indicate that in rapidly induced experimental anemia the heart is capable of responding to marked degrees of beta-adrenergic stimulation, representing a more than two-fold increase in the dP/dt.     

Modulation of stimulation frequency responses and calcium dependency of functional parameters in hyperthyroid rat ventricular papillary muscles

The effects of stimulation frequency (0.2-1.5 Hz) and extracellular calcium concentration ([Ca2+]o) (0.6-15.0 mM) on the contractile function of thin papillary muscles of euthyroid and hyperthyroid rats were studied. Hyperthyroidism led to a decrease in developed tension (DT) and time to peak tension (TPT), but it exhibited no influence on the maximal rates of contraction (+dT/dt) and relaxation (-dT/dt). Also, the mean rates of contraction were similar in euthyroid and hyperthyroid muscle groups. The increase in stimulation frequency brought about a marked decrease in DT, +dT/dt, and -dT/dt of euthyroid papillary muscles at lower frequencies in comparison to papillary muscles in the hyperthyroid group. At stimulation frequencies above 1.0 Hz, the absolute and relative levels of DT and -dT/dt of hyperthyroid myocardium were elevated over euthyroid preparations. At the same time, TPT was unchanged in any of the muscle groups. Hyperthyroidism modulated the relationships between contractile parameters and [Ca2+]o. At a [Ca2+]o of 1.0-4.0 mM, the DT of hyperthyroid papillary muscles was lower than in euthyroid muscle. At 4.0 and 8.0 mM of [Ca2+]o, the equal values of maximal DT were registered for euthyroid and hyperthyroid papillary muscles, respectively. An increase in the [Ca2+]o in the range of 1.0-15.0 mM was accompanied by an increase in TPT of both muscle groups, but to a greater extent in hyperthyroid myocardium. In conclusion, the myocardium of hyperthyroid rat appeared to exhibit decreased sensitivity to calcium as well as to the negative inotropic effect of enhanced stimulation frequency. Alterations of the processes of transsarcolemmal movement and intracellular recycling of Ca2 may be implicated.     

Mechanism of preserved positive lusitropy by cAMP-dependent drugs in heart failure

In tachycardia-induced heart failure (HF), positive lusitropic effects of milrinone or dobutamine were assessed by evaluating the time constant of left ventricular (LV) pressure decay (tau) and Ca(2+)-ATPase activity of the sarcoplasmic reticulum (SR). The peak value of the positive first derivative of LV pressure (+dP/dt) was less increased, either by dobutamine (2-10 microg x kg(-1) x min(-1)) or by milrinone (4-20 microg/kg), in HF than in control (P < 0.05), whereas tau was shortened to an extent similar to that in control with dobutamine [P = not significant (NS)] and to an even greater extent with milrinone (P < 0.05). Ca(2+)-ATPase activity increased similarly in HF and control with dobutamine (1 microM; +11% in HF vs. +12% in control, P = NS), whereas it increased more with milrinone (1 microM; +19% in HF vs. +11% in control, P < 0.05). Ca(2+)-ATPase activity-cAMP relationships were shifted to the left by milrinone or dobutamine in HF compared with control. Thus, in HF, the sensitivity of Ca(2+)-ATPase activity to cAMP was increased on addition of cAMP-dependent inotropic agents, contributing to the preservation of positive lusitropy.     

cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors: potential role for nitrosylation

Nitric oxide (NO) has concentration-dependent biphasic myocardial contractile effects. We tested the hypothesis, in isolated rat hearts, that NO cardiostimulation is primarily non-cGMP dependent. Infusion of 3-morpholinosydnonimine (SIN-1, 10(-5) M), which may participate in S-nitrosylation (S-NO) via peroxynitrite formation, increased the rate of left ventricular pressure rise (+dP/dt; 19 +/- 4%, P < 0.001, n = 11) without increasing effluent cGMP or cAMP. Superoxide dismutase (SOD; 150 U/ml) blocked SIN-1 cardiostimulation and led to cGMP elaboration. Sodium nitroprusside (10(-10)-10(-7) M), an iron nitrosyl compound, did not augment +dP/dt but increased cGMP approximately eightfold (P < 0.001), whereas diethylamine/NO (DEA/NO; 10(-7) M), a spontaneous NO. donor, increased +dP/dt (5 +/- 2%, P < 0.05, n = 6) without augmenting cGMP. SIN-1 and DEA/NO +dP/dt increase persisted despite guanylyl cyclase inhibition with 1H-(1,2,4)oxadiazolo-(4,3,-a)quinoxalin-1-one (10(-5) M, P < 0.05 for both donors), suggesting a cGMP-independent mechanism. Glutathione (5 x 10(-4) M, n = 15) prevented SIN-1 cardiostimulation, suggesting S-NO formation. SIN-1 also produced SOD-inhibitable cardiostimulation in vivo in mice. Thus peroxynitrite and NO donors can stimulate myocardial contractility independently of guanylyl cyclase activation, suggesting a role for S-NO reactions in NO/peroxynitrite-positive inotropic effects in intact hearts.     

The relationship between contractile force and intracellular [Ca2+] in intact rat cardiac trabeculae

The control of force by [Ca2+] was investigated in rat cardiac trabeculae loaded with fura-2 salt. At sarcomere lengths of 2.1-2.3 microns, the steady state force-[Ca2+]i relationship during tetanization in the presence of ryanodine was half maximally activated at a [Ca2+]i of 0.65 +/- 0.19 microM with a Hill coefficient of 5.2 +/- 1.2 (mean +/- SD, n = 9), and the maximal stress produced at saturating [Ca2+]i equalled 121 +/- 35 mN/mm2 (n = 9). The dependence of steady state force on [Ca2+]i was identical in muscles tetanized in the presence of the Ca(2+)-ATPase inhibitor cyclopiazonic acid (CPA). The force-[Ca2+]i relationship during the relaxation of twitches in the presence of CPA coincided exactly to that measured at steady state during tetani, suggesting that CPA slows the decay rate of [Ca2+]i sufficiently to allow the force to come into a steady state with the [Ca2+]i. In contrast, the relationship of force to [Ca2+]i during the relaxation phase of control twitches was shifted leftward relative to the steady state relationship, establishing that relaxation is limited by the contractile system itself, not by Ca2+ removal from the cytosol. Under control conditions the force-[Ca2+]i relationship, quantified at the time of peak twitch force (i.e., dF/dt = 0), coincided fairly well with steady state measurements in some trabeculae (i.e., three of seven). However, the force-[Ca2+]i relationship at peak force did not correspond to the steady state measurements after the application of 5 mM 2,3-butanedione monoxime (BDM) (to accelerate cross-bridge kinetics) or 100 microM CPA (to slow the relaxation of the [Ca2+]i transient). Therefore, we conclude that the relationship of force to [Ca2+]i during physiological twitch contractions cannot be used to predict the steady state relationship.     

Zinc-induced alterations in contractile properties of rat diaphragm muscle in vitro

The effect of zinc ions on the isometric contraction of rat diaphragm muscles in the presence and in the absence of external calcium was studied. Using a transducer, the isometric force was measured as a function of supramaximal electrical stimulation, either directly or indirectly applied to the muscle. The following parameters were measured: peak twitch tension, PT, twitch contraction time, CT, relaxation half-time, RT-1/2, and peak rates of tension increase and decrease, +dP/dt and -dP/dt. The following zinc-induced alterations were observed: an increase of the PT; a decrease of the RT-1/2; an increase in the +dP/dt and -dP/dt. The CT was not changed significantly. Our results suggest that zinc ions have a positive inotropic effect on isolated diaphragm muscle. The increase in PT may be explained by a zinc-activated Ca²⁺ uptake by sarcoplasmic reticulum. This was followed by an increase in the rate of rise of tension development, which was secondary to increased -dP/dt. The mechanism(s) by which extracellular Ca²⁺ contributes to this action of zinc is not known.     

Assessing left ventricular systolic dysfunction after myocardial infarction: are ejection fraction and dP/dt(max) complementary or redundant?

Among the various cardiac contractility parameters, left ventricular (LV) ejection fraction (EF) and maximum dP/dt (dP/dt(max)) are the simplest and most used. However, these parameters are often reported together, and it is not clear if they are complementary or redundant. We sought to compare the discriminative value of EF and dP/dt(max) in assessing systolic dysfunction after myocardial infarction (MI) in swine. A total of 220 measurements were obtained. All measurements included LV volumes and EF analysis by left ventriculography, invasive ventricular pressure tracings, and echocardiography. Baseline measurements were performed in 132 pigs, and 88 measurements were obtained at different time points after MI creation. Receiver operator characteristic (ROC) curves to distinguish the presence or absence of an MI revealed a good predictive value for EF [area under the curve (AUC): 0.998] but not by dP/dt(max) (AUC: 0.69, P < 0.001 vs. EF). Dividing dP/dt(max) by LV end-diastolic pressure and heart rate (HR) significantly increased the AUC to 0.87 (P < 0.001 vs. dP/dt(max) and P < 0.001 vs. EF). In na?ve pigs, the coefficient of variation of dP/dt(max) was twice than that of EF (22.5% vs. 9.5%, respectively). Furthermore, in n = 19 pigs, dP/dt(max) increased after MI. However, echocardiographic strain analysis of 23 pigs with EF ranging only from 36% to 40% after MI revealed significant correlations between dP/dt(max) and strain parameters in the noninfarcted area (circumferential strain: r = 0.42, P = 0.05; radial strain: r = 0.71, P < 0.001). In conclusion, EF is a more accurate measure of systolic dysfunction than dP/dt(max) in a swine model of MI. Despite the variability of dP/dt(max) both in na?ve pigs and after MI, it may sensitively reflect the small changes of myocardial contractility.     

Short-term exercise training can improve myocardial tolerance to I/R without elevation in heat shock proteins

We examined the effects of 3 days of exercise in a cold environment on the expression of left ventricular (LV) heat shock proteins (HSPs) and contractile performance during in vivo ischemia-reperfusion (I/R). Sprague-Dawley rats were divided into the following three groups (n = 12/group): 1) control, 2) exercise (60 min/day) at 4 degrees C (E-Cold), and 3) exercise (60 min/day) at 25 degrees C (E-Warm). Left anterior descending coronary occlusion was maintained for 20 min, followed by 30 min of reperfusion. Compared with the control group, both the E-Cold and E-Warm groups maintained higher (P < 0.05) LV developed pressure, first derivative of pressure development over time (+dP/dt), and pressure relaxation over time (-dP/dt) throughout I/R. Relative levels of HSP90, HSP72, and HSP40 were higher (P < 0.05) in E-Warm animals compared with both control and E-Cold. HSP10, HSP60, and HSP73 did not differ between groups. Exercise increased manganese superoxide dismutase (MnSOD) activity in both E-Warm and E-Cold hearts (P < 0.05). Protection against I/R-induced lipid peroxidation in the LV paralleled the increase in MnSOD activity whereas lower levels of lipid peroxidation were observed in both E-Warm and E-Cold groups compared with control. We conclude that exercise-induced myocardial protection against a moderate duration I/R insult is not dependent on increases in myocardial HSPs. We postulate that exercise-associated cardioprotection may depend, in part, on increases in myocardial antioxidant defenses.     

Overexpression of Na+/Ca2+ exchanger gene attenuates postinfarction myocardial dysfunction

We monitored myocardial function in postinfarcted wild-type (WT) and transgenic (TG) mouse hearts with overexpression of the cardiac Na(+)/Ca(2+) exchanger. Five weeks after infarction, cardiac function was better maintained in TG than WT mice [left ventricular (LV) systolic pressure: WT, 41 +/- 2; TG, 58 +/- 3 mmHg; P < 0.05; maximum rising rate of LV pressure (+dP/dt(max)): WT, 3,750 +/- 346; TG, 5,075 +/- 334 mmHg/s; P < 0.05]. The isometric contractile response to beta-adrenergic stimulation was greater in papillary muscles from TG than WT mice (WT, 13.2 +/- 0.9; TG, 16.3 +/- 1.0 mN/mm(2) at 10(-4) M isoproterenol). The sarcoplasmic reticulum (SR) Ca(2+) content investigated by rapid cooling contractures in papillary muscles was greater in TG than WT mouse hearts. We conclude that myocardial function is better preserved in TG mice 5 wk after infarction, which results from enhanced SR Ca(2+) content via overexpression of the Na(+)/Ca(2+) exchanger.     

Changes in the time course of potentiated and fatigued contractions of fast motor units in rat muscle

The contraction and relaxation times of the twitches and the last contractions within 32 unfused tetani of FF and 27 unfused tetani of FR motor units in the rat medial gastrocnemius muscle were studied during prolonged activity. The pattern of the MU stimulation included single pulses (to evoke twitches) and series of three trains of stimuli at 40, 50 and 60 Hz (to evoke unfused tetani), repeated 30 times. The analysis concerned changes of force and time parameters at the beginning of activity, during the potentiation and then during the fatigue. It was found that changes of force during the potentiation and the fatigue were mainly accompanied by changes in the course of relaxation. The significant prolongation of the half-relaxation time during the potentiation of either twitches or unfused tetani was revealed in both types of fast MU. The twitch contraction time did not change markedly, whereas significantly shortened in the last contractions of unfused tetani during the potentiation. These changes of time parameters correlated to the increase of the fusion degree. During the fatigue, the time parameters shortened, however, changes of the half-relaxation times were remarkably higher. The shortening of relaxation was responsible for the decrease of the fusion degree. Changes of the fusion index exceeding 0.75 during the potentiation or decreasing below this value during the fatigue, were accompanied by respective appearance or disappearance of the biphasic relaxation.