Peak Developed Tension Research Articles

Exaggerated blood pressure response to static exercise in hindlimb ischemia-reperfusion.

Peripheral artery disease (PAD) reduces the blood flow supply in the affected limbs as one of the significant cardiovascular concerns. Revascularization surgery in the femoral artery plays a central role in treating PAD. Exercise is also a rehabilitation strategy suggested for PAD patients to improve vascular functions. However, the effects of limb ischemia-reperfusion (IR), one of the most predominant complications in revascularization surgery, on exercise-induced arterial blood pressure (BP) response are poorly understood. In the present study, we determined 1) the blood flow status in the hindlimb muscles of rats (plantar muscle, red and white portions of gastrocnemius) with different time points of the hindlimb IR; and 2) the BP response to static muscle contraction in rats at different time points after the blood flow reperfusion procedure. Results of this study indicated that, compared with the Sham group, the blood flow in the hindlimb muscles evaluated by Evans blue concentration was significantly reduced at 6h of femoral artery occlusion (FAO 6h) (vs. sham control, p < 0.05). The decreased blood flow was gradually recovered after the blood flow reperfusion for 18 (IR 18h), 66 (IR 66h), and 114 (IR 114h) hours (p < 0.05 vs. FAO 6h for all IR groups). The response of mean arterial pressure was 20 ± 4mmHg in Sham rats (n = 7); 32 ± 10mmHg in IR 18h rats (n = 10); 27 ± 7mmHg in IR 66h rats (n = 13); 26 ± 4mmHg in IR 114h rats (n = 9) (p < 0.05 vs. Sham for all groups). No significant difference was observed in the peak-developed tension during muscle contraction among all the groups (p > 0.05). In conclusion, static exercise-induced BP response is exaggerated following IR. Whereas the BP response is not statistically significant but tends to decrease with a prolonged IR time, the exaggerated BP response remains through time points from post-IR 18h-114h.

Abstract 10234: Exaggerated Blood Pressure Response to Static Exercise Following Muscle Ischemia-Reperfusion: A Time-Course Investigation

Background: Peripheral artery disease (PAD) is one of the major cardiovascular concerns and dramatically reduces the blood flow supply in the affected limbs. A combination of revascularization surgery in the femoral artery and supervised exercise intervention is among the most general approaches for the treatment of PAD. However, the effects of ischemia-reperfusion (IR), which is one of the most predominant complications resulting from the revascularization surgery, on exercise-induced arterial blood pressure (BP) response are poorly understood. Methods: We examined the BP response to static muscle contraction in rats at different time points after the IR procedure. Four groups were included: 1. Sham rats; 2. Rats with 18 hours following IR (IR 18h); 3. Rats with 66 hours following IR (IR 66h); 4. Rats with 114 hours following IR (IR 114h). One-way ANOVA with LSD post-hoc test was applied to analyze the difference among groups. Data were presented as Mean ± Standard Deviation. Results: Compared with Sham group, the BP response to static muscle contraction was significantly increased in rats with all the investigated time points. The response of mean arterial pressure was 19±3 mmHg in Sham rats (n=6); 29±9 mmHg in IR 18h rats (n=8); 26±7 mmHg in IR 66h rats (n=10); 26±4 mmHg in IR 114h rats (n=9) ( P &lt;0.05; the groups at three time courses vs. Sham). There was no significant difference observed in the peak developed tension during muscle contraction among all the groups (Sham rats: 543±101g; IR 18h rats: 520±28g; IR 66h rats: 554±66g; IR 114h rats: 562±45g; P &gt;0.05). Conclusions: IR significantly exaggerates the static exercise-induced BP response. Whereas the BP response tends to decrease with the prolonged IR time, the exaggerated BP response remains through time points from post IR 18 hours to 114 hours. The data suggest that a chronic time course should be considered to alleviate IR-induced ischemic injury in PAD patients for clinical interventions appropriated and exercise.

Administration of Losartan Improves Myocardial Functional Performance in Rats with High‐Fat Diet‐Induced Obesity

Extensive evidence has shown that high‐fat diet is associated with chronic activation of the renin‐angiotensin system (RAS) and left ventricular remodeling. This study was developed to evaluate the impact of angiotensin‐1 (AT1) receptor antagonism on myocardial function in rats with high‐fat diet‐induced obesity.MethodsMale Wistar rats (n=48) were fed a control (2.9 kcal/g, C) or high‐fat (3.6 kcal/g, O) diet for 20 weeks. After the 16th week, the rats were assigned into four groups: C, O, CL, and OL. CL and OL groups received Losartan (30 mg/kg/day) in drinking water during four weeks. At the end of the experiment, body composition and systolic blood pressure were assessed, and echocardiogram analysis was performed. Mechanical performance of papillary muscles was evaluated under basal condition with 2.5 mM calcium ([Ca+2])o and after inotropic stimulation: post‐rest contraction (PRC) and change in extracellular [Ca+2]o from 1.0 to 2.5 mM.ResultsBoth O and OL groups presented higher body weight and adiposity than their respective controls (p&lt;0.05). Systolic blood pressure did not differ among groups. O and OL groups had greater left ventricular weight‐to‐tibia length ratio and posterior wall shortening velocity (C 42.92±4.45; O 48.72±4.81; CL 42.82±3.60; OL 47.96±4.03 mm/s). In papillary muscles evaluation, CL presented reduced negative tension derivative (‐dT/dt) in comparison to the C group at basal condition. After 60 seconds of PRC, both O and CL had lower relative variations in ‐dT/dt (C 55.9±20.9; O 47.1±13.3; CL 47.7±15.9; OL 51.1±14.5%) and peak developed tension than C. Also, OL had higher relative variation in DT than CL and O (C 65.7±23.6; O 56.3±13.9; CL 58.0±17.4; OL 66.4±17.4%), while variation of positive tension derivative (+dT/dt) was increased in OL compared to CL and O groups. After increasing [Ca2+]o to 2.0 and 2.5 mM, the relative variation in DT and +dT/dt were higher in OL than CL and O, respectively. OL showed increased ‐dT/dt in comparison to CL at extracellular calcium concentrations of 1.5, 2.0, and 2.5 mM.ConclusionAngiotensin II antagonism with losartan improves myocardial functional performance in rats with high‐fat diet induced‐obesity.Support or Funding InformationFinancial support: CAPES; CNPq; FUNDECT/MS.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Taurine protects cardiac contractility in killifish, Fundulus heteroclitus, by enhancing sarcoplasmic reticular Ca2+ cycling.

Intracellular taurine is abundant in many animals and it influences an array of physiological processes, including osmoregulation, metabolism, and cardiac contractility. Taurine is an important osmolyte in teleost hearts, but its role in stress tolerance, cardiac metabolism, and contractility has not been assessed. The goal of this study was to determine if ventricular taurine concentration changes in response to environmental stress and to characterize its influence on contractility. Cardiac taurine concentrations varied in killifish (Fundulus heteroclitus) but were generally maintained following acute environmental challenges. In isometrically contracting ventricular strips, supplemental taurine (40mmol L-1) protected peak tension development (F max) at high stimulation frequencies, an effect abolished by treatment with ryanodine, a blocker of sarcoplasmic reticulum Ca2+ release. In the presence of ryanodine, taurine-treated preparations were also better able to maintain F max at supraphysiological extracellular Ca2+ levels, but a prior anoxia exposure abolished this effect. Taurine had no impact on basal F max during or after anoxia, but it provided additive protection to high-frequency contractility post-anoxia. Tissue oxygen consumption and extracellular glucose utilization were unaffected by taurine in non-contracting preparations, indicating that it does not impact energy metabolism. Overall, the results suggest that cardiac taurine levels are well maintained on acute time scales in this highly stress-tolerant species. Supplemental taurine has no effect on aerobic metabolism in vitro, but it significantly improved cardiac contractility in a manner dependent upon sarcoplasmic reticulum Ca2+ cycling. The data indicate that taurine likely plays an important role in the regulation of cardiac performance in teleosts.

Cytosolic calcium transients are a determinant of contraction-induced HSP72 transcription in single skeletal muscle fibers.

The intrinsic activating factors that induce transcription of heat shock protein 72 (HSP72) in skeletal muscle following exercise remain unclear. We hypothesized that the cytosolic Ca(2+) transient that occurs with depolarization is a determinant. We utilized intact, single skeletal muscle fibers from Xenopus laevis to test the role of the cytosolic Ca(2+) transient and several other exercise-related factors (fatigue, hypoxia, AMP kinase, and cross-bridge cycling) on the activation of HSP72 transcription. HSP72 and HSP60 mRNA levels were assessed with real-time quantitative PCR; cytosolic Ca(2+) concentration ([Ca(2+)]cyt) was assessed with fura-2. Both fatiguing and nonfatiguing contractions resulted in a significant increase in HSP72 mRNA. As expected, peak [Ca(2+)]cyt remained tightly coupled with peak developed tension in contracting fibers. Pretreatment with N-benzyl-p-toluene sulfonamide (BTS) resulted in depressed peak developed tension with stimulation, while peak [Ca(2+)]cyt remained largely unchanged from control values. Despite excitation-contraction uncoupling, BTS-treated fibers displayed a significant increase in HSP72 mRNA. Treatment of fibers with hypoxia (Po2: <3 mmHg) or AMP kinase activation had no effect on HSP72 mRNA levels. These results suggest that the intermittent cytosolic Ca(2+) transient that occurs with skeletal muscle depolarization provides a sufficient activating stimulus for HSP72 transcription. Metabolic or mechanical factors associated with fatigue development and cross-bridge cycling likely play a more limited role.

Vascular Remodeling–Associated Hypertension Leads to Left Ventricular Hypertrophy and Contractile Dysfunction in Profilin-1 Transgenic Mice

Hypertension is a major health problem and a main risk factor for cardiovascular diseases. We have shown that overexpression of profilin-1 in blood vessels of transgenic mice generates mechanical tone and led to vascular remodeling/hypertension. However, little is known whether cardiac contractile performance in these mice is compromised. We investigated the in vivo contractile function and in vitro contractile performance using isolated papillary muscles from both right ventricle and left ventricle of profilin-1 mice at older age. Our results showed mild left ventricular hypertrophy and moderate systolic dysfunction in profilin-1 mice as evident by increased heart/body weight ratio and echocardiography analysis. Under near physiological conditions, right ventricle papillary muscles of profilin-1 mice maintained their peak isometric active developed tension, and the rate of force development over the entire frequency range of 4-14 Hz. Positive inotropic responses to increasing Ca and β-adrenergic stimulation were also maintained. Conversely, left ventricular papillary muscles of profilin-1 mice exhibited depressed peak isometric, peak isometric active developed tension and rate of force development, and depressed positive inotropic responses to increasing Ca and β-adrenergic stimulation. We here provide functional evidence that a significant contractile dysfunction in profilin-1 mice exists. Targeting vascular profilin-1 signaling could represent a promising therapeutic approach in hypertensive patients.

Cократительные свойства и мышечно-сухожильная жесткость трехглавой мышцы голени и их изменения в результате продолжительного постельного режима

The effect of a 120-day 5 degree head-down tilt (HDT) bed rest on the mechanical properties and electromechanical delay (EMD) of the human triceps surae (TS) muscle was studied in four (mean age 31.5+/-1.7 yr) healthy young women subjects. The TS mechanical properties were evaluated based on the following indicators: maximal voluntary contraction (MVC), maximal strength (Po; frequency 150 Hz), peak twitch force (Poc), time-to-peak tension (TPT), half-relaxation time (1/2 RT) and tension development time to reach 25, 50, 75 and 90% of maximal tension. Force deficit (Pd) were estimated. In response to a light signal,the subject was supposed to make a voluntary foot flexion, with the instruction "to exert the fastest and greatest tension". EMD measurements were recorded from each subject during voluntary contraction. Surface electrodes sensed electromyographic (EMG) activity in the soleus muscle. A separate timer was used to determine total reaction time (TRT). Premotor time (PMT) was taken to be the time interval from the delivery of the signal to change in EMG. EMD was the time interval between the change in EMG and movement i.e. the time interval between EMG and the onset of muscle tension. After HDT Poe, MVC and Po decreased by 24.4, 36.1 and 11.5%, respectively, while Pd increased by 38.8%. TPT increased by 13.6%, while 1/2RT decreased by 19.2%. The rate of increase of voluntary contractions calculated according to a relative scale significantly increased, while the rate of development of electrically evoked contraction did not show any significant differences. The voluntary contraction EMD increased by 27.4%; PMT by 8.7%, and TRT by 13.6%. Thus, the mechanical changes suggest that weightlessness changes not only the peripheral processes associated with contractions but also the central and neural command. EMD is a simple and quick method for evaluation of muscle stiffness changes. Moreover, EMD can serve as an indicator of the functional condition of the neuromuscular system.

The Positive Inotropic Effect of Relaxin-2 in Human Atrial Myocardium is Preserved in End-Stage Heart Failure: Role of G i-Phosphoinositide-3 Kinase Signaling

Background Relaxin-2, a candidate drug for acute heart failure, has been tested successfully in the first human trials. We investigated relaxin’s inotropic effects in human myocardium. Methods and Results In atrial samples from donor (n = 7) and failing (n = 7) hearts, relaxin-2 evoked remarkable positive inotropic effects: showing a half maximum effective concentration of < 1 nmol/L, the maximum peak developed tension (PDT) rose to approximately 270% of baseline, without differences between failing and nonfailing myocardium. The effects critically depended on protein kinase A activation and inhibition of the transient potassium outward current; phosphoinositide-3 kinase inhibition and pertussis toxin pretreatment moderately blunted the effects in nonfailing but markedly suppressed them in failing myocardium. Action potential recordings revealed identical effects of inhibition of the transient potassium outward current and relaxin. In ventricular myocardium, however, relaxin did not show any inotropic effects. The expression of the RXFP1 receptor was moderately decreased in failing compared with nonfailing atrial myocardium but not detectable in any ventricular samples. Conclusions Relaxin is a positive inotrope in nonfailing and failing human atria, with critical involvement of protein kinase A and inhibition of the transient potassium outward current and an increasing role for G i protein–phosphoinositide-3 kinase signaling in failing myocardium.

Abstract 1595: Positive Inotropic Effect Of Relaxin-2 In Atrial Myocardium Of Terminally Failing Hearts: Role Of Protein Kinase A And Potassium Channels

The insulin-like peptide relaxin, a pregnancy hormone, exerts anti-fibrotic, renal, central nervous, and vascular effects, and is a positive inotropic agent in rat atrial myocardium. We have recently demonstrated that relaxin acts as compensatory mediator in human heart failure. This is the first investigation of the inotropic effects of relaxin-2 in human myocardium. We used human right and left atrial as well as right and left ventricular myocardial samples obtained from donor hearts that were not transplanted for technical reasons (n=5) and from explanted, terminally failing hearts (n=8; 4 patients with dilated cardiomyopathy, 4 patients with ischemic cardiomyopathy). In right and left atrial preparations from both donor and failing hearts, human relaxin-2 evoked positive inotropic effects (EC50 of peak developed tension for isometric twitches; donor, 0.5 ± 0.1 nM [right atrium] and 0.6 ± 0.1 nM [left atrium]; failing, 0.6 ± 0.1 nM [right atrium] and 0.6 ± 0.1 nM [left atrium]; maximum peak developed tension in percent of baseline; donor, 283 ± 35 % [right atrium] and 267 ± 30 % [left atrium]; failing, 258 ± 38 % [right atrium] and 268 ± 34 % [left atrium]). These effects could be prevented by treatment with the protein kinase A inhibitor 5–24 amide and with glibenclamide, a blocker of ATP-sensitive potassium channels. Staurosporine, a protein kinase C inhibitor, and KT-5823, a protein kinase G inhibitor, had no effects. On the other hand, a positive inotropic effect of relaxin-2 could be found neither in donor nor in failing right and left ventricular myocardium although all preparations showed similar inotropic responses to increased extracellular calcium concentrations. In conclusion, our findings indicate that the positive inotropic atrial effect of human relaxin-2 is well preserved in terminally failing human myocardium. The effect is mediated via protein kinase A and ATP-sensitive potassium channels. In ventricular myocardium, there is no such inotropic action of relaxin.

Myocardial contractile dysfunction contributes to the development of heart failure in rats with aortic stenosis

Objectives To analyze the potential contribution of contractility state and ventricular geometry to the development of heart failure in rats with aortic stenosis. Methods Rats were divided into three groups: compensated aortic stenosis (AS, n = 11), heart failure AS ( n = 12) and control rats (C, n = 13). Results After 21 weeks, failing AS rats presented higher systolic (C = 36.6 ± 3.1, AS = 78.6 ± 4.8 ⁎, failing AS = 104.6 ± 7.8 ⁎ †) and diastolic meridian stress (C = 6.9 ± 0.4, AS = 20.1 ± 1.1 ⁎, failing AS = 43.2 ± 3.2 ⁎ †), hydroxyproline (C = 3.6 ± 0.7 mg/g, AS = 6.6 ± 0.6 ⁎ mg/g, failing AS = 9.2 ± 1.4 ⁎ † mg/g) and cross-sectional area (C = 338 ± 25 μm 2, AS = 451 ± 32 ⁎ μm 2, failing AS = 508 ± 36 ⁎ † μm 2), in comparison with control and compensated AS animals ( ⁎ p < 0.05 vs. control, † p < 0.05 vs. AS). In the isometric contraction study, considering the time from peak tension to 50% relaxation (RT 50), the relative variation responses, following post-rest contraction and increase in Ca 2+ concentration, were higher in failing AS than compensated AS animals. In contrast, following post-rest contraction, compensated AS group presented higher values of the peak developed tension (DT) than failing AS group. Following beta-adrenergic stimulation, control animals presented higher values of + d T/d t and − d T/d t than AS animals. In addition, failing AS animals presented higher TPT values than compensated AS animals. Conclusion Myocardial contractile dysfunction contributes to the development of heart failure in rats with aortic stenosis.

Impact of Diabetes on Microvascular PO2 and Tension in Rat Extensor Digitorum Longus (EDL) Muscle

Microvascular PO (PO m) on-kinetics are accelerated in the spinotrapezius muscle of diabetic rats (Am J Physiol 283: H926, 2002). The faster PO2m on-kinetics in diabetic skeletal muscle appear to be associated with the structural and functional changes in the microcirculation, however direct correlations to muscle tension development have not been performed. PURPOSE: To test the hypotheses that; (1) the faster PO2m on-kinetics in diabetic rat skeletal muscle are associated with greater oxygen utilization due to greater tension development, and (2) that insulin therapy will ameliorate the changes in PO2m on-kinetics and tension development. METHODS: Female Sprague-Dawley rats were divided into control (C, n=9; blood glucose, 105 ± 13 mg/dL) and diabetic groups (n=17, 50 mg/kg STZ). Diabetics were subdivided into untreated (D, n=9; glucose, 435 ± 37 mg/dL), and insulin treated diabetic (I, n=8; 4 units insulin glargine/day; glucose, 355 ± 31 mg/dL) groups. Experiments were performed 8–10 wks later. PO2m (phosphorescence quenching) was measured at rest and during electrically stimulated muscle contractions (1 Hz, 6.5 V, 2 ms duration). The distal tendon of the EDL was attached to a force transducer and muscle tension analyzer. Significance at P<0.05. RESULTS: D rats had lower body weight (C, 302 ± 8; D, 225 ± 17; I, 289 ± 5 g) and EDL weight (C, 168 ± 8; D, 90 ± 11; I, 150 ± 4 mg) compared to C and I. Mean arterial pressure (C, 131 ± 10; D, 128 ±7; I, 125 ± 6 mmHg) and arterial PO2 (C, 85 ± 2; D, 76 ± 4; I, 72 ± 2 mmHg) were similar. Resting PO2m was not different among groups (C, 32 ± 3; D, 30 ± 2; I, 25 ± 2 mmHg), however the fall in PO2m during steady-state contractions was less in D and I (C, −20 ± 2; D, −11 ± 2; I, −13 ± 1 mmHg) compared to C. At the onset of contractions, the time delay was similar (C, 5 ± 1; D, 6 ± 1; I, 5 ± 1 s), but the time constant was less in D and I rats (C, 21 ± 3; D, 14 ± 2; I, 12 ± 1 s). Absolute peak twitch tension (g) was less in D rats, however, due to marked atrophy in D, peak tension per muscle mass was not different (C, 165 ± 19; D, 226 ± 18; I, 180 ±17g/g) CONCLUSION: Insulin treatment prevented the diabetes-induced decreases in body weight and muscle atrophy, but did not restore the PO2m on-kinetics, or magnitude of fall in PO2m. Average peak tension development per g EDL was not different among C, D and I, suggesting that oxygen consumption was similar. These data imply there is a slower increase in oxygen delivery relative to consumption at the onset of contractions in D and I, but that steady-state oxygen delivery is greater, as reflected in a reduced fall in PO m. (Supported by KCOM Graduate Program Committee and the American Heart Association, Heartland Affiliate.)

Prenatal cocaine alone and combined with nicotine alters ANG II and IGF-1 induced left atrial contractions in aging male offspring

Prenatal cocaine or nicotine affects inotropic activity in the hearts of rat offspring. However, the long-term consequence of this exposure on the cardiac response to hormonal challenge is unknown. We assessed the inotropic effects of angiotensin II (ANG II) and insulin-like growth factor 1 (IGF-1) in the left atria of 19.0-24.5 month-old male rats exposed on gestation days 8-21 to 1 of 6 treatments: low cocaine (LC) (20 mg/kg) or high cocaine (HC) (40 mg/kg); 20 mg/kg cocaine and high nicotine (5 mg/kg nicotine) (LC/HN); 40 mg/kg cocaine and low nicotine (2.5 mg/kg nicotine) (HC/LN); pair fed: yoked to HC (PF); saline: injection of 0.9% NaCl (SAL). Isometric contractions were assessed by electrical stimulation of isolated left atria superfused with Tyrode solution (control) to which ANG II (10-7 mol/L, 20 min) and IGF-1 (10-8 mol/L, 20 min) in the presence of ANG II were added sequentially. Offspring in all cocaine groups showed a higher peak tension development (PTD) to ANG II than PF controls. This increase in PTD was attenuated by subsequent addition of IGF-1 in all except HC offspring. However, with the HC/LN combination the IGF-1 effect on PTD was again evident. The velocities of contraction and relaxation were positively affected by ANG II only in the combined prenatal drug groups; IGF-1 reduced only contraction velocity. Our data demonstrate that IGF-1 reverses the positive inotropic effect of ANG-II in atrial muscle of aging rats and that gestational exposure to only high doses of cocaine eliminates this protective response. It appears that combined prenatal exposure to cocaine and nicotine does not exacerbate the decline in cardiac function and responsiveness to inotropic drugs seen in the aging heart.

Comparison between the effect of static contraction and tendon stretch on the discharge of group III and IV muscle afferents

The exercise pressor reflex is evoked by both mechanical and metabolic stimuli. Tendon stretch does not increase muscle metabolism and therefore is used to investigate the mechanical component of the exercise pressor reflex. An important assumption underlying the use of tendon stretch to study the mechanical component of the exercise pressor reflex is that stretch stimulates the same group III mechanosensitive muscle afferents as does static contraction. We have tested the veracity of this assumption in decerebrated cats by comparing the responses of group III and IV muscle afferents to tendon stretch with those to static contraction. The tension-time indexes as well as the peak tension development for both maneuvers did not significantly differ. We found that static contraction of the triceps surae muscles stimulated 18 of 30 group III afferents and 8 of 11 group IV afferents. Similarly, tendon stretch stimulated 14 of 30 group III afferents and 3 of 11 group IV afferents. However, of the 18 group III afferents that responded to static contraction and the 14 group III afferents that responded to tendon stretch, only 7 responded to both stimuli. On average, the conduction velocities of the 18 group III afferents that responded to static contraction (11.6 +/- 1.6 m/s) were significantly slower (P = 0.03) than those of the 14 group III afferents that responded to tendon stretch (16.7 +/- 1.5 m/s). We have concluded that tendon stretch stimulated a different population of group III mechanosensitive muscle afferents than did static contraction. Although there is some overlap between the two populations of group III mechanosensitive afferents, it is not large, comprising less than half of the group III afferents responding to static contraction.

Modulation of atrial contraction by PKA and PKC during the compensated phase of eccentric cardiac hypertrophy.

Calcium homeostasis is intimately regulated by protein kinase phosphorylation cascades that are also involved in the induction and maintenance of cardiac hypertrophy. In addition, the development of cardiac hypertrophy has been associated with alteration in the activation of the adrenergic system. Therefore, we investigated the specific role of protein kinase A (PKA) and C (PKC) on cardiac muscle contractile activity in the presence and absence of adrenergic stimulation. Isolated left atrial preparations from sham- and volume overload-induced cardiac hypertrophied rats were superfused with Tyrode and electrically stimulated at 0.75 Hz. Contraction was assessed in the basal and pre-stimulated (norepinephrine, 10(-9)M) states. Specific inhibitors, KT 5720 for PKA and Ro-32-0432 for PKC, were used. Peak tension development in left atria from sham-operated rats was more sensitive to PKC- than PKA-inhibition, whereas this differential sensitivity was abolished in the hypertrophied hearts. This difference was mainly due to an increase in the role of PKA in the contractile response. Developed peak tension by left atria from shunt rats was higher than that from sham rats, but when expressed to relative tissue mass, hypertrophied muscle showed weaker contraction than that from the sham group. In addition, the left atrial velocity of contraction in the sham is PKA-sensitive, while that of the shunt is PKC-sensitive. Furthermore, the velocity of relaxation shows dependency on both protein kinases, with PKC having a greater effect than PKA in the hypertrophied group. NE increased the PTD and the velocity of contraction (+dT/dt) through PKA and PKC dependent mechanisms, without affecting the velocity of relaxation (-dT/dt) in atrial muscle from sham rats. In contrast, during eccentric hypertrophy NE effectively reduced PTD as well as the -dT/dt through a PKC-dependent mechanism. The present study demonstrates that during early development of moderate eccentric cardiac hypertrophy there is: (1) a reduced specific peak tension developed due to an imbalance in the PKA and PKC activation; (2) a change in the protein kinase dependence of the velocity of contraction and relaxation from PKA to PKC with atrial hypertrophy; and (3) a negative inotropic response to adrenergic receptor stimulation. These functional responses may play a critical role in the cardiac performance during the progression of eccentric cardiac hypertrophy into the decompensated phase and heart failure.

Effects of hindlimb unweighting on the mechanical and structure properties of the rat abdominal aorta.

Previous studies have shown that hindlimb unweighting of rats, a model of microgravity, reduces evoked contractile tension of peripheral conduit arteries. It has been hypothesized that this diminished contractile tension is the result of alterations in the mechanical properties of these arteries (e.g., active and passive mechanics). Therefore, the purpose of this study was to determine whether the reduced contractile force of the abdominal aorta from 2-wk hindlimb-unweighted (HU) rats results from a mechanical function deficit resulting from structural vascular alterations or material property changes. Aortas were isolated from control (C) and HU rats, and vasoconstrictor responses to norepinephrine (10(-9)-10(-4) M) and AVP (10(-9)-10(-5) M) were tested in vitro. In a second series of tests, the active and passive Cauchy stress-stretch relations were determined by incrementally increasing the uniaxial displacement of the aortic rings. Maximal Cauchy stress in response to norepinephrine and AVP were less in aortic rings from HU rats. The active Cauchy stress-stretch response indicated that, although maximum stress was lower in aortas from HU rats (C, 8.1 +/- 0.2 kPa; HU, 7.0 +/- 0.4 kPa), it was achieved at a similar hoop stretch. There were also no differences in the passive Cauchy stress-stretch response or the gross vascular morphology (e.g., medial cross-sectional area: C, 0.30 +/- 0.02 mm(2); HU, 0.32 +/- 0.01 mm(2)) between groups and no differences in resting or basal vascular tone at the displacement that elicits peak developed tension between groups (resting tension: C, 1.71 +/- 0.06 g; HU, 1.78 +/- 0.14 g). These results indicate that HU does not alter the functional mechanical properties of conduit arteries. However, the significantly lower active Cauchy stress of aortas from HU rats demonstrates a true contractile deficit in these arteries.

Length-dependent twitch contractile characteristics of skeletal muscle.

The length dependence of force development of mammalian skeletal muscles was evaluated during twitch, double-pulse, and tetanic contractions, and the relation between muscle length and the time-dependent characteristics of twitch and double-pulse contractions were determined. In situ isometric contractions of the rat gastrocnemius muscle were analyzed at seven different lengths, based on a reference length at which the maximal response to double-pulse contractions occurred (Lopt-2P). Twitch and double-pulse contractions were analyzed for developed tension (DT), contraction time (tC), average rate of force development (DT-tC(-1)), half-relaxation time (t50%R), peak rate of relaxation (DT x dtmin(-1)), and 90%-relaxation time (t90%R). Considering the length at which maximal tetanic DT occurred to be the optimal length (Lo-TET), the peak DT for twitch contractions and double-pulse contractions was observed at Lo-TET + 0.75 mm (p < 0.05) and Lo-TET + 0.1 mm (p > 0.05), respectively. When measured at the length for which maximal twitch and double-pulse contractions were obtained, tetanic DT was 95.2 +/- 3 and 99.0 +/- 2% of the maximal value, respectively. These observations suggest that double-pulse contractions are more suitable for setting length for experimental studies than twitch contractions. Twitch and double-pulse contraction tC were 15.53 +/- 1.14 and 25.0 +/- 0.6 ms, respectively, at Lopt-2P, and increased above Lopt-2P and decreased below Lopt-2P. Twitch t50%R was 12.18 +/- 0.90 ms at Lopt-2P, and increased above Lopt-2P and below Lopt-2P. Corresponding changes for double-pulse contractions were greater. Stretching the muscle leads to slower twitch contractions and double-pulse contractions, but the mechanisms of this change in time course remain unclear.

Cardiovascular responses to static and dynamic contraction during comparable workloads in humans.

Previous studies suggest that the blood pressure response to static contraction is greater than that caused by dynamic exercise. In anesthetized cats, however, pressor responses to electrically induced static and dynamic contraction of the same muscle group are similar during equivalent workloads and peak tension development [i.e., similar tension-time index (TTI)]. To determine if the same relationship exists in humans, where contraction is voluntary and central command is present, dynamic (180 s; 1/s) and static (90 s) contractions at 30% of maximal voluntary contraction (MVC) were performed. Dynamic contraction also was repeated at the same TTI for 90 s at 60% MVC. Mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), MAP during postexercise arterial occlusion (an index of the metaboreceptor-induced activation of the exercise pressor reflex), and relative perceived exertion (RPE) (an index of central command) were assessed. No differences in these variables were found between static and dynamic contraction at a tension of 30% MVC. During dynamic contraction at 60% MVC, changes in MAP (16 +/- 3 vs. 19 +/- 4 mmHg) and absolute HR (92 +/- 6 vs. 69 +/- 5 beats/min), CO (7.9 +/- 0.4 vs. 6.3 +/- 0.3 l/min), RPE (16 +/- 1 vs. 13 +/- 1), and MAP during postexercise arterial occlusion (115 +/- 3 vs. 100 +/- 4 mmHg) were greater than during static contraction (P < 0.05). Thus increases in MAP and HR, activation of central command, and muscle metabolite-induced stimulation of the exercise pressor reflex during static and dynamic contraction in humans seem to be similar when peak tension and TTI are equal. Augmented responses to dynamic contraction at 60% MVC are likely related to greater activation of these two mechanisms.

Short-term administration of insulin-like growth factor I (IGF-1) does not induce myocardial IGF-1 resistance.

The advent of recombinant technology has revealed attractive therapeutic profile of insulin-like growth factor I (IGF-1) in the treatment of chronic cardiovascular diseases such as diabetes and heart failure. However, the safety and potential adverse effect of IGF-1 have not been well defined. This study was designed to evaluate the impact of short-term IGF-1 administration on myocardial contractile function. Adult rats were given recombinant human IGF-1 (3mg/kg/d, s.c.) for 8 weeks. Mechanical properties were evaluated in left-ventricular papillary muscles using a force-transducer. Myocardial contractile properties analyzed included peak tension development (PTD), time-to-peak tension (TPT), time-to-90% relaxation (RT(90)), and maximal velocity of tension development/decline (+/-VT). Short-term IGF-1 treatment enhanced the plasma IGF-1 level but had no effect on body and organ weights. The myocardium from IGF-1-treated rats exhibited enhanced PTD associated with similar TPT, RT(90), and +/-VT compared to the control group. IGF-1-treated myocardium exhibits an enhanced PTD-Ca(2+) response and a better intracellular Ca(2+) replenishing ability at the low stimulus frequencies. Acute application of IGF-1 (1-500 ng/ml) elicited a comparable concentration-dependent increase in PTD in myocardium from both control and the IGF-1-treated groups. Acute IGF-1 application had no effect on +/-VT, TPT, and RT(90) in either group tested. Pretreatment with the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester blunted the IGF-1-induced positive response in myocardium from both control and IGF-1-treated groups. These results suggest that short-term IGF-1 treatment is unlikely to induce IGF-1 resistance in myocardial contractile function.

Influence of prenatal alcohol exposure on myocardial contractile function in adult rat hearts: role of intracellular calcium and apoptosis.

To assess the teratogenic action of ethanol on cardiac contractile function in offspring exposed to ethanol in utero, pregnant Sprague-Dawley rats were fed with ethanol during gestation. Left-ventricular papillary muscles and myocytes were isolated from the offspring of the ethanol-ingesting and control pregnant rats. Mechanical parameters measured were peak tension development (PTD, indicating the myocardial force-generating capacity), peak cell shortening (PS), time-to-PTD/PS (TPT/TPS), time-to-90% relaxation/re-lengthening (RT(90)/TR(90)), and maximal velocities of contraction/shortening and relaxation/re-lengthening (+/- VT and +/- dL/dt). Intracellular Ca(2+) levels and apoptosis were evaluated with fura-2 fluorescent dye and Caspase-3 activation assay, respectively. Offspring of the ethanol group displayed decreased heart weight associated with comparable body, liver and kidney weight, and papillary muscle weight/size, compared to the control group. However, prenatal ethanol exposure depressed myocardial PTD and +/- VT. The myocardium from the ethanol group also exhibited slightly but significantly shortened TPT, accompanied with normal RT(90). Muscles from both groups exhibited comparable responses to post-rest potentiation, increasing extracellular Ca(2+) concentration, noradrenaline and acute ethanol challenge. Ventricular myocytes from both the control and ethanol groups possessed similar PS, TPS, TR(90) and +/- dL/dt. Both resting and peak intracellular Ca(2+) levels were elevated in myocytes from the ethanol group. Additionally, acute ethanol application depressed caffeine-induced intracellular Ca(2+) rise in myocytes from both groups. Myocytes from the ethanol group displayed an enhanced Caspase-3 activation, compared to control myocytes. These results suggest that prenatal ethanol exposure alters myocardial contractile function and may contribute to the development of postnatal cardiac dysfunction through, in part, increased intracellular Ca(2+) loading and apoptosis.

The influence of gender, diabetes, and acetaldehyde on the intrinsic contractile properties of isolated rat myocardium.

Diabetes is associated with ventricular dysfunction. Ethanol consumption increases the risk of cardiovascular disease among diabetics. Acetaldehyde (ACA), the main ethanol metabolite, depresses cardiac contraction and contributes to ethanol-induced cardiac dysfunction. This study examined the influence of gender and diabetes on ACA-induced myocardial dysfunction. Adult male and female rats were made diabetic with streptozotocin (55 mg/kg). Left ventricular papillary muscles were isolated and stimulated to contract at 0.5 Hz. The mechanical parameters measured were peak tension development, time-to-peak tension (TPT), time-to-90% relaxation (RT90), and maximum velocities of tension development and decline (+/-VT). TPT and RT90 were comparably similar between genders. The +/-VT appeared to be slower in myocardium from female rats when compared to that of male counterparts, although the difference was not significant. Experimental diabetes elicited severe hyperglycemia, cardiac hypertrophy, hepatomegaly, and renal hypertrophy in both male and female animals. Myocardial mechanical properties exhibited prolonged TPT and RT90 in diabetic myocardium from both genders. The +/-VT was significantly reduced by diabetes in male but not in female myocardium. Acute ACA exposure decreased myocardial tension development and the +/-VT and shortened TPT and RT90 in myocardium from normal and diabetic rats of both genders. The ACA-induced depressant response on tension development was slightly enhanced by the diabetic state. In conclusion, these data suggest that the development of diabetes-induced myocardial dysfunction is similar between male and female animals and that the ACA-induced myocardial depressant action may be affected by diabetes but not by gender.