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PubMed1977

End-systolic force-length relationship of nonexcised canine papillary muscle.

End-systolic force-length (F-L) relationships were studied in blood-perfused papillary muscles remining in the canine right ventricle. The muscles contracted spontaneously at a regular rate of 114 +/- 4 (SE, N = 31) beats/min at 37 degrees C. In each muscle, end-systolic F-L curves were obtained in different modes of contraction at different diastolic lengths between the unstressed length (9.4 +/- 0.7 mm) and 143 +/- 4% of it. At the latter length, muscles developed a peak isometric force of 46 +/- 4 g (5.1 +/- 0.5 g/mm2). The isotonic F-L curve was lower than the isometric F-L curves to various extents. An auxotonic F-L curve fell between the two curves. At identical end-systolic lengths peak isometric forces were greater than isotonic forces by 14.4 +/- 1.4% in the first transient beats after switching the contraction mode from isometric to isotonic. The difference increased to 28.5 +/- 3.5% in the steady-state beats. The reduced force in the first isotonic beat was suspected to be due to the uncoupling effect of shortening. The further reduction of isotonic force in the steady-state beats was caused by viscous properties (creep and stress relaxation) and by a gradual decrease in contractility.

Animals↗
PubMed2002

Effects of modulation of nitric oxide on rat diaphragm isotonic contractility during hypoxia.

Nitric oxide (NO) is essential for optimal myofilament function of the rat diaphragm in vitro during active shortening. Little is known about the role of NO in muscle contraction under hypoxic conditions. Hypoxia might increase the NO synthase (NOS) activity within the rat diaphragm. We hypothesized that NO plays a protective role in isotonic contractile and fatigue properties during hypoxia in vitro. The effects of the NOS inhibitor N(G)-monomethyl-l-arginine (l-NMMA), the NO scavenger hemoglobin, and the NO donor spermine NONOate on shortening velocity, power generation, and isotonic fatigability during hypoxia were evaluated (Po(2) approximately 7 kPa). l-NMMA and hemoglobin slowed the shortening velocity, depressed power generation, and increased isotonic fatigability during hypoxia. The effects of l-NMMA were prevented by coadministration with the NOS substrate l-arginine. Spermine NONOate did not alter isotonic contractile and fatigue properties during hypoxia. These results indicate that endogenous NO is needed for optimal muscle contraction of the rat diaphragm in vitro during hypoxia.

Animals↗
PubMed1966

Tetrodotoxin and manganese ions: effects on electrical activity and tension in taenia coli of guinea pig.

Tetrodotoxin, at concentrations up to 5 x 10(-6) gram per milliliter, has no effect on the spontaneous discharge in the smooth muscle of taenia coli. However, the spontaneous discharge is abolished by Mn(++) at a concentration of 0.5 millimole per liter. The contraction induced by immersing the muscle in isotonic KCl solution is also suppressed in the presence of Mn(++). Because Mn(++) is a specific suppressor of the spike induced by Ca(++) and tetrodotoxin is an inhibitor of the spike induced by Na(+), we suggest that Ca(++) is a charge carrier in the production of spike potential in the smooth muscle and that the entry of intervening Ca(++) through the membrane acts as a trigger for the contraction of smooth muscle.

Animals↗
PubMed1987

Dynamics of cardiac muscle: analysis of isotonic, isometric, and isochronal curves.

Canine papillary muscle force-length-time relation (F-L-t) was investigated under pentobarbital sodium anesthesia. The time intervals taken from end diastole to any point (P) on the force-length plane was determined for isometric (t1) and isotonic (t2) systole and corrected for excitation contraction coupling duration. The ratio t1/t2, designated km, was approximately constant for widely scattered positions of P chosen systematically. The km in the 10 dogs ranged from 0.36 to 0.94 with means +/- SD of 0.66 +/- 0.16; km correlated negatively with muscle average cross-sectional area (r = -0.82; P less than 0.005). Assuming constancy of km, a general relationship was derived between (delta F/delta t)t1L, the rate of isometric force development at P; (delta L/delta t)t2F, the velocity of isotonic shortening at P; (delta F/delta L)(t1,t2)t, the stiffness; and (delta L/delta F)(t1,t2)t, the compliance of the myocardium (all taken at P) as follows (delta F/delta L)t1,t2t = -km(delta F/delta t)t1L/(delta L/delta t)t2F and (delta L/delta F)t1,t2t = -km-1(delta L/delta t)t2F/(delta F/delta t)t1t. The ratio of (delta F/delta t)t1L to (delta L/delta t)t2F defines functional proclivity and measures the differential propensity to force development relative to shortening. Thus myocardial stiffness or compliance determines functional proclivity by acting as an impedance-matching transformer that steps up or steps down force development of shortening as warranted by the loading conditions.

Animals↗
PubMed1999

Ascending neural pathways in the isolated guinea-pig ileum: effect of muscarinic M1, M2 and M3 cholinergic antagonists.

The effect of muscarinic cholinoceptor antagonists was investigated on the ascending neural pathways activated by electrical stimulation in the guinea-pig ileum. For comparison, prejunctional and postjunctional effects of muscarinic cholinoceptor antagonists were also studied on circular smooth muscle. A two-compartment (oral and anal compartments) bath was used to study the ascending neural pathways. These were activated by electrical field stimulation in the anal compartment and the resulting contraction of the intestinal circular muscle in the oral compartment was recorded isotonically. Pirenzepine (10-300 nM), a muscarinic M1 cholinoceptor antagonist, reduced the ascending neural contractions in a concentration-dependent fashion when applied either to the oral or anal compartments (11-52% and 13-55% inhibition, respectively, P < 0.05). Pirenzepine inhibited (31+/-7%, P < 0.05) the acetylcholine (100 nM)-induced contractions at a higher non-selective concentration (300 nM), while its effect on the electrically-induced contractions was biphasic (10 and 30nM: 8-15% increase, P<0.05; 100 and 300 nM: 16-28% inhibition, P<0.05). The muscarinic M2 cholinoceptor antagonist methoctramine (3-100 nM) did not modify the contractions produced by 100 nM acetylcholine, electrically-induced contractions and the ascending neural contractions (when applied to either compartment). Parafluorohexahydrosiladifenidol (3-100 nM), a muscarinic M3 cholinoceptor antagonist, inhibited the contractions produced by 100 nM acetylcholine (19-81% and 15-69%), electrically-induced contractions (11-71% and 12-72%) and the ascending neural contractions (13-76% and 866%) when applied to the oral compartment, but it was without effect when applied to the anal compartment. These studies suggest that in the enteric ascending neural pathway, muscarinic M1 receptors are involved in neuroneuronal transmission, muscle contraction is mediated by muscarinic M3 cholinergic receptors, whereas muscarinic M2 receptors do not seem to participate.

Acetylcholine↗
PubMed1997

Measurements of active myocardial tension under a wide range of physiological loading conditions.

Active tension developed while cardiac muscle shortens has been studied extensively under afterloaded isotonic or isovelocity conditions. However, these are not true in vivo loading conditions. To obtain more physiological loading, we controlled sarcomere length to follow the time courses that we observed previously in a beating canine left ventricle. Sarcomere length was measured by laser diffraction in 12 rat cardiac trabeculae, superfused with Krebs-Henseleit solution (25 degrees C; [Ca] = 1.5 mM). Force was measured by a silicon strain gauge. Sarcomere length time courses were scaled slightly in time to account for temperature and species differences. We examined the relationships between active tension and sarcomere length under loading observed over a wide range of left ventricular preloads and afterloads, and at two sites. Under all loading conditions, active tension was not isotonic but declined steadily throughout the ejection period. While there were major differences in peak tension dependent on loading conditions and the incidence of 'pre-ejection' sarcomere shortening, these factors did not influence the relationship between sarcomere length and peak active tension. This study provides excellent illustrations of the potential differences in stress (1) within a ventricular wall, and (2) under different operating conditions. Moreover, it provides data for developing models of fiber contraction to be synthesized into a whole heart for predicting potential differences in stress at all sites and under all loading conditions.

Animals↗
PubMed1976

The myocardial energetic active state. I. Oxygen consumption during tetanus of cat papillary muscle.

The potential role of active state maintenance as a determinant of myocardial oxygen consumption (MVO2) has not been defined. Right ventricular papillary muscles from 15 cats were studied in a polarographic myograph at 23 degrees C in a Krebs-Ringer solution containing 7.5 mM Ca2+ and 10 mM caffeine. MVO2 was determined for isometric tetani at Lmax of 1-5 seconds' duration. Increases in tetanus duration related linearly to increments in both active tension time (delta active tension) and MVO2. In order to examine the oxygen cost of active state maintenance not attributable to associated tension generation, both the same isometric and 2.5- to 10.0-second lightly preloaded isotonic tetani were produced in nine muscles. For each tetanus duration the contribution throughout the contraction of developed force (preload) to MVO2 could be subtracted from overall isotonic MV02. In the absence of the MVO2 associated with force development, the active state duration was related linearly to MVO2, with a mean active state MVO2 of 2.42 +/- 0.29 nl O2/mg dry muscle/sec of isotonic tetanus; this MVO2 is 68% of the value of 3.58 +/- 0.42 nl O2/mg dry muscle/sec that was obtained for isometric tetanus at Lmax. This study identifies active state maintenance as the major determinant of MVO2 during myocardial tetanus and, furthermore, suggests the possibility that alterations in ative state intensity and duration may be the biochemical mechanism by which other determinants of MVO2 act in a more physiological setting.

Animals↗
PubMed1993

Contraction and relaxation of isolated cardiac myocytes of the frog under varying mechanical loads.

The mechanics of cardiac systole and relaxation have been studied primarily at the level of the whole heart or intact muscle. End-systolic pressure-volume relations of frog hearts have been found to be load dependent, whereas those of the mammal are relatively load independent. On the other hand, myocardial relaxation as studied at the muscle level is load independent in the frog but markedly load dependent in the mammal. Interpretation of these studies is complicated because of the unknown contribution of extracellular connective tissue, neurohumoral factors, and, in the case of the heart, the complex chamber geometry. Therefore, it is valuable to study cardiac mechanics at the level of the basic unit of contractile activity--the isolated myocyte. The goal of this study was to subject isolated frog cardiomyocytes to mechanical loading paradigms that mimic those presented to the cells within the heart. In the first part of this study, the afterload and preload of contracting cells were varied to study their effects on the end-systolic force-length relation, which was consistently found to be load independent over the range of isotonic shortening tested (typically 5%). We also investigated the force-length-time response of the cells to test the concept of the heart behaving as a time-varying elastance. Our results suggest that in this regard the frog myocyte behaves like mammalian muscle, and they are consistent with the presence of a small viscosity within the cell. We conclude that the tissue structure of the frog heart may contribute to disparity in mechanical behavior at the different structural levels. In the second part of this study, we subjected isolated frog cardiomyocytes to four different loading paradigms to test the hypothesis that myocardial relaxation in the frog is independent of load. These sequences consisted of afterloaded contractions followed by conventional isotonic-isometric relaxation (ACCR) or afterloaded contractions followed by physiologically reversed isometric-isotonic relaxation (ACPR). Relaxation was measured under isometric conditions using a variable afterload with either the ACCR or ACPR paradigms. The decay of force was independent of the cell length at which it occurred or the amount of shortening prior to it within the contractile cycle. Relaxation also was measured as relengthening of the cell under isotonic late-load conditions, using the ACPR paradigm either with a variable afterload or variable late load. Relengthening had a time course that was unaffected by changes in afterload (i.e., extents of shortening) or late load (equivalent to the filling pressure for the heart).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1998

Force-velocity-power and force-pCa relationships of human soleus fibers after 17 days of bed rest.

Soleus muscle fibers from the rat display a reduction in peak power and Ca2+ sensitivity after hindlimb suspension. To examine human responses to non-weight bearing, we obtained soleus biopsies from eight adult men before and immediately after 17 days of bed rest (BR). Single chemically skinned fibers were mounted between a force transducer and a servo-controlled position motor and activated with maximal (isotonic properties) and/or submaximal (Ca2+ sensitivity) levels of free Ca2+. Gel electrophoresis indicated that all pre- and post-BR fibers expressed type I myosin heavy chain. Post-BR fibers obtained from one subject displayed increases in peak power and Ca2+ sensitivity. In contrast, post-BR fibers obtained from the seven remaining subjects showed an average 11% reduction in peak power (P < 0.05), with each individual displaying a 7-27% reduction in this variable. Post-BR fibers from these subjects were smaller in diameter and produced 21% less force at the shortening velocity associated with peak power. However, the shortening velocity at peak power output was elevated 13% in the post-BR fibers, which partially compensated for their lower force. Post-BR fibers from these same seven subjects also displayed a reduced sensitivity to free Ca2+ (P < 0.05). These results indicate that the reduced functional capacity of human lower limb extensor muscles after BR may be in part caused by alterations in the cross-bridge mechanisms of contraction.

Adult↗
PubMed1983

[Effect of acidosis on Ca2+ binding by the sarcoplasmic reticulum and on relaxation of the cardiac muscle].

A value of Ca2+ binding in 1 second by sarcoplasmic reticulum fragments from guinea pig hearts increased proportionally to elevation of Ca2+ concentration from 0.1 to 3.0(-6) M at pH 7.2. Decline of pH to 6.8 and 6.2 decreased the Ca2+ bound in 1 second, but increased the Ca2+ bound in 30 seconds when membrane permeability has become a crucial factor in determining Ca2+ bound. In experiments on guinea pig papillary muscles, a decline of pH from 7.35 to 6.83 resulted in a nearly equal fall in velocities of isometric contraction and relaxation (27 and 21%, respectively), but during isotonic shortening when the relaxation proceeds much faster, a fall in relaxation velocity (44 +/- 3%) was significantly more profound as compared to the fall in contraction velocity (29 +/- 4%). This effect as well as a decrease in initial rate of Ca2+ binding by sarcoplasmic reticulum suggest a direct inhibitory effect of acidosis on Ca2+ removal from myofibrils in myocardial cells.

Acidosis↗
PubMed1997

Effect of papaverine on synaptic transmission in the guinea-pig ileum.

1. The effect of papaverine, a well known smooth muscle relaxant, was investigated on neural transmission within the enteric nervous system. Segments of guinea-pig ileum were placed in a partitioned bath to enable drugs, including papaverine, to be applied to enteric nerve pathways without interfering with the recording of the smooth muscle contraction. Ascending excitatory enteric nerve pathways were activated by electrical field stimulation in the anal compartment (10 Hz for 2 s, 45 mA, 0.5 ms pulse duration) and the resulting contraction of the intestinal circular muscle in the oral compartment was recorded isotonically. 2. Tetrodotoxin (0.6 microM) and hexamethonium (100 microM) both abolished, or greatly reduced, the contractions when applied to either compartment indicating that nicotinic synapses are involved in this pathway. 3. Papaverine (0.3-30 microM) applied independently to each compartment depressed in a concentration-dependent manner, the nerve-mediated contractions. The IC50 of this inhibitory effect was 3.53 microM for the oral and 4.76 microM for the anal compartments, respectively. Two other phosphodiesterase (PDE) inhibitors, 3-isobutyl-1-methylxanthine (IBMX 10-300 microM) and theophylline (30-1000 microM) added to the anal compartment also inhibited the nerve mediated contractions. Papaverine applied to the anal bath, after IBMX 100 microM (or theophylline 300 microM) further inhibited the nerve-mediated contractions, but was less effective than when applied alone. 4. Phentolamine (1 microM), an alpha-adrenoceptor antagonist, reduced the inhibitory effect of papaverine, but not that of IBMX (100 microM) or theophylline (300 microM). A combination of phentolamine and IBMX (or theophylline) prevented the inhibitory effect of papaverine. 5. Tetrodotoxin, but not papaverine or hexamethonium, inhibited the contraction elicited by electrical stimulation just anal to the partition indicating that papaverine did not affect the generation or conduction of nerve action potentials. 6. Verapamil (1 microM) and nifedipine (1 microM), two smooth muscle relaxants which act by blocking L-type calcium channels, only inhibited the contractions when applied directly to the recording (oral) compartment. This indicates that L-type Ca2+ channels are probably not involved in synaptic transmission in these ascending pathways and thus that the PDE inhibitors do not inhibit synaptic transmission by acting on these channels. omega-Conotoxin GVIA (10 nM), a potent inhibitor of the N-type Ca2+ channels, blocked the nerve-mediated contractions applied to either compartment. Whether the PDE inhibitors exert their inhibitory actions via these channels remains to be established. 7. The results indicate that the PDE inhibitors, papaverine, IBMX and theophylline inhibit excitatory enteric neural pathways by depressing synaptic transmission. The inhibitory effect of papaverine (but not IMBX or theophylline) involves, at least in part, the release of noradrenaline from sympathetic nerves acting on alpha-adrenoceptors on enteric neurones.

1-Methyl-3-isobutylxanthine↗
PubMed1998

The role of receptor-operated CA2+ influx in endothelin-induced contraction of the muscularis mucosae.

We examined the role of receptor-operated Ca2+ influx in endothelin-1 (ET-1)- or sarafotoxin S6c (S6c)-induced contraction of the muscularis mucosae. Responses of the esophageal muscularis mucosae isolated from guinea-pigs were recorded by an isotonic transducer and a polygraph. ET-1 and S6c produced contraction of the esophageal muscularis mucosae in a concentration-dependent manner. The contractile responses to ETs were abolished in a Ca(2+)-free EGTA-containing medium, weakly inhibited by nicardipine, and markedly inhibited by SK&F96365. In addition, both H-7 and U-73122 strongly inhibited the ET-induced contractions, but U-73343 weakly inhibited these responses. These results indicate that the esophageal muscularis mucosae of guinea pigs has ET receptors that are coupled mainly to receptor-operated Ca2+ influx and linked with the phospholipase C-protein kinase C pathway.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMedDate not supplied

Mechano-electric interactions in heterogeneous myocardium: development of fundamental experimental and theoretical models.

The heart is structurally and functionally a highly non-homogenous organ, yet its main function as a pump can only be achieved by the co-ordinated contraction of millions of ventricular cells. This apparent contradiction gives rise to the hypothesis that 'well-organised' inhomogeneity may be a pre-requisite for normal cardiac function. Here, we present a set of novel experimental and theoretical tools for the study of this concept. Heterogeneity, in its most condensed form, can be simulated using two individually controlled, mechanically interacting elements (duplex). We have developed and characterised three different types of duplexes: (i) biological duplex, consisting of two individually perfused biological samples (like thin papillary muscles or a trabeculae), (ii) virtual duplex, made-up of two interacting mathematical models of cardiac muscle, and (iii) hybrid duplex, containing a biological sample that interacts in real-time with a virtual muscle. In all three duplex types, in-series or in-parallel mechanical interaction of elements can be studied during externally isotonic, externally isometric, and auxotonic modes of contraction and relaxation. Duplex models, therefore, mimic (patho-)physiological mechano-electric interactions in heterogeneous myocardium at the multicellular level, and in an environment that allows one to control mechanical, electrical and pharmacological parameters. Results obtained using the duplex method show that: (i) contractile elements in heterogeneous myocardium are not 'independent' generators of tension/shortening, as their ino- and lusitropic characteristics change dynamically during mechanical interaction-potentially matching microscopic contractility to macroscopic demand, (ii) mechanical heterogeneity contributes differently to action potential duration (APD) changes, depending on whether mechanical coupling of elements is in-parallel or in-series, which may play a role in mechanical tuning of distant tissue regions, (iii) electro-mechanical activity of mechanically interacting contractile elements is affected by their activation sequence, which may optimise myocardial performance by smoothing intrinsic differences in APD. In conclusion, we present a novel set of tools for the experimental and theoretical investigation of cardiac mechano-electric interactions in healthy and/or diseased heterogeneous myocardium, which allows for the testing of previously inaccessible concepts.

Animals↗
PubMed1983

Effects of calcium and verapamil on vesicourethral smooth muscle of rabbits.

Isolated smooth muscle strips from the rabbit bladder body, bladder base, and proximal urethra were contracted with ionic calcium (Ca2+) alone and with the calcium-selective ionophore A23187, acetylcholine, norepinephrine, adenosine triphosphate (ATP), and direct electrical stimulation. The effects of Ca2+ and the calcium entry blocker verapamil on spontaneous muscle activity and on contractions induced by these agonists were examined. Ca2+ -free Tyrode's solution and verapamil, 1 x 10(-7)M and above, relaxed all of the vesicourethral smooth muscle strips. In addition verapamil, 1 x 10(-8) to 1 x 10(-6) M depending on the particular stimulant employed, noncompetitively inhibited smooth muscle contractions elicited by Ca2+, acetylcholine, norepinephrine, ATP, and direct electrical stimulation. It was concluded that transmembrane Ca2+ influx was important not only in the maintenance of tone and spontaneous phasic muscle activity, but also for the activation of contractions induced by all of the stimulants tested. The data also suggest that intracellular Ca2+ fraction(s) participate in the contractile responses to acetylcholine and norepinephrine challenge, but not to contractions evoked by ATP or electricity.

Acetylcholine↗
PubMed1984

The contractile properties of wound granulation tissue.

A systematic examination of the contractile properties of wound granulation tissue is presented. Shortening of and tension generated by granulation tissue in the presence of 30 mM diphenhydramine HCl have been measured. Analysis of the stress (load per unit area)/strain (extent of shortening) results from isotonic shortening studies showed that over the range of 0 to 2.5% shortening there was an approximately linear relationship between stress and strain with a high modulus of elasticity. At lower stresses, wide variations in the amount of shortening occurred with little change in stress. Our interpretation of these findings is that diphenhydramine HCl caused an active shortening of the granulation tissue by 2.5% of its length and contractions greater than this were the result of secondary effects such as coiling and bending of the strips. It is shown that the granulation tissue would have to shorten by 2% once every 3 days to account for observed in vivo rates of contraction for large human wounds and once every 13 hr for rapidly contracting experimental rabbit wounds. The time course of the development of isometric tension by the granulation tissue is shown to be consistent with the proposal that each contractile cell contributes equally to the overall tension developed and that each cell is individually activated by a critical concentration of diphenhydramine HCl which is transported through the tissue by diffusion.

Animals↗
PubMed1981

Isotonic velocity transients in frog muscle fibres following quick changes in load.

1. The isotonic velocity transients following quick changes in load were studied on tetanized frog skeletal muscle fibres with special reference to those following quick increases in load. 2. When the load was increased quickly from the maximum isometric force P0 to 1.05-1.3 P0, the fibres exhibited markedly oscillatory length changes with distinct reversal in the direction of movement before starting to lengthen with a nearly constant velocity. 3. The period of the oscillatory length changes increased with increasing magnitude of the load step, and decreased with increasing temperature. The amplitude of oscillatory length changes never exceeded 0.5% of the slack length L0, i.e. about 50 A per half-sarcomere. 4. If the load was increased quickly from P0 to 1.3-1.6 P0, the fibres lengthened continuously with velocities decreasing with time. 5. The response of fibres, shortening isotonically under a large load (about 0.8 P0), to quick increases in load was qualitatively similar to that of isometrically contracting fibres. 6. When quick increases in load were applied during isotonic shortening under a moderate or small load (0.1-0.6 P0), the fibres showed initial transient lengthening before starting to shorten against a new load, indicating a decrease in the ability of the fibres to sustain a load after a period of isotonic shortening and its restoration during the transient lengthening. 7. The extent of decrease in load-sustaining ability as well as its subsequent restoration process was dependent on both the amount of load and the duration of preceding isotonic shortening. 8. The decrease in the load-sustaining ability during the course of isotonic shortening appeared to be complete within 30-50 msec after the beginning of shortening. 9. These results are discussed in relation to the kinetic properties of the crossbridges responsible for muscle contraction.

Animals↗