Validity of the Force-Velocity Relation for Muscle Contraction in the Length Region, l ≤ l0

Considerable attention has been directed to the characteristic force-velocity relation discovered by A. V. Hill in the study of muscle kinematics. Models of contractile process were tested on the basis of their compatibility with the Hill equation. However, almost all the isotonic data have been restricted to one length, l₀, the maximum length with almost no resting tension; the velocities measured are those initial values when the load begins to move. The force-velocity curve extrapolates to zero velocity for isometric tension, but only for the tension at that one length. Very few efforts have been made to study the profiles of the curves throughout the range of lengths over which shortening takes place. In examining the length region, l ≤ l₀, for an isotonically contracting muscle, not only is the force-velocity relation valid for the initial reference length, l₀, but also for any other length. The analysis in this report indicates that the constants a/P₀ and b/l₀ remain fixed throughout the length change of afterloaded isotonic shortening in the Rana pipiens sartorius muscles.     

Energetics of Shortening Muscles in Twitches and Tetanic Contractions : II. Force-Determined Shortening Heat

The extra heat liberation accompanying muscular shortening, the force-determined shortening heat, is defined as the difference between the heat produced when shortening occurs and that produced in an isometric contraction developing the same amount of force and performing the same amount of internal work. Based on this definition, the initial energy production in twitches and tetanic contractions (E) is given by E = A + f (P, t) + α_Fx + W, where A is the activation heat, f(P, t), the tension-related heat (a heat production associated with the development and maintenance of tension), α_Fx, the force-determined shortening heat, and W, the external work. It is demonstrated that this equation accurately accounts for the time-course of heat evolution and the total initial energy production in both twitches and tetani at 0°C. The force-determined shortening heat is liberated, during shortening, in direct proportion to (a) the distance shortened, and (b) the force against which shortening occurs. The normalized value of the force-determined shortening heat coefficient, α_F/P_o, is the same in both the twitch and the tetanus. Finally, this formulation of the muscle's energy production also accounts for the total energy production in afterload isotonic twitches at 20°C, where a Fenn effect is not demonstrable.     

Theoretical series elastic element length in Rana pipiens sartorius muscles

Assuming a two component system for the muscle, a series elastic element and a contractile component, the analyses of the isotonic and isometric data points were related to obtain the series elastic stiffness, dP/dl_s, from the relation, See PDF for Equation From the isometric data, dP/dt was obtained and shortening velocity, v, was a result of the isotonic experiments. Substituting (P₀ - P)/T for dP/dt and (P₀ - P)/(P + a) times b for v, dP/dl_s = (P + a) /bT, where P < P₀, and a, b are constants for any lengths l ≤ l₀ (Matsumoto, 1965). If the isometric tension and the shortening velocity are recorded for a given muscle length, l₀, although the series elastic, l_s, and the contractile component, l_c, are changing, the total muscle length, l₀ remains fixed and therefore the time constant, T. Integrating, See PDF for Equation the stress-strain relation for the series elastic element, See PDF for Equation is obtained; l_sc0 - l_s + l_c0where l_co equals the contractile component length for a muscle exerting a tension of P₀. For a given P/P₀, l_s is uniquely determined and must be the same whether on the isotonic or isometric length-tension-time curve. In fact, a locus on one surface curve can be associated with the corresponding locus on the other.     

Energetics of Shortening Muscles in Twitches and Tetanic Contractions : I. A Reinvestigation of Hill''s Concept of the Shortening Heat

Shortening heat was defined by Hill as the "difference between heat produced when shortening occurs and that produced in a similar contraction without shortening." For the tetanus the "similar contraction" was an isometric one at or near l_o. By contrast, in a twitch the "similar contraction" was one in which only activation heat was produced. The applicability of Hill's concept of the shortening heat has been reexamined in both the twitch and tetanus of Rana pipiens semitendinosus muscles. Results of this investigation confirm the existence of an extra heat production accompanying shortening in the twitch and tetanus. In both cases, this shortening heat was proportional to distance shortened and relative afterload. However, at a given afterload the amount of shortening heat produced per distance shortened was greater in the twitch than the tetanus. This difference suggests that the base lines or "similar contractions" employed for the twitch and tetanus are not equivalent. The discrepancy is not remedied by utilizing in the tetanus the activation heat as the myothermic baseline and suggests that some heat producing factor(s) has been omitted in Hill's formulation of the shortening heat. Finally, the existence of Hill's feedback heat, an energy liberation associated with the presence of tension during mechanical relaxation, was not confirmed. This result strongly indicates that relaxation is energetically passive.     

Unloaded speed of shortening in voltage-clamped intact skeletal muscle fibers from wt, mdx, and transgenic minidystrophin mice using a novel high-speed acquisition system

Skeletal muscle unloaded shortening has been indirectly determined in the past. Here, we present a novel high-speed optical tracking technique that allows recording of unloaded shortening in single intact, voltage-clamped mammalian skeletal muscle fibers with 2-ms time resolution. L-type Ca²⁺ currents were simultaneously recorded. The time course of shortening was biexponential: a fast initial phase, τ₁, and a slower successive phase, τ_2, with activation energies of 59 kJ/mol and 47 kJ/mol. Maximum unloaded shortening speed, v_u,max, was faster than that derived using other techniques, e.g., ∼14.0 L₀ s⁻¹ at 30°C. Our technique also allowed direct determination of shortening acceleration. We applied our technique to single fibers from C57 wild-type, dystrophic mdx, and minidystrophin-expressing mice to test whether unloaded shortening was affected in the pathophysiological mechanism of Duchenne muscular dystrophy. v_u,max and a_u,max values were not significantly different in the three strains, whereas τ₁ and τ₂ were increased in mdx fibers. The results were complemented by myosin heavy and light chain (MLC) determinations that showed the same myosin heavy chain IIA profiles in the interossei muscles from the different strains. In mdx muscle, MLC-1f was significantly increased and MLC-2f and MLC-3f somewhat reduced. Fast initial active shortening seems almost unaffected in mdx muscle.     

Monovalent Cationic Channel Activity in the Inner Membrane of Nuclei from Skeletal Muscle Fibers

Nuclear ion channels remain among the least studied and biophysically characterized channels. Although considerable progress has been made in characterizing calcium release channels in the nuclear membrane, very little is known regarding the properties of nuclear monovalent cationic channels. Here, we describe a method to isolate nuclei from adult skeletal muscle fibers that are suitable for electrophysiological experiments. Using this approach, we show for the first time, to our knowledge, that a nuclear monovalent cationic channel (NMCC) is prominently expressed in the inner membrane of nuclei isolated from flexor digitorum brevis skeletal muscle fibers of adult mice. In isotonic 140 mM KCl, the skeletal muscle NMCC exhibits a unitary conductance of ∼160 pS and high, voltage-independent open probability. Based on single-channel reversal potential measurements, NMCCs are slightly more permeable to potassium ions over sodium (P_K/P_Na = 2.68 ± 0.21) and cesium (P_K/P_Cs = 1.39 ± 0.03) ions. In addition, NMCCs do not permeate divalent cations, are inhibited by calcium ions, and demonstrate weak rectification in asymmetric Ca²⁺-containing solutions. Together, these studies characterize a voltage-independent NMCC in skeletal muscle, the properties of which are ideally suited to serve as a countercurrent mechanism during calcium release from the nuclear envelope.     

Phosphate and ADP Differently Inhibit Coordinated Smooth Muscle Myosin Groups

Actin filaments propelled in vitro by groups of skeletal muscle myosin motors exhibit distinct phases of active sliding or arrest, whose occurrence depends on actin length (L) within a range of up to 1.0 μm. Smooth muscle myosin filaments are exponentially distributed with ≈150 nm average length in vivo—suggesting relevance of the L-dependence of myosin group kinetics. Here, we found L-dependent actin arrest and sliding in in vitro motility assays of smooth muscle myosin. We perturbed individual myosin kinetics with varying, physiological concentrations of phosphate (P_i, release associated with main power stroke) and adenosine diphosphate (ADP, release associated with minor mechanical step). Adenosine triphosphate was kept constant at physiological concentration. Increasing [P_i] lowered the fraction of time for which actin was actively sliding, reflected in reduced average sliding velocity (ν) and motile fraction (f_mot, fraction of time that filaments are moving); increasing [ADP] increased the fraction of time actively sliding and reduced the velocity while sliding, reflected in reduced ν and increased f_mot. We introduced specific P_i and ADP effects on individual myosin kinetics into our recently developed mathematical model of actin propulsion by myosin groups. Simulations matched our experimental observations and described the inhibition of myosin group kinetics. At low [P_i] and [ADP], actin arrest and sliding were reflected by two distinct chemical states of the myosin group. Upon [P_i] increase, the probability of the active state decreased; upon [ADP] increase, the probability of the active state increased, but the active state became increasingly similar to the arrested state.     

Mitogen-activated protein kinase kinase 1/2 inhibition and angiotensin II converting inhibition in mice with cardiomyopathy caused by lamin A/C gene mutation

Background

Mutations in the LMNA gene encoding A-type nuclear lamins can cause dilated cardiomyopathy with or without skeletal muscular dystrophy. Previous studies have shown abnormally increased extracellular signal-regulated kinase 1/2 activity in hearts of Lmna^H222P/H222P mice, a small animal model. Inhibition of this abnormal signaling activity with a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor has beneficial effects on heart function and survival in these mice. However, such treatment has not been examined relative to any standard of care intervention for dilated cardiomyopathy or heart failure. We therefore examined the effects of an angiotensin II converting enzyme (ACE) inhibitor on left ventricular function in Lmna^H222P/H222P mice and assessed if adding a MEK1/2 inhibitor would provide added benefit.

Methods

Male Lmna^H222P/H222P mice were treated with the ACE inhibitor benazepril, the MEK1/2 inhibitor selumetinib or both. Transthoracic echocardiography was used to measure left ventricular diameters and fractional shortening was calculated.

Results

Treatment of Lmna^H222P/H222P mice with either benazepril or selumetinib started at 8 weeks of age, before the onset of detectable left ventricular dysfunction, lead to statistically significantly increased fractional shortening compared to placebo at 16 weeks of age. There was a trend towards a great value for fractional shortening in the selumetinib-treated mice. When treatment was started at 16 weeks of age, after the onset of left ventricular dysfunction, the addition of selumetinib treatment to benazepril lead to a statistically significant increase in left ventricular fractional shortening at 20 weeks of age.

Conclusions

Both ACE inhibition and MEK1/2 inhibition have beneficial effects on left ventricular function in Lmna^H222P/H222P mice and both drugs together have a synergistic benefit when initiated after the onset of left ventricular dysfunction. These results provide further preclinical rationale for a clinical trial of a MEK1/2 inhibitor in addition to standard of care in patients with dilated cardiomyopathy caused by LMNA mutations.     

Evidence for the allosteric regulation of bacterial glycogen synthesis in vivo

In stationary-phase cultures of either Escherichia coli W4597(K) or G34 in various nutrient conditions there is a 10-fold range of steady-state rates of glycogen synthesis with an essentially constant steady-state level of ATP, presumably reflecting an essentially constant energy charge. The steady-state level of fructose-1,6-diphosphate in these cultures varies from experiment to experiment as a function of the observed rate of glycogen synthesis. These data were fitted to the Hill equation using an assumed Hill coefficient of 2: a plot of [Fru-P₂]²/rate of glycogen synthesis versus [Fru-P₂]² is linear with a correlation coefficient greater than 0.999, indicating a causal relationship between the concentration of Fru-P₂ and the rate of glycogen synthesis. These data provide further evidence that allosteric effects observed in vitro function in vivo.     

The phenomenological model of muscle contraction with a controller to simulate the excitation–contraction (E–C) coupling

We previously proposed a systematic motor model for muscle with two parallel Maxwell elements and a force generator P. The motor model showed the non-linear behavior of a muscle, such as the force–velocity relation and the force depression and enhancement, by using weight functions. Our newly proposed muscle model is based on the molecular mechanism of myosin cross-bridges. We assume that each parallel Maxwell element represents the mechanical properties of weak and strong binding of the myosin head to actin. Furthermore, we introduce a controller to simulate the excitation–contraction coupling of the muscle. The new muscle model satisfies all the properties obtained in our previous model and reduces the wasted energy of the viscous component to less than 5% of the total energy. The controller enables us to simulate contractions of slow and fast twitch muscles, which are driven by an artificial action potential or a processing electromyography signal despite their same mechanical components. The maximum velocities are calculated to be 3.4L₀ m/s for the fast twitch muscle model and 2.5L₀ m/s for the slow twitch muscle model, where L₀ is the initial length of the muscle model.     

Effects of Partial Sarcoplasmic Reticulum Calcium Depletion on Calcium Release in Frog Cut Muscle Fibers Equilibrated with 20 mM EGTA

Resting sarcoplasmic reticulum (SR) Ca content ([Ca_SR]_R) was varied in cut fibers equilibrated with an internal solution that contained 20 mM EGTA and 0–1.76 mM Ca. SR Ca release and [Ca_SR]_R were measured with the EGTA–phenol red method (Pape et al. 1995. J. Gen. Physiol. 106:259–336). After an action potential, the fractional amount of Ca released from the SR increased from 0.17 to 0.50 when [Ca_SR]_R was reduced from 1,200 to 140 μM. This increase was associated with a prolongation of release (final time constant, from 1–2 to 10–15 ms) and of the action potential (by 1–2 ms). Similar changes in release were observed with brief stimulations to −20 mV in voltage-clamped fibers, in which charge movement (Q _cm) could be measured. The peak values of Q _cm and the fractional rate of SR Ca release, as well as their ON time courses, were little affected by reducing [Ca_SR]_R from 1,200 to 140 μM. After repolarization, however, the OFF time courses of Q _cm and the rate of SR Ca release were slowed by factors of 1.5–1.7 and 6.5, respectively. These and other results suggest that, after action potential stimulation of fibers in normal physiological condition, the increase in myoplasmic free [Ca] that accompanies SR Ca release exerts three negative feedback effects that tend to reduce additional release: (a) the action potential is shortened by current through Ca-activated potassium channels in the surface and/or tubular membranes; (b) the OFF kinetics of Q _cm is accelerated; and (c) Ca inactivation of Ca release is increased. Some of these effects of Ca on an SR Ca channel or its voltage sensor appear to be regulated by the value of [Ca] within 22 nm of the mouth of the channel.     

Exploring Muscle Activation during Nordic Walking: A Comparison between Conventional and Uphill Walking

Nordic Walking (NW) owes much of its popularity to the benefits of greater energy expenditure and upper body engagement than found in conventional walking (W). Muscle activation during NW is still understudied, however. The aim of the present study was to assess differences in muscle activation and physiological responses between NW and W in level and uphill walking conditions. Nine expert Nordic Walkers (mean age 36.8±11.9 years; BMI 24.2±1.8 kg/m²) performed 5-minute treadmill trials of W and NW at 4 km/h on inclines of 0% and 15%. The electromyographic activity of seven upper body and five leg muscles and oxygen consumption (VO₂) were recorded and pole force during NW was measured. VO₂ during NW was 22.3% higher at 0% and only 6.9% higher at 15% than during W, while upper body muscle activation was 2- to 15-fold higher under both conditions. Lower body muscle activation was similarly increased during NW and W in the uphill condition, whereas the increase in erector spinae muscle activity was lower during NW than W. The lack of a significant increase in pole force during uphill walking may explain the lower extra energy expenditure of NW, indicating less upper body muscle activation to lift the body against gravity. NW seemed to reduce lower back muscle contraction in the uphill condition, suggesting that walking with poles may reduce effort to control trunk oscillations and could contribute to work production during NW. Although the difference in extra energy expenditure between NW and W was smaller in the uphill walking condition, the increased upper body muscle involvement during exercising with NW may confer additional benefit compared to conventional walking also on uphill terrains. Furthermore, people with low back pain may gain benefit from pole use when walking uphill.     

Unloaded shortening velocity of voluntarily and electrically activated human dorsiflexor muscles in vivo

We have previously shown that unloaded shortening velocity (V ₀) of human plantar flexors can be determined in vivo, by applying the “slack test” to submaximal voluntary contractions (J Physiol 567:1047–1056, 2005). In the present study, to investigate the effect of motor unit recruitment pattern on V ₀ of human muscle, we modified the slack test and applied this method to both voluntary and electrically elicited contractions of dorsiflexors. A series of quick releases (i.e., rapid ankle joint rotation driven by an electrical dynamometer) was applied to voluntarily activated dorsiflexor muscles at three different contraction intensities (15, 50, and 85% of maximal voluntary contraction; MVC). The quick-release trials were also performed on electrically activated dorsiflexor muscles, in which three stimulus conditions were used: submaximal (equal to 15%MVC) 50-Hz stimulation, supramaximal 50-Hz stimulation, and supramaximal 20-Hz stimulation. Modification of the slack test in vivo resulted in good reproducibility of V ₀, with an intraclass correlation coefficient of 0.87 (95% confidence interval: 0.68–0.95). Regression analysis showed that V ₀ of voluntarily activated dorsiflexor muscles significantly increased with increasing contraction intensity (R ² = 0.52, P<0.001). By contrast, V ₀ of electrically activated dorsiflexor muscles remained unchanged (R ²<0.001, P = 0.98) among three different stimulus conditions showing a large variation of tetanic torque. These results suggest that the recruitment pattern of motor units, which is quite different between voluntary and electrically elicited contractions, plays an important role in determining shortening velocity of human skeletal muscle in vivo.     

Monovalent Cationic Channel Activity in the Inner Membrane of Nuclei from Skeletal Muscle Fibers

Nuclear ion channels remain among the least studied and biophysically characterized channels. Although considerable progress has been made in characterizing calcium release channels in the nuclear membrane, very little is known regarding the properties of nuclear monovalent cationic channels. Here, we describe a method to isolate nuclei from adult skeletal muscle fibers that are suitable for electrophysiological experiments. Using this approach, we show for the first time, to our knowledge, that a nuclear monovalent cationic channel (NMCC) is prominently expressed in the inner membrane of nuclei isolated from flexor digitorum brevis skeletal muscle fibers of adult mice. In isotonic 140 mM KCl, the skeletal muscle NMCC exhibits a unitary conductance of ∼160 pS and high, voltage-independent open probability. Based on single-channel reversal potential measurements, NMCCs are slightly more permeable to potassium ions over sodium (P_K/P_Na = 2.68 ± 0.21) and cesium (P_K/P_Cs = 1.39 ± 0.03) ions. In addition, NMCCs do not permeate divalent cations, are inhibited by calcium ions, and demonstrate weak rectification in asymmetric Ca²⁺-containing solutions. Together, these studies characterize a voltage-independent NMCC in skeletal muscle, the properties of which are ideally suited to serve as a countercurrent mechanism during calcium release from the nuclear envelope.     

Comparison of Caplan's Irreversible Thermodynamic Theory of Muscle Contraction with Chemical Data

Recently Caplan (1) applied the concepts of irreversible thermodynamics and cybernetics to contracting muscle and derived Hill's force-velocity relation. Wilkie and Woledge (2) then compared Caplan's theory to chemical rates inferred from heat data and concluded that the theory was not consistent with the data. Caplan defended his theory in later papers (3, 4) but without any direct experimental verifications. As Wilkie and Woledge (2) point out, the rate of phosphorylcreatine (PC) breakdown during steady states of shortening has not been observed because of technical difficulties. In this paper it is shown that the rate equations may be directly integrated with time to obtain relations among actual quantities instead of rates. The validity of this integration is based on experimental evidence which indicates that certain combinations of the transport coefficients are constant with muscle length. These equations are then directly compared to experimental data of Cain, Infante, and Davies (5) with the following conclusions: (a) The measured variations of ΔPC for isotonic contractions are almost exactly as predicted by Caplan's theory. (b) The value of the chemical rate ratio, ν_m/ν_o, obtained from these data was 3.53 which is close to the value of 3 suggested by Caplan (3). (c) The maximum value of the chemical affinity for PC splitting was found to be 10.6 k cal/mole which is as expected from in vitro measurements (2). Because of the excellent agreement between theory and experiment, we conclude that Caplan's theory definitely warrants further investigation.     

A macroscopic ansatz to deduce the Hill relation

In this study, we derive the hyperbolic force-velocity relation of concentric muscular contraction, first formulated empirically by A.V. Hill in 1938, from three essential model assumptions: (1) the structural assembly of three well-known elements - i.e. active, parallel damping, and serial - fulfilling a force equilibrium, (2) the parallel damping coefficient explicitly depending on muscle force output and three parameters, and (3) the kinematic gearing ratio between active and serial element being assigned to a parameter. The energy source within the muscle represented by the force of the active element is an additional fifth parameter. As a result we find the Hill “constants” A and B as functions of our five model parameters. Using A and B values from literature on experimental data, we predict heat power release of our model. By calculating enthalpy rate and mechanical efficiency, we compare the model heat power to predictions from another Hill-type model, to Hill's original findings, and to findings from modern muscle heat measurements. We reconsider why the biggest share of heat rate during isometric contractions (maintenance heat) and the velocity-dependent heat rate during concentric contractions in addition to maintenance heat rate (shortening heat rate) may be traced back to the same mechanism represented by the kinematic gearing ratio. Namely, we suggest that the serial element transfers attachment-detachment fluctuations of actin-myosin crossbridges within one sarcomere to others in the same sarcomere and to those in parallel and in series. Numerically, in case of negligible passive muscular damping, we find the ratio between A and isometric force (relative A) to depend exclusively on the kinematic gearing ratio, whereas the maintenance heat rate scales with the square of relative A. Moreover, this mechanical coupling internal to the muscle fibres may also be behind the macroscopic force dependency of the overall parallel damping coefficient.     

Inorganic phosphate speeds loaded shortening in rat skinned cardiac myocytes

Force generation in striated muscle is coupled with inorganic phosphate (P_i) release from myosin, because force falls with increasing P_i concentration ([P_i]). However, it is unclear which steps in the cross-bridge cycle limit loaded shortening and power output. We examined the role of P_i in determining force, unloaded and loaded shortening, power output, and rate of force development in rat skinned cardiac myocytes to discern which step in the cross-bridge cycle limits loaded shortening. Myocytes (n = 6) were attached between a force transducer and position motor, and contractile properties were measured over a range of loads during maximal Ca²⁺ activation. Addition of 5 mM P_i had no effect on maximal unloaded shortening velocity (V_o) (control 1.83 ± 0.75, 5 mM added P_i 1.75 ± 0.58 muscle lengths/s; n = 6). Conversely, addition of 2.5, 5, and 10 mM P_i progressively decreased force but resulted in faster loaded shortening and greater power output (when normalized for the decrease in force) at all loads greater than 10% isometric force. Peak normalized power output increased 16% with 2.5 mM added P_i and further increased to a plateau of 35% with 5 and 10 mM added P_i. Interestingly, the rate constant of force redevelopment (k_tr) progressively increased from 0 to 10 mM added P_i, with k_tr 360% greater at 10 mM than at 0 mM added P_i. Overall, these results suggest that the P_i release step in the cross-bridge cycle is rate limiting for determining shortening velocity and power output at intermediate and high relative loads in cardiac myocytes. muscle mechanics; force-velocity relationship; cross-bridge cycle     

Autonomic energy conversion. II. An approach to the energetics of muscular contraction

All discussions of muscle energetics concern themselves with the Hill force-velocity relation, which is also the general output relation of a class of self-regulated energy converters and as such contains only a single adjustable parameter —the degree of coupling. It is therefore important to see whether in principle muscle can be included in this class. One requirement is that the muscle should possess a working element characterized by a dissipation function of two terms: mechanical output and chemical input. This has been established by considering the initial steady phase of isotonic and isometric tetanic contraction to represent a stationary state of the fibrils (a considerable body of evidence supports this). Further requirements, which can be justified for the working element, are linearity and incomplete coupling. Thus the chemical input of the muscle may be expected to follow the inverse Hill equation (see Part I). The relatively large changes in activities of reactants which the equation demands could only be controlled by local operation of the regulator, and a scheme is outlined to show how such control may be achieved. Objections to this view recently raised by Wilkie and Woledge rest on at least two important assumptions, the validity of which is questioned: (a) that heat production by processes other than the immediate driving reaction is negligible, which disregards the regulatory mechanism (possibly this involves the calcium pump), and (b) that the affinity of the immediate driving reaction is determined by over-all concentrations. The division of heat production into “shortening heat” and “maintenance heat” or “activation heat” is found to be arbitrary.     

Cardiovascular adaptations to mechanical overload

The cardiac changes resulting from mechanical overload of the left ventricle have been well documented and a variety of compensatory mechanisms described. These include a decrease in maximum velocity (V₀) of shortening in the absence of reduction in active tension (P₀), and a reversible decrease in myofibrillar adenosine triphosphatase activity resulting from isoenzymic shift from, predominantly, a form of myosin with high ATPase activity (V₁) to another with low (V₃). The thermodynamic advantage of the transition is the hypertrophied muscle possesses a more energy-efficient form of contraction. These reversible transitions resulted from altered gene expression of isoenzymic forms of myosin heavy chain. It must be borne in mind that the adaptational modifications just described appear to occur only in smaller animals such as the rat, that possesses several myosin isozymes. In large mammals it is mainly the V₃ form of myosin that is present, which does not change with altered contractile state. Responses of the large arteries to hypertension have been poorly studied. This is surprising when one recalls that degenerative disease of such vessels, that include the aorta, carotids and ileo-femoral arteries is almost an obligatory concomitant of hypertension. Such studies as have been carried out indicate that hyperplasia is specific for abdominal aortic stenosis while hypertrophy is found in aortic smooth muscle in rats with systemic hypertension. Mechanically, an increase in V₀ with no change in P₀ have been reported; an increase in myofibrillar ATPase activity was also reported. Though two myosin heavy chain isozymes have been found in aortic smooth muscle densitometry did not reveal any difference in distribution between tissues from control and hypertensive rats. The cause of the increased ATPase activity must be in increased phosphorylation of the muscles' 20,000 dalton light chain.