Bryan K. Slinker

Coordinated expression of species-specific myosin heavy chain (MHC) and troponin (Tn) isoforms may bring about a dynamic complementarity to match muscle contraction speed with species-specific heart rates. Contractile system function and dynamic force-length measurements were made in muscle fibers from mouse and rat hearts and in muscle fibers after reconstitution with either recombinant homologous Tn or orthologous Tn. The rate constants of length-mediated cross-bridge (XB) recruitment ( b) and tension redevelopment ( k_tr) of mouse fibers were significantly faster than those of rat fibers. Both the tension cost (ATPase/tension) and rate constant of length-mediated XB distortion ( c) were higher in the mouse than in the rat. Thus the mouse fiber was faster in all dynamic and functional aspects than the rat fiber. Mouse Tn significantly increased b and k_trin rat fibers; conversely, rat Tn significantly decreased b and k_trin mouse fibers. Thus the length-mediated recruitment of force-bearing XB occurs much more rapidly in the presence of mouse Tn than in the presence of rat Tn, demonstrating that the speed of XB recruitment is regulated by Tn. There was a significant interaction between Tn and MHC such that changes in either Tn or MHC affected the speed of XB recruitment. Our data demonstrate that the dynamics of myocardial contraction are different in the mouse and rat hearts because of sequence heterogeneity in MHC and Tn. At the myofilament level, coordinated expression of complementary regulatory contractile proteins produces a functional dynamic phenotype that allows the cardiovascular systems to function effectively at different heart rates.

A new dynamic model of left ventricular (LV) pressure-volume relationships in beating heart was developed by mathematically linking chamber pressure-volume dynamics with cardiac muscle force-length dynamics. The dynamic LV model accounted for >80% of the measured variation in pressure caused by small-amplitude volume perturbation in an otherwise isovolumically beating, isolated rat heart. The dynamic LV model produced good fits to pressure responses to volume perturbations, but there existed some systematic features in the residual errors of the fits. The issue was whether these residual errors would be damaging to an application where the dynamic LV model was used with LV pressure and volume measurements to estimate myocardial contractile parameters. Good agreement among myocardial parameters responsible for response magnitude was found between those derived by geometric transformations of parameters of the dynamic LV model estimated in beating heart and those found by direct measurement in constantly activated, isolated muscle fibers. Good agreement was also found among myocardial kinetic parameters estimated in each of the two preparations. Thus the small systematic residual errors from fitting the LV model to the dynamic pressure-volume measurements do not interfere with use of the dynamic LV model to estimate contractile parameters of myocardium. Dynamic contractile behavior of cardiac muscle can now be obtained from a beating heart by judicious application of the dynamic LV model to information-rich pressure and volume signals. This provides for the first time a bridge between the dynamics of cardiac muscle function and the dynamics of heart function and allows a beating heart to be used in studies where the relevance of myofilament contractile behavior to cardiovascular system function may be investigated.

Objective—To define relationships between hoofacceleration patterns of galloping horses and dynamic properties of the track. Animals—8 Thoroughbred horses without lameness. Procedure—Acceleration-time curves were recorded by use of accelerometers attached to each hoof as each horse galloped over the track straightaway. Four sessions were conducted for each horse, with the track surface modified by sequentially adding water before each session. These acceleration-time curves were analyzed to determine peak accelerations during the support phase of the stride. Track dynamic properties (hardness, rebound, deceleration rate, rebound rate, and penetration) were recorded with a track-testing device. Moisture content and dry density were measured from soil samples. Stepwise multiple regression was used to identify relationships between hoof-acceleration variables and track dynamic properties. Results—Track rebound rate was most consistently related to hoof variables, especially through an inverse relationship with negative acceleration peaks for all hooves. Also, rebound rate was related to initial acceleration peak during propulsion of the hooves of the forelimb and the nonlead hind limb as well as to the second acceleration peak during propulsion of the lead hooves of the hind limb and nonlead forelimb. Conclusions and Clinical Relevance—The inverse relationship between track rebound rate and negative acceleration peaks for all hooves reflects the most important dynamic property of a track. Any factor that reduces negative acceleration of the hooves will increase stride efficiency by allowing smoother transition from retardation to propulsion and therefore may be important in determining the safety of racing surfaces. (Am J Vet Res 2005;66:589–595)

To better understand the relationship between kinetic processes of contraction and the dynamic features of an isometric twitch, studies were conducted using a mathematical model that included: (1)...

Recent interest in so-called calcium-sensitizing positive inotropic drugs has highlighted the potential problem of a positive effect on force development being offset, at least partially, by the negative effect that many of these drugs have on relaxation. The purpose of this study was to examine the interplay of contraction and relaxation in determining the overall cardiac effect of different positive inotropic drugs. Using a buffer-perfused isolated rabbit heart preparation, we studied four drugs (calcium, dobutamine, EMD 57033, and CGP 48506) that were given at doses sufficient to increase similarly left ventricular pressure-generating capability by ∼20%. We show that, even though they produce equivalent changes in pressure-generating capability, these four agents produce dissimilar changes in relaxation capability, with dobutamine speeding relaxation, EMD 57033 slowing relaxation, and calcium and CGP 48506 having little effect of relaxation. Similar relative effects were observed for drug-induced changes in the timing of pressure-generation events. These effects combine to produce different drug-induced changes in overall cardiac pump function judged by the relation between cardiac output and heart rate. Dobutamine shifted the maximal cardiac output to a higher heart rate. In contrast, both calcium sensitizers shifted the maximum in cardiac output to a lower heart rate, whereas calcium had no effect. Thus even though positive inotropic drugs may have similar effects on left ventricular pressure generation, the overall benefit of such drugs on ventricular pump function will depend on how the drug also affects ventricular relaxation and ejection capabilities.

Objective: A novel angiotensin receptor has been described and named AT₄. Ligands for this receptor include the angiotensin II (Ang II) metabolite Ang II (3–8), known as angiotensin IV (Ang IV). There is 10-fold more AT₄ receptor than AT₁ receptor in rabbit myocardium. The AT₄ receptor has a high affinity for Ang IV (K_i in rabbit myocardium 10⁻⁶). Although several functions have been attributed to the novel Ang IV peptide/AT₄ receptor system, the effect of this system on left ventricular (LV) function has not been studied. We hypothesized (1) that Ang IV would affect LV function and (2) that any effects would be opposite to those of Ang II. Methods: Using the buffer-perfused (30°C) isolated rabbit heart, we studied the effect of the AT₄ agonist Nle¹-Ang IV on LV systolic function, quantified using both Frank–Starling and end-systolic pressure–volume relationships, and relaxation. We also studied the effect of the AT₁/AT₂ agonist, Sar¹-Ang II on LV function. Finally, because the profile of effect of Nle¹-Ang IV was similar to the reported effect of nitric oxide (NO), we also studied the effect of Nle¹-Ang IV in the presence of the NO synthase inhibitor N^G-monomethyl-l-arginine. Results: Nle¹-Ang IV reduced LV pressure-generating capability at any volume but increased the sensitivity of pressure development to volume change. Nle¹-Ang IV reduced LV ejection capability. Sar¹-Ang II had the opposite effect – increasing both pressure generation and ejection capability. Finally, both Sar¹-Ang II and Nle¹-Ang IV speeded LV relaxation. Inhibition of NO synthase did not alter the effect of Nle¹-Ang IV on LV systolic function or relaxation. Conclusions: AT₄ receptor agonism has mixed effects on LV systolic function, depressing pressure-generation and ejection capabilities, but enhancing the sensitivity of pressure development to volume change. It also speeds relaxation. The effect of Ang IV on systolic function is generally opposite to the effect of Ang II, whereas the Ang IV influence on relaxation is similar to the effect of Ang II.

Intrinsic oscillatory activity, or vasomotion, within the microcirculation has many potential functions, including modulation of vascular resistance. Alterations in oscillatory activity during pregnancy may contribute to the marked reduction in vascular resistance. The purpose of this study was 1) to mathematically model the oscillatory changes in vessel diameter and determine the effect on vascular resistance and 2) to characterize the vasomotion in resistance arteries of pregnant and nonpregnant (virgin) rats. Mesenteric arteries were isolated from Sprague-Dawley rats and studied in a pressurized arteriograph. Mathematical modeling demonstrated that the resistance in a vessel with vasomotion was greater than that in a static vessel with the same mean radius. During constriction with the α₁-adrenergic agonist phenylephrine, the amplitude of oscillation was less in the arteries from pregnant rats. We conclude that vasomotor activity may provide a mechanism to regulate vascular resistance and blood flow independent of static changes in arterial diameter. During pregnancy the decrease in vasomotor activity in resistance arteries may contribute to the reduction in peripheral vascular resistance.

Experiments were conducted in 10 isolated rabbit hearts at 25°C to test the hypothesis that vibration-induced depression of myocardial contractile function was the result of increased cross-bridge breakage. Small-amplitude sinusoidal changes in left ventricular volume were administered at frequencies of 25, 50, and 76.9 Hz. The resulting pressure response consisted of a depressive response [ΔP_d( t), a sustained decrease in pressure that was not at the perturbation frequency] and an in-frequency response [ΔP _f ( t), that part at the perturbation frequency]. ΔP_d( t) represented the effects of contractile depression. A cross-bridge model was applied to ΔP _f ( t) to estimate cross-bridge cycling parameters. Responses were obtained during Ca²⁺ activation and during Sr²⁺ activation when the time course of pressure development was slowed by a factor of 3. ΔP_d( t) was strongly affected by whether the responses were activated by Ca²⁺ or by Sr²⁺. In the Sr²⁺-activated state, ΔP_d( t) declined while pressure was rising and relaxation rate decreased. During Ca²⁺ and Sr²⁺ activation, velocity of myofilament sliding was insignificant as a predictor of ΔP_d( t) or, when it was significant, participated by reducing ΔP_d( t) rather than contributing to its magnitude. Furthermore, there was no difference in cross-bridge cycling rate constants when the Ca²⁺-activated state was compared with the Sr²⁺-activated state. An increase in cross-bridge detachment rate constant with volume-induced change in cross-bridge distortion could not be detected. Finally, processes responsible for ΔP_d( t) occurred at slower frequencies than those of cross-bridge detachment. Collectively, these results argue against a cross-bridge detachment basis for vibration-induced myocardial depression.

Because it is not known whether ejection influences the negative effect of the Ca²⁺-sensitizing drugs on ventricular relaxation, we extended our previous analysis of stress-dependent relaxation in isovolumic beats to encompass ejecting beats and evaluated the relationships between both the time of onset of relaxation and the rate of relaxation and wall stress in a broader analysis framework. Furthermore, because the sites of action of the Ca²⁺-sensitizing drugs CGP-48506 and EMD-57033 may be different, and thus CGP-48506 may have fewer adverse effects on resting muscle length or force, we compared these two drugs to test the hypothesis that CGP-48506 would have less effect than EMD-57033 on relaxation in the isolated buffer-perfused rabbit heart. This analysis of stress-dependent relaxation in both ejecting and isovolumic beats readily differentiates between the negative lusitropic effect of 2 × 10⁻⁶M EMD-57033, the negligible lusitropic effect of 6 × 10⁻⁶M CGP-48506, and the positive lusitropic effect of 1.25 × 10⁻⁶M dobutamine. Furthermore, comparison of the effect of the two Ca²⁺-sensitizing drugs in ejecting versus isovolumic contractions shows that CGP-48506 affects relaxation differently in ejecting contractions than it does in isovolumic contractions, whereas EMD-57033 affects relaxation similarly in both ejecting and isovolumic contractions.