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Cardiac effects of a selective rho-associated kinase inhibitor, Y-27632, assessed in canine isolated, blood-perfused heart preparations.

Chronotropic, inotropic and coronary effects of Y-27632 ((+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride, monohydrate), a specific inhibitor of Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK), were assessed using canine isolated, blood-perfused heart preparations. Y-27632 slightly enhanced sinoatrial automaticity and significantly increased coronary blood flow, while it decreased ventricular contraction. The concentrations of Y-27632 needed to cause the currently observed changes were similar to those inhibiting ROCK in a previous in vitro study. These results suggest that the constitutional ROCK in the heart mainly regulates the ventricular contractility and coronary vascular tone rather than the sinoatrial automaticity.

Amides↗

A case report of surgical treatment of a dog with atrioventricular septal defect (incomplete form of endocardial cushion defect).

A 3-month-old female collie was diagnosed as having atrioventricular septal defect with ostium primum atrial septal defect (PASD). The diagnosis was made by echocardiographic observation of the PASD and goose-neck deformity on left ventriculogram. The PASD was treated surgically with a patch graft under cross-circulation cardiopulmonary bypass (CC). The PASD was identified above the ventricular septum after right atriotomy. The patch graft was sutured along the fibrous tissue of the tricuspid annulus on the ventricular side of the PASD to avoid injuring the conduction system. After the operation, cardiac function and renal output were well preserved, but the dog died 33 hr later. At postmortem examination, a mitral cleft was identified.

Animals↗

Analysis of cardiac actions of nitroprusside in intact dogs and in isolated atria.

The effects of intravenous administration of sodium nitroprusside to a donor dog on cardiac pacemaker activity and contractility were investigated in a cross-circulated dog heart preparation; i.e., the isolated atrial muscle was perfused with blood from a pentobarbital anesthetized donor dog. Intravenous administration of nitroprusside (1-10 micrograms/Kg) caused a hypotension with tachycardia, and occasionally with bradycardia. This effect was blocked by atropine injections into the donor dog, but no significant chronotropic and inotropic changes were observed in the isolated atria. Larger doses (over 100 micrograms/Kg) of nitroprusside produced positive chronotropic and inotropic effects in isolated atria, which were inhibited completely by propranolol. Moreover, direct intraarterial injection of nitroprusside (10-1,000 micrograms) had no significant chronotropic and inotropic effects in isolated atria, although acetylcholine (0.01-0.1 micrograms) induced negative chronotropic and inotropic effects. From these results, it is concluded that nitroprusside has no direct cardiac effect and that it causes a release of catecholamines in doses which produce a profound hypotension.

Acetylcholine↗

Cardiovascular effects of budralazine in the dog.

Cardiovascular effects of budralazine were investigated in isolated and cross-circulated dog atrial preparations. When budralazine was injected into the jugular vein of the donor dog, a hypotension was produced with slight tachycardia in a dose-related manner. At the same time, slight positive chronotropic and biphasic inotropic effects were induced in the isolated atrium perfused with donor's arterial blood. When budralazine was injected into the cannulated sinus node artery of the isolated atrial preparation, it produced only slight negative chronotropic and inotropic responses, occasionally followed by positive responses. Vehicle injections induced monophasic negative chronotropic and inotropic effects. It is concluded that budralazine has a potent vasodilator action, a reflex-induced sympathomimetic action, but no direct cardiac stimulating properties. Moreover, a direct catecholamine releasing action of budralazine does not appear to be prominent.

Animals↗

The instantaneous impedance frequency curve of the ventricle with the regional ischemia.

We studied the feasibility of using the impedance frequency curve method (IFM) to detect the myocardial physical heterogeneity of a cross-circulated isolated canine left ventricle with regional ischemia. The curve changed from a single-peak configuration to a double-peak configuration after the LAD coronary flow cessation and returned to the single-peak configuration with the reperfusion of LAD coronary flow. We concluded that IFM can be a useful tool to describe the physical heterogeneity of the ventricular muscle under the regional ischemia.

Animals↗

Effect of left ventricular volume on the magnitude of functional depression by external minute vibration.

We examined the effect of the left ventricular (LV) volume on the magnitude of the vibration induced functional depression (VID) using four canine cross-circulated isovolumically beating LV preparations. A sinusoidal, 50 Hz vibration (1.5 mm in amplitude) was applied to the ventricular anterior epicardium at different values of LV volume which was stepwisely increased by 1-2 ml from 0 to 30 ml. VID was estimated as the difference of the peak LV pressure between control and during external vibration. VID increased as an increment in LV volume when the volume was below 7-8 ml and when peak LV pressure was less than 70 mmHg. However, VID remained constant when the volume increased further. We concluded that VID was independent of LV volume at physiological range.

Animals↗

Nipradilol depresses cardiac contractility and O2 consumption without decreasing coronary resistance in dogs.

Nipradilol (3,4-dihydro-8-(2-hydroxy-3-isopropylamino) propoxy-3-nitroxy-2H-1-benzopyran) is a newly synthesized chemical agent designed to possess beta-adrenoceptor blocking and vasodilating actions. Nipradilol decreased left ventricular contractility index (Emax, slope of the ventricular end-systolic pressure-volume relation), systolic pressure-volume area (PVA, a measure of ventricular total mechanical energy) and oxygen consumption in cross-circulated excised dog hearts. However, nipradilol did not decrease total coronary resistance. These results indicate that nipradilol, like propranolol, depresses myocardial mechanoenergetics and that the vasodilating action of nipradilol could not be detected in the present study.

Adrenergic beta-Antagonists↗

Critical evaluation of left ventricular systolic pressure volume areas as predictor of oxygen consumption rate.

Left ventricular systolic pressure volume area (PVA) has been reported to be a reliable predictor of cardiac oxygen consumption rate per beat (VO2) in a given heart with a stable inotropic background. PVA has been defined as the specific area in the pressure-volume (P-V) plane that is bounded by the end-systolic and end-diastolic P-V relationship lines and the systolic segment of the P-V loop trajectory. In the present experimental study, we separated PVA into two parts: EW and PE. EW is the area surrounded by the P=V loop, corresponding to the external mechanical work. PE is the area surrounded by the end-systolic and end-diastolic P-V lines and the relaxation segment of the P-V loop, corresponding to what is considered the end-systolic elastic potential energy in terms of a time-varying elastance model of the ventricle. We attempted to find an optimal weighting coefficient K of PE for the best correlation between VO2 and PVAW = EW + K . PE, changing K from 0 to infinity. Results in 7 canine excised cross-circulated hearts showed that PVAW best correlated with VO2 at K = 1.03 +/- 0.03 (SE). Since PVAW at K = 1 is identical with the original PVA, we concluded that PVA could serve as a reliable predictor of VO2. PVA is concluded to be physiologically significant in the coupling between cardiac mechanics and energetics.

Animals↗

Depressive effects of active shortening on stroke volume of left ventricle and shortening amount of isolated ventricular muscle.

In the cross-circulated canine heart-lung preparation, the stroke volume (SV) or the end-systolic volume increased linearly with increasing end-diastolic volume (EDV) when the afterloading impedance was fixed. Exactly the same result was obtained in the relation between the initial length (I) and the amount of shortening (S) for the tetanic contraction of isolated frog ventricular muscle. The slope of the EDV-SV or I-S relation was less than 1.0, suggesting that a kind of depressive effect or a deactivation of contraction was working during the active shortening of cardiac muscle. The slope, which inversely reflects the degree of deactivation, slightly tended to 1.0 with decreasing load and markedly by inotropic intervention, but it was not changed by partial ischemia. The horizontal axis intercept of the EDV-SV or I-S relation, which reflects the ability of the cardiac muscle to shorten under a specified afterloaded condition, shifted to the right (the ability decreased) at a larger load or under partial ischemia but shifted to the left with inotropic intervention. The deactivation increased linearly with the amount of active shortening but no deactivation was observed when there was no active shortening or no load. The mechanism of the deactivation is not due to a shortage of active-state duration but probably due to a depressive effect on Ca2+ utilization of the contractile system during the sliding phase of myofilaments.

Animals↗

Constant mechanical efficiency of contractile machinery of canine left ventricle under different loading and inotropic conditions.

We have recently proposed that the total mechanical energy generated in each cardiac contraction can be quantified by the systolic pressure-volume area (PVA). PVA is the area in the pressure-volume (P-V) diagram that is circumscribed by the end-systolic and end-diastolic P-V relation curves and the systolic segment of the P-V trajectory. This area has dimensions of energy and comprises the external mechanical work and the elastic potential energy. In the left ventricle of cross-circulated canine hearts, we studied the relation between PVA and oxygen consumption per beat (VO2) above VO2 for mechanically unloaded contraction. We assumed that this excess VO2 is utilized for mechanical contraction by the contractile machinery. The percentage of PVA in the excess VO2, both in the same unit of energy, J, would then represent the efficiency of energy conversion from the excess VO2 to the total mechanical energy in the contractile machinery. We obtained this efficiency in variously loaded contractions in both control and enhanced contractile states with epinephrine and calcium. We found that the efficiency was constant at 30-50 (mean 40) % regardless of the changes in both loading conditions and contractile states. By this constant efficiency and a variable fraction of external work in PVA, we accounted for the load- and contractility-dependent variability of the conventional mechanical efficiency (0-30%) of the heart.

Animals↗

Approach for quantifying the overall function of the ascending central neural integration to release vasopressin in rats.

Electrical stimulation of the intermediate portion of the solitary nucleus (SOL) is known to consistently elicit a pressor response and increase in the release of vasopressin (VP) in rats, when the cervical spinal cord and vago-sympathetic trunks are cut. The aim of the present study was to provide a methodological assessment for this technique, in order to quantify the central neuroendocrine function to release VP. Experiments were conducted on rats with cervical cordotomy and vagotomy, under 60% N2O anesthesia and artificial ventilation. The animals were maintained at their normal arterial blood pressure by infusing phenylephrine, which itself exerted little influence on the arterial plasma VP concentration (pVP) during SOL stimulation. In order to prevent blood loss, cross circulation with a donor rat was utilized in the blood sampling for pVP determination. We confirmed that this technique itself did not significantly affect the pVP level. A monopolar stimulus at a frequency of 50 Hz was found to produce the pressor response most effectively. The current spread of the stimulation (0.5 ms duration; 1 s on/1 s off; up to at least 120 microA) did not induce a false-positive pressor response mediated by other structures adjacent to the SOL. We suggest that electrical stimulation of the SOL in rats with cervical cordotomy and vagotomy, for observing the pressor response and/or increase of pVP, represents a rapid approach for screening the overall function of the ascending efferent part of the reflex mechanisms to release VP.

Animals↗

Comparison between Bretschneider's total myocardial energy demand (Et) and our total mechanical energy (PVA) as a predictor of cardiac oxygen consumption in dogs.

We compared the predictive capability of two indexes of ventricular oxygen consumption (VO2) in excised cross-circulated dog hearts. One of the indexes was Bretschneider's Et, formulated as the sum of energies for 5 different mechanical and nonmechanical activities of myocardium. The other one was the left ventricular systolic pressure-volume area (PVA), originally proposed by Suga. PVA is a measure of total mechanical energy and has been combined with Emax (ventricular contractility index) to predict VO2 in different inotropic states. When all data sampled from different hearts under various loading and inotropic conditions were pooled, both VO2 (Bret) predicted from Bretschneider's index and VO2 (Suga) predicted from Suga's index correlated well with the measured VO2 (VO2 (Measured)). However, VO2 (Bret) was more affected by the contraction mode as compared with VO2 (Suga), because the former includes ejection period as a parameter. Among the 5 terms of VO2 (Bret), the major correlate of VO2 (Measured) was found to be tension development energy term E3 which includes dP/dtmax as a parameter. VO2(Suga), as a predictive index of VO2 (Measured), was more reliable in each heart than in pooled data from all the hearts because of the interindividual variations of the coefficients. We conclude that both indexes have usefulness and limitations, and should be chosen depending on the application.

Animals↗

Logistic characterization of left ventricular isovolumic pressure-time curve.

Although some investigators have attempted to express the left ventricular pressure-time curve by mathematical functions such as exponential and sinusoidal functions, none of them reasonably fits the left ventricular pressure-time curve. In the present study, we hypothesized that a ventricular isovolumic pressure-time curve could be expressed as the difference between two S-shaped curves for pressure rising and falling, and proposed a new "hybrid logistic" function to express the left ventricular isovolumic pressure-time curve. We investigated how well this hybrid logistic function fits left ventricular isovolumic pressure curves experimentally observed under physiological preload and contractility in the excised cross-circulated left ventricles of 10 dogs. The new function precisely fitted the isovolumic pressure curves regardless of preload and contractility with correlation coefficients above 0.9996, much better than the previously proposed functions. The observed values characterizing the magnitude and time course of the isovolumic pressure curve such as peak +/- dP/dt also closely correlated with the corresponding theoretical values calculated by the present best-fit function. We conclude that our new hybrid logistic function reasonably characterizes the canine left ventricular isovolumic pressure-time curve within physiological ranges of preload and contractility. The present results indicate that this hybrid logistic function is useful to evaluate left ventricular contraction and relaxation comprehensively.

Animals↗

Similarities and differences in the time course of mechanical activity of the canine myocardium and isovolumic left ventricle.

BACKGROUND: The isovolumic non-ejecting left ventricle (LV) is functionally analogous to the isometric myocardium and the curve of the time course of left ventricular isovolumic pressure, P(t), resembles the curve of the time course of myocardial isometric force, F(t). In this study therefore, we first tested the hypothesis that the same general empirical model that fit F(t) and L(t), the isotonic shortening curve, will also fit P(t) by evaluating the model P(t) = P0 + C(t/A)B exp[1-(t/A)]B in 8 Suga-Sagawa isolated cross-circulated canine left ventricles. P0 is the end-diastolic pressure; A, B, and C are parameters. We went further to compare the time course of P(t) to those of F(t) and L(t) exploiting their common basic analytical models not only to characterize similarities but also to highlight differences between them. METHODS: To obtain curves of P(t), we inserted a latex balloon in the LV and injected water into it and recorded the isovolumic pressure curve, P(t), in each of 8 ventricles. Eight in situ right ventricular papillary muscles of the isolated canine heart were also studied with a servo system that clamped length or force to produce F(t) or L(t). Each curve, P(t), F(t), or L(t) was fit with the above model by Marquardt's algorithm and A, B, and C determined. RESULTS: The model fit the curves closely, the coefficient of determination being 0.995 +/- 0.003 for P(t); 0.994 +/- 0.003 for F(t), and 0.990 +/- 0.004 for L(t). The common model allowed direct quantitative comparison of the time course of either myocardial isometric or isotonic dynamics with the time course of left ventricular isovolumic dynamics by comparing the ventricular parameters A and B, which determine details of time course, with their corresponding myocardial counterparts. Under basal (i.e. control) conditions, A and B averaged 0.194 +/- 0.015 and 2.09 +/- 0.065 respectively for P(t). Mean A for isotonic shortening was 0.219 +/- 0.022 (p < 0.02 compared to mean A for P(t)). Mean B for F(t) was 1.87 +/- 0.100 (p < 0.001 compared to mean B for P(t)). The values of A for P(t) and F(t) were not different and the values of B for P(t) and L(t) were closely similar. CONCLUSION: The same empirical model that fits F(t) and L(t) also fits P(t). Comparison of myocardial to ventricular curves showed that during contraction, P(t) corresponded closely to F(t) and L(t). However during relaxation, P(t) led both F(t) and L(t) both of which pursued a similar time course. This suggests that myocardial contraction may be isometric during LV isovolumic contraction and it may be valid to extrapolate information about myocardial isometric contraction directly to left ventricular isovolumic contraction and vice versa. On the other hand during left ventricular isovolumic relaxation, myocardial dynamics may well involve some length changes. It is difficult, however, to reconcile such presumed length changes to the putative isometricity of myocardial function during contraction.

Animals↗

Pressure-interval relationship characterizes left ventricular irregular beat contractilities and their mean level during atrial fibrillation.

How left ventricular (LV) contractility relates to irregular RR intervals during atrial fibrillation (AF) is still unclear. We investigated the relationship between the LV contractility (Emax) of individual beats and their preceding RR intervals during AF in isovolumic contractions is excised cross-circulated canine hearts, and additionally in ejecting contractions in in situ canine hearts. Atrial high-frequency electrical stimulation induced AF. We recorded a LV electrocardiogram, volume and pressure, and calculated the Emax of every arrhythmic beat. Multiple linear regression analysis between Emax and the six preceding RR intervals of all arrhythmic beats during 1 min AF showed the preceding RR interval (RR1) and the pre-preceding interval (RR2) to be the predominant predictors of Emax. The Emax-RR1/RR2 scattergram was closely fitted by a linear regression line. We found Emax at RR1/RR2 = 1 on the regression line to be virtually identical with both mean Emax during AF and stable Emax obtained during irregular atrial pacing at the same intervals as the mean RR interval during AF. These results newly indicate that the pressure-interval relationship predominantly characterizes LV irregular beat contractilities and their mean level during AF.

Animals↗

2,3-Butanedione monoxime suppresses excitation-contraction coupling in the canine blood-perfused left ventricle.

The negative inotropism of 2,3-butanedione monoxime (BDM) < or = 5 mmol/l has been attributed primarily to directly suppressed crossbridge force development without much suppressed intracellular Ca2+ handling. However, there is evidence that BDM simultaneously or even primarily suppresses myocardial excitation-contraction (E-C) coupling. We therefore studied the mechanoenergetic effects of intracoronary BDM in the left ventricle (LV) of 11 canine excised cross-circulated hearts. We fully utilized the VO2-PVA-Emax framework that we have developed, where VO2 is myocardial O2 consumption, PVA is the systolic pressure-volume area as a measure of the total mechanical energy, and Emax is a contractility index. We gradually depressed Emax from 5.9 to 3.4 mmHg/(ml/100 g) on average by increasing intracoronary BDM to 2.6 +/- 2.1 mmol/l, and then gradually restored Emax to the pre-BDM level by increasing intracoronary CaCl2. We compared the O2 cost of Emax between BDM and Ca2+. We found that BDM and Ca2+ had a similar O2 cost of Emax. BDM did not affect the concentrations of blood-borne catecholamines. We therefore conclude that the negative inotropism of BDM is primarily due to suppressed E-C coupling in canine blood-perfused hearts.

Analysis of Variance↗

Hybrid logistic characterization of isometric twitch force-time curve of intact blood-perfused canine right ventricular papillary muscle.

We previously found that a ventricular isovolumic pressure-time curve could be well fitted by the difference between two S-shaped logistic curves for the pressure rising and falling components, and called it "hybrid logistic" function: P(t)=A/[1+exp[-(4B/A)(t-C)]]-D/[1+exp[-(4E/D)(t-F)]]+G. We reported that the parameters of this hybrid logistic function are useful to characterize left ventricular contraction and relaxation comprehensively. In this study, we investigated how well this hybrid logistic function could fit the isometric twitch force-time curves of cross-circulated right ventricular papillary muscles of 7 dogs. This function precisely fitted the isometric force curves with correlation coefficients above 0.9996, much better than another fitting function (F(t)=C(t/A)(B)exp[1-(t/A)(B)]) proposed by Nwasokwa. The present results indicate that our hybrid logistic function can also reasonably express the canine right ventricular papillary muscle isometric twitch force-time curve. We suggest the possibility that the parameters of this hybrid logistic function are also useful to comprehensively characterize right ventricular papillary muscle twitch contraction and relaxation.

Animals↗

Ryanodine decreases internal Ca2+ recirculation fraction of the canine heart as studied by postextrasystolic transient alternans.

We tested our hypothesis that the O2 wasting of Ca2+ handling in the excitation-contraction (E-C) coupling in ryanodine-treated failing hearts could be reflected by a decrease in the internal Ca2+ recirculation fraction (RF). We have reported, using canine excised cross-circulated hearts, that intracoronary ryanodine (40 nmol/l blood) halved left ventricular contractility without decreasing myocardial O2 consumption for the E-C coupling. We previously suspected this mechanoenergetic state to manifest energy wasting of Ca2+ handling due to ryanodine causing leakage of Ca2+ from the sarcoplasmic reticulum. To test this hypothesis, we analyzed all the sporadic spontaneous cases of postextrasystolic potentiation (PESP) obtained during the ryanodine experiments. We calculated RF from the beat constant of the exponential decay component of not only the monotonic type but also the transient alternans type of PESP. Results showed that ryanodine significantly decreased the beat constant in both types of PESP from about 2 to 1.5 beats and hence RF from 0.6 to 0.5 on the average, supporting the hypothesis. This organ-level systems approach to Ca2+ handling using transient alternans PESP as well as monotonic PESP may help obtain better insights into the mechanoenergetics of failing hearts.

Animals↗