Cat Heart Research Articles

Role of prostacyclin in the preservation of ischemic myocardial tissue in the perfused cat heart.

SUMMARY Prostacyclin (PGI2) and some of its major breakdown products (6-keto-PGFi,,, 6-ketoPGEi, and 13,14-dihydro 6,15-diketo-PGFia) were studied in an isolated perfused cat heart preparation during myocardial ischemia. At an infusion rate of 10 ng/g heart weight per minute, PGI2 and the related compounds caused no changes in perfusion pressure, contractile force (CF), the first derivative of the contractile force (dF/dt), and heart rate in control hearts perfused at coronary flows of 20-35 ml/min. Induction of global ischemia by perfusion at 0.6 to 0.7 ml/min for 120 minutes resulted in a significant release of creatine kinase (CK) activity and compounds having a free amino-nitrogen group into the perfusate. Ischemic hearts exhibited an increase in resting tension of 2.3 ± 0.2 g, mean ± SEM. Upon reperfusion, untreated ischemic hearts showed a partial restoration of mechanical performance, CF = 43 ± 5%, and dF/dt = 40 ± 5% of control. PGI2 infusion inhibited the ischemic-induced CK release and the increase in perfusate amino-nitrogen concentration. Resting tension also remained low (i.e., 0.8 ± 0.1 g). Recovery of CF and dF/dt upon reperfusion was significantly higher (86 ± 8% and 88 ± 10%, respectively) than in the untreated ischemia group. Myocardial CK activity was significantly higher in PGI2-infused hearts (35.8 ± 2.6 IU/mg protein) compared to those infused with its vehicle (26.3 ± 2.8, P < 0.01).' Breakdown products of PGI2 only slightly protected against ischemia. PGI2 is beneficial in myocardial ischemia in vitro, even without its well known action preventing platelet aggregation and independent of its induction of coronary vasodilation. CircRes 47: 757-763, 1980

The contractile state of cat and dog heart in relation to the interval between beats.

We induced atrioventricular dissociation and initiated ventricular pacing in intact dogs and isolated cat hearts. Left ventricular pressure, its time derivative (dP/t), and action potentials were recorded. When a test pulse was introduced at varying intervals after a period of steady pacing, an optimum contractile response was obtained at an average interval of 720 msec. A similar optimum interval was obtained after pacing at various frequencies and after paired pulse stimulation but was shortened to 560 msec after infusion of epinephrine. The magnitude of the optimum contractile response increased with an increase in the frequency of prior pacing which was accompanied by an increase in the time the cell membrane was depolarized. The optimum contractile response following paired pulse stimulation was greater than that following regular pacing, with the same number of stimuli per minute and the same time of membrane depolarization. The results are explicable in terms of intracellular calcium ion recirculation with separate compartments for release to and uptake from the contractile proteins. A negative feedback control of Ca2+ inflow to the cell by intracellular Ca2+ content is postulated to explain the effect of paired pulse stimulation and shortening of action potential duration following an increase in regular pacing frequency.

Comparative myocardial protection with calcium-free versus calcium-containing potassium cardioplegic solutions

The present study was designed to determine if the addition of calcium to a potassium cardioplegic solution results in improved myocardial protection during ischemic arrest. An isolated perfused cat heart preparation was used. Hearts were made ischemic for 60 min and then reperfused for 45 min. Four groups were studied with the myocardial temperature during ischemia being maintained at 37°C in one and at 27°C in the remaining three groups. Two of these latter three groups received cardioplegic solutions while one remaining hypothermic group served as a hypothermic control. The cardioplegic solutions differed in that one was a calcium-free moderately hyperkalemic solution while the other contained 2 m M calcium, 16 m M magnesium, and 1 m M procaine in addition to being moderately hyperkalemic. Myocardial gas tensions were monitored by mass spectrometry and isovolumic ventricular function assessed by developed pressure and maximum dP/dt. Hypothermia alone resulted in significantly better recovery of ventricular function than normothermic ischemia. Recovery was further enhanced by the addition of cardioplegia. The best return of left ventricular function was seen in the group which had received the calcium-free cardioplegic solution and this group also developed the least myocardial edema following reperfusion. This study demonstrates that the omission of calcium as well as magnesium and procaine, from a cardioplegic solution, rather than being hazardous, may in fact be beneficial.

Interaction between the rigt heart ventricle and its arterial load: a quantitative solution.

Piene and Sund (Cardiovasc. Res., 1980) have recently demonstrated that the performance of the ventricle can be expressed by relating the principal variables pressure (P), volume (V), and time after onset of contraction (t): P = function (V,t). The function can be mapped experimentally as a three-dimensional surface, denoted the PVt surface, and can thereafter be approximated by an empirical equation. The vascular load of the ventricle is defined by the arterial input impedance vs. frequency graph, Z(f), which can be converted to the time domain by inverse Fourier transformation. This report describes how flow and pressure generated by the ventricle can be calculated when the independent expressions for the ventricle and for the load are given. The method is applied on right ventricular contractions of isolated cat hearts, and excellent fit between calculated and observed flow and pressure curves was obtained.

Effect of vanadate on myocardial force of contraction.

Ammonium vanadate (NH4VO3; 50-1000 microM) increases the force of contraction of isolated electrically driven cat papillary muscles in a concentration-dependent manner. The positive inotropic effect (PIE) of NH4VO3 became significant at 50 microM and was maximal at 500 to 1000 microM. It was accompanied by an increase in the rate of force development, in the rate of relaxation and in relaxation time of the isometric contraction. Similar results as with NH4VO3 were also observed in the presence of 1 microM propranolol, 5 microM phentolamine or after reserpine-pretreatment (5 mg/kg i.p.). These results indicate that vanadate produces a direct PIT in ventricular cardiac muscle which is unlikely to be mediated by alpha- or beta-adrenoceptor stimulation. In cat left atrial strips, however, vanadate ions produced a negative inotropic effect through a hitherto unknown mechanism. Vanadate effects similar to those observed in the cat heart were obtained in ventricular and atrial preparations from bovine hearts.

The effect of elevated chronic loading on the action potential of mammalian myocardium

Action potentials of various regions of hypertrophied and non-hypertrophied rat and cat hearts were recorded. It was found that the action potential duration is a function of the recording position within the heart: prolonged action potentials are characteristic for cells which are exposed to high chronic wall stress, both in hypertrophied and non-hypertrophied hearts. This is true for cells of sub-endo-cardial as compared to sub-epicardial wall layers, as well as cells of left ventricular as compared to right ventricular myocardium. The prolongation of the action potential is certainly responsible to some extent for the longer lasting mechanical activity of the corresponding heart muscle preparations measured in the isometric contraction mode.

Left and right ventricular pump function and consequences of having two pumps in one heart. A study on the isolated cat heart.

SUMMARY We compared pump function of left and right ventricles in isolated ejecting cat hearts in which the natural series arrangement between the two sides of the heart was broken. The relationship between mean ventricular pressure and output obtained by varying the arterial load, the so-called pump function graph, and the mean external power output found at the various load levels, was taken as the basis for the comparison. The way in which pressures and flow generated by the right ventricle are changed by alterations in resistance and compliance of the loading arterial system, is qualitatively similar to what has been found in a previous study for the left side of the heart, in spite of the structural differences. The right ventricular pump function curve differs from the left ventricular curve in the absolute scale for the mean pressure axis, but if the scale is adjusted appropriately, the two curves look alike. Both ventricles appear matched to the input impedances of their respective arterial systems because both of them generate the maximum external power under the normal loading conditions. Right ventricular pump function is dependent on the left ventricular contraction mode. The presence of an isovolumic beat on the left side of the heart enhances right ventricular pump function. This is in contrast to the very small effect of the right ventricular contraction pattern on the pump function of the left side of the heart. Circ Res 46: 564-574, 1980

Performance of the right ventricle: a pressure plane analysis.

A load invariant presentation of the heart's ventricular performance has been investigated. Flow from the right ventricle of isolated cat hearts was passed through a controlled, variable load. Ventricular pressure and flow were recorded and ventricular volume computed by flow integration. The three-dimensional trajectories of ventricular pressure, ventricular volume and time after onset of contraction all closely followed a single three-dimensional surface, which was denoted as the PVt surface. The PVt surface depends on the inotropic condition of the heart, but is load invariant. It is therefore a measure of the intrinsic ventricular performance. Given the arterial load on the ventricle, it can be applied for predictions of pressure and flow profiles, as well as any parameter related to them.

Insulin-like stimulation of glucose oxidation in rat adipocytes by vanadyl (IV) ions

The mechanism of insulin action is still unknown1. One approach to this problem is to apply substances which mimic the action of the hormone to target cells. Ouabain and deprivation of extracellular K+ (refs 2,3), which inhibit the active transport of Na+ and K+ ions, are both known to activate glucose transport and oxidation in isolated adipocytes. Vanadate (V) ions have recently been shown to act as very efficient inhibitors of the sodium pump or (Na+ + K+)ATPase in in vitro preparations4. They have a natriuretic and diuretic effect in rats5 and a positive inotropic effect on cat heart muscle6. Many tissues contain vanadium at a concentration of about 0.1–1.0 μM (ref. 7) and so endogenous vanadate could be a physiological regulator of the sodium pump. But this is still open to debate, because the bulk of the vanadium is probably in the vanadyl (IV) form8,9 and VO2+ ions bind tightly to proteins8,10. VO2+ is a relatively ineffective inhibitor of (Na+ + K+) ATPase in vitro8,11. We report here that externally applied vanadate ions at low concentrations mimic fully the effect of insulin on glucose oxidation in rat adipocytes. However, this simulation seems to be due mainly to the effects of vandyl (IV) ions, probably produced within the cells, and not primarily to inhibition of the sodium pump. Also, externally applied vanadyl (IV) ions stimulate glucose oxidation substantially. Vanadyl ions are known to be powerful inhibitors of alkaline phosphatase12 and we therefore consider the possibility that they inhibit a cellular phosphatase activity. An early event in insulin action may involve alteration of the degree of phosphorylation of protein(s) involved in regulation of sugar transport.

Some mechanical considerations in the selection and testing of papillary muscles.

Measurements of segmental deformation made on papillary muscles obtained from cat, rabbit, dog and pig hearts suggest that the deformational behavior in these specimens is appreciably nonuniform both in the resting (passive) state and in the stimulated (active) state. In view of this, in the mechanical testing of papillary muscles, it is necessary to establish a minimum size of segment "sufficiently" far from the disturbing influence of end fixtures generally used to hold the specimen in the testing machine. The segment size should be large enough to average out the nonuniform aspects of deformation. Thus, the shape and size of the specimen dictated by the nonuniformities in the mechanical response, the thinness of the specimen dictated by the viability considerations and aspects of the testing machines and method dictated by the visco-elastic features of the specimen should be given due consideration in the selection and testing of papillary muscles.

Alterations in excitation of mammalian myocardium as a function of chronic loading and their implications in the mechanical events.

It is shown that hypertrophied rat myocardium exhibits marked prolongation of its action potential during non-essential changes both in the resting potential, as well as in the amplitude of the action potential, and during a moderate but nonsignificant reduction in the maximum upstroke velocity. When examining action potentials of various myocardial regions of the same heart, it can be demonstrated that high chronic loading involves broad action potentials both in rat and cat hearts. After depression of the fast inward current either by TTX or by partial depolarization under high extracellular K+ concentrations, the prolongation of the Ca2+ mediated action potentials of myocardial cells under high chronic loading is still manifest. The broadening of the action potential is certainly responsible to some extent for the prolonged activity of the corresponding myocardial cells, which is expressed in the significant increase in the isometric peak time and in the augmentation of isometric force.

Cardiac mass, blood temperature and ventricular fibrillation: A study of the comparative physiology of the three-toed sloth and the domestic cat

Abstract o 1. 10 three-toed sloths, Bradypus triadactylus, and 20 domestic cats were subjected to potentially fibrillating electrical stimulation repeated at a series of temperatures while cooling blood from 38 to 28°C and also during warming back to 38°C. 2. It was more difficult to produce cardiac fibrillation in the sloth than in the domestic cat of the same body size or of the same heart size. 3. When fibrillation was produced in the sloth the heart recovered more quickly than did the heart of the cat in the same situation. 4. Cooling did not predispose to fibrillation in the sloth as much as it did in the cat and when fibrillation occurred the time to recovery was not as greatly prolonged. 5. Fibrillation responses in the same species were similar at the same temperature, whether on cooling or re-warming. 6. Arterial blood pressures varied considerably in both cats and sloths but average pressures were slightly lower in sloths. 7. Plasma ion concentration, blood gases, pH and osmolarity were determined at various temperature levels and considered for possible relationship to fibrillation. 8. Cooling to 28°C reduced the heart rate of the cat to 50% of the initial rate and that of the sloth to 55% of the initial rate.

Antihypertensive and cardiac effects of two novel beta-adrenoceptor blocking drugs.

Two new beta-adrenoceptor blocking drugs with acute antihypertensive and positive inotropic effects are described: Compound A (2-[4-(3-tert.butylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole) and MK-761 (2-(3-tert.butylamine-2-hydroxypropoxy)-3-cyanopyridine hydrochloride). In SH rats both compounds, given orally, lowered arterial pressure and were more potent than hydralazine. The antihypertensive effect of compound A but not of MK-761 was antagonized by timolol. Both compounds had positive inotropic activity on cat heart papillary muscles; these effects were antagonized by timolol. The pretreatment of animals with reserpine greatly reduced the positive inotropic effect of MK-761 but not of compound A. The acute antihypertensive and positive inotropic effects of compound A are like to be at least partially due to stimulation of beta-adrenoceptors, e.g. intrinsic sympathomimetic activity. The effects of MK-761 on the same parameters appear to be mediated by different mechanisms.

The protective effects of dietary fish oil on focal cerebral infarction

The protective effect of the (n-3) fatty acids in menhaden fish oil on acute cerebral ischemia was investigated in cats. Cerebral ischemia was produced by ligation of the left middle cerebral artery of cats fed either a basal diet of feline cat chow or the basal diet supplemented with 8% of the calories as menhaden oil for 18–24 days. Fatty acid esters of 20:5(n-3) were increased and the 18:2(n-6) decreased in the heart and liver of cats fed supplemental fish oil, but the brain lipid showed no effect of the diet. We found that the neurological deficit and the volume of brain infarction in the group treated with fish oil was less than that of the control group. The present findings suggest that moderate dietary supplements of fish oil may be beneficial in the prophylactic treatment of ischemic cerebral vascular disease.

Purified cardiac cell membranes with high (Na+ + K+) ATPase activity contain significant NADH-vanadate reductase activity

Vanadium compounds have been reported to inhibit the (Na+ + K+)ATPase activity of several cell membrane preparations1–3, to have a positive inotropic effect on ventricular cardiac muscle4, slightly increase myocardial cyclic AMP levels5, stimulate fat cell adenylate cyclase6, and cause natriuresis in rats7. Recently we have reported that vanadate produces a transient, initial stimulation of (Na+ + K+) ATPase activity in a cat heart cell membrane preparation, in addition to its well known inhibitory action on this enzyme system8. The transient stimulation occurred at the same concentration range as did the inotropic effects. There was, however, a serious discrepancy between the time courses of the two events. The former lasted only a few minutes, whereas the latter remained virtually stable for at least 30 min. The supposed stimulatory action of vanadate on (Na+ + K+)ATPase was deduced from an initial rapid loss of NADH in the ATPase assay used (optical coupled assay with an ATP regenerating system9). The oxidation of NADH was followed photometrically by continuous recording8. We now report that the rapid loss of NADH and hence the claimed transient stimulatory action of high concentrations of vanadate on the (Na+ + K+)ATPase activity is caused rather by an oxidation of NADH as a result of a NADH-dependent reduction of vanadate.

The orthograde labeling of postganglionic sympathetic cardiac nerves in the dog and cat as demonstrated by autoradiography

Previous functional and anatomical techniques have characterized the cardiac nerves and plexuses. They cannot, however, determine the course of fibers arising from a specific ganglion. This study has found that the intraaxonal orthograde labeling of axons can be used to determine the course of postganglionic sympathetic cardiac fibers in the dog and cat. The canine left caudal cervical ganglion and the feline right stellate ganglion were exposed through appropriate thoracotomies. Each ganglion received multiple injections of tritiated leucine (500 μCi/animal). Following a 3–14-day survival period the anesthetized animals were sacrificed by vascular perfusion. The injected ganglia, extracardiac nerves and selected portions of the heart were processed for autoradiography. Autoradiographs from the dog demonstrated labeled postganglionic sympathetic nerves in the extracardiac plexus, left atrial epicardium and the epicardium beneath the coronary sulcus. Labeled nerves in the cat heart were found within the epicardial layers and associated with blood vessels in the left ventricular myocardium. Neither myelinated fibers traveling through the injection site nor intrinsic cardiac ganglion cells were labeled, although the latter were often closely approximated to heavily labeled fibers.

Cardiotonic effects of anthopleurin-A, a polypeptide from a sea anemone.

The positive inotropic effect of anthopleurin-A (AP-A) was studied in vitro on isolated cat heart papillary muscles and in vivo in anesthetized and conscious dogs. In vitro, in low Ca2+ solution (1.27 mM), AP-A increased the force of contractions of isolated cat heart papillary muscles at concentrations from 0.2 x 10(-8) M and higher; on a molar basis, AP-A was more than 200 times as potent as digoxin and on a weight basis, 33 times as potent. In vivo in anesthetized dogs, AP-A at 0.2 microgram/kg/min i.v. increased myocardial contractile force; the geometric mean dose of AP-A required to increase the contractile force by 25% was 2.6 micrograms/kg; the corresponding dose of digoxin (infused at 2.8 micrograms/kg/min) was 107.4 micrograms/kg. The geometric mean lethal dose of AP-A for 8 dogs was 19.3 and that of digoxin 263.2 micrograms/kg i.v. The therapeutic index of AP-A was significantly higher than that of digoxin. All animals that received either AP-A or digoxin died in ventricular fibrillation. The reversal of t-wave was typical for AP-A. As measured by left ventricular pressure telemetry, AP-A, 2 micrograms/kg i.v. single dose, increased LV dp/dt max in conscious dogs for longer than 2 hr.

Ouabain potentiation of Ca release from fragmented cardiac sarcoplasmic reticulum from isolated cat heart.

The present study was performed to determine the effect of ouabain on Ca release from fragmented sarcoplasmic reticulum (FSR) isolated from cat cardiac muscles. The results clearly demonstrate that ouabain potentiates the Ca release from FSR by changing the ionic environment.

Flow and power output of right ventricle facing load with variable input impedance.

The output from the right ventricle (RV) was studied at different load impedances. Isolated cat hearts were perfused with Tyrode solution with erythrocytes. Coronary perfusion pressure and RV end-diastolic pressure were kept constant. The RV pumped into an artificial hydraulic load with independently variable resistance (R) and compliance (C). Mean RV flow (RVO) decreased after R increase or C reduction. For each heart, RVO and mean RV pressure were linearly related. The slope of the regression line is interpreted as an "apparent source resistance" (Rs). Rs was on average 3.4 X 10(3) (dyn.s.cm-5). The static hydraulic power output was maximum at a certain load R (Rm). Rm was C dependent at an average high C of 5 X 10(-5) dyn-1.cm5, Rm was 9.4 X 10(3) dyn.s.cm-5 on average and shifted to 5.4 X 10(3) at low C (avg 0.8 X 10(-5). Theoretical considerations show that Rm/Rs will be equal to total heart period divided by ejection period in the extreme case C leads to infinity, and Rm/Rs leads to 1 when C leads to 0. Experimentally, Rm/Rs was 2.4 (avg) for high C, and approached 1 for low C, which fits the theoretical predictions. The results indicate that high C facilitates the matching between the right heart and the vascular resistance in the lung.

Actions of prostaglandin precursors and other unsaturated fatty acids on conduction time and refractory period in the cat heart in situ.

1 The effect of arachidonic, dihomo-gamma-linolenic, linoleic, alpha-linolenic and oleic acid, given by intravenous infusion, on conduction time and functional refractory period have been studied in the cat heart in situ. 2 The prostaglandin precursors, arachidonic acid and dihomo-gamma-linolenic acid, prolonged the conduction time and the functional refractory period. Linoleic acid was also effective but to a lesser degree. alpha-Linolenic acid and oleic acid showed no or only a weak effect in thie respect. 3 Pretreatment was indomethacin diminished or abolished the actions of the three effective fatty acids but not those of prostaglandin E2. 4 The results suggest that the effects of prostaglandin prostaglandin precursors on conduction time and refractory period are responsible for their antiarrhythmic effectiveness and that these effects are attributable to their endogenous conversion into prostaglandins.