Effect of platelet-activating factor (PAF) on human cardiac muscle

The effect of platelet activating factor (PAF) on three mechanical [maximal mechanical tension (Pmax); time to peak tension; maximal rate of rise of tension (+dP/dt)] and four electrical [action potential duration (APD); resting membrane potential; overshoot; maximum rate of depolarization] parameters of cardiac function was studied on fragments of isolated human cardiac papillary muscle. 20 specimens of small tissue fragments excised from the left ventricle by open heart surgery were challenged with various doses of synthetic PAF (10(-10)-10(-6) M). PAF, but not its biologically inactive 2-lyso-derivative (lyso-PAF), induced a biphasic dose-dependent effect, characterized by a transient positive effect on inotropism (increased Pmax, +dP/dt) and of APD, followed by a marked, prolonged negative effect on both inotropism (decreased Pmax, time to peak tension, +dP/dt) and APD. No changes in resting membrane potential, overshoot and maximum rate of depolarization were detected after PAF challenge. Propranolol (2 X 10(-7) M) completely prevented the positive inotropic effect suggesting a stimulation of beta-receptors, possibly exerted by endogenous catecholamines. Indomethacin (1 X 10(-4) M) did not modify the initial positive effect, but markedly reduced the subsequent negative effect induced by PAF on inotropism. These findings are consistent with the interpretation that the effect of PAF on the inotropism is related to liberation of cyclooxygenase-derived metabolites.     

The maximum derivatives of left ventricular pressure and transverse internal diameter as indices of the inotropic state of the left ventricle in conscious dogs

1. In normal, conscious dogs, I.V. infusion of isoprenaline caused inases in heart rate and the maximal derivatives of left ventricular pressure (dP/dt max) and left ventricular internal diameter (dD/dt max). The changes in both derivatives were linearly related to the increase in heart rate.2. Increments in heart rate produced by right atrial pacing caused only minimally significant increases in both dP/dt max and dD/dt max at heart rates of 180 beats/min. Increases in heart rate, with end diastolic diameter maintained constant, resulted in small but significant increases in dP/dt max and no significant increase in dD/dt max.3. Increasing preload by volume infusion had little effect on either derivative, while increasing afterload by phenylephrine administration produced a small but significant increase in dP/dt max and no change in dD/dt max.4. Both dP/dt max and dD/dt max are equally reliable as indices of the inotropic state of the myocardium and are minimally influenced by changes in preload, afterload or heart rate.     

Contractile properties of rat soleus muscle: effects of training and fatique.

The effects of exercise training and fatique on the contractile properties of rat soleus muscles have been investigated. Prolonged exercise, consisting of 2 h or daily treadmill running, induced small but significant decrease in contraction time, one-half relaxation time, and maximum tetanic tension (Po), and increase in the peak rate of tension development (dP/dt) during a twitch, and an increase in maximum shortening velocity (Vmax). The 20% increase in Vmax was proportional to the previously reported increase in actomyosin ATPase induced by 2 h of daily running. These results indicate that prolonged training can induce modifications of the neurally determined contractile properties of skeletal muscle. To investigate the effects of fatigue, soleus muscles were stimulated in situ with 250-ms trains of 100 Hz at a rate of 110 trains per minute for 30 min. This resulted in a 32% decrease in Po, a 48% decline in peak tetanic dP/dt, and a 12% decrease in Vmax in muscles of untrained animals. Muscles that had adapted to exercise were significantly protected against the decrease in Po (only an 8% decrease) and Vmax (no significant decrease) but not against the decline in peak dP/dt.     

Force velocity relationships in vascular smooth muscle

Force velocity relationships of isolated vascular smooth muscle preparations were examined in the tetanized rat portal--anterior mesenteric vein by means of afterloaded isotonic contractions. Lowering of the temperature from 37 degrees C to 25 degrees C caused an average decrease of the follwoing parameters: maximal velocity of shortening at zero load from 0.51 to 0.28 muscle length/sec; maximal rate of tension increase (dT/dt) from 847 to 362 dyn/sec; mechanical tension developed at the maximum of dT/dt from 43 to 34% of the peak force generation; constant b of Hill's equation from 0.18 to 0.09 muscle length/sec. The latency was prolonged from 0.33 to 0.56 sec, and the time-to-maximum of dT/dt from 0.9 to 1.6 sec. Between 27 degrees C and 37 degrees C the following Q10 values were calculated: for the maximal velocity of shortening at zero load 1.56; for the maximal rate of tension increase 1.88; for the latency 1.63. No distinct influence of temperature could be observed on the extent of isotonic shortening at zero load (3.69 muscle length at 37 degrees C), on the extent of peak force generation (1107 dyn at 37 degrees C), and on constant a of Hill's equation (0.35 at 37 degrees C). It is concluded that parameters of contraction velocity in vascular smooth muscle depend on temperature, whereas the extent of contraction is independent of temperature. These findings are discussed in connection with the theory of the sliding-filament mechanism.     

Left ventricular inotropic and peripheral vasomotor responses from independent changes in pressure in the carotid sinuses and cerebral arteries in anaesthetized dogs

1. The pressure perfusing the isolated carotid sinuses and the pressure perfusing the cerebral circulation were changed independently, and the resulting inotropic responses in the left ventricle and peripheral vasomotor responses were determined.2. Inotropic responses were assessed by measuring changes in the maximum rate of change of left ventricular pressure (dP/dt max) with heart rate and mean aortic pressure held constant. Vascular resistance changes were usually assessed by perfusing the descending thoracic aorta at constant flow and measuring changes in perfusion pressure.3. Decreases in carotid sinus pressure over the baroreceptor sensitivity range resulted in a 45% increase in dP/dt max and a 59% increase in vascular resistance.4. Unless arterial oxygen tension was abnormally low, lowering cerebral perfusion pressure to 50 mm Hg resulted in little or no inotropic and vasomotor responses. In the presence of hypoxaemia (P(a,O2) < 60 mm Hg), lowering cerebral perfusion pressure to below about 80 mm Hg resulted in marked responses.5. These experiments suggest that, unless arterial oxygen tension is abnormally low, the carotid sinus reflex and not cerebral hypotension is important in the control of the inotropic state of the heart and of vasomotor activity. With hypoxaemia, responses from cerebral hypotension may also be important.     

Negative inotropic influence of hyperosmotic solutions on cardiac muscle.

In cardiac muscle, moderate degrees of hyperosmolality of the type encountered physiologically or clinically (i.e., less than 200 mosM above control) characteristically exert a positive inotropic effect, which presumably is mediated by increased Ca2+ availability for binding to troponin. In contrast, skeletal muscle displays significant contractile depression on exposure to hyperosmotic solutions, even at mild degrees of hypertonicity. To determine whether a similar potential for hyperosmolarity-induced depression also exists in cardiac muscle, right ventricular papillary muscles from cats were exposed to hypertonic solutions of mannitol or sucrose under circumstances in which positive inotropic effects were precluded by prior exposure to a bathing solution of 4.0 mM Ca2+ and paired electrical stimulation to maximize intracellular Ca2+ before addition of the hyperosmotic substances. In contrast to their usual positive inotropic effects, hypertonic solutions under these conditions caused cardiac depression at all osmolarities tested. Developed tension and its maximal rate of development (dT/dt) decreased by 18% at 50 mosM above control, by 30% at 100 mosM, by 36% at 150 mosM, and by 42% at 200 mosM (P less than 0.01 for all). Time to peak tension and resting tension were not changed significantly. When the muscles were returned to control solutions, tension development also returned toward normal. The data are compatible with the hypothesis that, within the range tested, all degrees of hyperosmolarity exert a significant negative inotropic influence on cardiac muscle, as is true in skeletal muscle; manifestation of this effect of increased tonicity normally would be obscured at low degrees of hyperosmolality, however, by an overriding positive influence that is absent in skeletal muscle.     

Contractile properties of bundles of fiber segments from skeletal muscles

Our purpose was to determine whether contractile properties of bundles of skeletal muscle fiber segments were significantly different from those of bundles of intact fibers. In frog muscles, the only difference between the contractile properties of fiber segments and intact fibers was a lower maximum velocity of shortening (Vo) for the fiber segments. In mammalian muscles, the contraction time (TPT), relaxation time (RT1/2), and maximum tetanus tension (Po) of bundles of fiber segments were not different from those of intact fibers, but the rate of tension development (dP/dt), twitch-to-tetanus ratio (Pt/Po) and Vo were lower. The lower dP/dt and Pt/Po resulted from increased compliance due to damaged sarcomeres near cut ends. Within 4-9 mm of a cut end, membrane potentials were less than control values, and sarcomeres lengthened during a fixed-end contraction. after the length of fiber segments was corrected for the exact portion that was not shortening, the Vo of fiber segments was not different from that of intact fibers. We conclude that valid estimates of contractile properties can be obtained from bundles of skeletal muscle fiber segments.     

Reflex effects on the heart of stimulating left atrial receptors

1. Stimulation of left atrial receptors, by distension of the pulmonary vein/left atrial junctions, is known to cause a reflex increase in heart rate; the efferent pathway is known to be solely in the sympathetic nerves.2. In expectation of a concomitant positive inotropic response the effect of stimulating the left atrial receptors on the inotropic state of the left ventricle was studied, using as a known sensitive index of inotropic changes the maximal rate of rise of pressure in the left ventricle (dP/dt max).3. Stimulation of left atrial receptors resulted in an increase in heart rate but there were no significant concomitant changes in dP/dt max.4. It is concluded that activity in this discrete efferent pathway does not include an inotropic effect on the left ventricle and therefore the reflex involves only those sympathetic nerves which innervate the sinu-atrial node.5. The possible function of atrial receptors in the regulation of heart volumes is discussed.     

Performance of the hypertrophied left ventricle in spontaneously hypertensive rats. Effects of adrenergic stimulation

The performance of isolated hearts from adult male spontaneously hypertensive rats (SHR) and matched normotensive controls (NCR) was investigated in an antegrade perfusion system, where preload and afterload could be varied independently. During electrical pacing of the heart to constant heart rate, increases in afterload, but not in preload, considerably raised cardiac contractility, measured as left ventricular max dP/dt. At afterloads equalling their respective in vivo ones, max dP/dt was similar in SHR and NCR. This indicates that the SHR hearts by myocardial hypertrophy are so well adapted to their raised afterload that an increased inotropic state of the heart is not required. Upon adrenaline addition, SHR and NCR did not differ concerning either "chronotropic sensitivity", i.e. per cent increase in heart rate of the spontaneously beating heart or in "inotropic sensitivity", measured as increase in max dP/dt. However, in this in vitro situation adrenaline increased stroke volume only when the hearts worked at reduced inotropism, induced by lowered temperature (30 degrees C). At maximal inotropic stimulation by adrenaline and occluded outflow, the SHR hearts produced higher systolic pressures than the NCR ones. This reveals an increased maximal contractile capacity of the hypertrophied SHR left ventricle, rather than a reduced one as sometimes suggested.     

The effect of changes in cardiac frequency on left and right ventricular dP/dt max at different contractile states of the myocardium

Summary In 17 canine heart-lung preparations the dependence of frequency potentiation of the right and left ventricular myocardium on the basic inotropic state of the heart was investigated. The effect of unipolar stimulation of the right atrium on dP/dt max in both ventricles was measured. The aortic pressure was maintained constant.Shortly after isolation of the heart, a stepwise increase of rate from 140 to 200 beats/min only had a very weak influence on left ventricular dP/dt max. With deterioration of the myocardium the frequency potentiation of dP/dt max increased considerably. End-diastolic pressure regularly decreased with rising cardiac frequency. Since the real positive inotropic effect is masked by the concomitant fall in diastolic loading, the end-diastolic pressure was maintained constant in a second group of 8 hearts during rate variation. The most pronounced inotropic effect was now found shortly after isolation of the heart. A rate increase of 30 beats/min resulted in a 20% rise of dP/dt max. The frequency potentiation decreased with deterioration of the heart resulting in a 12% dP/dt max increase at an estimated inotropic state of 50% of control. When the contractile state of the heart was improved above the control state by calcium application the frequency potentiation of the myocardium decreased.In the right ventricle similar results were obtained except for the fact that no significant correlation between the steepness of the frequency characteristics and the contractile state of the heart could be found when the end-diastolic pressure was kept constant.Portions of this study have been presented at the 45th Congress of the German Physiological Society     

Correlations between alterations in length-dependent Ca2+ activation of cardiac myofilaments and the end-systolic pressure–volume relation

We have tested the hypothesis that alterations in length dependent activation (LDA) of cardiac myofilaments represent an important regulatory mechanism affecting the Frank-Starling mechanism as determined by the slope (E(es)) of the relation between left ventricular (LV) volume and end-systolic pressure. We employed a transgenic (TG) mouse model in which the cardiac isoform of TnI (cTnI) has been completely replaced with slow skeletal TnI (ssTnI), the embryonic/neonatal isoform in the heart. Compared to non-transgenic (NTG) controls, myofilaments from TG-ssTnI hearts demonstrate an increase in Ca(2+) sensitivity and a substantially blunted LDA that is unaffected by PKA-dependent phosphorylation. We measured in situ LV pressure and volume relations during basal conditions and isoproterenol (ISO) stimulation. In the basal state in TG-ssTnI hearts there was significant increase in end-systolic pressure and slight decrease in heart rate. ISO stimulation resulted in a significant increase in heart rate, ejection fraction, maximum dP/dt, preload-recruitable stroke work, maximum dP/dt versus end diastolic volume and cardiac output in both groups. During basal conditions there was no difference in the E(es) relation between NTG and TG-ssTnI groups. However, during ISO stimulation the E(es) relation was significantly different between NTG and TG-ssTnI groups. Our study provides the first direct evidence that enhancement in differences in LDA between cardiac myofilaments from NTG and TG-ssTnI hearts induced by post-translational modifications of sarcomeric proteins are reflected in the in situ beating heart by a different change in E(es). Thus, changes in LDA should be considered in interpreting results from in situ experiments on inotropic effects associated with physiological and patho-physiological states of the heart.     

Inotropic responsiveness of atrial myocardium bathed in Tris- or bicarbonate-buffered solutions.

Atrial muscle of guinea pigs was used to study the inotropic influences of substituting a tris(hydroxymethyl)-aminomethane-buffered solution aerated with 100% O2 for a bicarbonate-buffered solution aerated with 95% O2-5% CO2 under otherwise equivalent in vitro conditions. Basal values of isometric contractile tension and its first derivative (dT/dt) were smaller and time to peak tension and time to 90% relaxation were longer in Tris- than in bicarbonate-bathed muscles. Both groups responded similarly to changes in stimulation frequently (0.1--2.2 Hz) and Ca2+ concentration (1.0--7.0 mM); however, maximal inotropic responses to these variables were smaller in the Tris-bathed atria. The negative inotropic effects of D600 and gentamicin were greater in the Tris group. Tris-bathed atria developed pulsus alternans when exposed to Mn2+ or a reduced Ca2+ concentration, whereas pulsus alternans did not occur in the bicarbonate group. A transient increase in contractility occurred in bicarbonate-bathed atria after treatment with 0.125 mM Mn2+, but only a negative response occurred in the Tris group. Thus important, and seemingly Ca2+-dependent, differences exist between the inotropic influences of Tris and bicarbonate solutions that may affect the utility of Tris-buffered (and/or bicarbonate deprived) heart muscle for studying certain inotropic interventions.     

The inotropic effect on the heart of stimulating the vagus in the dog, duck and toad

1. The chronotropic and inotropic effects of stimulating the vagus on the hearts of the dog, duck and toad were studied.2. The maximum rate of rise of pressure in the left ventricle (dP/dt max) measured at a constant heart rate and mean aortic pressure was used as an index of the inotropic changes.3. The sensitivity of dP/dt max as an index of inotropic changes brought about by stimulating the vagus was established in the toad where a 49% reduction in heart rate was associated with a 30% reduction in dP/dt max.4. In the dog stimulation of the vagus resulted in a reduction in heart rate of 38% and only a small reduction in dP/dt max of 6%.5. Results similar to those found in the dog were obtained in the duck where the reduction in heart rate of 44% was associated with reduction in dP/dt max of only 3%.6. It is concluded that the vagus has only a small and negligible negative inotropic effect on the ventricles of the dog and duck.     

Reflex inotropic responses of the heart from lung inflation in anaesthetized dogs

In anaesthetized dogs a tracheal divider was inserted to allow inflation of one lung with various pressures. Left ventricular inotropic responses were assessed by measuring the maximum rate of change of left ventricular pressure (dP/dt max) using a preparation in which aortic pressure, carotid sinus pressure and heart rate were held constant.Heart responses to lung inflation were variable. In five dogs there was a consistent tachycardia, in three bradycardia and in six there was no change. In the dogs in which heart rate increased, inflation of one lung with pressures between 0.5 and 2.0 kPa (5 and 20 cm H₂O) resulted in no significant change in dP/dt max. In the remaining dogs there was a decrease in dP/dt max which was more pronounced at the higher inflation pressures. The negative inotropic response was shown to be a reflex with afferent nerve endings in the lung and with the efferent pathway in the sympathetic nerves.     

Negative inotropic effects of phenol on isolated cardiac muscle.

Phenol appears in high concentrations in renal failure with uremia. The effects of this material on contractile activity of isolated cardiac muscle were studied in right ventricular moderator band (MB) of piglets and papillary muscle (PM) of cats and kittens. The muscles were bathed in modified Krebs solution containing 5.6 mM glucose at 30 C and gassed with 95% O2 and 5% CO2. They were paced at 24 contractions per minute, isometrically at Lmax. Over the range 2.5-119.0 mg%, phenol produced dose-related decreases in both developed tension (DT) and maximal rate of tension development (max dT/dt) in MB of piglets. In contrast, the dose-dependent negative inotropic effect of phenol was not detected in feline PM until concentrations in excess of 12.5 mg% were used. Increasing extracellular Ca2+ from 2.5 to 5.0 mM as well as the addition of norepinephrine (3.94 x 10(-7) M) attenuated the phenol-induced cardiac depression in porcine MB. There were no further changes in either DT or max dT/dt when the extracellular Ca2+ was increased to 10 mM. These findings demonstrate that phenol elicits a direct negative inotropic effect on mammalian cardiac muscle that is modified by calcium and norepinephrine. Phenol may participate in the biochemical alterations leading to cardiac failure and death in uremia.     

Cardiovascular effects of haemorrhagic shock in spleen intact and in splenectomized dogs

Cardiac performance was evaluated during haemorrhagic shock in 27 dogs with spleens intact, 24 splenectomized, and 23 splenectomized transfused dogs that were given a volume of packed red blood cells simulating splenic contraction. Contractile changes were evaluated by calculating dP/dt at 20 mmHg developed pressure (dP/dt DP20), and by relating stroke work to left ventricular end-diastolic volume measured by biplane cinefluorography. Although heart rate increased comparably during early shock, cardiac output, stroke volume, maximal dP/dt, dP/dt DP20, and arterial blood pressure decreased more in splenectomized and splenectomized transfused dogs than in those with spleens intact. During shock dP/dt DP20 was more depressed in the splenectomized and splenectomized transfused dogs than in those with spleens intact. In addition, an increase in left ventricular end-diastolic volume was accompanied by an increase in left ventricular stroke work in dogs with spleens intact. In contrast, stroke work remained depressed in both splenectomized groups despite increased left ventricular volume. Progressive acidosis and decreased left ventricular blood flow were similar in all dogs during haemorrhage. The greater reduction in left ventricular performance during haemorrhagic shock in the splenectomized and splenectomized transfused dogs was not related to excess lactate, changes in plasma volume, or red blood cell mass. Decreased left ventricular performance, despite improved ventricular filling, indicates greater cardiac dysfunction during haemorrhagic shock. This study suggests that, in dogs, the spleen maintains left ventricular performance during haemorrhage by mechanisms other than autotransfusion.     

Cardiovascular actions of beta-phenylethylamine.

beta-Phenylethylamine increased mean aortic blood pressure, total peripheral vascular resistance, left ventricular dP/dt, and (dP/dt)/P in chloralose-anesthetized dogs. Pretreatment with phentolamine reduced the increases in aortic blood pressure and total peripheral vascular resistance produced by beta-phenylethylamine, whereas, the effects of beta-phenylethylamine on left ventricular dP/dt and (dP/dt)/P were abolished by propranolol. beta-Phenylethylamine pretreatment, but increased both after phentolamine pretreatment. Furthermore, both the cardiac and vascular effects of beta-phenylethylamine were abolished by desipramine. These results indicate that beta-phenylethylamine exerts both positive inotropic and vasoconstrictory effects, probably by releasing endogenous norepinephrine from the adrenergic nerve endings.     

Inspiratory muscle adaptations following pressure or flow training in humans

Skeletal muscle adapts differently to training with high forces or with high velocities. The effects of these disparate training protocols on the inspiratory muscles were investigated in ten healthy volunteers. Five subjects trained using high force (pressure) loads (pressure trainers) and five trained using high velocity (flow) loads (flow trainers). Pressure training entailed performing 30 maximal static inspiratory efforts against a closed airway. Flow training entailed performing 30 sets of three maximal dynamic inspiratory efforts against a minimal resistance. Training was supervised and carried out 5 days a week for 6 weeks. Inspiratory flow rates and oesophageal pressure-time curves were measured before and after training. Peak inspiratory pressures during maximal static and dynamic efforts and peak flows during the maximal dynamic efforts were calculated. The time-to-peak pressure and rate of rise in peak pressure during maximal static and dynamic manoeuvres were also calculated before and following training. Maximal static pressure increased in the pressure training group and maximal dynamic pressure increased in the flow training group. Both groups increased the rate of pressure production (dP/dt) during their respective maximal efforts. The post-training decrease in time-to-peak pressure was proportionately greater in the flow trainers than in the pressure trainers. The differences in time-to-peak pressure between the two groups were consistent with the different effects of force and velocity training on the time-to-peak tension of skeletal muscle.     

The effect of an increase in aortic pressure upon the inotropic state of eat and dog left ventricles

1. The effect of increased aortic pressure on the inotropic state of the left ventricle was studied in isolated cat hearts, perfused with bovine red cells in Tyrode solution, ejecting into a hydraulic model with the same input impedance as that of the cat aorta.2. Inotropic state was assessed at a controlled left ventricular end-diastolic pressure by interpolating single isovolumic beats by means of an occluder in the aortic cannula.3. When such isovolumic beats during periods of raised aortic pressure were compared with those during control periods, the difference in peak isovolumic pressure ranged from -0.3 to +0.5 kPa indicating differences in inotropic state which were small and inconsistent in direction.4. The maximum rate of rise of left ventricular pressure (dP/dt(max).) of ejecting beats was little affected by a rise of aortic pressure and the direction of changes was inconsistent.5. The effect of increased aortic pressure was studied in intact dogs after cardiac denervation; left ventricular end-diastolic pressure was uncontrolled and therefore rose to a higher steady level.6. No consistent change of dP/dt(max). was found during the period of increased aortic pressure.7. All flow and pressure variables remained steady during the period of increased aortic pressure after the higher level of left ventricular end-diastolic pressure had been established.8. These results demonstrate that neither the positive inotropic effect nor the negative inotropic effect of increased load dominates in these preparations. This may be the result of a balance between the two effects, or they may be of unimportant magnitude under physiological conditions.     

Contractile dysfunction of atrial myocardium from endotoxin-shocked guinea pigs

Atrial muscle isolated from guinea pigs subjected to Escherichia coli endotoxin shock was used to study the myocardial changes associated with this experimental disease state. Isometric contractile tension and its first derivative (dT/dt) consistently were depressed by about 45% in muscle from the shock group (P less than 0.001), but contraction time intervals of the shock tissues were not significantly altered. The inotropic deficit of shock was completely antagonized by high concentrations of Ca2+ (greater than 4.5 mM). However, the maximal positive inotropic response to increased frequency of stimulation (0.1-2.2 Hz) only partially antagonized shock-induced cardiac depression. Heart muscle from shocked animals exhibited increased sensitivity to the negative inotropic effects of Mn2+, low Ca2+, and gentamicin; recovery from the depressant actions of these agents was prolonged 3.6- to 4.8-fold in shock. However, the negative inotropic potency of slow Ca2+ channel blockers, D 600 and nifedipine, was unaffected by shock. Similarly, studies with an isoproterenol-activated slow Ca2+ channel technique demonstrated equivalent inotropic responses of shock and control heart muscle. Present data provide evidence for a disruption of myocardial Ca2+ metabolism associated with endotoxin-induced inotropic depression of the heart but suggest that slow Ca2+ channels of the sarcolemma remain functional in this disease state.