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.     

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.     

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.     

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.     

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     

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.     

Inotropic changes in the left ventricle: the effect of changes in heart rate, aortic pressure and end-diastolic pressure

1. Under conditions where heart rate, mean aortic pressure and enddiastolic pressure in the left ventricle are held constant, the intravenous infusion of isoprenaline is accompanied by large changes in dP/dt max in the left ventricle.

2. Under similar conditions, during stepwise increments in the rate of infusion of isoprenaline the changes in dP/dt max (measured at a constant paced heart rate) were proportional to changes in the free (intrinsic) heart rate. It is concluded that dP/dt max is a quantitative index of inotropic changes in the left ventricle.

3. In comparison to dP/dt max, three other variables which have been used to indicate inotropic changes in the heart (peak pressure in the left ventricle, duration of systole and stroke work at constant end-diastolic pressure), were shown to be unreliable indices of inotropic changes.

4. Using dP/dt max to indicate inotropic changes, alteration in the heart rate while mean aortic pressure and end-diastolic pressure in the left ventricle were held constant, and in mean aortic pressure while heart rate ane end-diastolic pressure in the left ventricle were held constant, were each shown to be accompanied by small inotropic changes in the heart.

5. Under similar conditions, changes in end-diastolic pressure in the left ventricle alone were not accompanied by inotropic changes as indicated by dP/dt max.

     

Chronotropic and inotropic effects on the dog heart of stimulating the efferent cardiac sympathetic nerves

1. The chronotropic and inotropic responses of the dog heart to stimulation of the ansae subclaviae were studied.2. The maximum rate of rise of pressure in the left ventricle (dP/dt max) was used as an index of the inotropic changes.3. In experiments in which the secondary inotropic effects of changes in heart rate and blood pressure were prevented it was shown that, using stimuli which produced the same chronotropic response, stimulation of the left ansa subclavia resulted in an inotropic change which was about eight times greater than that which resulted from stimulation of the right ansa subclavia.4. In experiments in which heart rate and blood pressure were allowed to change freely it was shown that the secondary inotropic effects of changes in blood pressure and heart rate amounted to about 70% of the total inotropic change when the right ansa subclavia was stimulated and about 20% of the total change when the left ansa subclavia was stimulated.     

Norepinephrine and isoprenaline induced changes of peripheral blood flow acceleration caused by changes of cardiac inotropy

Summary In anesthetized dogs the norepinephrine (NE) and isoprenaline (ISO) (1–1024 ng/kg i.v.)-induced increase of maximum peripheral flow acceleration (celiac artery, cranial mesenteric artery, renal artery, and femoral artery) and the changes of the maximum first derivative of arterial pressure were compared with the increases of maximum ascending aortic flow acceleration and maximum first derivative of left ventricle pressure (LV dP/dt max).The maximum effect of each dose on maximum acceleration of flows (dF/dt max) and maximum first derivative of pressures (dP/dt max) occurred simultaneously for all variables. The effect was dose-dependent. Sensitivity was similar for NE (D₅₀:2256–512 ng/kg) and for ISO (D₅₀: 128–256 ng/kg).We demonstrated that other variables than inotropic action (heart rate, left ventricular end diastolic pressure and diastolic aortic pressure) played only a minor role in the increases of LV dP/dt max in our studies.In contrast with the uniform response of dF/dt max and dP/dt max, the reaction of peripheral vascular resistance varied. In particular in the gastrointestinal tract the resistance could either be increased (NE, D₅₀: 115 ng/kg) or decreased (ISO, D₅₀: 15 ng/kg). Gastrointestinal resistance was a more sensitive variable for catecholamine stimulation than dF/dt max and dP/dt max.The data show that under the present experimental conditions enhancement of peripheral flow acceleration induced by NE and ISO is due to increase of cardiac inotropy.Supported by the Foundation for Medical Research FUNGO     

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.     

Erythropoietin changes contractility, cAMP, and nitrite levels of isolated rat hearts

There is enough evidence that erythropoietin (EPO) may be involved in cardiovascular function. Therefore we have investigated the possible effects of EPO on left ventricular developed pressure, +dP/dt(max), heart rate, tissue cAMP, and nitrite levels. Isolated rat hearts were perfused under constant flow (10 ml/min) conditions with modified Krebs-Henseleit solution and recombinant human erythropoietin at doses of 100, 200, 500, and 1,000 IU/kg was administered as bolus injections. EPO at 100 IU/kg decreased, but higher doses (500 and 1,000 IU/kg) raised the developed pressure and +dP/dt(max). However, it did not affect heart rate or coronary perfusion pressure when all the respective doses were applied. EPO at 100 IU/kg increased nitrite, and at 1,000 IU/kg it raised cAMP. Our results suggest that EPO may produce dose-dependently negative and positive inotropic effects on myocardial contractility in isolated rat hearts. NO and cAMP may be involved in negative and positive inotropic effects of EPO, respectively.     

Adrenal contribution to coronary regulation in the newborn.

Evidence for adrenergic regulation of the coronary vessels was sought in 27 newborn lambs. Sympathetic activity was altered by temporarily lowering cephalic perfusion pressure (CPP) from 90 to 20 mmHg while aortic pressure was held constant. Heart rate (HR) and left ventricular dP/dt max increased markedly, while end-diastolic pressure and stroke volume fell. These changes were accompanied by an increase in coronary blood flow (CBF), myocardial O2 consumption (MVO2), and reduced coronary resistance (CF) (P less than 0.005). After beta blockade, which prevented an augmentation of metabolic demand, the same maneuver resulted in coronary vasoconstriction, reflected by reduced CBF and increased CR (P less than 0.02). This response was eliminated by alpha blockade with phentolamine (2 mg/kg). In 13 lambs subjected to bilateral adrenalectomy or sham operation, lowering CPP elicited similar positive chronotropic and inotropic changes, increases of MVO2 and CBF, and reduced CR. Following beta blockade, lowering CPP in the sham group caused coronary constriction. However, no changes in CBF or CR were elicited in the adrenalectomized lambs. These observations indicate that integrity of the adrenal glands is required for adrenergic control of the coronary vessels in the newborn. Chronotropic and inotropic regulation is mediated by direct neural action and is not dependent on adrenal function.     

Effects of acid-base changes, hypoxia, and catecholamines on ventricular performance.

Extracellular pH changes were produced in dogs with tris (hydroxy-methyl)-aminomethane (Tris) or NaHCO3 in the presence or absence of hypoxemia and before and after beta-adrenergic blockade with propranolol. Ventricular performance (VP) was evaluated by measurement of maximum rate of rise of left ventricular pressure (dp/dt max) and left ventricular end-diastolic pressure in the canine right heart bypass preparation with aortic pressure, heart rate, and cardiac output held constant. Low pH diminished VP. Hypoxemia did not alter VP within the pH, suggesting that decreased V observed with acidosis before propranolol was due primarily to decreased myocardial response to catecholamines. Increase of pH with Tris increased VP significantly more than with NaHCO3. Beta blockade diminished the response of VP to Tris at a high pH;prior administration of reserpine abolished the inotropic effect of Tris. The data suggest that Tris can influence VP independent of its effect on pH. This effect is probably mediated by the interaction between endogenous catecholamines and myocardial beta receptors.     

Effect of hyperosmotic mannitol on myocardial oxygen consumption.

Hyperosmotic mannitol produces salutary hemodynamic and histologic effects during experimental myocardial ischemia. However, the administration of hyperosmotic mannitol is associated with a positive inotropic influence. Positive inotropic interventions, which increase myocardial oxygen consumption (MVO2), also tend to increase the extent of ischemic myocardial injury. Thus, the purpose of this study was to determine the effect of mannitol on MVO2. Anesthetized dogs on right-heart bypass under conditions of controlled hemodynamics were studied. Both coronary arteries were perfused; mannitol was infused via the coronary perfusion cannulas to produce a 35 mosmol increase in osmolality. Heart rate was maintained constant. Cardiac output was held constant or deliberately increased so that left ventricular end-diastolic pressure and tension-time index, two other hemodynamic correlates of MVO2, remained constant or increased. MVO2 significantly decreased under conditions of decreased myocardial perfusion (P less than 0.025). This was in spite of a significant increase (P less than 0.001) in the peak rate of rise of left ventricular pressure (LV dP/dt), a hemodynamic correlate of MVO2. Thus, hyperosmotic mannitol under conditions of reduced coronary perfusion increases myocardial efficiency.     

Reflex vascular responses to changes in left ventricular pressures, heart rate and inotropic state in dogs.

Dogs were anaesthetized with chloralose, artificially ventilated and the chests widely opened. Left ventricular mechanoreceptors, including those in or near the coronary arteries, were stimulated by changing the pressure in the aortic root. The pressures distending the left atrium and the aortic and carotid baroreceptors were controlled. Reflex vascular responses were assessed from changes in perfusion pressures to a hind limb and to the rest of the systemic circulation, which were perfused independently at constant flows. Physiological increases in peak left ventricular and coronary arterial pressures resulted in vasodilatation in both regions. These responses were not influenced by changes in the heart rate. Stimulation of the left cardiac sympathetic nerves resulted in increases in peak ventricular pressure and in the maximal rate of change of pressure (dP/dtmax). This also resulted in increases in perfusion pressures (vasoconstriction) at all levels of peak ventricular pressure although there was little effect on the responses to changes in ventricular pressure. Sympathetic stimulation had little effect on the relationship between perfusion pressures and aortic root pressure. Increases in ventricular filling also resulted in vasoconstriction at all levels of peak ventricular pressure. Increases in filling, however, did not affect the relationship between either perfusion pressure and aortic root pressure. Conversely, decreases in left ventricular filling, by bypassing some of the left atrial blood, resulted in vasodilatation at all levels of peak ventricular pressures but had no effect on the perfusion pressures at any aortic root pressure. The combination of sympathetic stimulation with decreased ventricular filling resulted in little effect on perfusion pressures or on their responses to changes in either aortic root or ventricular systolic pressures. We conclude that the vascular responses to stimulation of left ventricular mechanoreceptors are not enhanced by sympathetic stimulation, decreases in ventricular filling or the combination of the two. The apparent effects of each of these interventions alone on the relationships between perfusion pressures and ventricular, but not aortic root, pressure, could be explained if the receptors responsible were sensitive more to changes in aortic root and coronary arterial pressures than to pressure changes in the ventricle itself.     

Effect of a new nitric oxide donor on the biomechanical performance of the isolated ischaemic rat heart

The effect of a new nitric oxide (NO) donor, a meso-ionic 3-aryl substituted oxatriazole-5-imine derivative, GEA 3162 was studied on constant flow-perfused ischaemic Langendorff rat heart. The perfusion was kept constant at a rate of 16 mL min^?1. Ischaemia was induced by a low flow rate of 0.8 mL min^?1 for 30 min, and was followed by a 40-minute reperfusion. In the first set of experiments the effects of GEA 3162-infusion were examined on perfusion pressure, left ventricular pressure, heart rate and left ventricular dP/dt. GEA 3162 infusion did not affect the pre-ischaemic maximum of left ventricular pressure. During reperfusion, maximal left ventricular pressure, maximal and minimal dP/dt values in the GEA 3162-treated group significantly exceeded those of the untreated controls (by 19.3, 36.0 and 18.0%, respectively). During reperfusion, perfusion pressure increased continuously in the control group indicating an increasing coronary resistance, but it was kept at a continuous low level with GEA 3162 treatment. In a second set of experiments bradykinin was infused in order to test the endothelial function before ischaemia and during late reperfusion. Bradykinin elicited significant vasodilation in the control group during reperfusion, meanwhile it did not cause further change in coronary resistance in the GEA 3162-infused group. We suggest, that GEA 3162 may have a protective effect on isolated rat heart in ischaemia and reperfusion, that results in an improved cardiac performance compared with untreated hearts.     

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.     

Contraction and relaxation indices in the study of neural inotropic and loositropic influences on the heart

The possibility of using contraction and relaxation indices for evaluation of inotropic and loositropic influences on the heart was studied in experiments on cats. Increased pre- and afterload were used as the stimuli, which are simultaneously loading and reflexogenic. Under conditions of preserved innervation both stimuli elevated the indices selected according to the highest sensitivity/specificity ratio. Ganglionic blocker arfonad potentiated the effects of these stimuli. This attests to a considerable contribution of the myogenic component to the changes in the studied indices in response to increased pre- and afterload and to the existence of negative inotropic and loositropic influences on the heart under conditions of preserved innervation. These conclusions were supported when more specific indices were used: in most cases they decreased during load tests. Thus, when the contraction and relaxation indices are used for evaluation inotropic and loositropic influences on the heart, it seems reasonable either to compare heart responses under conditions of preserved or blocked innervation, or to apply more specific indices. Analysis of changes in most widely used indices (dP/dt)max and t showed that t reliably reflects neural loositropic influences, while the use of (dP/dt)max without proper control can be erroneous.     

Effect of regional myocardial ischemia on cardiac pump performance during exercise

The effect of brief periods of regional ischemia upon left ventricular pump performance was studied in nine dogs standing quietly at rest and during running exercise on a treadmill. Transient occlusions of the left circumflex coronary artery resulted in increase in heart rate at rest (+30 beats/min) but not during exercise. Other changes due to occlusion were similar at rest and during exercise and included decreases in stroke volume (-25% standing, -23% running); in dP/dt max, the maximum first derivative of the left ventricular pressure (-20% standing or running); and in left ventricular peak systolic pressure (-13% standing, -21% running); and rises in left ventricular end-diastolic pressure (+4.5 mmHg standing, +6.3 mmHg running). Cardiac output was unchanged by occlusions at rest but fell (-18%) during occlusions while the dogs were running. Propranolol reduced absolute levels of cardiac performance during exercise occlusions but had no effect at rest. Inotropic agents with ischemia had some effects at rest but did not alter exercise hemodynamics. It is concluded that integrated left ventricular function during ischemia is not impaired by exercise, probably because of beta-adrenergic stimulation of nonischemic myocardium.