Left ventricular reflex control of venous return and systemic vascular capacitance in dogs

The reflex effects of left ventricular distension on venous return, vascular capacitance, vascular resistance, and sympathetic efferent nerve activity were examined in dogs anesthetized with sodium pentobarbital. In addition, the interaction of left ventricular distension and the carotid sinus baroreflex was examined. Vascular capacitance was assessed by measuring changes in systemic blood volume, using extracorporeal circulation with constant cardiac output and constant central venous pressure. Left ventricular distension produced by balloon inflation caused a transient biphasic change in venous return; an initial small increase was followed by a late relatively large decrease. Left ventricular distension increased systemic blood volume by 3.8 +/- 0.6 mL/kg and decreased systemic blood pressure by 27 +/- 2 mmHg (1 mmHg = 133.3 Pa) at an isolated carotid sinus pressure of 50 mmHg. These changes were accompanied by a simultaneous decrease in sympathetic efferent nerve activity. When the carotid sinus pressure was increased to 125 and 200 mmHg, these responses were attenuated. It is suggested that left ventricular mechanoreceptors and carotid baroreceptors contribute importantly to the control of venous return and vascular capacitance.     

Blood volume, the venous system, preload, and cardiac output

Cardiac output is determined by heart rate, by contractility (maximum systolic elastance, Emax) and afterload, and by diastolic ventricular compliance and preload. These relationships are illustrated using the pressure-volume loop. Diastolic compliance and Emax place limits determined by the heart within which the pressure-volume loop must lie. End-diastolic and end-systolic pressures and hence the exact position of the loop within these limits are determined by the peripheral circulation. In the presence of minimal sympathetic tone, some 60% of total blood volume is hemodynamically inactive and constitutes a blood volume reserve (the unstressed volume). The remainder of the blood volume (the stressed volume) and the compliance of the venous system determine the venous pressure. This venous pressure together with venous resistance determines venous return, right atrial pressure, cardiac preload, and hence cardiac output. Venoconstriction causes conversion of unstressed volume to the stressed volume, the blood volume reserve is converted into hemodynamically active blood volume. After hemorrhage this replaces the lost stressed volume, while in other situations where total blood volume is not reduced, it allows a sustained increase in cardiac output. The major blood volume reserve is in the splanchnic bed: the liver and intestine, and in animals but not man, the spleen. A major unsolved problem is how the conversion of unstressed volume to stressed volume by venoconstriction is reflexly controlled.     

Right and left ventricular pressure-volume response to respiratory maneuvers

With respiration, right ventricular end-diastolic volume fluctuates. We examined the importance of these right ventricular volume changes on left ventricular function. In six mongrel dogs, right and left ventricular volumes and pressures and esophageal pressure were simultaneously measured during normal respiration, Valsalva maneuver, and Mueller maneuver. The right and left ventricular volumes were calculated from cineradiographic positions of endocardial radiopaque markers. Increases in right ventricular volume were associated with changes in the left ventricular (LV) pressure-volume relationship. With normal respiration, right ventricular end-diastolic volume increased 2.3 +/- 0.7 ml during inspiration, LV transmural diastolic pressure was unchanged, and LV diastolic volume decreased slightly. This effect was accentuated by the Mueller maneuver; right ventricular end-diastolic volume increased 10.4 +/- 2.3 ml (P less than 0.05), while left ventricular end-diastolic pressure increased 3.6 mmHg (P less than 0.05) without a significant change in left ventricular end-diastolic volume. Conversely, with a Valsalva maneuver, right ventricular volume decreased 6.5 +/- 1.2 ml (P less than 0.05), and left ventricular end-diastolic pressure decreased 2.2 +/- 0.5 mmHg (P less than 0.05) despite an unchanged left ventricular end-diastolic volume. These changes in the left ventricular pressure-volume relationship, secondary to changes in right ventricular volumes, are probably due to ventricular interdependence. Ventricular interdependence may also be an additional factor for the decrease in left ventricular stroke volume during inspiration.     

Prediction of circulatory equilibrium in response to changes in stressed blood volume

Accurate prediction of cardiac output (CO), left atrial pressure (PLA), and right atrial pressure (PRA) is a prerequisite for management of patients with compromised hemodynamics. In our previous study (Uemura et al. Am J Physiol Heart Circ Physiol 286: H2376-H2385, 2004), we demonstrated a circulatory equilibrium framework, which permits the prediction of CO, PLA, and PRA once the venous return surface and integrated CO curve are known. Inasmuch as we also showed that the surface can be estimated from single-point CO, PLA, and PRA measurements, we hypothesized that a similar single-point estimation of the CO curve would enable us to predict hemodynamics. In seven dogs, we measured the PLA-CO and PRA-CO relations and derived a standardized CO curve using the logarithmic function CO = SL[ln(PLA - 2.03) + 0.80] for the left heart and CO = SR[ln(PRA - 2.13) + 1.90] for the right heart, where SL and SR represent the preload sensitivity of CO, i.e., pumping ability, of the left and right heart, respectively. To estimate the integrated CO curve in each animal, we calculated SL and SR from single-point CO, PLA, and PRA measurements. Estimated and measured CO agreed reasonably well. In another eight dogs, we altered stressed blood volume (-8 to +8 ml/kg of reference volume) under normal and heart failure conditions and predicted the hemodynamics by intersecting the surface and the CO curve thus estimated. We could predict CO [y = 0.93x + 6.5, r2 = 0.96, standard error of estimate (SEE) = 7.5 ml.min(-1).kg(-1)], PLA (y = 0.90x + 0.5, r2= 0.93, SEE = 1.4 mmHg), and PRA (y = 0.87x + 0.4, r2= 0.91, SEE = 0.4 mmHg) reasonably well. In conclusion, single-point estimation of the integrated CO curve enables accurate prediction of hemodynamics in response to extensive changes in stressed blood volume.     

Splanchnic vascular capacitance and positive end-expiratory pressure in dogs

We have investigated the effect of positive end-expiratory pressure ventilation (PEEP) on regional splanchnic vascular capacitance. In 12 anesthetized dogs hepatic and splenic blood volumes were assessed by sonomicrometry. Vascular pressure-diameter curves were defined by obstructing hepatic outflow. With 10 and 15 cmH2O PEEP portal venous pressure increased 3.1 +/- 0.3 and 5.1 +/- 0.4 mmHg (P less than 0.001) while hepatic venous pressure increased 4.9 +/- 0.4 and 7.3 +/- 0.4 mmHg (P less than 0.001), respectively. Hepatic blood volume increased (P less than 0.01) 3.8 +/- 0.9 and 6.3 +/- 1.4 ml/kg body wt while splenic volume decreased (P less than 0.01) 0.8 +/- 0.2 and 1.3 +/- 0.2 ml/kg body wt. The changes were similar with closed abdomen. The slope of the hepatic vascular pressure-diameter curves decreased with PEEP (P less than 0.01), possibly reflecting reduced vascular compliance. There was an increase (P less than 0.01) in unstressed hepatic vascular volume. The slope of the splenic pressure-diameter curves was unchanged, but there was a significant (P less than 0.05) decrease in unstressed diameter during PEEP. In conclusion, hepatic blood volume increased during PEEP. This was mainly a reflection of passive distension due to elevated venous pressures. The spleen expelled blood and thus prevented a further reduction in central blood volume.     

Pericardium modulates left and right ventricular stroke volumes to compensate for sudden changes in atrial volume

The pericardium may modulate acute compensatory changes in stroke volumes seen with sudden changes in cardiac volume, but such a mechanism has never been clearly demonstrated. In eight open-chest dogs, we measured left and right ventricular pressures, diameters, stroke volumes, and pericardial pressures during rapid (approximately 300 ms) systolic infusions or withdrawals of approximately 25 ml blood into and out of the left atrium and right atrium. Control beats, the infusion/withdrawal beat, and 4-10 subsequent beats were studied. With infusions, ipsilateral ventricular end-diastolic transmural pressure, diameter, and stroke volume increased. With the pericardium closed, there was a compensatory decrease in contralateral transmural pressure, diameter, and stroke volume, mediated by opposite changes in transmural end-diastolic pressures. The sum of the ipsilateral increase and contralateral decrease in stroke volume approximated the infused volume. Corresponding changes were seen with blood withdrawals. This direct ventricular interaction was diminished when pericardial pressure was <5 mmHg and absent when the pericardium was opened. Pericardial constraint appears essential for immediate biventricular compensatory responses to acute atrial volume changes.     

Haemodynamic effects of respiratory alkalosis independent of changes in airway pressure in anaesthetized newborn dogs

We have recently reported a decrease in cardiac output in newborn dogs during respiratory alkalosis which is independent of changes in airway pressure. The present study was designed to characterize the mechanism responsible for this reduction in cardiac output. Twelve newborn coonhounds were anaesthetized with pentobarbital, paralyzed with pancuronium and hyperventilated to an arterial carbon dioxide tension (PaCO2) of 20 torr. Subsequent changes in PaCO2 were achieved by altering the FiCO2. Measurements were made after 30 min at either 40 or 20 torr PaCO2. The sequence of PaCO2 levels was randomized. Compared to normocarbia, respiratory alkalosis resulted in significantly decreased cardiac output (279 +/- 16 to 222 +/- 10 ml/min per kg, mean +/- SEM, P less than 0.001), stroke volume (1.60 +/- 0.10 to 1.24 +/- 0.06 ml/kg; P less than 0.001), maximum left ventricular dP/dt (1629 +/- 108 to 1406 +/- 79 mmHg/s, P less than 0.01) and left ventricular end diastolic pressure (3.9 +/- 0.4 to 2.9 +/- 0.3 mmHg; P less than 0.001). The decrease in cardiac output during respiratory alkalosis is manifest through a decrease in stroke volume, which is due, at least in part, to the decrease in left ventricular end diastolic pressure. The decrease in maximum left ventricular dP/dt is likely a reflection of the decrease in preload, however, a change in myocardial contractility cannot be excluded. We speculate the decrease in filling pressure may be due to an increase in venous capacitance.     

Theoretical analysis of the noncardiac limits to maximum exercise

When right atrial pressure (Pra) is greater than zero (atmospheric pressure), cardiac output is determined by the intersection of two functions, cardiac function and return function, which is used here to mean the determinants of venous return. When Pra < or = 0, flow is only determined by circuit function. The objective of this analysis was to determine the potential changes in return function that need to occur to allow the maximum cardiac output during exercise when Pra < or = 0 or is constant. The analysis expands on the model of Green and Jackman and includes the effects of changes in circuit parameters, including venous resistance, changes in capacitance, and muscle contractions. The analysis is based on the model of the circulation proposed by Permutt and co-workers, which assumes that the systemic circulation has two lumped compliant regions in parallel with independent inflow and outflow resistances. Changes in total flow in this model can come about by changes in the distribution of flow between the regions, recruitment of unstressed vascular volume, and changes in the regional venous resistances. The data for the analysis are from previous animal studies and are normalized to a 70-kg man. The major conclusions are that, to achieve the high cardiac output that occurs at peak exercise, there need to be marked changes in the distribution of blood flow, recruitment of unstressed volume, and the venous resistance draining vascular beds. A consequence of the increase in peripheral flow is a marked increase in pressure in the veins of the working muscle. Muscle contractions are potentially a very important mechanism for transiently decreasing this pressure and preventing excessive filtration of plasma during exercise.     

Enhanced systolic function of the right ventricle during respiratory distress syndrome in newborn lambs

Respiratory distress syndrome (RDS) causes pulmonary hypertension. It is often suggested that this increased afterload for the right ventricle (RV) might lead to cardiac dysfunction. To examine this, we studied biventricular function in an experimental model. RDS was induced by lung lavages in seven newborn lambs. Five additional lambs served as controls. Cardiac function was quantified by indexes derived from end-systolic pressure-volume relations obtained by pressure-conductance catheters. After lung lavages, a twofold increase of mean pulmonary arterial pressure (from 15 to 34 mmHg) was obtained and lasted for the full 4-h study period. Stroke volume was maintained (5.2 +/- 0.6 ml at baseline and 6.1 +/- 1.4 ml at 4 h of RDS), while RV end-diastolic volume showed only a slight increase (from 6.5 +/- 2.3 ml at baseline to 7.7 +/- 1.3 ml at 4 h RDS). RV systolic function improved significantly, as indicated by a leftward shift and increased slope of the end-systolic pressure-volume relation. Left ventricular systolic function showed no changes. In control animals, pulmonary arterial pressure did not increase and right and left ventricular systolic function remained unaffected. In the face of increased RV afterload, the newborn heart is able to maintain cardiac output, primarily by improving systolic RV function through homeometric autoregulation.     

Measurement of limb venous compliance in humans: technical considerations and physiological findings.

We conducted a series of studies to develop and test a rapid, noninvasive method to measure limb venous compliance in humans. First, we measured forearm volume (mercury-in-Silastic strain gauges) and antecubital intravenous pressure during inflation of a venous collecting cuff around the upper arm. Intravenous pressure fit the regression line, -0.3 +/- 0.7 + 0.95 +/- 0.02. cuff pressure (r = 0.99 +/- 0.00), indicating cuff pressure is a good index of intravenous pressure. In subsequent studies, we measured forearm and calf venous compliance by inflating the venous collecting cuff to 60 mmHg for 4 min, then decreasing cuff pressure at 1 mmHg/s (over 1 min) to 0 mmHg, using cuff pressure as an estimate of venous pressure. This method produced pressure-volume curves fitting the quadratic regression (Deltalimb volume) = beta(0) + beta(1). (cuff pressure) + beta(2). (cuff pressure)(2), where Delta is change. Curves generated with this method were reproducible from day to day (coefficient of variation: 4.9%). In 11 subjects we measured venous compliance via this method under two conditions: with and without (in random order) superimposed sympathetic activation (ischemic handgrip exercise to fatigue followed by postexercise ischemia). Calf and forearm compliance did not differ between control and sympathetic activation (P > 0.05); however, the data suggest that unstressed volume was reduced by the maneuver. These studies demonstrate that venous pressure-volume curves can be generated both rapidly and noninvasively with this technique. Furthermore, the results suggest that although whole-limb venous compliance is under negligible sympathetic control in humans, unstressed volume can be affected by the sympathetic nervous system.     

MRI-determined left ventricular "crescent effect": a consequence of the slight deviation of contents of the pericardial sack from the constant-volume state

During one cardiac cycle, the volume encompassed by the pericardial sack in healthy subjects remains nearly constant, with a transient +/-5% decrease in volume at end systole. This "constant-volume" attribute defines a constraint that the longitudinal versus radial pericardial contour dimension relationship must obey. Using cardiac MRI, we determined the extent to which the constant-volume attribute is valid from four-chamber slices (two-dimensional) compared with three-dimensional volumetric data. We also compared the relative percentage of longitudinal versus radial (short-axis) change in cross-sectional area (dimension) of the pericardial contour, thereby assessing the fate of the +/-5% end-systolic volume decrease. We analyzed images from 10 normal volunteers and 1 subject with congenital absence of the pericardium, obtained using a 1.5-T MR scanner. Short-axis cine loop stacks covering the entire heart were acquired, as were single four-chamber cine loops. In the short-axis and four-chamber slices, relative to midventricular end-diastolic location, end-systolic pericardial (left ventricular epicardial) displacement was observed to be radial and maximized at end systole. Longitudinal (apex to mediastinum) pericardial contour dimension change and pericardial area change on the four-chamber slice were negligible throughout the cardiac cycle. We conclude that the +/-5% end-systolic decrease in the volume encompassed by the pericardial sack is primarily accounted for by a "crescent effect" on short-axis views, manifesting as a nonisotropic radial diminution of the pericardial/epicardial contour of the left ventricle. This systolic drop in cardiac volume occurs primarily at the ventricular level and is made up during the subsequent diastole when blood crosses the pericardium in the pulmonary venous Doppler D wave during early rapid left ventricular filling.     

Methods for assessing hepatic distending pressure and changes in hepatic capacitance in pigs

The equilibrium pressure obtained during simultaneous occlusion of hepatic vascular inflow and outflow was taken as the reference estimate of hepatic vascular distending pressure (P(hd)). P(hd) at baseline was 1.1 +/- 0.2 (mean +/- SE) mmHg higher than hepatic vein pressure (P(hv)) and 0.7 +/- 0.3 mmHg lower than portal vein pressure (P(pv)). Norepinephrine (NE) infusion increased P(hd) by 1. 5 +/- 0.5 mmHg and P(pv) by 3.7 +/- 0.6 mmHg but did not significantly increase P(hv). Hepatic lobar vein pressure (P(hlv)) measured by a micromanometer tipped 2-Fr catheter closely resembled P(hd) both at baseline and during NE-infusion. Dynamic pressure-volume (PV) curves were constructed from continuous measurements of P(hv) and hepatic blood volume increases (estimated by sonomicrometry) during brief occlusions of hepatic vascular outflow and compared with static PV curves constructed from P(hd) determinations at five different hepatic volumes. Estimates of hepatic vascular compliance and changes in unstressed blood volume from the two methods were in close agreement with hepatic compliance averaging 32 +/- 2 ml. mmHg(-1). kg liver(-1). NE infusion reduced unstressed blood volume by 110 +/- 38 ml/kg liver but did not alter compliance. In conclusion, P(hlv) reflects hepatic distending pressure, and the construction of dynamic PV curves is a fast and valid method for assessing hepatic compliance and changes in unstressed blood volume.     

Hemodynamic basis for cocaine-induced pulmonary edema in dogs.

We tested the hypothesis that cocaine-induced impairment of left ventricular function results in cardiogenic pulmonary edema. Mongrel dogs, anesthetized with alpha-chloralose, were injected with two doses of cocaine (5 mg/kg iv) 27 min apart. Cocaine produced transient decreases in aortic and left ventricular systolic pressures that were followed by increases exceeding control. As aortic pressure recovered, left ventricular end-diastolic, left atrial (Pla), pulmonary arterial (Ppa), and central venous pressures rose. Cardiac output and stroke volume were reduced when measured 4-5 min after cocaine administration. Peak Ppa and Pla were 31 +/- 5 (SE) mmHg (range 17-51 mmHg) and 26 +/- 5 mmHg (range 12-47 mmHg), respectively. Increases in extravascular lung water content (4.10 to 6.24 g H2O/g dry lung wt) developed in four animals in which Pla exceeded 30 mmHg. Analysis of left ventricular function curves revealed that cocaine depressed the inotropic state of the left ventricle. Cocaine-induced changes in hemodynamics spontaneously recovered and could be elicited again by the second dose of the drug. Our results show that cocaine-induced pulmonary hypertension, associated with decreased left ventricular function, produces pulmonary edema if pulmonary vascular pressures rise sufficiently.     

Effects of glossopharyngeal insufflation on cardiac function: an echocardiographic study in elite breath-hold divers.

Glossopharyngeal insufflation (GI), a technique used by breath-hold divers to increase lung volume and augment diving depth and duration, is associated with untoward hemodynamic consequences. To study the cardiac effects of GI, we performed transthoracic echocardiography, using the subcostal window, in five elite breath-hold divers at rest and during GI. During GI, heart rate increased in all divers (mean of 53 beats/min to a mean of 100 beats/min), and blood pressure fell dramatically (mean systolic, 112 to 52 mmHg; mean diastolic, 75 mmHg to nondetectable). GI induced a 46% decrease in mean left ventricular end-diastolic area, 70% decrease in left ventricular end-diastolic volume, 49% increase in mean right ventricular end-diastolic area, and 160% increase in mean right ventricular end-diastolic volume. GI also induced biventricular systolic dysfunction; left ventricular ejection fraction decreased from 0.60 to a mean of 0.30 (P = 0.012); right ventricular ejection fraction, from 0.75 to a mean of 0.39 (P < 0.001). Wall motion of both ventricles became significantly abnormal during GI; the most prominent left ventricular abnormalities involved hypokinesis or dyskinesis of the interventricular septum, while right ventricular wall motion abnormalities involved all visible segments. In two divers, the inferior vena cava dilated with the appearance of spontaneous contrast during GI, signaling increased right atrial pressure and central venous stasis. Hypotension during GI is associated with acute biventricular systolic dysfunction. The echocardiographic pattern of right ventricular systolic dysfunction is consistent with acute pressure overload, whereas concurrent left ventricular systolic dysfunction is likely due to ventricular interdependence.     

Influence of pregnancy on mean systemic filling pressure and the cardiac function curve in guinea pigs.

To assess the degree of circulatory fullness and to evaluate the influence of peripheral and cardiac factors in the regulation of cardiac output during pregnancy, the following studies were conducted using pentobarbital-anesthetized, open-chest nonpregnant and late term pregnant guinea pigs. Mean circulatory filling pressure was taken as the equilibrium pressure when the pulmonary artery was constricted. Total vascular compliance was assessed by +/- 5-mL changes in blood volume performed while this constriction was maintained. A separate group of guinea pigs was prepared with a pulmonary artery electromagnetic flow probe and right atrial catheter. Rapid infusion of saline was used to increase right atrial pressure while the cardiac output was determined. Pregnancy was characterized by the following changes relative to nonpregnant controls: 51Cr-labelled RBC blood volume increased from 55 +/- 3 to 67 +/- 3 mL/kg; mean circulatory filling pressure increased from 7.1 +/- 0.2 to 8.0 +/- 0.5 mmHg (1 mmHg = 133.322 Pa); right atrial pressure decreased from 3.4 +/- 0.2 to 2.1 +/- 0.3 mmHg; and cardiac output increased from 71.8 +/- 3.9 to 96.8 +/- 3.3 mL.min-1.kg-1. Total vascular compliance was not changed (2.1 +/- 0.1 mL.kg-1.mmHg-1) and most of the expanded blood volume was accommodated as unstressed volume. The cardiac function curve was shifted upwards in pregnant animals. The resistance to venous return, as determined from the slope of the venous return curves, was not changed. These data suggest that the circulation of the pregnant guinea pig is slightly overfilled.(ABSTRACT TRUNCATED AT 250 WORDS)     

RV filling modulates LV function by direct ventricular interaction during mechanical ventilation

During mechanical ventilation, phasic changes in systemic venous return modulate right ventricular output but may also affect left ventricular function by direct ventricular interaction. In 13 anesthetized, closed-chest, normal dogs, we measured inferior vena cava flow and left and right ventricular dimensions and output during mechanical ventilation, during an inspiratory hold, and (during apnea) vena caval constriction and abdominal compression. During a single ventilation cycle preceded by apnea, positive pressure inspiration decreased caval flow and right ventricular dimension; the transseptal pressure gradient increased, the septum shifted rightward, reflecting an increased left ventricular volume (the anteroposterior diameter did not change); and stroke volume increased. The opposite occurred during expiration. Similarly, the maneuvers that decreased venous return shifted the septum rightward, and left ventricular volume and stroke volume increased. Increased venous return had opposite effects. Changes in left ventricular function caused by changes in venous return alone were similar to those during mechanical ventilation except for minor quantitative differences. We conclude that phasic changes in systemic venous return during mechanical ventilation modulate left ventricular function by direct ventricular interaction.     

Autonomic nervous control of postprandial hemodynamic changes at rest and upright exercise

Postprandial hemodynamic changes were studied in healthy subjects at rest and during exercise in the upright position with and without autonomic blockade of the heart. At rest cardiac output increased 61% mostly because of a stroke volume increase accomplished by left ventricular end-diastolic dilation. These changes seemed to be dependent on the autonomic nervous system, whereas the postprandial heart rate increase did not. During exercise cardiac output was 23% higher after food intake due to a rise in both stroke volume and heart rate. These changes were apparently under influence of the autonomic nervous system, whereas left ventricular dilation was not. The present findings indicate that most of the postprandial changes in the central circulation are under control of the autonomic nervous system.     

Hemodynamic effects of blood loss during a passive response to a stressor in the conscious rabbit

In the conscious rabbit, exposure to an air jet stressor increases arterial pressure, heart rate, and cardiac output. During hemorrhage, air jet exposure extends the blood loss necessary to produce hypotension. It is possible that this enhanced defense of arterial pressure is a general characteristic of stressors. However, some stressors such as oscillation (OSC), although they increase arterial pressure, do not change heart rate or cardiac output. The cardiovascular changes during OSC resemble those seen during freezing behavior. In the present study, our hypothesis was that, unlike air jet, OSC would not affect defense of arterial blood pressure during blood loss. Male New Zealand White rabbits were chronically prepared with arterial and venous catheters and Doppler flow probes. We removed venous blood until mean arterial pressure decreased to 40 mmHg. We repeated the experiment in each rabbit on separate days in the presence and absence (SHAM) of OSC. Compared with SHAM, OSC increased arterial pressure 14 +/- 1 mmHg, central venous pressure 3.3 +/- 0.4 mmHg, and hindquarter blood flow 34 +/- 4% while decreasing mesenteric conductance 32 +/- 3% and not changing heart rate or cardiac output. During normotensive hemorrhage, OSC enhanced hindquarter and renal vasoconstriction. Contrary to our hypothesis, OSC (23.5 +/- 0.6 ml/kg) increased the blood loss necessary to produce hypotension compared with SHAM (16.8 +/- 0.6 ml/kg). In nine rabbits, OSC prevented hypotension even after a blood loss of 27 ml/kg. Thus a stressful stimulus that resulted in cardiovascular changes similar to those seen during freezing behavior enhanced defense of arterial pressure during hemorrhage.     

Effect of 4-Pyridone-3-Carboxamide Ribonucleoside (4PYR)-Potential Cardiovascular Toxin in Perfused Rat Heart

We recently described a new nicotinamide derivative: 4-pyridone-3-carboxamide ribonucleoside (4PYR) and its conversion to intracellular metabolites (4PYR monophosphate: 4PYMP and 4PYR adenylate diphosphate: 4PYRAD). The aim of this study was to clarify the metabolism and physiological effects of brief exposure to 4PYR in perfused rat heart. Rat hearts were perfused in Langendorff mode. After 15 min equilibration, 100 μM 4PYR (or solvent in controls) was infused into coronary circulation for 5 min. Coronary flow was recorded with electromagnetic flow meter and left ventricular mechanical function was assessed with intraventricular baloon by constructing pressure–volume relations. After perfusion hearts were freeze-clamped and analyzed using HPLC for phosphocreatine, creatine, ATP with metabolites as well as 4PYR metabolites. 4PYR infused into the coronary circulation was rapidly converted in the heart into 4PYMP and 4PYRAD with concentrations reaching 85.6 ± 46.9 and 43.9 ± 6.4 nmol/g dry weight, respectively, while control concentrations were below 20 nmol/g. 4PYR had no effect on baseline coronary flow (11.9 ± 2.3 ml/min versus 11.0 ± 2.7 ml/min in control) or stimulated by shear stress (23.2 ± 4.5 ml/min versus 23.1 ± 5.2 ml/min in control). Both systolic and diastolic left ventricular mechanical function were not affected by 4PYR. No difference was noted for heart rate. Myocardial concentrations of ATP or phosphocreatine were also not affected by 4PYR. We conclude that 4PYR has no immediate effect on coronary endothelium or cardiomyocyte functions such as coronary flow, rhythm, diastolic properties, or contractility despite rapid incorporation into intracellular metabolites. This study also indicates the lack of effect on purinergic receptors.