Cetamolol: cardiovascular effects of a new cardioselective beta-adrenoceptor blocker possessing partial agonistic activity and lacking membrane-stabilizing activity

The cardiovascular effects of cetamolol, a new beta-adrenoceptor blocker, were studied in the anesthetized dog and cat and in the conscious dog and monkey. The compound was compared with other beta-blockers known to possess various degrees of cardioselectivity, partial agonistic effects, and membrane-stabilizing activity. In the anesthetized open-chest dog, cetamolol and pindolol produced similar cardiovascular effects in that the partial agonistic activity predominated over the blockade of beta-adrenoceptors. The partial agonistic activity of pindolol was greater than that of cetamolol. Unlike pindolol, cetamolol had no significant vasodilating property. However, the beta-blocking effects of these two drugs predominated in the anesthetized closed-chest dog, conscious dog and monkey. Atenolol, nadolol, and propranolol, which lack partial agonistic activity, produced cardiovascular changes characteristic of this type of beta-blocker in the animal preparation in which they were tested. In the anesthetized cat, comparison of the mean effective doses for the heart rate and blood pressure responses induced by isoproterenol showed that cetamolol was more cardioselective than metoprolol but less than acebutolol and atenolol. Evidence of the cardioselectivity of cetamolol was also obtained in the anesthetized closed-chest dog, although the degree of cardioselectivity of both cetamolol and atenolol was less marked than in the cat. When given orally to the conscious dog and monkey, cetamolol appeared to be well absorbed. The peak effect was observed after 1-2 h and persisted for the 5-h test period. It is concluded that cetamolol is a potent beta-blocker with a moderate degree of partial agonistic activity and cardioselectivity in in vivo experiments.     

Oxygen free radicals in volume overload heart failure

It has been suggested that oxygen free radicals (OFR) depress the excitation-contraction coupling in cardiac muscle. It is possible that a decrease in the cardiac contractility in the failing heart may be due to an increased OFR producing activity of polymorphonuclear (PMN) leukocytes. We studied the OFR producing activity (chemiluminescence) of PMN leukocytes from blood in dogs with heart failure due to chronic volume overload. The animals were divided into two groups: I) normal, (n = 10): II) dogs with mitral insufficiency (MI) of 6 to 9 months duration, (n = 10). Hemodynamic studies were done to establish the presence of heart failure. Blood samples were collected to measure PMN leukocyte chemiluminescence. There was a decrease in the cardiac index and index of myocardial contractility (dp/dt/IIP) and an increase in the left ventricular end-diastolic pressure in dogs with MI indicating left ventricular failure. The peak chemiluminescent activity of the PMN leukocytes in blood of dogs with failure was about four folds greater than that in the blood from normal dogs. These results suggest that there may be an increased OFR generation in dogs with volume overload heart failure. The decrease in the myocardial contractility in the failing heart might be due to an increase in the OFR produced by the PMN leukocytes.     

A comparative study of the acute effects of cetamolol (AI-27,303), atenolol, propranolol, and dexpropranolol on blood pressure, sympathetic nerve and ganglion activity of cats

The effects of cetamolol (AI-27,303, Betacor), atenolol, propranolol, and dexpropranolol were evaluated in 36 chloralose-urethane anesthetized cats. Blood pressure, sympathetic nerve discharge, and ganglionic activity (from the superior cervical ganglion) were recorded after the intravenous administration of 2.5, 5.0, and 10 mg/kg doses of the compounds. The results indicate that cetamolol and atenolol decreased blood pressure and discharge in the postganglionic sympathetic nerve and impaired transmission at the level of sympathetic ganglia. Propranolol and dexpropranolol given at the same doses produced a larger decrease in blood pressure, but increased the sympathetic discharge and had no effect on ganglionic spike amplitude.     

Magnesium attenuates isoproterenol-induced acute cardiac dysfunction and beta-adrenergic desensitization

Sympathetic nervous activation is a crucial compensatory mechanism in heart failure. However, excess catecholamine may induce cardiac dysfunction and beta-adrenergic desensitization. Although magnesium is known to be a cardioprotective agent, its beneficial effects on acute cardiac dysfunction remain to be elucidated. We examined the effects of magnesium on left ventricular (LV) dysfunction induced by a large dose of isoproterenol in dogs. Sixteen anesthetized dogs underwent a continuous infusion of isoproterenol (1 micro g.kg(-1).min(-1)) with or without a magnesium infusion (1 mg.kg(-1).min(-1)). The dose response to small doses of isoproterenol (0.025-0.2 micro g.kg(-1).min(-1)) was tested hourly. A large dose of isoproterenol decreased LV systolic function, increased the time constant of LV isovolumic relaxation, and suppressed the dose response to small doses of isoproterenol in a time-dependent manner. Magnesium significantly attenuated isoproterenol-induced LV systolic and diastolic dysfunction and preserved the dose response to isoproterenol. Serum-ionized calcium significantly decreased with a large dose of isoproterenol but was fully maintained at baseline level with magnesium. A large dose of isoproterenol increased serum lipid peroxide levels and serological markers of myocardial damage, which were significantly suppressed by magnesium. In conclusion, magnesium significantly attenuated excess isoproterenol-induced acute cardiac dysfunction and beta-adrenergic desensitization.     

Effect of lithium preparations on cardiac arrhythmias resulting from ligation of the common carotid arteries

In experiments on cats with dissected vagus and aortal nerves under chloralose-urethane anesthesia, ventricular disorders of the cardiac rhythm were induced by ligation of the common carotid arteries. Appearance of arrhythmias was preceded by an increase in the sympathetic activity (recorded from the inferior cardiac or renal nerve) accompanied by a rise of the arterial blood pressure and of the heart rate. Intravenous injection of lithium chloride or hydroxybutyrate resulted in lowering of the sympathetic activity, arterial blood pressure, and heart rate, and led to the recovery of the sinus rhythm.     

Abnormal cardiac wall motion and early matrix metalloproteinase activity

Activation of matrix metalloproteinases (MMPs) in the heart is known to facilitate cardiac remodeling and progression to failure. We hypothesized that regional dyskinetic wall motion of the left ventricle would stimulate activation of MMPs. Abnormal wall motion at a target site on the anterior lateral wall of the left ventricle was induced by pacing atrial and ventricular sites of five open-chest anesthetized dogs. Changes in shortening at the left ventricular (LV) pacing site and at a remote site at the anterior base of the left ventricle were monitored with piezoelectric crystals. Simultaneous atrial and ventricular pacing resulted in abnormal motion at the LV pacing site, yielding early shortening and late systolic lengthening, whereas the shortening pattern at the remote site remained unaffected. Assessment of global myocardial MMP activity showed a sevenfold increase in substrate cleavage (P < 0.02) at the LV pacing site relative to the remote site. Gelatin zymography revealed increases in 92-kDa MMP-9 activity and 86-kDa MMP-9 activity at the LV pacing site relative to the remote site, whereas MMP-2 activity was unaffected. Abnormal wall motion was associated with increases in collagen degradation (approximately 2-fold; P < 0.03), plasmin activity (approximately 1.5-fold; P < 0.05), nitrotyrosine levels (approximately 20-fold; P = 0.05), and inflammatory infiltrate (approximately 2-fold; P < 0.02) relative to the remote site. Results indicate that regional dyskinesis induced by epicardial activation is sufficient to stimulate significant MMP activity in the heart, suggesting that abnormal wall motion is a stimulus for MMP activation.     

Cause and effect relationship between myocardial mast cell number and matrix metalloproteinase activity

The objectives of this study were to investigate the temporal response of left ventricular (LV) matrix metalloproteinase (MMP) activity and collagen volume fraction (CVF) induced by an aortocaval fistula and the role of cardiac mast cells in regulating MMP activity. LV tissue was analyzed for MMP activity, CVF, and mast cell number in rats euthanized at 0.5, 1, 2, 3, 5, 14, 21, 35, and 56 days. Additional rats treated with the mast cell membrane-stabilizing drug cromolyn sodium were euthanized 1, 2, and 3 days postfistula. Marked increases in MMP activity occurred rapidly and remained significantly elevated for 5 days before returning toward normal. A significant decrease in CVF occurred by day 5, but thereafter CVF rebounded to normal or above normal values. The number of myocardial mast cells also significantly increased postfistula, and there was a close association between mast cell density and MMP activity. Cromolyn treatment prevented the increase in mast cell number and MMP activity. Thus it is concluded that cardiac mast cells play a major role in the regulation of MMP activity.     

Carbon monoxide affects electrical and contractile activity of rat myocardium

Background

Carbon monoxide (CO) is a toxic gas, which also acts in the organism as a neurotransmitter. It is generated as a by-product of heme breakdown catalyzed by heme oxygenase. We have investigated changes in electrical and contractile activity of isolated rat atrial and ventricular myocardium preparations under the influence of CO.

Methods

Standard microelectrode technique was used for intracellular registration of electrical activity in isolated preparations of atrial and ventricular myocardium. Contractions of atrial myocardial stripes were registered via force transducer.

Results

CO (10^-4 - 10^-3 M) caused prominent decrease of action potential duration (APD) in working atrial myocardium as well as significant acceleration of sinus rhythm. In addition CO reduced force of contractions and other parameters of contractile activity. Inhibitor of heme oxygenase zinc protoporphyrin IX exerts opposite effects: prolongation of action potential, reduction of sinus rhythm rate and enhancement of contractile function. Therefore, endogenous CO, which may be generated in the heart due to the presence of active heme oxygenase, is likely to exert the same effects as exogenous CO applied to the perfusing medium. In ventricular myocardium preparations exogenous CO also induced shortening of action potential, while zinc protoporphyrin IX produced the opposite effect.

Conclusions

Thus, endogenous or exogenous carbon monoxide may act as an important regulator of electrical and contractile cardiac activity.     

Electrophysiological effects of ouabain in 6-hydroxydopamine pretreated dogs

Chemical sympathectomy and bilateral vagotomy were used to evaluate the contribution of each division of the autonomic nervous system in the electrophysiological actions of ouabain. Intact and chemically sympathectomized dogs were given successive and cumulative doses of ouabain until toxicity became manifest (ventricular extrasystoles and (or) ventricular tachycardia). An additional group of normal and sympathectomized animals was also submitted to bilateral vagotomy in the presence of a therapeutic dose of ouabain. Sinus cycle length, AH interval of the His bundle electrogram, atrioventricular junctional effective and functional refractory periods were increased by ouabain at therapeutic doses. These effects were no different in sympathectomized dogs than in intact dogs, indicating the absence of any significant contribution of efferent sympathetic neural activity. However, our results suggested that vagal enhancement was the main mechanism whereby ouabain produced sinus bradycardia and depression of atrioventricular conduction. Sympathectomy with 6-OHDA did not modify nor abolish ouabain toxicity. However, toxic doses were significantly higher in sympathectomized animals than in normal animals. Considering that increasing heart rate by cardiac pacing or vagotomy significantly lowered toxic doses of ouabain in both intact and sympathectomized dogs, it is possible that sympathectomy could influence ouabain toxicity by altering heart rate alone.     

Volume expansion potentiates cardiac sympathetic afferent reflex in dogs

Our previous study (27) showed that the cardiac sympathetic afferent reflex (CSAR) was enhanced in dogs with congestive heart failure. The aim of this study was to test whether blood volume expansion, which is one characteristic of congestive heart failure, potentiates the CSAR in normal dogs. Ten dogs were studied with sino-aortic denervation and bilateral cervical vagotomy. Arterial pressure, left ventricular pressure, left ventricular epicardial diameter, heart rate, and renal sympathetic nerve activity were measured. Coronary blood flow was also measured and, depending on the experimental procedure, controlled. Blood volume expansion was carried out by infusion of isosmotic dextran into a femoral vein at 40 ml/kg at a rate of 50 ml/min. CSAR was elicited by application of bradykinin (5 and 50 microg) and capsaicin (10 and 100 microg) to the epicardial surface of the left ventricle. Volume expansion increased arterial pressure, left ventricular pressure, left ventricular diameter, and coronary blood flow. Volume expansion without controlled coronary blood flow only enhanced the RSNA response to the high dose (50 microg) of epicardial bradykinin (17. 3 +/- 1.9 vs. 10.6 +/- 4.8%, P < 0.05). However, volume expansion significantly enhanced the RSNA responses to all doses of bradykinin and capsaicin when coronary blood flow was held at the prevolume expansion level. The RSNA responses to bradykinin (16. 9 +/- 4.1 vs. 5.0 +/- 1.3% for 5 microg, P < 0.05, and 28.9 +/- 3.7 vs. 10.6 +/- 4.8% for 50 microg, P < 0.05) and capsaicin (29.8 +/- 6.0 vs. 9.3 +/- 3.1% for 10 microg, P < 0.05, and 34.2 +/- 2.7 vs. 15.1 +/- 2.7% for 100 microg, P < 0.05) were significantly augmented. These results indicate that acute volume expansion potentiated the CSAR. These data suggest that enhancement of the CSAR in congestive heart failure may be mediated by the concomitant cardiac dilation, which accompanies this disease state.     

Canine Cardiac Digitalis Receptors are Preserved in Congestive Heart Failure Induced by Rapid Ventricular Pacing

Abstract

In dogs, it has been reported that acute ischemia or severe and terminal heart failure results in a selective reduction of myocardial α₃ isoform of Na, K-ATPase activity. The aim of this study was to evaluate if a similar change in the two canine digitalis receptor isoforms occurs following 4 weeks of rapid ventricular pacing-induced heart failure without profound necrosis. Heart failure was induced in dogs by rapid ventricular pacing (240 beats × min^-1). Digitalis receptors were quantitated by [³H]-ouabain binding with isolated microsomal membranes from sham-operated (n = 3) and heart failure dogs (n = 4) and by Western blot analysis using specific α₁ and α₃ polyclonal antibodies. In kinetic studies, similar dissociation rates of 19 to 22 × 10^-4 s^-1 and 1.3 to 2.4 10^-4 s^-1 corresponding to high and low affinity sites respectively, were found in sham-operated and CHF dogs. Immunoblotting showed similar abundance of α₁ isoform in the two groups; however, levels of α₃ were increased by at least 50% in pacing-induced heart failure animals. In conclusion, heart failure selectively modulates the expression of cardiac α₃ isoform in dogs.     

Sodium channel enhancer restores baroreflex sensitivity in conscious dogs with heart failure

We compared the cardiac inotropic, lusitropic, and chronotropic responses to the Na(+) channel enhancer LY-368052 in conscious dogs before and after development of congestive heart failure (CHF). We also examined the effect of LY-368052 on baroreflex sensitivity and the efferent neural mechanisms of the bradycardic response in heart failure. Dogs were chronically instrumented, and heart failure was induced by right ventricular pacing at 240 beats/min for 3-4 wk. LY-368052 dose-dependently increased left ventricular contractile performance before and after the development of CHF to a similar extent. The inotropic effect of LY-368052 in heart failure was not altered by either ganglionic or beta-adrenergic receptor blockade. LY-368052 improved cardiac relaxation and induced bradycardia in dogs with heart failure but not in normal dogs. The negative chronotropic effect of LY-368052 was eliminated by ganglionic blockade but not beta-adrenergic blockade, suggesting that the bradycardia was mediated by the autonomic nervous system via enhanced parasympathetic tone. Baroreflex sensitivity was assessed as the pulse interval-mean arterial pressure slope in response to temporary pharmacological (nitroglycerin or phenylephrine) and mechanical (brief occlusion of inferior vena cava) alterations of arterial pressure in conscious dogs before and after development of heart failure. Baroreflex sensitivity was significantly depressed in heart failure and restored completely by acute treatment with LY-368052. Thus the Na(+) channel enhancer LY-368052 maintains its beta-receptor-independent inotropic effect in chronic CHF and specifically improves ventricular relaxation and depressed baroreflex function.     

Determinants of cardiac augmentation by elevations in intrathoracic pressure

We studied the cardiovascular effects of phasic increases in intrathoracic pressure (ITP) by high-frequency jet ventilation in an acute pentobarbital-anesthetized intact canine model both before and after the induction of acute ventricular failure by large doses of propranolol. Chest and abdominal pneumatic binders were used to further increase ITP. Respiratory frequency, percent inspiratory time, mean ITP, and swings in ITP throughout the respiratory cycle were independently varied at a constant-circulating blood volume. We found that pertubations in mean ITP induced by ventilator adjustments accounted for all observable steady-state hemodynamic changes independent of respiratory frequency, inspiratory time, or phasic respiratory swings in ITP. Changes in ITP were associated with reciprocal changes in both intrathoracic vascular pressures (P less than 0.01) and blood volume (P less than 0.01). When cardiac function was normal, left ventricular (LV) stroke volume decreased, whereas in acute ventricular failure, LV stroke volume increased in response to increasing ITP when apneic LV filling pressure was high (greater than or equal to 17 Torr) and did not change if apneic LV filling pressure was low (less than or equal to 12 Torr). However, in all animals in acute ventricular failure, LV stroke work increased with increasing ITP. Our study demonstrates that the improved cardiac function seen with increasing ITP in acute ventricular failure is dependent upon adequate LV filling and decreased LV afterload in a manner analogous to that seen with arterial vasodilator therapy in heart failure.     

Modelling of ventricular tachycardia against a background of an elongated Q-T interval

During the experiments on dogs we've created a mood of stable ventricular tachycardia induced by electrical stimulation of the left stellate ganglion at the elongated Q-T interval. The elongated cardiac systole--Q-T interval on ECG is induced by intravenous cesium chloride (l mmol/kg of dog's weight), which results in the disturbed myocardial electrolyte balance seen as tissue hypokalemia. In the dogs with electrical cardiac instability irritation of the left stellate ganglion resulted in polymorphic ventricular tachyarrhythmia in 83% of the animals. The created model has documented a role played by intracardiac pathology (electrolyte imbalance) in combination with the increased activity of the stellate ganglion in the mechanism of ventricular arrhythmia seen at the elongated Q-T interval.     

刺激腓深神经对低血压或休克狗心血管活动的影响

实验在麻醉狗中进行。静脉内匀速注射硝普钠时,平均动脉压和左心室收缩压明显降低,左心室dp/dt_(max)、-dp/dt_(max)和心力环面积均明显减小。此时电刺激一侧腓深神经可使动脉血压和左心室收缩压明显升高,dp/dt_(max)和心力环面积也显著增加。停止刺激后,动脉血压和左心室收缩压逐渐回向刺激前的水平。停止注射硝普钠5～15分钟后,上述各项观察指标基本恢复到注药前的水平。在用大肠杆菌内毒素造成休克的狗中,电刺激一侧腓深神经,也能使平均动脉压和左心室收缩压升高,同时dp/dt_(max)、-dp/dt_(max)和肠系膜血管阻力明显增高,但肾血管阻力增加不明显。本实验结果与以往的实验资料一起表明,在用扩血管药造成低血压时,躯体神经刺激引起的升压效应似乎以心肌收缩力增加为主;而在内毒素休克时,躯体神经刺激可通过改善心肌收缩功能和增加内脏血管阻力而引起升压作用。     

Effects of garlic (Allium sativum) extract on the heart rate, rhythm and force of contraction in frog: a dose-dependent study

Garlic juice (dose equivalent to 3.3 g to 33 g garlic) mainly caused bradycardia in frog Rana tigerina. The disturbance in ventricular rhythm was observed prior to than that of atria. Rhythm was specially disturbed at higher doses causing bizarre pattern. Force of contraction of the heart also decreased with higher dose of the garlic extract. The results suggest that garlic extract has some beneficial effect on heart rate modulating the rate, rhythm and force of contraction positively but very high doses may exert non-desirable effects as well.     

Early activation of cardiac and renal endothelin systems in experimental heart failure

We investigated the time course of the expression of cardiac and renal endothelin systems in tachycardia-induced heart failure in dogs. Eleven beagles underwent rapid pacing at a progressively increased rate over a period of 5 wk, with a weekly clinical examination, echocardiography, measurement of circulating and urinary endothelin-1 (ET-1), and myocardial and renal tissue biopsies. Real-time quantitative PCR was used for determinations of tissue prepro-ET-1 (ppET-1), ET-1-converting enzyme (ECE-1), and ETA and ETB receptor mRNA. Cardiac and renal tissue ET-1 contents were evaluated by immunostaining and measured by radioimmunoassay at autopsy. Rapid pacing caused a progressive increase in end-systolic and end-diastolic ventricular volumes (P < 0.05) from week 2 together with a decrease in ejection fraction and in mean velocity of circumferential shortening (P < 0.05) from week 1. These changes were tightly correlated to myocardial ppET-1 and renal ETA receptor mRNA and less so to myocardial ECE-1 mRNA, and they occurred before any increase in plasma and urinary ET-1 (P < 0.05 from week 4) and clinical signs of heart failure. Renal ppET-1 did not change. Both cardiac and renal ET-1 peptide contents were increased at autopsy. We conclude that tachycardia-induced heart failure in dogs is characterized by an early activation of the cardiac and renal tissue endothelin systems, which occurs before any changes in circulating and urinary ET-1 and is closely related to altered ventricular function.     

Implications of QRS duration in dogs with pacing-induced heart failure

The objective of this study was to find out the implication of QRS duration in dogs with rapid pacing-induced heart failure. Sixteen Beagle dogs were implanted with transvenous cardiac pacemakers and underwent rapid right ventricular pacing for 3 weeks at 260 bpm to induce heart failure. Dogs were divided into two groups according to the QRS duration: 9 with normal QRS duration (<100 ms) and 7 with prolonged QRS duration (≥100 ms). Cardiac systolic function and size was analyzed by real time 3-dimensional echocardiography and left ventricular dyssynchrony was assessed by speckle tracking strain imaging. Congestive heart failure developed 3 weeks after rapid right ventricular pacing. Dogs with prolonged QRS duration showed more extensive radial strain and circumferential strain dyssynchrony than dogs with normal QRS duration. At the end of 4-week recovery, greater improvement of left ventricular ejection fraction and left ventricular end-systolic volume was detected in dogs with normal QRS duration. The findings suggested that left ventricular dyssynchrony, indicated by a prolonged QRS duration, predicted an unsatisfying recovery in dogs with rapid pacing-induced heart failure. QRS duration had the potential to be a prognostic indicator for dogs with heart failure.     

Importance of antioxidant and antiapoptotic effects of beta-receptor blockers in heart failure therapy

The present study was carried out to determine whether beneficial effects of carvedilol in congestive heart failure (CHF) are mediated via its beta-adrenergic blocking, antioxidant, and/or alpha-adrenergic blocking action. Rabbits with heart failure induced by rapid cardiac pacing were randomized to receive subcutaneous carvedilol, metoprolol, propranolol plus doxazosin, or placebo pellets for 8 wk and compared with sham-operated rabbits without pacing. We found rapid cardiac pacing produced clinical heart failure, left ventricular dilation, and decline of left ventricular fractional shortening. This was associated with an increase in left ventricular end-diastolic pressure, decrease in left ventricular first derivative of left ventricular pressure, and myocyte hypertrophy. Tissue oxidative stress measured by GSH/GSSG was increased in the heart with increased oxidation product of mitochondrial DNA, 8-oxo-7,8-dihydro-2'-deoxyguanosine, increase of Bax, decrease of Bcl-2, and increase of apoptotic myocytes as measured by anti-single-stranded DNA monoclonal antibody. Administration of carvedilol and metoprolol, which had no effect in sham animals, attenuated cardiac ventricular remodeling, cardiac hypertrophy, oxidative stress, and myocyte apoptosis in CHF. In contrast, propranolol plus doxazosin, which has less antioxidant effects, produced smaller effects on left ventricular function and myocyte apoptosis. In all animals, GSH/GSSG correlated significantly with changes of left ventricular end-diastolic dimension (r = -0.678, P < 0.0001), fractional shortening (r = 0.706, P < 0.0001), and apoptotic myocytes (r = -0.473, P = 0.0001). Thus our findings suggest antioxidant and antiapoptotic actions of carvedilol and metoprolol are important determinants of clinical beneficial effects of beta-receptors in the treatment of CHF.     

Effects of positive end-expiratory pressure on the right ventricle

Transmural cardiac pressures, stroke volume, right ventricular volume, and lung water content were measured in normal dogs and in dogs with oleic acid-induced pulmonary edema (PE) maintained on positive-pressure ventilation. Measurements were performed prior to and following application of 20 cmH2O positive end-expiratory pressure (PEEP). Colloid fluid was given during PEEP for ventricular volume expansion before and after the oleic acid administration. PEEP significantly increased pleural pressure and pulmonary vascular resistance but decreased right ventricular volume, stroke volume, and mean arterial pressure in both normal and PE dogs. Although the fluid infusion during PEEP raised right ventricular diastolic volumes to the pre-PEEP level, the stroke volumes did not significantly increase in either normal dogs or the PE dogs. The fluid infusion, however, significantly increased the lung water content in the PE dogs. Following discontinuation of PEEP, mean arterial pressure, cardiac output, and stroke volume significantly increased, and heart rate did not change. The failure of the stroke volume to increase despite significant right ventricular volume augmentation during PEEP indicates that positive-pressure ventilation with 20 cmH2O PEEP decreases right ventricular function.