Increased extravascular forces limit endothelium-dependent and -independent coronary vasodilation in congestive heart failure.

OBJECTIVE: The increase in coronary blood flow (CBF) in response to endothelium-dependent vasodilators is reduced in congestive heart failure (CHF) suggesting endothelial dysfunction. However, increases in extravascular compressive forces secondary to elevated left ventricular diastolic pressure (LVEDP) in CHF might contribute to this abnormality. METHODS: We measured CBF responses to intracoronary doses of the endothelium-dependent vasodilators acetylcholine (ACH) and bradykinin (BK) and the endothelium-independent vasodilator sodium nitroprusside (SNP) in the same eight dogs before (control) and after CHF was produced by 23+/-3 days of rapid ventricular pacing. In five of the dogs with CHF the zero-flow pressure (P(zf)), which reflects extravascular compressive forces in the maximally vasodilated coronary circulation (adenosine) was measured and found to strongly correlate with LVEDP (r=0.91). Coronary vascular resistance (CVR) at each concentration of vasodilator before and after the development of CHF was corrected for estimated coronary back pressure: CVR=(P(Ao)-LVEDP)/CBF, where P(Ao) is mean aortic pressure. RESULTS: CHF resulted in a significant decrease in CBF and increase in heart rate and LVEDP compared to control (P<0.05). The CBF responses to ACH, BK and SNP were all significantly reduced in the failing hearts (P<0.01). However, after correction for the elevated LVEDP in CHF, the response of CVR to the endothelium-dependent vasodilators was not different from normal. CONCLUSION: These findings suggest that endothelium mediated vasodilation is preserved in CHF, but that increased extravascular compressive forces act to limit the increase in CBF.

Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy.

BACKGROUND: Clinical impact of atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) is largely unresolved. Thus, we analyzed the prognostic implications of AF in a large, community-based HCM population assembled from Italian and US cohorts. METHODS AND RESULTS: Occurrence of AF and outcome were assessed in 480 consecutive HCM patients (age at diagnosis, 45+/-20 years; 61% male) who were followed up for 9.1+/-6.4 years. AF occurred in 107 patients (22%; incidence, 2%/y) and was independently predicted by advancing age, congestive symptoms, and increased LA size at diagnosis. Patients with AF had increased risk for HCM-related death (OR, 3.7; P<0.002) because of excess heart failure-related mortality but not sudden, unexpected death. This risk associated with AF was substantially greater in patients with outflow obstruction or with earlier development of AF (

Selective blockade of mitochondrial K(ATP) channels does not impair myocardial oxygen consumption.

Opening of mitochondrial ATP-sensitive potassium (K(ATP)) channels has been postulated to prevent inhibition of respiration resulting from matrix contraction during high rates of ATP synthesis. Glibenclamide, which blocks K(ATP) channels on the sarcolemma of vascular smooth muscle cells and myocardial myocytes as well as on the inner mitochondrial membrane, results in a decrease of myocardial oxygen consumption (MVO2) both at rest and during exercise. This study examined whether this represents a primary effect of blockade of mitochondrial K(ATP) channels or occurs secondary to coronary resistance vessel constriction with a decrease of coronary blood flow (CBF) and myocardial oxygen availability. MVO2 was measured at rest and during treadmill exercise in 10 dogs during control conditions, after selective mitochondrial K(ATP) channel blockade with 5-hydroxydecanoate (5-HD), and after nonselective K(ATP) channel blockade with glibenclamide. During control conditions, exercise resulted in progressive increases of CBF and MVO2. Glibenclamide (50 microg x kg(-1) x min(-1) ic) resulted in a 17 +/- 6% decrease of resting CBF with a downward shift of CBF during exercise and a decrease of coronary venous PO2, indicating increased myocardial oxygen extraction. In contrast with the effects of glibenclamide, 5-HD (0.7 mg x kg(-1) x min(-1) ic) had no effect on CBF, MVO2, or myocardial oxygen extraction. These findings suggest that glibenclamide decreased MVO2 by causing resistance vessel constriction with a decrease of CBF and oxygen available to the myocardium rather than to a primary reduction of mitochondrial respiration.

Effect of sildenafil on coronary active and reactive hyperemia.

Sildenafil, a selective inhibitor of phosphodiesterase type 5, produces relaxation of isolated epicardial coronary artery segments by causing accumulation of cGMP. Because shear-induced nitric oxide-dependent vasodilation is mediated by cGMP, this study was performed to determine whether sildenafil would augment the coronary resistance vessel dilation that occurs during the high-flow states of exercise or reactive hyperemia. In chronically instrumented dogs, sildenafil (2 mg/kg per os) augmented the vasodilator response to acetylcholine, with a leftward shift of the dose-response curve relating coronary flow to acetylcholine dose. Sildenafil caused a 6. 7 +/- 2.1 mmHg decrease of mean aortic pressure, which was similar at rest and during treadmill exercise (P < 0.05), with no change of heart rate, left ventricular (LV) systolic pressure, or LV maximal first time derivative of LV pressure. Sildenafil tended to increase myocardial blood flow at rest and during exercise (mean increase = 14 +/- 3%; P < 0.05 by ANOVA), but this was associated with a significant decrease in hemoglobin, so that the relationship between myocardial oxygen consumption and oxygen delivery to the myocardium (myocardial blood flow x arterial O(2) content) was unchanged. Furthermore, sildenafil did not alter coronary venous PO(2), indicating that the coupling between myocardial blood flow and myocardial oxygen demands was not altered. In addition, sildenafil did not alter the peak coronary flow rate, debt repayment, or duration of reactive hyperemia that followed a 10-s coronary occlusion. The findings suggest that cGMP-mediated resistance vessel dilation contributes little to the increase in myocardial flow that occurs during exercise or reactive hyperemia.

Coronary nitric oxide production in response to exercise and endothelium-dependent agonists.

BACKGROUND: Endothelium-derived nitric oxide (NO) contributes to epicardial coronary artery vasodilation during exercise. However, blockade of NO production does not impair the increase in coronary blood flow (CBF) during exercise, suggesting that NO is not obligatory for exercise-induced coronary resistance vessel dilation. In contrast, the increases in CBF produced by endothelium-dependent agonists are decreased after NO blockade. Consequently, this study was performed to determine whether the increase in coronary NO production in response to agonists is greater than that which occurs during exercise. METHODS AND RESULTS: We measured the oxidation products of NO (nitrate+nitrite=NO(x)) in aortic and coronary sinus plasma using chemiluminescence to assess NO(x) production across the coronary circulation in chronically instrumented dogs during a 3-stage treadmill exercise protocol and in response to intracoronary administration of the endothelium-dependent agonists acetylcholine (37.5 microg/min) and bradykinin (3.0 microg/min). No coronary NO(x) production could be detected at rest or during the first 2 stages of exercise; only at the highest level of exercise was a small increase in coronary NO(x) production measured. In contrast, coronary production of NO(x) was significantly increased in response to endothelium-dependent agonists. CONCLUSIONS: Coronary NO production in response to endothelium-dependent agonists is greater than in response to the increase in shear stress associated with exercise. These findings support previous studies suggesting that NO is not required for the coronary vasodilation that occurs in the normal heart during exercise.

Cyclic nucleotide phosphodiesterase type 5 activity limits blood flow to hypoperfused myocardium during exercise.

BACKGROUND: Nitric oxide (NO) causes vasodilation by stimulation of guanylate cyclase in vascular smooth muscle to produce cGMP. The resultant vasodilator effect is regulated by a family of cGMP phosphodiesterases (PDEs). Sildenafil, a selective inhibitor of PDE5 used for treatment of erectile dysfunction, has been found to cause relaxation of isolated epicardial coronary artery segments. The present study examined the effects of sildenafil on coronary blood flow and hemodynamics during exercise in normal and ischemic heart. METHODS AND RESULTS: In chronically instrumented normal dogs, sildenafil 2 mg/kg PO caused a slight but significant increase in left anterior descending (LAD) coronary blood flow during resting conditions, with a nonsignificant trend toward increased coronary flow during treadmill exercise. Exercise in the presence of LAD stenosis that decreased distal coronary pressure to 57+/-2 mm Hg reduced LAD flow during exercise from 69+/-8 to 41+/-7 mL/min (P:<0. 05), with hypoperfusion most severe in the subendocardium. At the same distal coronary pressure, sildenafil increased LAD flow in the ischemic region to 50+/-11 mL/min (P:<0.05). Increase in ischemic region blood flow produced by sildenafil was uniform across the LV wall, given that no change occurred in the transmural distribution of perfusion. CONCLUSIONS: Inhibition of PDE5 with sildenafil caused vasodilation of coronary resistance vessels with an increase of blood flow into an ischemic myocardial region during exercise in the presence of coronary artery stenosis.

Nitroglycerin dilates coronary collateral vessels during exercise after blockade of endogenous NO production.

In a previous study nitroglycerin failed to dilate coronary collateral vessels during exercise. This study tested the hypothesis that failure of nitroglycerin to increase collateral flow occurred because endogenous nitric oxide (NO) had activated the guanylate cyclase vasodilator pathway so that additional NO from nitroglycerin could have no additional effect. Six dogs were collateralized using intermittent 2-min occlusions of the left anterior descending coronary artery followed by permanent occlusion. One week after permanent coronary occlusion, dogs were exercised on a treadmill (heart rate 202 +/- 5 beats/min), while blood flow was measured with radioactive microspheres. Blood flow to the collateral zone during control exercise was 1.90 +/- 0.11 ml. min(-1). g(-1) compared with 2.28 +/- 0.15 ml. min(-1). g(-1) in the normal zone (P < 0.05); systolic wall thickening was 23 +/- 3% in the collateral zone compared with 27 +/- 2% in the normal zone. When N(G)-nitro-L-arginine (L-NNA; 20 mg/kg iv) was administered to block NO production, collateral zone flow during exercise decreased to 1. 43 +/- 0.20 ml. min(-1). g(-1) (P < 0.05), and systolic wall thickening decreased to 12 +/- 4% (P < 0.05). A subsequent infusion of nitroglycerin (2 microg. kg(-1). min(-1) iv) increased collateral zone blood flow to 1.65 +/- 0.16 ml. min(-1). g(-1) (P < 0.05) and increased systolic wall thickening to 22 +/- 5% (P < 0.05). These findings demonstrate that endogenous NO contributes to collateral zone blood flow during exercise. If endogenous NO synthesis is blocked, then nitroglycerin is effective in improving collateral zone blood flow and contractile function during exercise.

Role of K(+)(ATP) channels and adenosine in regulation of coronary blood flow in the hypertrophied left ventricle.

In the hypertrophied heart, increased extravascular forces acting to compress the intramural coronary vessels might require augmentation of metabolic vasodilator mechanisms to maintain adequate coronary blood flow. Vascular smooth muscle ATP-sensitive potassium (K(+)(ATP)) channel activity is important in metabolic coronary vasodilation, and adenosine contributes to resistance vessel dilation in the hypoperfused heart. Consequently, this study was performed to determine whether K(+)(ATP) channels and adenosine have increased importance in exercise-induced coronary vasodilation in the hypertrophied left ventricle. Studies were performed in dogs in which banding of the ascending aorta had resulted in a 66% increase in left ventricular mass in comparison with historic normal animals. Treadmill exercise resulted in increases of coronary blood flow that were linearly related to the increase of heart rate or rate-pressure product. During resting conditions, K(+)(ATP) channel blockade with glibenclamide caused a 17 +/- 5% decrease in coronary blood flow, similar to that previously observed in normal hearts. Unlike normal hearts, however, glibenclamide blunted the increase in coronary flow that occurred during exercise, causing a significant decrease in the slope of the relationship between coronary flow and the rate-pressure product. Adenosine receptor blockade with 8-phenyltheophylline did not alter coronary blood flow at rest or during exercise. Furthermore, even after K(+)(ATP) channel blockade with glibenclamide, the addition of 8-phenyltheophylline had no effect on coronary blood flow. This finding was different from normal hearts, in which the addition of adenosine receptor blockade after glibenclamide impaired exercise-induced coronary vasodilation. The data suggest that, in comparison with normal hearts, hypertrophied hearts have increased reliance on opening of K(+)(ATP) channels to augment coronary flow during exercise. Contrary to the initial hypothesis, however, adenosine was not mandatory for exercise-induced coronary vasodilation in the hypertrophied hearts either during control conditions or when K(+)(ATP) channel activity was blocked with glibenclamide.

Effect of NO on transmural distribution of blood flow in hypertrophied left ventricle during exercise.

When exercise in the presence of a coronary artery stenosis results in subendocardial ischemia, administration of a nitric oxide (NO) donor increases subendocardial blood flow, whereas NO synthesis blockade worsens subendocardial hypoperfusion. Because left ventricular hypertrophy (LVH) is also associated with subendocardial hypoperfusion during exercise, this study tested the hypothesis that alterations of NO availability can similarly influence subendocardial blood flow in the hypertrophied heart. Studies were performed in seven dogs in which ascending aortic banding resulted in an 80% increase in LV weight. Myocardial blood flow was measured with microspheres during treadmill exercise that increased heart rates to 216 +/- 8 beats/min. During control exercise, mean myocardial blood flow in animals with LVH was similar to that in historic controls, but the ratio of subendocardial to subepicardial blood flow was lower in animals with hypertrophy (0.88 +/- 0.07) than in controls (1.36 +/- 0.08; P < 0.05). Blockade of NO synthesis with NG-nitro-L-arginine (L-NNA; 1.5 mg/kg ic) caused no change in heart rate or LV systolic pressure during exercise. Furthermore, L-NNA did not worsen subendocardial hypoperfusion during exercise. Intracoronary infusion of nitroglycerin (0.4 microgram. kg-1. min-1) did not significantly alter either mean blood flow or the transmural distribution of perfusion during exercise in the hypertrophied hearts. Thus, unlike the subendocardial underperfusion that occurs when a stenosis limits coronary blood flow, alterations of NO availability did not alter subendocardial hypoperfusion in the hypertrophied hearts.

Regulation of myocardial blood flow by oxygen consumption is maintained in the failing heart during exercise.

The hemodynamic abnormalities and neurohumoral activation that accompany congestive heart failure (CHF) might be expected to impair the increase in coronary blood flow that occurs during exercise. This study was performed to determine the effects of CHF on myocardial oxygen consumption and coronary blood flow during exercise. Coronary blood flow was measured in chronically instrumented dogs at rest, during 2 stages of graded treadmill exercise under control conditions (n=10), and after the development of CHF produced by 3 weeks of rapid ventricular pacing (n=9). In the normal dogs, coronary blood flow increased during exercise in proportion to the increase in the heart rate x the left ventricular systolic blood pressure product (RPP). After the development of CHF, resting myocardial blood flow was 25% lower than normal (P<0.05). Myocardial blood flow increased during the first stage of exercise, but then failed to increase further during the second stage of exercise despite an additional increase in the RPP. Myocardial oxygen consumption during exercise was significantly lower in animals with CHF and paralleled coronary flow. Despite the lower values for coronary blood flow in animals with CHF, there was no evidence for myocardial ischemia. Thus, even during the second level of exercise when coronary flow failed to increase, myocardial lactate consumption continued and coronary venous pH did not fall. In addition, the failure of coronary flow to increase as the exercise level was increased from stage 1 to stage 2 was not associated with a further increase in myocardial oxygen extraction. Thus, cardiac failure was associated with decreased myocardial oxygen consumption and failure of oxygen consumption to increase with an increase in the level of exercise. This abnormality did not appear to result from inadequate oxygen availability, but more likely represented a reduction of myocardial oxygen usage with a secondary decrease in metabolic coronary vasodilation.

Nitric oxide inhibition impairs blood flow during exercise in hearts with a collateral-dependent myocardial region.

OBJECTIVES: We sought to determine the importance of nitric oxide (NO) production in maintaining coronary blood flow during exercise in hearts with collateral-dependent myocardium. BACKGROUND: Coronary collateral vessels demonstrate endothelium-mediated NO-dependent vasodilation in response to agonists such as acetylcholine. However, the contribution of endogenous NO production to maintaining vasodilation of coronary collateral vessels during exercise has not been previously studied. METHODS: Collateral vessel growth was induced in 13 chronically instrumented dogs by intermittent 2-min occlusions, followed by permanent occlusion of the left anterior descending coronary artery (LAD). One week after permanent LAD occlusion, myocardial blood flow was measured with microspheres during rest and treadmill exercise at 6.4 km/h at a 15% grade. Measurements were then repeated after blockade of NO production with N-nitro-L-arginine (LNNA) (20 mg/kg body weight intravenously). RESULTS: LNNA caused a 62 +/- 4% (mean +/- SEM) inhibition of the coronary vasodilation produced by acetylcholine. During rest conditions, LNNA caused a slight decrease in blood flow to the collateral region (p = NS), with no change in normal zone blood flow. During exercise, LNNA caused a decrease in mean blood flow to the collateral region (from 2.24 +/- 0.19 to 1.78 +/- 0.26 ml/min per g after LNNA, p < 0.05). This decrease resulted from a near doubling of the collateral vascular resistance (p < 0.05), with a trend toward an increase in small vessel resistance in the collateral zone. LNNA also reduced myocardial blood flow to the normal region during exercise (from 2.99 +/- 0.24 to 2.45 +/- 0.28 ml/min per g, p < 0.05) as the result of a 44 +/- 13% increase in coronary vascular resistance (p < 0.05). CONCLUSIONS: NO contributes to the maintenance of coronary collateral blood flow during exercise. In contrast to the normal heart, endogenous NO production also maintains blood flow in remote myocardial regions during exercise. These results suggest that control of blood flow during exercise in normal myocardium is altered by the presence of an occluded coronary artery.

Dose-dependent effect of endothelin-1 on blood flow to normal and collateral-dependent myocardium.

BACKGROUND: Plasma levels of endothelin-1 (ET-1) increase during ischemia and could potentially contribute to impairment of myocardial blood flow (MBF). Because collateral vessels demonstrate enhanced responsiveness to certain vasoconstrictors, blood flow to collateral-dependent myocardium could be particularly sensitive to increases in ET-1 levels. METHODS AND RESULTS: Studies were performed in 13 dogs in which collateral vessel development was produced by fluoroscopic embolization of the midleft anterior descending coronary artery with a hollow plug 4 to 6 weeks before the study. MBF was measured with radioactive microspheres at baseline and during 30-minute infusions of ET-1 (1, 10, and 100 ng/min) into the left main coronary artery. Because ET-1 stimulates endothelial prostacyclin release, aortic and coronary sinus levels of ET-1 and 6-keto-prostaglandin F1 alpha were measured at the end of each infusion. ET-1 increased MBF from 0.82 mL.min-1.g-1 at baseline to 0.92 mL.min-1.g-1 at 10 ng/min (P < .05), which corresponded to a coronary plasma concentration of 73 +/- 16 pg/mL. Blood flow in the collateral zone was less (0.74 mL.min-1.g-1) than in the normal zone (P < .05) and did not increase at an ET-1 dose of 10 ng/min. MBF in the normal and collateral zones significantly decreased when ET-1 was increased to 100 ng/min, corresponding to a coronary sinus concentration of 175 +/- 45 pg/mL (P < .05). ET-1 produced dose-related increases in aortic and coronary sinus 6-keto-prostaglandin F1 alpha and the transcoronary difference (P < .05). To assess the importance of prostacyclin in opposing the vasoconstriction produced by ET-1, additional studies were performed after cyclooxygenase blockade with indomethacin. After indomethacin administration, ET-1 (10 ng/min) caused a 120 +/- 23% increase in collateral vascular resistance (P < .05) and abolished the vasodilation that this dose produced in the normal zone. CONCLUSIONS: Blood flow to normal myocardium is increased at moderate plasma elevations of ET-1, whereas collateral blood flow is unchanged. Only at significantly elevated plasma concentrations of ET-1 is blood flow to normal and collateral-dependent myocardium impaired. Coronary endothelial production of prostacyclin in response to increasing concentrations of ET-1 represents an important means of blunting the vasoconstrictor properties of ET-1 in the canine coronary circulation. Coronary collateral vessels demonstrate a much greater dependence on prostacyclin production in blunting the vasoconstrictor properties of ET-1.

Effect of beta-adrenergic receptor blockade on blood flow to collateral-dependent myocardium during exercise.

BACKGROUND: beta-Adrenergic receptors have been identified in isolated coronary collateral blood vessels, but their functional significance in the intact heart has not been demonstrated. METHODS AND RESULTS: We measured myocardial blood flow with radioactive microspheres in normal and collateral-dependent myocardium in eight dogs trained to run on a treadmill before and after beta-adrenergic blockade with propranolol, 200 micrograms/kg, a dose that effectively inhibited the increase in coronary blood flow produced by selective beta 1- and beta 2-adrenergic agonists. Collateral vessel growth was stimulated with 2-minute intermittent occlusions of the left anterior descending artery followed by permanent occlusion. During control exercise, blood flow in the collateral zone was 38 +/- 5% less than in the normal zone. At identical levels of exercise, with heart rate maintained constant by atrial pacing, propranolol decreased mean blood flow in the collateralized myocardium from 1.93 +/- 0.17 to 1.50 +/- 0.14 mL.min-1.g-1 (P < .01), while increasing the subendocardial to subepicardial blood flow ratio from 0.78 +/- 0.11 to 0.91 +/- 0.10 (P < .05). The decrease in collateral zone blood flow in response to propranolol resulted from an increase in both transcollateral resistance from 25.9 +/- 2.3 to 35.2 +/- 4.3 mm Hg.mL-1.min.g (P < .05) and small-vessel resistance in the collateral-dependent myocardium from 30.9 +/- 4.7 to 44.0 +/- 8.8 mm Hg.mL-1.min.g (P < .07). Blood flow to the normal zone was also significantly reduced from 3.14 +/- 0.21 to 2.23 +/- 0.12 mL.min-1.g-1 (P < .01) after propranolol. CONCLUSIONS: beta-Adrenergic blockade decreased blood flow to collateral-dependent myocardium during exercise. These results indicate that beta-adrenergic receptor activation contributes to vasodilation of coronary collateral vessels during exercise.

Effect of ventilatory strategy on cardiac output during high frequency jet ventilation.

STUDY OBJECTIVE: The aim was to study the effects of changes in ventilation variables on cardiac function during high frequency jet ventilation. DESIGN: Controlled changes in mean airway pressure (2-10 cm H2O), tidal volume (4 and 8 ml), and frequency (4-8 Hz) were used to assess the effects of ventilatory variables on cardiac output in cats with normal and reduced lung compliance during high frequency jet ventilation. Cardiac output was continuously measured with an electromagnetic flow probe placed around the aorta. Respiratory compliance was reduced by lung lavage. EXPERIMENTAL MATERIAL: Seven anaesthetised adults cats, weight 3.0(SEM 0.2) kg, were used in the study. MEASUREMENTS AND MAIN RESULTS: Cardiac output fell as mean airway pressure was raised from 2 to 10 cm H2O at all frequencies and tidal volumes. At identical levels of minute ventilation and mean airway pressure, cardiac output was improved with combinations of smaller tidal volumes and higher frequencies. Reducing respiratory compliance by lung lavage dampened the effect of mean airway pressure on cardiac output, but maintained the relationship between ventilatory variables observed before lavage. CONCLUSION: At identical settings of minute ventilation and mean airway pressure, cardiac output may be improved with smaller tidal volumes during high frequency jet ventilation.

Cardiovascular effects of high-frequency oscillatory and jet ventilation.

To determine the effects of mean airway pressure on hemodynamics during high-frequency ventilation, we ventilated five cats (wt 2.8 +/- 0.6 kg) using both HFOV (frequencies 3 to 20 Hz) and HFJV (frequencies 4 to 8 Hz) at Paw values ranging from 2 to 12 cm H2O. Combinations of frequency and tidal volume that maintained normocapnia were employed in random order before and after reduction of static compliance of the respiratory system by lung lavage. Heart rate was comparable during both modes of high-frequency ventilation. During both HFOV and HFJV, the cardiac output decreased and PVR increased in normal and surfactant-deficient cats as Paw was elevated (all p less than 0.01, ANOVA). For both HFOV and HFJV linear regression of Paw and cardiac output yielded comparable slopes and y-intercepts. Lung lavage reduced the effect of Paw but did not eliminate it. Changes in ventilatory frequency did not affect cardiac output or PVR. We conclude that the interaction between high-frequency ventilation and cardiovascular function is largely determined by Paw and compliance and is independent of ventilator frequency and the type of ventilator used.

Impairment of hemodynamics with increasing mean airway pressure during high-frequency oscillatory ventilation.

We investigated the effects of changes in mean airway pressure (Paw), oscillatory frequency and lung compliance on cardiac output (CO) and pulmonary vascular resistance in seven adult cats (3.0 +/- 0.6 kg) during high-frequency oscillatory ventilation (HFOV). The cats were anesthetized with chloralose and urethane and ventilated with a high-frequency oscillator at Paw of 4, 8, 12, and 16 cm H2O and frequencies of 3, 6, 12, 16, and 20 Hz. Saline lavage was used to reduce lung compliance. CO was continuously recorded with an electromagnetic flow probe placed around the aorta and pulmonary vascular resistance was calculated from left atrial and pulmonary artery pressures. Lung lavage reduced static compliance of the respiratory system but did not change CO during pressure-limited ventilation. During HFOV, CO was higher in animals after lung lavage at each Paw. As Paw was raised from 4 to 16 cm H2O during HFOV, CO decreased from 133 +/- 36 to 87 +/- 31 ml/min kg in animals with normal lungs and decreased from 153 +/- 33 to 107 +/- 19 ml/min kg after lung lavage (both p less than 0.001). Increasing Paw was also associated with an increase in pulmonary vascular resistance both before and after lung lavage (both p less than 0.005). Changes in frequency did not significantly alter CO or pulmonary vascular resistance. We conclude that the interaction between the heart and lungs during HFOV is largely mediated by Paw and compliance of the respiratory system. Furthermore, regardless of the degree of lung compliance, cardiac function may be impaired during HFOV as Paw is elevated.