Biomedical subjects

S M Scharf

Publications and source records attributed to S M Scharf.

At least 19 recordsLinked to original sources

PubMed2001

Renal effects of nitric oxide in endotoxemia.

Nitric oxide (NO) is postulated to play a key role in the pathophysiology of renal failure in sepsis. Whether the renal effects of increased NO are beneficial or harmful remains unclear. In a porcine model of lipopolysaccharide (LPS)-induced shock, we evaluated the effect of LPS on glomerular filtration rate (GFR) and renal blood flow (RBF). We then administered the nonselective nitric oxide synthase (NOS) inhibitor N(G)-L-arginine methyl ester (L-NAME), and compared its effects on GFR and RBF with those of S-methylisothiourea (SMT), a selective NOS inhibitor, and those of saline. We postulated that SMT, by maintaining constitutive NO, would be more beneficial than either L-NAME or saline. LPS infusion decreased mean arterial pressure (MAP), and increased cardiac output, RBF, and medullary NO content. The increased RBF was diverted to the medulla. There was no evidence of renal dysfunction in the saline-resuscitated group. Both NOS inhibitors increased MAP but decreased RBF, but only L-NAME reduced GFR and increased sodium excretion and renal oxygen extraction. We conclude that NO in endotoxemia is beneficial because it maintains RBF and GFR. Additionally, selective NOS inhibition did not offer any advantages over saline resuscitation.

Acute Kidney Injury↗

PubMed2000

Chronic-intermittent hypoxia induces immediate early gene expression in the midline thalamus and epithalamus.

Chronic-intermittent hypoxia (CIH) was postulated to activate thalamic regions that are synaptically related to autonomic-related areas of the cerebral cortex. Animals exposed to CIH for 30 days exhibited c-fos labeling in paraventricular thalamic and lateral habenular nuclei. Our findings strongly suggest activation of a diencephalic network that participates in behavioral responses to chronic stress.

Animals↗

PubMed2000

Immediate-early gene expression in cerebral cortex following exposure to chronic-intermittent hypoxia.

Chronic-intermittent hypoxia (CIH) was postulated to evoke c-fos expression in cortical regions that modulate sympathetic discharge. Animals exposed to CIH for 30 days exhibited c-fos labeling in medial prefrontal, cingulate, retrosplenial, and insular cortices. Our findings strongly suggest activation of cortical circuits that adaptively regulate sympathetic and cardiovascular activities.

Adaptation, Physiological↗

PubMed2000

Chronic-intermittent hypoxia: a model of sympathetic activation in the rat.

This review focuses upon the development of a small animal model that incorporates exposure to chronic-intermittent hypoxia to produce systemic hypertension similar to that experienced by humans with the obstructive sleep apnea syndrome. It has been suggested that experimentally-induced hypertension, like human hypertension, is due to activation of the sympathetic nervous system. That hypothesis is supported by physiological studies carried out in humans with obstructive sleep apnea as well as in animals exposed to chronic-intermittent hypoxia. Furthermore, recent anatomical studies of exposed animals strongly suggested that activation was widespread and included cortical and brainstem components of the sympathetic system. Such findings, while illustrating the complexity of modeling human disease in animals, also demonstrate the heuristic value of chronic-intermittent hypoxia as an experimental approach.

Animals↗

PubMed2000

Comparison between selective and nonselective nitric oxide synthase inhibition and phenylephrine in normal and endotoxic swine.

OBJECTIVE: To compare the cardiopulmonary and peripheral circulatory effects of the nonselective nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) to the more selective inducible NOS inhibitor S-methylisothiourea (SMT) and to phenylephrine (PE) in endotoxic and normal swine. DESIGN: Prospective, randomized, unblinded study. SETTING: Research laboratory of academic medical center. SUBJECTS: Nonanesthetized, sedated, mechanically ventilated, minimally invasive swine model. INTERVENTIONS: Animals received either lipopolysaccharide (LPS, LPS groups) or equivalent volume of saline (normal groups). LPS animals were further randomized into four groups when mean arterial pressure (MAP) had dropped to <60 mm Hg: the LPS/saline group received saline only; the other groups received either L-NAME, SMT, or PE. These were titrated to elevate MAP by 20-25 mm Hg, and animals were followed for another 3 hrs. Pulmonary artery occlusion pressure was maintained at one to two times baseline with the infusion of saline. Normal groups received the same agents 1 hr after baseline measurements, and drugs were titrated to achieve similar increases in MAP. We measured gastric-arterial PCO2 gradient by tonometry as an index of gastric mucosal perfusion. Left ventricular volumes were determined echocardiographically; right ventricular volumes were determined by a pulmonary arterial catheter equipped with a rapid thermistor. Plasma nitrite/nitrate (NOx) concentrations were measured hourly. MEASUREMENTS AND MAIN RESULTS: In the LPS groups, all agents elevated MAP and systemic vascular resistance similarly. By hr 4, cardiac output had decreased in all groups, but the decrease with L-NAME (35% +/- 16%) occurred earlier (at hr 3) and was larger than the decrease with SMT at hrs 3 and 5 and larger than the decrease with saline at hrs 3 to 5. L-NAME resulted in a larger increase in mean pulmonary arterial pressure (MPAP) when compared with saline (130% +/- 44% vs. 61% +/- 25%; p < .001) and SMT groups (130% vs. 97% +/- 80%; p < .007). Only L-NAME had detrimental effects on right ventricular function as indicated by an increase in right ventricular end-systolic volume (54 +/- 10 to 87 +/-6 mL; p < .05) and right ventricular end-diastolic volume (90 +/-11 to 128 +/- 18 mL; p < .05). SMT decreased both left ventricular end-systolic volume (10.4 +/- 2 to 7.7 +/- 4 mL; p < .05) and left ventricular end-diastolic volume (18.5 +/- 3 to 14.2 +/- 5 mL; p < .05), indicating improved left ventricular function, whereas L-NAME did not affect left ventricular volumes. Both SMT and PE corrected LPS-induced gastric mucosal acidosis, but L-NAME did not. We did not detect changes in plasma NOx concentrations in any of LPS groups. In the normal groups, all agents increased MAP without changes in plasma NOx concentrations. L-NAME caused a larger decrease in cardiac output, but the increase in MPAP was higher with SMT. Both NOS inhibitors led to left ventricular dilation, but PE did not. Only L-NAME caused right ventricular dilation. There were no changes in gastric-arterial PCO2 gradient. CONCLUSIONS: In LPS animals, we failed to detect changes in plasma NOx concentrations. Furthermore, for similar increases in MAP, SMT improved gastric mucosal acidosis, had less adverse effects on right ventricular function and MPAP, and may have improved left ventricular function. However, apart from its bene-ficial effects on left ventricular function, SMT was not superior to PE. The results from normal animals indicate that both NOS inhibitors have adverse effects on cardiac function beyond those attributed to increased MAP.

Animals↗

PubMed2000

Hemodynamic effects of periodic obstructive apneas in sedated pigs with congestive heart failure.

Because of similar physiological changes such as increased left ventricular (LV) afterload and sympathetic tone, an exaggerated depression in cardiac output (CO) could be expected in patients with coexisting obstructive sleep apnea and congestive heart failure (CHF). To determine cardiovascular effects and mechanisms of periodic obstructive apnea in the presence of CHF, 11 sedated and chronically instrumented pigs with CHF (rapid pacing) were tested with upper airway occlusion under room air breathing (RA), O(2) breathing (O2), and room air breathing after hexamethonium (Hex). All conditions led to large negative swings in intrathoracic pressure (-30 to -39 Torr) and hypercapnia (PCO(2) approximately 60 Torr), and RA and Hex also caused hypoxia (to approximately 42 Torr). Relative to baseline, RA increased mean arterial pressure (from 97.5 +/- 5.0 to 107.3 +/- 5.7 Torr, P < 0.01), systemic vascular resistance, LV end-diastolic pressure, and LV end-systolic length while it decreased CO (from 2.17 +/- 0.27 to 1.52 +/- 0.31 l/min, P < 0.01), stroke volume (SV; from 23.5 +/- 2.4 to 16.0 +/- 4.0 ml, P < 0.01), and LV end-diastolic length (LVEDL). O2 and Hex decreased mean arterial pressure [from 102.3 +/- 4.1 to 16.0 +/- 4.0 Torr (P < 0.01) with O2 and from 86.0 +/- 8.5 to 78.1 +/- 8.7 Torr (P < 0.05) with Hex] and blunted the reduction in CO [from 2.09 +/- 0.15 to 1.78 +/- 0.18 l/ml for O2 and from 2.91 +/- 0.43 to 2.50 +/- 0.35 l/ml for Hex (both P < 0.05)] and SV. However, the reduction in LVEDL and LV end-diastolic pressure was the same as with RA. There was no change in systemic vascular resistance and LVEDL during O2 and Hex relative to baseline. In the CHF pigs during apnea, there was an exaggerated reduction in CO and SV relative to our previously published data from normal sedated pigs under similar conditions. The primary difference between CHF (present study) and the normal animals is that, in addition to increased LV afterload, there was a decrease in LV preload in CHF contributing to SV depression not seen in normal animals. The decrease in LV preload during apneas in CHF may be related to effects of ventricular interdependence.

Animals↗

PubMed2000

Effects of aortic nerve on hemodynamic response to obstructive apnea in sedated pigs.

In this study we test the hypothesis that aortic nerve traffic is responsible for the pressor response to periodic apneas. In nine intubated, sedated chronically instrumented pigs, periodic obstructive apneas were caused by occlusion of the endotracheal tube for 30 s, followed by spontaneous breathing for 30 s. This was done under control (C) conditions, after section of the aortic nerve (ANS), and after bilateral cervical vagotomy (Vagot). Blood-gas tensions and airway pressure changed similarly under all conditions: PO(2) decreased to 50-60 Torr, PCO(2) increased to approximately 55 Torr, and airway pressure decreased by 40-50 mmHg during apnea. With C, mean arterial pressure (MAP) increased from 111 +/- 4 mmHg at baseline to 120 +/- 5 mmHg at late apnea (P < 0.01). After ANS and Vagot, there was no change in MAP with apneas compared with baseline. Relative to baseline, cardiac output and stroke volume decreased with C but not with ANS or Vagot during apneas. Increased MAP was due to increased systemic vascular resistance. Heart rate behaved similarly with C and ANS, being greater at early interapnea than late apnea. With Vagot, heart rate increased throughout the apnea-interapnea cycle relative to baseline. We conclude that, in sedated pigs, aortic nerve traffic mediates the increase in MAP and systemic vascular resistance observed during periodic apneas. Increase in MAP is responsible for decreased cardiac output and stroke volume. Additional vagal reflexes, most likely parasympathetic efferents, are responsible for interacting with sympathetic excitatory influences in modulating heart rate.

Animals↗

PubMed2000

Selective NOS inhibition restores myocardial contractility in endotoxemic rats; however, myocardial NO content does not correlate with myocardial dysfunction.

The role of nitric oxide (NO) in lipopolysaccharide (LPS)-induced myocardial dysfunction remains controversial as some investigators concluded that inhibition of NO synthesis improves left ventricular (LV) contractility, whereas others did not. We investigated the relationship between LPS-induced LV dysfunction and LV NO production. We postulated that high myocardial NO concentrations would correspond to decreased contractility and low NO concentrations would correspond to recovery. In a rat model of endotoxemia, we used the isolated papillary preparation to assess inotropic dysfunction. We measured LV NO content and hemodynamics at baseline, 4, 16, and 48 h after LPS administration. LPS caused a decrease in LV contractility at 16 h with recovery at 48 h. Myocardial NO levels were elevated at all time periods. However, at 48 h in spite of normalization of LV contractility, myocardial NO content remained elevated. Pretreatment of LPS animals with the nonselective nitric oxide synthase (NOS) inhibitor N (G)-nitro-L-arginine methyl ester (L-NAME) worsened LV contractility, decreased LV NO content, and increased mortality. However, pretreatment with the relatively selective inducible NOS (iNOS) inhibitor S-methylisothiourea sulfate (SMT) restored LV contractility. Myocardial NO content in the SMT was lower than that of the LPS only group, but higher than the L-NAME group. We conclude that SMT is beneficial to myocardial contractility in this model of endotoxemia, whereas pretreatment with L-NAME is associated with further deterioration of contractility and increased mortality. Moreover, our data indicate that high myocardial NO concentrations do not necessarily correlate with decreased contractility.

Animals↗

PubMed1999

Expression of c-fos in the rat brainstem after chronic intermittent hypoxia.

Chronic intermittent hypoxia (CIH) may cause sustained systemic hypertension by increasing sympathetic neural discharge (SND). We hypothesized that CIH alters brainstem circuits modulating SND. After 30 days of CIH exposure in rats, increased c-fos labeling was seen in the nucleus of the solitary tract and ventrolateral medulla as well as other brainstem regions involved in regulation of SND. Increased expression of c-fos after CIH may indicate changes in neuronal genetic transcription which ultimately modulate SND.

Animals↗

PubMed1999

Chronic intermittent hypoxia increases sympathetic responsiveness to hypoxia and hypercapnia.

We sought to determine whether chronic exposure to intermittent hypoxia (CIH) increases sympathetic responsiveness to subsequent chemoreflex stimulation. Sprague-Dawley rats were exposed to 30 days of CIH: exposure chamber %O2 [fractional concentration of chamber O2 (FcO2)] nadir 6.5-7% with return to 21% each minute for 8 h/day during the diurnal sleep period (Exp group). Sham controls (SC group) were similarly handled but kept at 21% FcO2 and compared with unhandled controls (UC group). Rats were then anesthetized with urethan, and preganglionic cervical sympathetic activity (CSA), diaphragm electromyogram, arterial pressure, and electrocardiogram were recorded while the rats were spontaneously breathing 100% O2, room air, 10% O2, 12% CO2, and 10% O2-12% CO2. CSA and heart rate were also recorded during phenylephrine infusion to assess baroreceptor function. Mean arterial pressure was significantly greater in Exp than in SC and UC rats during all conditions (P < 0. 05). A vasopressor response to 10% O2-12% CO2 was observed only in Exp rats. CSA was greater in Exp than in SC and UC rats during 10% O2, 12% CO2, and 10% O2-12% CO2 but not during room-air exposure. A significant increase in CSA compared with room air was noted during 10% O2, 12% CO2, and 10% O2-12% CO2 in Exp but not in SC or UC rats. No differences in baroreceptor function were observed among groups. We conclude that CIH leads to increased sympathetic responsiveness to chemoreflex stimulation.

Animals↗

PubMed1999

Mechanisms of acute cardiovascular response to periodic apneas in sedated pigs.

This study was designed to evaluate the importance of sympathoadrenal activation in the acute cardiovascular response to apneas and the role of hypoxemia in this response. In addition, we evaluated the contribution of the vagus nerve to apnea responses after chemical sympathectomy. In six pigs preinstrumented with an electromagnetic flow probe and five nonpreinstrumented pigs, effects of periodic nonobstructive apneas were tested under the following six conditions: room air breathing, 100% O2 supplementation, both repeated after administration of hexamethonium (Hex), and both repeated again after bilateral vagotomy in addition to Hex. With room air apneas, during the apnea cycle, there were increases in mean arterial pressure (MAP; from baseline of 108 +/- 4 to 124 +/- 6 Torr, P < 0.01), plasma norepinephrine (from 681 +/- 99 to 1,825 +/- 578 pg/ml, P < 0.05), and epinephrine (from 191 +/- 67 to 1,245 +/- 685 pg/ml, P < 0.05) but decreases in cardiac output (CO; from 3.3 +/- 0.6 to 2.4 +/- 0.3 l/min, P < 0.01) and cervical sympathetic nerve activity. With O2 supplementation relative to baseline, apneas were associated with small increases in MAP (from 112 +/- 4 to 118 +/- 3 Torr, P < 0.01) and norepinephrine (from 675 +/- 97 to 861 +/- 170 pg/ml, P < 0.05). After Hex, apneas with room air were associated with small increases in MAP (from 103 +/- 6 to 109 +/- 6 Torr, P < 0.05) and epinephrine (from 136 +/- 45 to 666 +/- 467 pg/ml, P < 0.05) and decreases in CO (from 3.6 +/- 0.4 to 3.2 +/- 0. 5 l/min, P < 0.05). After Hex, apneas with O2 supplementation were associated with decreased MAP (from 107 +/- 5 to 100 +/- 5 Torr, P < 0.05) and no other changes. After vagotomy + Hex, with room air and O2 supplementation, apneas were associated with decreased MAP (from 98 +/- 6 to 76 +/- 7 and from 103 +/- 7 to 95 +/- 6 Torr, respectively, both P < 0.01) but increased CO [from 2.7 +/- 0.3 to 3. 2 +/- 0.4 l/min (P < 0.05) and from 2.4 +/- 0.2 to 2.7 +/- 0.2 l/min (P < 0.01), respectively]. We conclude that sympathoadrenal activation is the major pressor mechanism during apneas. Cervical sympathetic nerve activity does not reflect overall sympathoadrenal activity during apneas. Hypoxemia is an important but not the sole trigger factor for sympathoadrenal activation. There is an important vagally mediated reflex that contributes to the pressor response to apneas.

Anesthesia↗

PubMed1999

Effects of vagotomy on cardiovascular response to periodic apneas in sedated pigs.

There are few studies investigating the influence of vagally mediated reflexes on the cardiovascular response to apneas. In 12 sedated preinstrumented pigs, we studied the effects of vagotomy during apneas, controlling for apnea periodicity and thoracic mechanical effects. Nonobstructive apneas were produced by paralyzing and mechanically ventilating the animals, then turning the ventilator off and on every 30 s. Before vagotomy, relative to baseline, apnea caused increased mean arterial pressure (MAP; +19 +/- 25%, P < 0.05), systemic vascular resistance (SVR; +33 +/- 16%, P < 0.0005), and heart rate (HR; +5 +/- 6%, P < 0.05) and decreased cardiac output (CO) and stroke volume (SV; -16 +/- 10% P < 0.001). After vagotomy, no significant change occurred in MAP, SVR, and SV during apneas, but CO and HR increased relative to baseline. HR was always greater ( approximately 14%, P < 0.01) during the interapneic interval compared with during apnea. We conclude that vagally mediated reflexes are important mediators of the apneic pressor response. HR increases after apnea termination are related, at least in part, to nonvagally mediated reflexes.

Animals↗

PubMed1999

Development of pulmonary hypertension after lung volume reduction surgery.

This prospective, longitudinal study was designed to assess the hemodynamic changes occurring in patients who undergo lung volume reduction surgery (LVRS). Patients with emphysema treated with LVRS underwent hemodynamic evaluation before and after surgery. The study group consisted of nine patients with an average age of 64.4 yr. FEV1 rose significantly from 0.64 preoperatively to 0.99 L postoperatively. After surgery, pulmonary artery (PA) systolic pressure rose to 47.9 +/- 12.4 mm Hg, meeting criteria for development of pulmonary hypertension. In six patients, the elevation in PA pressure was attributed to an increase in the pulmonary vascular resistance, but for all nine patients the change was not statistically significant. The pulmonary artery occulsion pressure (PAOP) did not change postoperatively. There was no correlation of PAOP with global left ventricular ejection fraction. While preoperatively there was a negative correlation between symptoms (Mahler dyspnea index) and PA pressure, after surgery the change in PA pressures did not correlate with the change in symptoms (Mahler transitional dyspnea index). We concluded that development of pulmonary hypertension may occur after LVRS in patients whose symptomatic status improves and in whom this condition was not present preoperatively.

Aged↗

PubMed1999

Clinical conference on management dilemmas: obstructive sleep apnea and respiratory failure.

Explore the source record for details and available documents.

Aged↗

PubMed1999

Development of a giant bulla after lung volume reduction surgery.

Lung volume reduction surgery (LVRS) is being evaluated in the treatment of emphysema. The proposed mechanisms of improvement are increased elastic recoil of the lung and improved mechanical efficiency of the muscles of respiration. We report a unique patient with emphysema who developed a giant bulla 3 years subsequent to LVRS. The patient underwent extensive evaluation, including measurements of lung mechanics. Bullectomy was performed, but it was unsuccessful. Although the mechanisms behind the development of giant bullous disease remain speculative, heterogeneous improvement in elastic recoil following LVRS may be one of the responsible mechanisms.

Fatal Outcome↗

PubMed1998

Changes in pulmonary mechanics after lung volume reduction surgery.

Lung volume reduction surgery (LVRS) is a promising new treatment for emphysema and leads to increased flow rates. We investigated the mechanisms by which flow rates could increase and the correlates of lessened dyspnea in patients undergoing LVRS before and 3 months after LVRS in patients with severe emphysema. The following were done: routine pulmonary function testing, measurements of elastic recoil (Pel), tidal breathing patterns, inspiratory work of breathing (Winsp), construction of static recoil-maximum flow curves, and measurement of baseline and transitional dyspnea index (TDI). There were increases in forced vital capacity (FVC: 2.24 +/- 0.71 to 2.92 +/- 0.63 liters; p < 0.05), forced expired volume in 1 (FEV1: 0.64 +/- .16 to 1.03 +/- 0.28 liters; p < 0.01), and decreases in all divisions of lung volume, e.g. total lung capacity (TLC: 6.86 +/- 1.41 to 5.96 +/- 1.49 liters; p < 0.01). Maximum Pel increased (11.7 +/- 3.7 to 19.8 +/- 7.8 cmH2O; p < 0.02) as did the coefficient of retraction (CR = Pel/TLC: 1.8 +/- 0.7 to 3.6 +/- 3.6 +/- 2.2 cmH2O/liter). However, the individual responses in other parameters were markedly different among patients. There was no consistent trend in changes in the slope or position of the static recoil-maximum flow curve or Winsp. The only positive correlate of improved dyspnea (TDI = 3.22 +/- 2.22; p < 0.01) was improvement in CR, FEV1 being a weak negative correlate and change in lung volume not being a correlate at all. We conclude that there is a heterogeneous response of the airways to LVRS. Increased elastic recoil was the primary determinant of improved flow rates after LVRS and is the only positive correlate for improvement in dyspnea.

Aged↗

PubMed1998

Role of hypoxemia and hypercapnia in acute cardiovascular response to periodic apneas in sedated pigs.

The effects of hypoxemia and hypercapnia in acute cardiovascular response to periodic non-obstructive apneas were explored in seven preinstrumented, sedated paralyzed and ventilated pigs under three conditions: room air breathing (RA), O2 supplementation (O2), and supplementation with O2 and CO2 (CO2). EEG monitoring showed no arousal under any conditions. RA apneas increased mean arterial pressure (MAP, from baseline 95.9 +/- 4.5 to late apnea 124.4 +/- 7.8 Torr, P < 0.01), left ventricular end-diastolic pressure, end-diastolic and end-systolic myocardial fiber lengths and systemic vascular resistance, but decreased cardiac output (CO, 3.09 +/- 0.34-2.37 +/- 0.26 L/min, P < 0.01), heart rate (HR, 115.1 +/- 7.5-102.0 +/- 7.8 bpm, P < 0.01), and stroke volume (SV, 29.6 +/- 0.7 21.1 +/- 1.8 ml, P < 0.01). 02 apneas produced similar decreases in HR (114.0 +/- 11.8-105.4 +/- 8.7 bpm, P < 0.05) as with RA apneas, but smaller increases in MAP (94.5 +/- 1.8-103.4 +/- 2.8 Torr, P < 0.01) and in the variables of pre- and after-load. CO and SV remained unchanged with O2 apneas. CO2 was associated with higher MAP, CO, and HR at baseline relative to RA, but similar cardiovascular response during apneas in direction and magnitude to those of O2 apneas. We conclude that in this model hypoxemia is a major but not the sole determinant of the pressor response during apneas. Hypercapnia cannot explain the pressor response seen when hypoxemia is abolished. The HR fall during apneas is independent of hypoxemia, hypercapnia and the pressor response.

Acute Disease↗

PubMed1998

Right ventricular overload causes the decrease in cardiac output after nitric oxide synthesis inhibition in endotoxemia.

OBJECTIVE: To determine whether the decrease in cardiac output after nitric oxide synthase inhibition in endotoxemia is due to increased left ventricular afterload or right ventricular afterload. DESIGN: Prospective, randomized, unblinded study. SETTING: Research laboratory at an academic, university medical center. SUBJECTS: Nonanesthetized, sedated, mechanically ventilated pigs. INTERVENTIONS: Pigs were infused with 250 microg/kg of endotoxin over 30 mins. Normal saline was infused to maintain pulmonary artery occlusion pressure (PAOP) at a value not exceeding 1.5 times the baseline value. Left ventricular dimensions and function were studied using echocardiography. Right ventricular volumes and ejection fraction were determined via a rapid thermistor pulmonary artery catheter. We also measured mean arterial pressure (MAP), cardiac output, pulmonary arterial pressure, and calculated pulmonary and systemic resistances. Gastric tonometry was used as an index of gastric mucosal oxygenation and peripheral oxygenation. When MAP had decreased to < or =60 mm Hg or had decreased 30 mm Hg from baseline, nine animals received NG-nitro-L-arginine methyl ester (L-NAME) at 15 mg/kg to restore MAP to baseline. A second group of animals (n = 6) continued to receive normal saline, ensuring that PAOP did not exceed 1.5 times its baseline value. A third group of pigs (n = 5) did not receive endotoxin and served as the time control. In this group, a balloon was used to occlude the descending thoracic aorta and to increase MAP by approximately the same amount as in the L-NAME group. MEASUREMENTS AND MAIN RESULTS: Endotoxin caused an increase in pulmonary arterial pressure and right ventricular volumes, and a decrease in gastric mucosal pH. Cardiac output was maintained in the animals receiving the saline infusion. By 2 hrs, pulmonary arterial pressure had decreased but was still notably higher than baseline. However, by this time, MAP had decreased to < or =60 mm Hg. L-NAME administration restored MAP to its baseline value but resulted in worsening pulmonary hypertension, increased right ventricular volumes, and decreased cardiac output, compared with the saline group. Three animals that received L-NAME died of right ventricular failure. We did not observe any evidence of left ventricular dysfunction with increased left ventricular afterload. Moreover, the restoration of MAP with L-NAME infusion did not correct gastric mucosal acidosis. No changes were noted in the time-control group. Occlusion of the thoracic aorta increased MAP but did not change cardiac output. This finding demonstrates that increases in left ventricular afterload of the magnitude seen with the infusion of L-NAME do not lead to decreases in cardiac output. CONCLUSION: The decrease in cardiac output after nitric oxide synthase inhibition in endotoxemia is due to increased right ventricular afterload and not to left ventricular afterload.

Animals↗