Paradoxical hypertension after reversal of heart failure in patients treated with intensive vasodilator therapy

Hypertension is a major cause of heart failure, evolving from left ventricular hypertrophy to systolic and diastolic dysfunction. Although effective heart failure therapy has been associated with a lowering or no change in systemic arterial blood pressure in long-term follow-up, this study describes the symptomatic, clinical, and left ventricular functional response of a subgroup of heart failure patients with a prior history of hypertension who demonstrated a paradoxical hypertensive response despite high-dose vasodilator therapy. We prospectively identified 45 patients with a past history of hypertension who had become normotensive with symptomatic heart failure. Of these 45 heart failure patients, 12 became hypertensive while receiving therapy in follow-up, with systolic blood pressure > or = 140 mm Hg (Group A). The remaining 33 patients did not have a hypertensive response to therapy (Group B). In the 12 Group A patients, 60+/-10 years old, with symptomatic heart failure for 6.3+/-4.3 years, vasodilator therapy was intensified in the 2.0+/-0.5 years of follow-up, achieving final doses of enalapril 78+/-19 mg and isosorbide dinitrate 293 +/-106 mg per day. New York Heart Association classification improved from 2.9+/-0.8 to 1.3+/-0.5 (P < or = .0001), with a reduction in heart-failure-related hospitalizations. Left ventricular ejection fraction increased from 17+/-6% to 40+/-10% (P < .0001). Follow-up blood pressure at 1 to 3 months was unchanged. However, both systolic and diastolic blood pressure increased at final follow-up, rising from 116+/-14 to 154+/-13 mm Hg (P = .0001) and from 71+/-9 to 85+/-14 mm Hg (P = .004), respectively. Renal function remained unchanged. Although both groups had similar clinical responses, there were more blacks and women in the hypertensive Group A. Effectively, 12 of 45 (27%) heart failure patients with an antecedent history of hypertension demonstrated a paradoxical hypertensive response to vasodilator therapy. The recurrence of hypertension in a significant portion of patients successfully treated for heart failure has important clinical implications.     

Endothelin-1 receptor antagonism does not influence myocardial function in hypertensive dogs

BACKGROUND: As endothelin-1 exerts positive inotropic effects, the present study evaluated whether the hypotensive effects of the endothelin-1 receptor antagonist bosentan were partially related to a decrease in myocardial performance. METHODS: In group I, eight anaesthetized open-chest dogs with perinephritic hypertension received four cumulative doses of bosentan (B1-B4). In group II, eight animals received the same doses of bosentan after autonomic blockade. Indices of heart function were derived from the pressure-length loops obtained during vena cava occlusion. RESULTS: In group I, bosentan decreased left ventricular systolic pressure (LVSP) and mean aortic pressure (MAP) dose dependently, reaching 21% and 23% respectively at B4 (LVSP from 190 +/- 8 to 150 +/- 5 mmHg, P < 0.001; MAP from 167 +/- 7 to 128 +/- 5 mmHg, P < 0.001). These effects were only related to peripheral vasodilatation, without depression of myocardial contractility, as systemic vascular resistance dropped (from 670 +/- 83 to 446 +/- 53 mmHg mL-1 min-1 x 10(4); P < 0.05), and the end-systolic pressure-length relationship (ESPLR) remained unchanged (4.0 +/- 0.4 vs. 4.3 +/- 0.7 mmHg mm-1 kg-1). Concomitantly with pressure decline, heart rate tended to increase in this group (from 150 +/- 4 to 156 +/- 6 beats min-1). When autonomic system was blocked (group II), administration of bosentan induced similar hypotensive effects as in group I (26% and 28% reduction in LVSP and MAP respectively, P < 0.001) whereas ESPLR did not change (3.0 +/- 0.9 vs. 3.1 +/- 0.5mmHg-1 mm kg-1 ). Under these sympathetically blocked conditions, heart rate significantly fell after bosentan infusion (from 120 +/- 4 to 110 +/- 6 beats min-1, P < 0.001). CONCLUSIONS: Without influencing heart function, bosentan is an efficient and safe therapy that opens up new therapeutic perspectives in human essential hypertension.     

Acute cardiovascular effects of insulin-like growth factor I in patients with chronic heart failure

Insulin-like growth factor I (IGF-I) enhances myofibrillar development in cardiomyocytes of rats in culture and in vivo. In addition, IGF-I has vasodilatory effects and improves cardiac function in healthy volunteers. This study was conducted to evaluate the acute hemodynamic effects of IGF-I in patients with chronic heart failure Eight patients with chronic heart failure were randomized to receive recombinant human IGF-I (60 micrograms/kg) or placebo, i.v., over 4 h in a cross-over, double blind study on 2 consecutive days. Electrocardiogram as well as systemic hemodynamics were continuously monitored over 7 h by flow-guided thermodilution and radial artery catheters. IGF-I was well tolerated by all patients, and no pathological changes on electrocardiogram were recorded. Compared with placebo, IGF-I increased the cardiac index by 27 +/- 3.7% (+/- SE; P < 0.0005) and the stroke volume index by 21 +/- 5.6% (P < 0.05), and decreased systemic vascular resistance by 28 +/- 4.4% (P < 0.0002), right atrial pressure by 33 +/- 9.0% (P < 0.003), and pulmonary artery wedge pressure by 25 +/- 6.1% (P < 0.03). Mean systemic and pulmonary artery pressure as well as heart rate and pulmonary vascular resistance were not significantly influenced by IGF-I treatment. Insulin and C peptide levels were decreased by IGF-I, whereas glucose and electrolyte levels remained unchanged. Urinary levels of norepinephrine decreased significantly (P < 0.05) during IGF-I infusion. Thus, acute administration of IGF-I in patients with chronic heart failure is safe and improves cardiac performance by afterload reduction and possibly by positive inotropic effects. Further investigations to establish whether the observed acute effects of IGF-I are maintained during chronic therapy appear to be warranted.     

Nitric oxide-endothelin-1 interaction in humans

Healthy men received NG-monomethyl-L-arginine (L-NMMA) intravenously to study cardiovascular and metabolic effects of nitric oxide synthase blockade and whether this alters the response to endothelin-1 (ET-1) infusion. Controls only received ET-1. L-NMMA effects were that heart rate (17%) cardiac output (17%), and splanchnic and renal blood flow (both 33%) fell promptly (all P < 0.01). Mean arterial blood pressure (6%), and systemic (28%) and pulmonary (40%) vascular resistance increased (P < 0.05 to 0.001). Arterial ET-1 levels (21%) increased due to a pulmonary net ET-1 release (P < 0.05 to 0.01). Splanchnic glucose output (SGO) fell (26%, P < 0.01). Arterial insulin and glucagon were unchanged. Subsequent ET-1 infusion caused no change in mean arterial pressure, heart rate, or cardiac output, as found in the present controls, or in splanchnic and renal blood flow or splanchnic glucose output as previously found with ET-1 (G. Ahlborg, E. Weitzberg, and J. M. Lundberg. J. Appl. Physiol. 79: 141-145, 1995). In conclusion, L-NMMA like ET-1, induces prolonged cardiovascular effects and suppresses SGO. L-NMMA causes pulmonary ET-1 release and blocks responses to ET-1 infusion. The results indicate that nitric oxide inhibits ET-1 production and thereby interacts with ET-1 regarding increase in vascular tone and reduction of SGO in humans.     

Reduced pulmonary clearance of endothelin-1 contributes to the increase of circulating levels in heart failure secondary to myocardial infarction

BACKGROUND: The pulmonary vascular bed is a major site for endothelin-1 (ET-1) clearance. A reduced clearance could contribute to the increase in circulating ET-1 levels found in heart failure (HF). We therefore evaluated the effect of HF on pulmonary ET-1 clearance and on plasma ET-1 concentrations. METHODS AND RESULTS: Rats with myocardial infarction (n=24) were compared with sham-operated rats (n=22). The lungs were isolated and perfused at a constant flow rate of 10 mL/min. Pulmonary ET-1 clearance was measured by the single-bolus indicator-dilution technique with 125I-labeled ET-1. Infarct rats developed HF with mild pulmonary hypertension. ET-1 extraction was reduced by HF from 63+/-1.5% to 41+/-4.5% (mean+/-SEM, P<0.001). Mixed venous (MV) and aortic ET-1 levels doubled with HF. There was a plasma ET-1 gradient across the lungs of sham rats (MV-aortic levels, 0.21+/-0.12 pg/mL) but not in lungs of HF rats (0.01+/-0.17 pg/mL). Plasma ET-1 levels correlated closely and inversely with ET-1 extraction (P<0.001). CONCLUSIONS: HF is associated with reduced pulmonary ET-1 clearance that contributes to the increase in circulating levels.     

Role of endogenous endothelin in the development of graft arteriosclerosis in rat cardiac allografts: antiproliferative effects of bosentan, a nonselective endothelin receptor antagonist

BACKGROUND: The purpose of this study was to determine whether endothelin-1 (ET-1) contributes to the development of graft arteriosclerosis and whether the orally active nonpeptide endothelin receptor antagonist bosentan, which blocks both ETA and ETB receptors, can protect against this pathologic damage. METHODS AND RESULTS: Recipient male Lewis rats were divided into three groups; group 1 received heterotopic heart transplantations from Lewis donors and groups 2 and 3 received transplantations from Brown-Norway donors; group 3 recipients also received bosentan orally at the dose of 20 mg/kg per day for 120 days. All recipients were given cyclosporine and were euthanized at examination 120 days after transplantation. Plasma ET-1 levels were significantly higher in group 2 than in group 1 (6.99+/-0.91 and 4.15+/-.83 pg/mL, respectively). Strong ET-1 immunoreactivity was seen in both the thickened neointima and the media of the coronary arteries in group 2 but not in group 1. The mean ratio of the coronary luminal area to the total vascular area in group 2 (19.0+/-11.7%) was significantly lower than that in group 1 (34.2+/-9.9%) and was significantly increased in group 3 (33.2+/-9.2%). CONCLUSIONS: These results show that local upregulation of ET-1, mainly in the thickened neointima and the media of the coronary arteries, may play an important role in the pathogenesis of graft arteriosclerosis by stimulating ETA receptors, ETB receptors, or both. Orally active bosentan might be a useful agent for the clinical prevention of graft arteriosclerosis.     

Hepatic blood flow and splanchnic oxygen consumption in patients with liver failure. Effect of high-volume plasmapheresis

Liver failure represents a major therapeutic challenge, and yet basic pathophysiological questions about hepatic perfusion and oxygenation in this condition have been poorly investigated. In this study, hepatic blood flow (HBF) and splanchnic oxygen delivery (DO2, sp) and oxygen consumption (VO2,sp) were assessed in patients with liver failure defined as hepatic encephalopathy grade II or more. Measurements were repeated after high-volume plasmapheresis (HVP) with exchange of 8 to 10 L of plasma. HBF was estimated by use of constant infusion of D-sorbitol and calculated according to Fick's principle from peripheral artery and hepatic vein concentrations. In 14 patients with acute liver failure (ALF), HBF (1.78 +/- 0.78 L/min) and VO2,sp (3.9 +/- 0.9 mmol/min) were higher than in 11 patients without liver disease (1.07 +/- 0.19 L/min, P <.01) and (2.3 +/- 0.7 mmol/min, P <.001). In 9 patients with acute on chronic liver disease (AOCLD), HBF (1.96 +/- 1.19 L/min) and VO2,sp (3.9 +/- 2.3 mmol/min) were higher than in 18 patients with stable cirrhosis (1.00 +/- 0.36 L/min, P <.005; and 2.0 +/- 0.6 mmol/min, P <.005). During HVP, HBF increased from 1.67 +/- 0.72 to 2.07 +/- 1.11 L/min (n=11) in ALF, and from 1.89 +/- 1.32 to 2.34 +/- 1.54 L/min (n=7) in AOCLD, P <.05 in both cases. In patients with ALF, cardiac output (thermodilution) was unchanged (6.7 +/- 2.5 vs. 6.6 +/- 2.2 L/min, NS) during HVP. Blood flow was redirected to the liver as the systemic vascular resistance index increased (1,587 +/- 650 vs. 2, 020 +/- 806 Dyne. s. cm-5. m2, P <.01) whereas splanchnic vascular resistance was unchanged. In AOCLD, neither systemic nor splanchnic vascular resistance was affected by HVP, but as cardiac output increased from 9.1 +/- 2.8 to 10.1 +/- 2.9 L/min (P <.01) more blood was directed to the splanchnic region. In all liver failure patients treated with HVP (n=18), DO2,sp increased by 15% (P <.05) whereas VO2,sp was unchanged. Endothelin-1 (ET-1) and ET-3 were determined before and after HVP. Changes of ET-1 were positively correlated with changes in HBF (P <.005) and VO2,sp (P <.05), indicating a role for ET-1 in splanchnic circulation and oxygenation. ET-3 was negatively correlated with systemic vascular resistance index before HVP (P <.05) but changes during HVP did not correlate. Our data suggest that liver failure is associated with increased HBF and VO2, sp. HVP further increased HBF and DO2,sp but VO2,sp was unchanged, indicating that splanchnic hypoxia was not present.     

Safety and efficacy of epoprostenol in patients with severe congestive heart failure. Epoprostenol Multicenter Research Group

Patients with advanced heart failure often remain severely symptomatic and have a high mortality rate despite currently available therapy. We studied the safety and efficacy of a new approach to the patient with refractory heart failure: continuous intravenous treatment via a portable infusion pump with epoprostenol (prostacyclin), a potent pulmonary and systemic vasodilator. A group of 33 patients with severe heart failure (64% New York Heart Association class IV and 36% class III) and profound ventricular dysfunction (median left ventricular ejection fraction, 0.15)--despite prior treatment with diuretics (100%), digitalis (91%), angiotensin-converting enzyme inhibitors (85%), and dobutamine (30%)--underwent a baseline 6-minute walk test prior to dose titration with epoprostenol during invasive hemodynamic monitoring. Subjects responding during the dose titration were randomized, on an open basis, to receive either continuous epoprostenol infusion via an indwelling central venous catheter plus conventional therapy or conventional therapy alone for 12 weeks. The initial dose-ranging study with epoprostenol produced a significant decline in systemic and pulmonary vascular resistance and a substantial increase in cardiac index despite a fall in pulmonary capillary wedge pressure. Symptoms related to vasodilation were noted within the first week after randomization to epoprostenol in 9 of 16 patients but resolved with adjustment of the infusion and concomitant medications in all but one subject. Dose adjustments during the chronic epoprostenol infusion were infrequent after the first week and complications related to the drug delivery system were rare. The change in distance walked from baseline to the last available 6-minute walk test was significantly greater in patients who received epoprostenol compared with patients assigned to standard therapy (72 +/- 40 vs -39 +/- 32 m, mean +/- SEM; p = 0.033). Our study suggests that long-term intravenous infusion of epoprostenol is feasible in patients with severe heart failure and our hemodynamic and functional results suggest clinical benefit as well. However, until recent results indicating an adverse effect of epoprostenol on survival are fully evaluated, the role of this drug in the treatment of advanced heart failure will remain uncertain.     

Effects of intravenous milrinone followed by titration of high-dose oral vasodilator therapy on clinical outcome and rehospitalization rates in patients with severe heart failure

This study evaluated the efficacy of intravenous milrinone in improving hemodynamics and facilitating the titration of high-dose oral vasodilator therapy to improve clinical status. Fourteen patients (mean age 52 +/- 12 years) with severe heart failure and a left ventricular ejection fraction of 18 +/- 6% underwent right-side heart catheterization and an intravenous milrinone infusion followed by titration of oral vasodilator and diuretic therapy. Milrinone significantly (p <0.05) improved right atrial pressure (12 +/- 5 to 8 +/- 5 mm Hg), pulmonary capillary wedge pressure (23 +/- 7 to 15 +/- 7 mm Hg), cardiac index (1.9 +/- 0.4 to 3.4 +/- 0.5 L/min/m2), systemic vascular resistance (1,809 +/- 526 to 891 +/- 144 dynes/s/cm(-5)), and pulmonary vascular resistance (285 +/- 151 to 163 +/- 68 dynes/s/cm(-5)), which was maintained in 10 patients with titration of high-dose oral vasodilator therapy. Oral angiotensin-converting enzyme inhibitor and diuretic doses were increased 318% and 89%, respectively. Four patients also received hydralazine to optimize hemodynamics. New York Heart Association functional class improved from 3.8 +/- 0.4 to 2.6 +/- 0.6 following therapy. Ten patients who responded to therapy had fewer hospitalized days during the subsequent year compared with the year before treatment (4 +/- 17 vs 17 +/- 15), and no patient died. In contrast, the 3 patients who responded poorly to therapy tended to have more hospitalized days at 12 months compared with pretreatment (31 +/- 11 vs 20 +/- 18; NS); 1 patient died. We conclude that intravenous milrinone followed by optimization of oral medical therapy may be used as a therapeutic trial to identify patients in need of cardiac transplantation.     

Effect of endothelin receptor antagonists (BQ-485, Ro 47-0203) on collagen deposition during the development of bleomycin-induced pulmonary fibrosis in rats

Previous evidence suggests a role for endothelin-1 (ET-1) in the pathogenesis of pulmonary fibrosis. To determine if ET-1 regulates collagen deposition in pulmonary fibrosis, we examined the effect of the non-selective ETA and ETB receptor antagonist bosentan (Ro 47-0203), and a selective ETA receptor antagonist, BQ-485, on collagen deposition during the development of bleomycin-induced pulmonary fibrosis in rats. Lung collagen content, derived from measurements of hydroxyproline and expressed as mg collagen/lung, was increased in the bleomycin-treated animals by day 7 (bleomycin, 22.88+/-1.46; control 18.50+/-0.98; P<0.05), continued to increase up to day 14 (bleomycin, 38.80+/-2.17; control 22.57+/-0.77; P<0.001) and then remained constant to 21 days. Daily treatment by gavage with bosentan (100 mg/kg) did not prevent the increase in collagen deposition induced by instillation of bleomycin at any of the times measured. Continuous administration of BQ-485, by subcutaneously implanted minipump (7.5 mg/day), also failed to prevent the bleomycin-induced collagen deposition at 14 days. These findings suggest that ET-1 does not modulate collagen deposition during the development of bleomycin-induced pulmonary fibrosis. Further studies are required to assess whether endothelin receptor antagonists modulate other components of the fibrotic response or play a role in man.     

Pulmonary vascular resistance of children treated with nitrogen during early infancy

BACKGROUND: We have empirically used supplemental nitrogen in newborns with a functional single ventricle and ductal-dependent systemic perfusion to prevent pulmonary vasodilation and deliver a greater proportion of flow to the systemic circulation. Thus, we reviewed patient outcome to determine whether adverse pulmonary vascular effects may be associated with this therapy. METHODS: From December 1991 to December 1995, the fraction of inspired oxygen was adjusted, with supplemental nitrogen if necessary, to maintain an oxygen saturation near 75% in 20 newborns awaiting heart transplantation. Medical records were reviewed to evaluate (1) the duration of nitrogen therapy, (2) pulmonary vascular histology, (3) postoperative pulmonary hemodynamics, and (4) survival. RESULTS: Thirteen patients underwent heart transplantation, 4 patients died without surgical intervention, and 3 patients underwent late aortic reconstruction. Supplemental nitrogen was used without exceeding a fraction of inspired oxygen of 0.21 for 38 +/- 6 days. One patient had evidence of changes of potentially irreversible pulmonary vascular disease. Pulmonary vascular resistance was not increased long-term in surviving patients. CONCLUSIONS: Supplemental nitrogen can be used to maintain a systemic oxygen saturation near 75% for an extended period in newborns with ductal-dependent systemic perfusion with no long-term adverse effect on pulmonary vascular resistance.     

Cyclooxygenase inhibition potentiates the renal vascular response to endothelin-1 in humans

Vascular endothelin-receptor stimulation results in vasoconstriction and concomitant production of the vasodilators prostaglandin I2 and nitric oxide. The vascular effects of cyclooxygenase (COx) blockade (diclofenac intravenously) and the subsequent vasoconstrictor response to endothelin-1 (ET-1) infusion 30 min after diclofenac were studied in healthy men. With COx blockade, cardiac output (7%) and splanchnic (14%) and renal (12%) blood flows fell (all P < 0.001). Splanchnic blood flow returned to basal value within 30 min. Mean arterial blood pressure increased (4%, P < 0.001). Splanchnic glucose output fell (22%, P < 0.01). Subsequent ET-1 infusion caused, compared with previous ET-1 infusion without COx blockade (G. Ahlborg, E. Weitzberg, and J. M. Lundberg. J. Appl. Physiol. 77: 121-126, 1994; E. Weitzberg, G. Ahlborg, and J. M. Lundberg. Biochem. Biophys. Res. Commun. 180: 1298-1303, 1991; E. Weitzberg, G. Ahlborg, and J. M. Lundberg. Clin. Physiol. (Colch.) 13: 653-662, 1993), the same increase in mean arterial blood pressure (4%), decreases in cardiac output (13%) and splanchnic blood flow (38%), but no significant change in splanchnic glucose output. Renal blood flow reduction was potentiated (33 +/- 3 vs. 23 +/- 2%, P < 0.02), with a total reduction corresponding to 43 +/- 3% (P < 0.01 vs. 23 +/- 3%). We conclude that COx inhibition induces renal and splanchnic vasoconstriction. The selectively increased renal vascular responsiveness to ET-1 emphasizes the importance of endogenous arachidonic acid metabolites (i.e., prostaglandin I2) to counteract ET-1-mediated renal vasoconstriction.     

Endothelin-1 regulates tone of isolated small arteries in the rat: effect of hyperendothelinemia

Chronic elevation of plasma endothelin-1 (ET-1) levels has been reported in several pathological conditions. To investigate the consequences of increased circulating ET-1 on vascular responsiveness, Sprague-Dawley rats (n=16) were chronically instrumented with a minipump delivering ET-1 at a constant dose for 7 days. Plasma ET-1 levels were more than doubled in treated (0.98+/-0.09 pmol/L; P<.05) versus untreated sham-operated rats (0.43+/-0.04 pmol/L), whereas systolic arterial blood pressure increased (139+/-5 versus 128+/-4 mm Hg in untreated rats; P<.05). After rats were killed, segments of middle cerebral (MCA) and mesenteric (MES) arteries were mounted on an isometric myograph. ET-induced contraction was shifted to the right in ET-1-treated animals and not modified by BQ123 (an ET(A) receptor antagonist); bosentan (ET(A/B) receptor antagonist) prevented ET-1-induced contraction in both groups. After inhibition of nitric oxide synthase with N(omega)-nitro-L-arginine (L-NNA), both phenylephrine and oxymetazoline (an alpha2-adrenoceptor agonist) induced MCA contraction. The sensitivity to phenylephrine was decreased in ET-1-treated compared with control rats (P<.05). Sensitivity to phenylephrine-induced contraction was decreased by BQ123 in control rats only. In contrast, L-NNA revealed greater oxymetazoline-induced contractions in treated compared with control MCA rings (P<.05); this potentiation was blunted by bosentan but unaffected by BQ123. Removal of the endothelium revealed a direct constrictor effect of oxymetazoline that was insensitive to L-NNA alone or combined with bosentan; however, oxymetazoline induced significantly lower constriction in treated rat MCA segments. Responses to oxymetazoline were also blunted in treated compared with untreated denuded MES arteries. In conclusion, chronic elevated plasmatic ET-1 decreases smooth muscle cell sensitivity to contractile agonists both in MCA and MES rings. In cerebral vessels, endothelial alpha2-adrenoceptor-dependent stimulation induced greater contractile responses in treated rats which were sensitive to bosentan, suggesting that oxymetazoline stimulates ET-1 release from the endothelium. This may represent a compensatory mechanism for the loss of smooth muscle sensitivity.     

Inhibition of hypoxic pulmonary hypertension by heparins of differing in vitro antiproliferative potency

Heparin inhibits smooth-muscle cell (SMC) growth in vitro and inhibits the development of hypoxic pulmonary hypertension and vascular remodeling in vivo. We wondered whether preparations of heparin with different antiproliferative potency in vitro would differ in their ability to inhibit the development of hypoxic pulmonary hypertension in vivo. Two such heparins, a weakly antiproliferative lot of Elkins-Sinn (E-S) (% inhibition of SMC growth at 10 micrograms/ml = 13 +/- 9% [mean +/- SEM, n = 24]) and a more active lot from Upjohn (UJ) (% inhibition = 71 +/- 12% [n = 12, p < 0.05 versus E-S]), were infused subcutaneously (300 U.S.P. units/day; E-S 300 versus UJ 300) via an osmotic pump into guinea pigs exposed to hypoxia (10% O2) for 10 d, after which pulmonary artery pressure (PAP; mm Hg) and cardiac index (CI; ml/min/kg) were measured in room air. Hypoxic controls (HC) received saline. PAP increased from 11 +/- 1 mm Hg in normoxic controls (NC) (n = 5) to 24 +/- 1 mm Hg in HC (n = 8, p < 0.05). The PAP was lower in the E-S 300 (21 +/- 1; n = 7, p < 0.05 versus HC and NC) and even lower in the UJ 300-treated group (18 +/- 0.5; n = 7, p < 0.05 versus HC and NC). Total pulmonary vascular resistance (TPR; mm Hg/ml/min/kg) increased significantly from 0.038 +/- 0.002 in NC to 0.076 +/- 0.003 (p < 0.05) in HC. There was no difference in TPR between the HC and the E-S 300-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endothelin-1 in the superior colliculus of rats induces depressor responses due to peripheral hemodynamic changes

Microinjection of endothelin-1 (ET-1; 10 pmol) into the superficial layer of the superior colliculus caused systemic and regional hemodynamic changes, as measured by injection of radioactive microspheres at the peak of the hypotensive effect of endothelin-1. Endothelin-1 decreased total peripheral resistance by 39 +/- 2% (n=5); the vascular resistances were decreased in the spleen, the mesentery, the large intestine and the small intestine. Moreover, we found that in consequence of the increased fraction of cardiac output received by the above organs, decreases in vascular resistances were associated with increases in blood flows in them. Interestingly, ET-1 also decreased the vascular resistances and increased the total blood flows in the kidneys. The haemodynamic changes induced by injection of endothelin-1 to the superior colliculus were associated with significant decreases in the mean arterial blood pressure (37 +/- 4 mmHg, n=6) and no changes in heart rate. Exogenous ET-1, therefore, within the SC decreases blood pressure due to peripheral hemodynamic changes.     

Autonomic control of cardiovascular performance and whole body O2 delivery and utilization in swine during treadmill exercise

OBJECTIVE: The present study determined the role of the autonomic nervous system (ANS) in the regulation of systemic and pulmonary circulation and of O2 delivery and utilization in swine at rest and during graded treadmill exercise. METHODS: Instrumented swine (n = 12) were subjected to treadmill exercise (1-5 km/h) under control conditions and in the presence of single and combined beta-adrenergic, alpha-adrenergic and muscarinic (M) receptor blockade. RESULTS: Exercise produced a four-fold increase in body O2 consumption, due to a doubling of both cardiac output and the arterio-mixed-venous O2 content difference. The latter resulted from an increase in O2 extraction, from 45 +/- 1% at rest to 74 +/- 1% at 5 km/h, as the O2 carrying capacity [haemoglobin concentration (Hb)] increased by only approximately 10%. The increase in cardiac output resulted from a doubling of the heart rate and a small (< 10%) increase in stroke volume. The mean aortic pressure (MAP) was unchanged, implying a 50% decrease in systemic vascular resistance (P < or = 0.05). In contrast, exercise had no significant effect on pulmonary vascular resistance. The sympathetic division of the ANS controlled O2 delivery via beta-adrenoceptors (heart rate and contractility) and Hb concentration via alpha-adrenoceptor-mediated splenic contraction. In addition, the sympathetic division modulated systemic vascular tone via alpha- and beta-adrenoceptors, but also exerted a vasodilator influence on the pulmonary circulation via beta-adrenoceptors. The parasympathetic division controlled O2 delivery in part directly (heart rate) and in part indirectly via inhibition of beta-adrenoceptor activity (heart rate and contractility), even during heavy exercise. In addition, the parasympathetic division exerted a direct vasodilator influence on the pulmonary, but not on the systemic, circulation. CONCLUSIONS: Thus, in swine, in a manner similar to that in humans, both the sympathetic and parasympathetic division of the ANS contribute to cardiovascular homeostasis during exercise up to levels of high intensity.     

Pulmonary hemodynamics and plasma endothelin-1 during hypoxemia and reoxygenation with room air or 100% oxygen in a piglet model

The immediate effect on the pulmonary circulation of reoxygenation with either room air or 100% O2 was studied in newborn piglets. Hypoxemia was induced by ventilation with 8% O2 until base excess was <-20 mmol/L or mean arterial blood pressure was <20 mm Hg. Reoxygenation was performed with either room air (n = 9) or 100% O2 (n = 9). Mean pulmonary artery pressure increased during hypoxemia (p = 0.012). After 5 min of reoxygenation, pulmonary artery pressure increased further from 24 +/- 2 mm Hg at the end of hypoxemia to 35 +/- 3 mm Hg (p = 0.0077 versus baseline) in the room air group and from 27 +/- 3 mm Hg at the end of hypoxemia to 30 +/- 2 mm Hg (p = 0.011 versus baseline) in the O2 group (NS between groups). Pulmonary vascular resistance index increased (p = 0.0005) during hypoxemia. During early reoxygenation pulmonary vascular resistance index decreased rapidly to values comparable to baseline within 5 min of reoxygenation in both groups (NS between groups). Plasma endothelin-1 (ET-1) decreased during hypoxemia from 1.5 +/- 0.1 ng/L at baseline to 1.2 +/- 0.1 ng/L at the end of hypoxemia (p = 0.003). After 30 min of reoxygenation plasma ET-1 increased to 1.8 +/- 0.3 and 1.5 +/- 0.2 ng/L in the room air and O2 groups, respectively (p = 0.0077 in each group versus end hypoxemia; NS between groups). We conclude that hypoxemic pulmonary hypertension and plasma ET-1 normalizes as quickly when reoxygenation is performed with room air as with 100% O2 in this hypoxia model with newborn piglets.     

Fibroelastolytic papulosis of the neck: a report of 20 cases

BACKGROUND: Reports of pulmonary edema complicating inhaled nitric oxide therapy in patients with chronic heart failure and pulmonary hypertension have raised the concern that inhaled nitric oxide may have negative inotropic effects. METHODS AND RESULTS: We investigated the effect of multiple doses of inhaled nitric oxide (20, 40 and 80 ppm) on left ventricular contractile state in 10 open-chest pigs. Pressure-volume loops were generated during transient preload reduction to determine the end-systolic pressure-volume relationship and the stroke work-end-diastolic volume relation. Inhaled nitric oxide had no effect on systemic vascular resistance, cardiac output, end-systolic pressure volume relationship or stroke work-end-diastolic volume relation under normal conditions. After induction of pulmonary hypertension (intravenous thromboxane A2 analog), inhalation of nitric oxide (80 ppm) resulted in a reduction in pulmonary vascular resistance (mean +/- standard error of the mean) from 10.4 +/- 3 to 6.5 +/- 2 Wood units (p < 0.001) and in pulmonary artery pressure from 44 +/- 4 to 33 +/- 4 mm Hg (p < 0.05). Left ventricular end-diastolic volume rose from 53 +/- 9 ml to 57 +/- 10 ml (p = 0.02). No statistically significant change in cardiac output or systemic vascular resistance was observed. Inhaled nitric oxide had no effect on end-systolic pressure-volume relationship or stroke work-end-diastolic volume relation. CONCLUSIONS: In a porcine model of pulmonary hypertension, inhaled nitric oxide does not impair left ventricular contractile function. Therefore the cause of pulmonary edema observed in some patients receiving inhaled nitric oxide is not due to a negative inotropic action of this therapy.     

Nonspecific endothelin-receptor antagonist blunts monocrotaline-induced pulmonary hypertension in rats

Endothelin-1 (ET-1), a potent vasoactive and mitogenic peptide, has been implicated in the pathogenesis of several forms of pulmonary hypertension. We hypothesized that nonspecific blockade of ET receptors would blunt the development of monocrotaline (MCT)-induced pulmonary hypertension in rats. A single dose of the nonspecific ET blocker bosentan (100 mg/kg) given to intact rats by gavage completely blocked the pulmonary vasoconstrictor actions of Big ET-1 and partially blunted hypoxic pulmonary vasoconstriction. After 3 wk, MCT-injected (105 mg/kg sc) rats gavaged once daily with bosentan (200 mg/kg) had lower right ventricular (RV) systolic pressure (RVSP), RV-to-body weight (RV/BW) and RV-to-left ventricular (LV) plus septal (S) weight [RV/(LV+S)] ratios and less percent medial thickness of small pulmonary arteries than control MCT-injected rats. Lower dose bosentan (100 mg/kg) had no effect on these parameters after MCT or saline injection. Bosentan raised plasma ET-1 levels but had no effect on lung ET-1 levels. Bosentan (200 mg/kg) also had no effect on wet-to-dry lung weight ratios 6 days after MCT injection. When given during the last 10 days, but not the first 11 days of a 3-wk period after MCT injection, bosentan reduced RV/(LV+S) compared with MCT-injected controls. We conclude that ET-1 contributes to the pathogenesis of MCT-induced pulmonary hypertension and acts mainly during the later inflammatory rather than the acute injury phase after injection.     

Effects of oxygen, positive end-expiratory pressure, and carbon dioxide on oxygen delivery in an animal model of the univentricular heart

OBJECTIVE: Respiratory manipulations are a mainstay of therapy for infants with a univentricular heart, but until recently little experimental information has been available to guide their use. We used an animal model of a univentricular heart to characterize the physiologic effects of a number of commonly used ventilatory treatments, including altering inspired oxygen tension, adding positive end-expiratory pressure, and adding supplemental carbon dioxide to the ventilator circuit. RESULTS: Lowering inspired oxygen tension decreased the ratio of pulmonary to systemic flow. This ratio was 1.29 +/- 0.08 at an inspired oxygen tension of 100%, 0.61 +/- 0.09 at an inspired oxygen tension of 21%, and 0.42 +/- 0.09 at an inspired oxygen tension of 15% (p < 0.05 compared with an inspired oxygen tension of 100% and a positive end-expiratory pressure of 0 cm H2O). High-concentration supplemental carbon dioxide (carbon dioxide tension of 80 to 90 mm Hg) added to the ventilator circuit decreased inspired oxygen tension from 1.29 +/- 0.11 to 0.42 +/- 0.12 (p < 0.05 compared with baseline). A mixture of 95% oxygen and 5% carbon dioxide (carbon dioxide tension of 50 to 60 mm Hg) did not decrease the pulmonary/systemic flow ratio significantly. All three types of interventions influenced systemic oxygen delivery, which was a function of the pulmonary/systemic flow ratio. As the pulmonary/systemic flow ratio decreased from initially high levels (greater than 1), oxygen delivery first increased and reached an optimum at a flow ratio slightly less than 1. As the pulmonary/systemic flow ratio decreased further, below 0.7, oxygen delivery decreased. The ability of systemic arterial and venous oxygen saturations to predict the pulmonary/systemic flow ratio was examined. Venous oxygen saturation correlated well with both pulmonary/systemic flow ratio and systemic oxygen delivery, whereas arterial oxygen saturation did not accurately predict either pulmonary/systemic flow ratio or oxygen delivery. CONCLUSION: This model demonstrated the value of estimating the pulmonary/systemic flow ratio before initiating therapy. When the initial ratio was greater than about 0.7, interventions that decreased the ratio increased oxygen delivery and were beneficial. When the initial pulmonary/systemic flow ratio was below 0.7, interventions that decreased the ratio decreased oxygen delivery and were detrimental. We conclude by presenting a framework to guide therapy based on the combination of arterial and venous oxygen saturations and the estimate of the pulmonary/systemic flow ratio that they provide.