Biomedical subjects

D A Fullerton

Publications and source records attributed to D A Fullerton.

At least 37 records · Page 2Linked to original sources

PubMed1997

Variable response to inhaled nitric oxide after cardiac surgery.

BACKGROUND: Inhaled nitric oxide (NO) is a promising therapy that may be valuable in the control of pulmonary hypertension in cardiac surgical patients. Patients with valvular heart disease have remodeling of the pulmonary vascular bed that contributes to pulmonary hypertension. The purpose of this study was to compare the efficacy of inhaled NO in cardiac surgical patients with pulmonary hypertension with and without valvular heart disease. METHODS: The effect of inhaled NO (40 ppm) on pulmonary hemodynamics in patients with pulmonary hypertension (mean pulmonary artery pressure > or = 30 mm Hg) was studied in the operating room after cardiac operation. Fifteen patients with valvular heart disease comprised the study group; 25 patients undergoing aortocoronary bypass grafting were controls. RESULTS: In patients undergoing aortocoronary bypass grafting, inhaled NO produced a 24% decrease in mean pulmonary artery pressure (33 +/- 1 to 25 +/- 1 mm Hg; p < 0.05), a 36% decrease in pulmonary vascular resistance (375 +/- 30 to 250 +/- 30 dyne.s.cm-5; p < 0.05), and no change in systemic arterial blood pressure. On the other hand, patients with pulmonary hypertension from valvular heart disease did not respond to inhaled NO: mean pulmonary artery pressure was 39 +/- 3 mm Hg and pulmonary vascular resistance was 620 +/- 30 dyne.s.cm-5 before, during, and after NO. CONCLUSIONS: Among cardiac surgical patients with pulmonary hypertension, the response to inhaled NO is variable. Despite the promise of inhaled NO as a pulmonary vasodilator in cardiac surgical patients, these data suggest that alternative therapies are needed to control pulmonary hypertension in patients with pulmonary hypertension from valvular heart disease.

Aged↗

PubMed1997

Fast-track cardiac surgery in a Department of Veterans Affairs patient population.

BACKGROUND: "Fast-track" (FT) cardiac surgery is popular in the private and university sectors. This study was designed to examine its safety and efficacy in the Department of Veterans Affairs elderly, male patient population, a population with multiple comorbid risk factors, often decreased social functioning, and impaired support systems. METHODS: Time to extubation, hospital length of stay, perioperative morbidity, and mortality were studied in two consecutive cohorts undergoing cardiac operations requiring cardiopulmonary bypass before (pre-FT: n = 255, January 1992 to September 1993) and after (FT: n = 304, October 1993 to October 1995) institution of an FT protocol at a university-affiliated teaching Department of Veterans Affairs medical center. Preoperative risk factors, including a Department of Veterans Affairs risk-adjusted estimate of operative mortality, and perioperative surgical and anesthetic processes of care were evaluated. RESULTS: The mean Department of Veterans Affairs risk estimate of perioperative mortality was not different between the pre-FT and FT cohorts (3.5% versus 3.7%, p = 0.13). In the FT cohort, median time to extubation decreased significantly (19.2 versus 10.2 hours; p < 0.001) along with median surgical intensive care unit stay (96 versus 49 hours; p < 0.001) and total postoperative length of stay (222 versus 167 hours; p < 0.001). Median postoperative day of hospital discharge decreased from day 10 to 7 (p < 0.001). One patient (0.3%) required emergent reintubation directly related to early extubation. Reintubation for medical reasons was unchanged between pre-FT and FT groups (6.3% versus 5.0%; p = 0.48). Postoperative morbidity was similar between groups except for nosocomial pneumonia, the rate of which decreased significantly in the FT cohort (14.7% versus 7.3%; p < 0.005). Thirty-day (3.9% versus 4.6%; p = 0.69) and 6-month mortality (6.7% versus 6.9%; p = 0.91) were unchanged. CONCLUSIONS: An FT cardiac surgery protocol has been instituted in a university-affiliated teaching Department of Veterans Affairs medical center, with decreased length of stay and no significant increase in postoperative morbidity, 30-day mortality, or 6-month mortality. It was associated with a lower rate of nosocomial pneumonia, a finding that must be validated in a prospective study.

Aged↗

PubMed1997

Lymphoepithelioma-like carcinoma of the lung.

Primary lymphoepithelioma-like carcinoma of the lung is rare; only 26 case reports have been identified in the literature. The present report presents a case of a 67-year-old white man with a T1 N1 M0 lymphoepithelioma-like carcinoma of the lung. He presented with severe arthritic complaints that resolved after resection of the tumor. The majority of these tumors have occurred in Asian patients who have shown evidence of previous exposure to the Epstein-Barr virus.

Aged↗

PubMed1997

Effective control of refractory pulmonary hypertension after cardiac operations.

OBJECTIVES: Inhaled nitric oxide is a promising therapy to control pulmonary hypertension. However, pulmonary hypertension caused by valvular heart disease is often refractory to inhaled nitric oxide. The objective of this study was to determine whether the combination of inhaled nitric oxide plus dipyridamole will cause a response in patients with pulmonary hypertension undergoing cardiac operations who had not responded to inhaled nitric oxide alone. METHODS: Responses in 10 patients (62 +/- 7 years) with pulmonary hypertension caused by aortic or mitral valvular disease (mean pulmonary artery pressure, > or = 30 mm Hg) were studied in the operating room after valve replacement. The effect of inhaled nitric oxide alone (40 ppm) on pulmonary vascular resistance, mean pulmonary artery pressure, cardiac output, and mean arterial pressure was determined. Inhaled nitric oxide administration was then stopped and patients were given dipyridamole (0.2 mg/kg intravenously); the effect of inhaled nitric oxide plus dipyridamole was then examined. RESULTS: Dipyridamole effected a response in patients who had not responded to nitric oxide. Pulmonary vascular resistance and mean pulmonary artery pressure were significantly reduced and cardiac output was increased without change in mean arterial pressure. CONCLUSIONS: Patients with refractory pulmonary hypertension in whom inhaled nitric oxide alone fails to cause a response may respond to combined therapy of inhaled nitric oxide plus dipyridamole. This therapy may be particularly valuable in patients with dysfunction of the right side of the heart as a result of pulmonary hypertension because of its effective lowering of right ventricular afterload.

Aged↗

PubMed1997

Endotoxin differentially impairs cyclic guanosine monophosphate-mediated relaxation in the pulmonary and systemic circulations.

OBJECTIVES: The purpose of this study was to determine the effect of endotoxin on alpha1-adrenergic receptor vasoconstriction and both endothelium-dependent and -independent cyclic guanosine monophosphate (cGMP)-mediated vasodilation in the pulmonary and systemic circulations. DESIGN: Prospective, multiple group, controlled experimental study. SETTING: Medical school research laboratory. SUBJECTS: Male Sprague-Dawley rats, weighing 250 to 350 g. INTERVENTIONS: Six hours after endotoxin (20 mg/kg intraperitoneally) or saline, the response to the a) alpha1-adrenergic receptor agonist, phenylephrine; b) endothelium-dependent vasodilator, acetylcholine; and c) the endothelium-independent vasodilator, sodium nitroprusside, was determined in isolated rat pulmonary artery and thoracic aortic rings. MEASUREMENTS AND MAIN RESULTS: Endotoxin caused a significant decrease in the response to phenylephrine in the aorta but did not affect the response in the pulmonary artery. Endotoxin caused significant impairment of relaxation to acetylcholine and sodium nitroprusside in the pulmonary circulation. In control rings, only 4 +/- 1% of the preconstricted tension remained in response to acetylcholine vs. 77 +/- 3% following endotoxin administration (p < .05). Similarly, sodium nitroprusside resulted in complete pulmonary ring relaxation in controls vs. 18 +/- 3% tension remaining following endotoxin administration (p < .05). On the other hand, only the response to acetylcholine was dysfunctional in the thoracic aorta. In thoracic aortic rings from control rats, acetylcholine caused complete relaxation; however, 23 +/- 5% of the preconstricted tension remained following endotoxin administration. The response to sodium nitroprusside in the thoracic aorta from endotoxin-treated rats was not different from control. CONCLUSIONS: From these data, we conclude that endotoxin causes organ-specific changes in vascular reactivity. These changes in vascular reactivity favor a decrease in vascular pressure and resistance in the systemic circulation, and an increase in vascular pressure and resistance in the pulmonary circulation in response to endotoxin.

Acetylcholine↗

PubMed1997

Neutrophils mediate pulmonary vasomotor dysfunction in endotoxin-induced acute lung injury.

BACKGROUND: The major hemodynamic feature of endotoxin (ETX)-induced acute lung injury is pulmonary hypertension secondary to increased pulmonary vascular resistance. Endotoxin causes dysfunction of pulmonary vasorelaxation, which is associated with increased lung neutrophil accumulation. We hypothesized that neutrophils mediate the dysfunction of cGMP-mediated pulmonary vasorelaxation in acute lung injury. In a rat model of ETX-induced lung injury, our purpose was to determine the effect of neutrophil depletion on the following mechanisms of pulmonary vasomotor control: endothelium-dependent cGMP-mediated relaxation (response to acetylcholine) and endothelium-independent relaxation (response to sodium nitroprusside). METHODS: Rats were studied 6 hours after ETX (20 mg/kg). Neutropenia (< 75 neutrophils/microL) was induced with anti-neutrophil serum 24 hours before ETX. Saline injected rats were controls. Dose-response curves to acetylcholine and sodium nitroprusside were generated in isolated pulmonary artery rings preconstricted with phenylephrine (n = 10 rings/5 rats per group). Lungs were harvested (n = 4 rats/group) and lung neutrophil accumulation was assessed with a myeloperoxidase assay. RESULTS: Endothelium-dependent and -independent cGMP-mediated pulmonary vasorelaxation was dysfunctional in ETX-induced ALI. Neutrophil depletion prevented lung neutrophil accumulation and attenuated pulmonary vasomotor dysfunction after endotoxin. CONCLUSIONS: These data suggest that neutrophils contribute to pulmonary endothelium and smooth muscle dysfunction in acute lung injury induced by endotoxemia.

Acetylcholine↗

PubMed1997

L-arginine decreases alveolar macrophage proinflammatory monokine production during acute lung injury by a nitric oxide synthase-dependent mechanism.

BACKGROUND: Recent clinical reports indicate that inhaled nitric oxide (NO) reduces lung parenchymal inflammation during acute lung injury; however, the mechanism of its protective effects remains incompletely understood. We hypothesized that the provision of substrate for local NO production (L-arginine) would reduce alveolar macrophage proinflammatory monokine production during endotoxin (ETX)-induced acute lung injury. Our purposes were to (1) determine alveolar macrophage tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) production after ETX-induced acute lung injury; (2) determine the effect of L-arginine on alveolar macrophage TNFalpha and IL-1beta production in ETX-induced acute lung injury; and (3) determine whether L-arginine's effects on the alveolar macrophage are mediated by NO. METHODS: Rats received ETX (0.5 mg/kg intraperitoneal (i.p.)) or vehicle, with or without (1) L-arginine supplementation (300 mg/kg i.p.) and (2) nitric oxide synthase inhibition (N(G)-monomethyl-L-arginine, 30 mg/kg i.p.). Four hours later, alveolar macrophage were harvested by bronchoalveolar lavage and incubated at 10(6) cells/mL + 1 microg/mL phorbol myristase acetate for 24 hours. Cell-free supernatants were collected and assayed (enzyme-linked immunosorbent assay) for TNFalpha and IL-1beta. RESULTS: Sublethal ETX increased alveolar macrophage capacity to produce TNFalpha and IL-1beta (p < 0.05, analysis of variance and Bonferroni/Dunn). L-Arginine decreased alveolar macrophage TNFalpha and IL-1beta release during acute lung injury. Concurrent inhibition of nitric oxide synthase abrogated L-arginine's protective effects, suggesting that L-arginine's anti-inflammatory effects are mediated by NO. CONCLUSIONS: (1) L-Arginine is an immunomodulating nutritional supplement; (2) L-arginine decreases alveolar macrophage proinflammatory monokine production during ETX-induced acute lung injury by a nitric oxide synthase-dependent mechanism; and (3) the provision of exogenous substrate for local NO production may reduce inflammation during acute lung injury.

Analysis of Variance↗

PubMed1997

Selective inhibition of receptor-mediated pulmonary vasorelaxation in endotoxin-induced acute lung injury.

We hypothesized that pulmonary vasorelaxation mediated by receptors that require generation of cyclic adenosine monophosphate (cAMP) is impaired in endotoxin-induced acute lung injury. The purpose of this study was to determine the effect of endotoxin on the following pathways of pulmonary vasorelaxation that require the generation of cAMP: 1) beta-adrenoreceptor stimulation (response to isoproterenol, ISO), 2) P2 purinoreceptor stimulation (response to adenosine diphosphate, ADP), 3) H2-histamine receptor stimulation (response to dimaprit), 4) adenosine A2 receptor stimulation (response to adenosine, ADO), 5) type 2 E prostaglandin (EP2) receptor stimulation (response to prostaglandin E1, PGE1), and 6) direct adenylate cyclase stimulation (response to forskolin, FSK). We used isolated pulmonary artery rings harvested from rats injected with endotoxin or saline. We found that endotoxin impaired the response to beta-adrenoreceptor stimulation (ISO) and P2 purinoreceptor stimulation (ADP). Endotoxin converted the vasorelaxant effect of H2-histamine receptor stimulation (dimaprit) to vasoconstriction. On the other hand, the response to A2 receptor stimulation (ADO) and EP2 receptor stimulation (PGE1), was normal. The dose response to direct adenylate cyclase stimulation (FSK) was the same as control except at a single concentration (10(-7) M). These data suggest that endotoxin causes selective impairment of pulmonary vasorelaxation through receptors coupled to cAMP generation. This impaired pulmonary vasorelaxation may contribute to the increased pulmonary vascular resistance seen in acute lung injury. These data may lead to therapy that will prevent or improve the pathophysiologic pulmonary circulation in acute lung injury.

Adenosine Diphosphate↗

PubMed1997

Nitric oxide synthase is not involved in cardiac contractile dysfunction in a rat model of endotoxemia without shock.

Endotoxin and proinflammatory cytokines induce nitric oxide synthase (NOS), and nitric oxide (NO) plays an important role in promoting endotoxin shock. However, the role of NOS in endotoxemic cardiac contractile dysfunction is not defined. To determine whether endotoxemic cardiac contractile dysfunction involves NOS, the present study used a rat model of endotoxemia without shock and examined the effects of glucocorticoids (dexamethasone, a potent inhibitor of inducible NOS, iNOS, expression), isoform nonselective NOS inhibitor (NG-monomethyl-L-arginine, L-NMA) and iNOS selective inhibitor (S-methylisothiourea sulfate, SMT) on cardiac contractile dysfunction. A sublethal dose of endotoxin (from Salmonella typhimurium, .5 mg/kg, i.p.) was given to adult rats, and left ventricular developed pressure (LVDP) examined by Langendorff technique was attenuated in hearts isolated at 4 or 6 h (66.7 +/- 3.4 and 60.3 +/- 5.5 mmHg, respectively, p < .05 vs. 102 +/- 2.4 mmHg in saline control) after endotoxin treatment. Pretreatment of rats with dexamethasone (4.0 mg/kg, i.v., -30 min) partially abolished endotoxin-induced contractile dysfunction at 6 h (LVDP 87.6 +/- 6.8 mmHg, p < .05 vs. endotoxin alone at 6 h). However, pretreatment with L-NMA (30 mg/kg, i.v., -5 min) or SMT (5.0 mg/kg, i.v., -1 min) failed to prevent the contractile dysfunction. Moreover, infusion of L-NMA or SMT in vitro could not restore contractile function in hearts isolated at 6 h after endotoxin treatment. In contrast, inhibition of NOS with L-NMA or SMT in vitro further attenuated coronary flow in endotoxin-treated hearts. Thus, endotoxemic cardiac contractile dysfunction in this non-shock rat model may not involve NOS, and inhibition of NOS may deteriorate coronary perfusion in endotoxemic heart.

Animals↗

PubMed1997

Endotoxin stuns cGMP-mediated pulmonary vasorelaxation.

Net pulmonary vascular tone is determined by the balance of pulmonary vasorelaxation and vasoconstriction. In endotoxemic rats, cGMP-mediated pulmonary vasorelaxation is impaired through neutrophil-dependent mechanisms, yet agonist stimulated vasoconstriction remains intact. Endotoxin-induced lung neutrophil accumulation is a transient response. In models of myocardial ischemia-reperfusion injury, "stunning" or reversible cardiac dysfunction is also associated with a reversible neutrophil presence. We hypothesized that lung neutrophil accumulation and dysfunction of cGMP-mediated pulmonary vasorelaxation is reversible after an endotoxin challenge. Our purpose was to examine lung neutrophil accumulation and endothelium-dependent and -independent mechanisms of cGMP-mediated pulmonary vasorelaxation 4 and 48 h after endotoxin challenge. Rats (n = 5 per group) were studied 4 and 48 h after injection of saline or endotoxin (500 micrograms/kg, intraperitoneal). Endothelium-dependent relaxation by receptor-dependent (acetylcholine) and -independent (A23187) mechanisms and endothelium-independent (sodium nitroprusside) relaxation were studied in isolated pulmonary artery rings preconstricted with phenylephrine. Lung neutrophil accumulation was examined by lung myeloperoxidase assay. Lung neutrophil accumulation was increased at 4 h (p < .05 vs. control) and was attenuated by 48 h (p < .05 vs. endotoxin x 4 h) following endotoxin challenge. Similarly, the endotoxin-induced dysfunction of endothelium-dependent and -independent cGMP-mediated pulmonary vasorelaxation at 4 h normalized by 48 h. Endotoxin appears to induce reversible dysfunction of pulmonary vasorelaxation through stunning of vascular endothelial and smooth muscle cells.

Acetylcholine↗

PubMed1997

KATP channels contribute to beta- and adenosine receptor-mediated pulmonary vasorelaxation.

ATP-sensitive K+ (KATP) channels have been implicated in the regulation of vasomotor tone in aortic, mesenteric, and pulmonary vascular smooth muscle. Several investigators have described an association between KATP channels and isoproterenol (Iso)-stimulated relaxation responses. To study the relationship between receptor-dependent pulmonary vasorelaxation and KATP channels, we examined the response to agonists that generate adenosine 3',5'-cyclic monophosphate at two distinct levels of the signal transduction pathway after inhibition or activation of KATP channels in isolated rat pulmonary artery rings. Cumulative concentration responses to beta-adrenergic receptor stimulation (Iso), purinergic receptor stimulation [adenosine (Ado)], and direct stimulation of adenylate cyclase [forskolin (FSK)] were studied with and without concurrent inhibition of KATP channels (glibenclamide or tolbutamide). In addition, the effect of direct KATP channel activation (cromakalim) on the response to beta-adrenergic and purinergic receptor stimulation was determined. Last, we investigated the influence of KATP channel inhibition on endothelium-dependent and -independent mechanisms of pulmonary vasorelaxation linked to guanosine 3',5'-cyclic monophosphate production. KATP channel inhibition impaired the response to Iso and Ado. Activation of KATP channels caused a leftward shift in the dose responses of Iso and Ado, with a significant decrease in the 50% effective concentration for each agent. KATP channel inhibition did not impair the pulmonary arterial vasorelaxation response to FSK, acetylcholine, or sodium nitroprusside. KATP channels appear to contribute to beta-adrenergic and purinergic receptor-stimulated vasorelaxation in rat pulmonary arteries.

ATP-Binding Cassette Transporters↗

PubMed1996

Pulmonary vascular smooth muscle contraction.

The purpose of this study was to determine the response of pulmonary vascular smooth muscle to (1) cellular depolarization (response to KC1), (2) alpha 1-adrenergic receptor stimulation (response to phenylephrine, epinephrine, and norepinephrine), and (3) eicosinoid receptor stimulation (response to prostaglandin F 2 alpha, serotonin, and U46619). Isolated rat pulmonary artery rings were suspended on a fine wire tensiometer in individual organ chambers. After confirming endothelial integrity (response to acetylcholine), dose-response curves were constructed for each vasoactive agonist. The maximal developed tension as well as the dose required to produce 50% of maximal contraction (EC50) was determined for each agonist. The U46619, a stable thromboxane A2 mimetic, and prostaglandin F 2 alpha, (PGF 2 alpha) produced the greatest maximal developed tension in pulmonary vascular smooth muscle. This maximal contraction to U46619 and PGF 2 alpha, was the same as the maximal tension in response to cellular depolarization (KCI). The maximal tension developed to KCI and U46619 was significantly greater than to alpha 1-adrenergic receptor stimulation and serotonin, 5HT. The maximal tension developed to PGF 2 alpha was greater than the developed tension to 5HT. The dose response curves of alpha 1-adrenergic receptor stimulation and U46619 were shifted to the left compared to PGF 2 alpha and 5HT. This study demonstrates that U46619, and PGF 2 alpha produce the greatest maximal developed tension in pulmonary vascular smooth muscle. Furthermore, U46619 has the same potency as alpha 1-adrenergic receptor stimulation, which is significantly greater than 5HT and PGF 2 alpha. These data may be helpful in the delineation of the pathophysiology of pulmonary hypertension due to adult respiratory distress syndrome.

Adrenergic alpha-Agonists↗

PubMed1996

Neutrophils are required for endotoxin-induced myocardial cross-tolerance to ischemia-reperfusion injury.

BACKGROUND: Although polymorphonuclear neutrophilic leukocytes (PMNs) contribute to oxidative stress after endotoxemia, it is unknown whether preischemic PMN induction is required for endotoxin-mediated myocardial resistance to ischemia-reperfusion (I/R). OBJECTIVE: To determine whether neutrophils mediate endotoxin-induced myocardial cross-tolerance to I/R. DESIGN AND INTERVENTIONS: Rats received sublethal endotoxin (0.5 mg/kg intraperitoneally) with and without rabbit anti-rat PMN antibody (anti-PMN antibody, 0.15 mL intravenously, to achieve an absolute neutrophil count of < 200/microL) or antibody alone, 24 hours prior to global myocardial I/R (20-40 minutes, Langendorff mode). SETTING: The University of Colorado Surgical Research Laboratories, Denver. MAIN OUTCOME MEASURES: Myocardial developed pressure, coronary flow, end diastolic pressure, and time to ischemic contracture were recorded with a pressure amplifier-digitizer (MacLab, AD Instruments Inc, Milford, Mass). Myocyte damage was assessed by determining creatine kinase leakage in the coronary flow effluent by creatine kinase assay. RESULTS: Sublethal endotoxin induced cross-tolerance to I/R, as demonstrated by improved recovered developed pressure and coronary flow, and decreased time to ischemic contracture, end diastolic pressure, and creatine kinase leak (P < .05, analysis of variance and Bonferroni-Dunn). Anti-PMN antibody administered prior to sublethal endotoxin abolished these protective effects (P < .05). Polymorphonuclear neutrophil leukocyte depletion alone failed to abrogate the deleterious effects of I/R. CONCLUSIONS: (1) Sublethal endotoxin induces myocardial cross-tolerance to I/R; (2) PMN induction is required for endotoxin-mediated myocardial resistance to I/R; and (3) while myocardial I/R injury is equally severe after antibody-mediated PMN depletion, endotoxin-induced tolerance to I/R does not occur in the neutropenic host.

Animals↗

PubMed1996

Pulmonary vascular smooth muscle relaxation by cAMP-mediated pathways.

Adenosine 3',5'-cyclic monophosphate (cAMP)-mediated pulmonary vascular smooth relaxation is a principle mechanism of pulmonary vasomotor control. The purpose of this study was to compare the potency and efficacy of the following receptor-linked pathways of pulmonary vasorelaxation which are mediated by cAMP: (1) beta2-adrenergic receptor activation (response to isoproterenol) (2) Adenosine A2-receptor activation (response to adenosine) (3) Prostaglandin EP2-receptor activation (response to prostaglandin E1) (4) Histamine H2-receptor activation (response to the H2-receptor agonist dimaprit) and (5) Purinergic P2-receptor activation (response to ADP). Cumulative concentration-response curves were generated in isolated rat pulmonary artery rings suspended on individual tensiometers. Five rats/ten pulmonary artery rings were studied for each agonist. Relaxation by beta2-adrenergic receptor activation was most effective as complete ring relaxation was achieved at 10(-6) M isoproterenol with a median effective dose of 10(-7) M. A2, P2, and EP2-receptor activation all achieved complete ring relaxation at concentrations up to 10(-3) M. Relaxation by H2-receptor activation was least effective as 30% ring tension remained at a concentration of 10(-3) M. We conclude that these receptor-linked pathways, although all mediated through cAMP, have significant differences in potency and efficacy.

Adenosine↗

PubMed1996

Antibody-mediated neutrophil depletion preserves pulmonary vasomotor function.

Neutrophil depletion is commonly used to examine the role of neutrophils in lung injury. However, the effect of neutrophil depletion per se on mechanisms of pulmonary vascular smooth muscle relaxation is unknown. The purpose of this study was to examine the effect of neutropenia on the following mechanisms of cGMP-mediated pulmonary vasorelaxation: (1) receptor-dependent endothelium-dependent relaxation (response to acetylcholine (ACh)), (2) receptor-independent endothelium-dependent relaxation (response to the calcium ionophore A23187), and (3) endothelium-independent relaxation (response to sodium nitroprusside (SNP)). Neutropenia (<75 neutrophils/mu l) was induced with anti-neutrophil antibody serum 24 hr prior to lung harvest in five rats. Saline-injected rats were controls (n = 5). Dose-response curves to ACh, A23187, and SNP were generated in isolated pulmonary artery rings preconstricted with phenylepherine. Statistical comparison was performed using one-way ANOVA with post-hoc Bonferroni-Dunn, and P < 0.05 was accepted as significant. Relaxation to ACh, A23187, and SNP was complete in both control and neutropenic rats. Thus, antibody-mediated depletion does not impair endothelial-dependent or -independent cGMP-mediated pulmonary vasorelaxation.

Acetylcholine↗

PubMed1996

Microtubules regulate pulmonary vascular smooth muscle contraction.

Microtubules are ubiquitous in eukaryotic cells. However, the role of microtubules in the mechanisms of pulmonary vascular smooth contraction has not previously been described. The purpose of this study was to examine the effect of microtubular inhibition (vinblastine) on the following mechanisms of pulmonary vascular smooth muscle contraction in rats using isolated pulmonary artery rings: (1) receptor-independent, calcium-dependent contraction via smooth muscle cell depolarization (response to KCl); (2) receptor-dependent, calcium-dependent contraction via alpha 1-adrenergic receptor stimulation (response to phenylephrine, PE); (3) receptor-dependent, calcium-independent contraction via thromboxane A2 receptor stimulation (response to the thromboxane mimetic, U-46619). Rats were studied 4 days after administration of vinblastine (750 micrograms/kg i.v.). Concentration-response curves were generated for KCl (5 mM to 100 mM) and for PE and U-46619 (10(-9) to 10(-4) M) (n = 8 rings/4 rats per group). Saline injected rats were controls. Pulmonary vascular smooth muscle contraction by calcium-dependent and -independent mechanisms was significantly increased following microtubular inhibition. These findings suggest that microtubules have an important role in the response of pulmonary vascular smooth muscle to vasoconstricting agonists.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1996

NO prevents neutrophil-mediated pulmonary vasomotor dysfunction in acute lung injury.

The purpose of this study was to examine the effect of administration of inhaled nitric oxide (NO) on lung neutrophil accumulation and pulmonary vascular endothelial cell function in endotoxin-induced acute lung injury. Mechanically ventilated rats were studied 4 hr after endotoxin (0.5 mg/kg IP). Inhaled NO (20 ppm) was administered for either the entire 4 hr after endotoxin (continuous group) or for only the first 2 of 4 hr after endotoxin (abbreviated group). Endothelial-dependent (acetylcholine, ACh) and -independent cGMP-mediated relaxation (nitroprusside, SNP) pulmonary vasorelaxation were studied in isolated pulmonary arterial rings. Lung neutrophil accumulation was determined by myeloperoxidase assay (MPO). Inhaled NO prevented endotoxin-induced lung neutrophil accumulation as well as pulmonary endothelial cell dysfunction. However, this protection required continuous administration of inhaled NO. We conclude that inhaled NO prevents neutrophil-mediated pulmonary vascular endothelial cell dysfunction in acute lung injury.

Acetylcholine↗

PubMed1996

Magnesium is essential in mechanisms of pulmonary vasomotor control.

Magnesium (Mg2+) is an important cofactor in many intracellular biochemical reactions; however, its role in the signal transduction pathways of pulmonary vascular smooth muscle is poorly defined. The purpose of this study was to examine the following mechanisms of pulmonary vascular smooth relaxation in the presence and in the absence of Mg2+: (1) Endothelium-dependent cGMP-mediated relaxation (response to acetylcholine, ACh), (2) Endothelium-independent cGMP-mediated relaxation (response to sodium nitroprusside, SNP), and (3) beta2-adrenergic cAMP-mediated relaxation (response to isoproterenol, ISO). Dose response curves were generated in isolated rat pulmonary artery rings preconstricted with phenylephrine. With Mg2+, ACh 10(-6) M produced complete ring relaxation but in the absence of Mg2+, only 66% relaxation was produced in response to ACh 10(-6) M (P < 0.05). On the other hand, endothelium-independent cGMP-mediated relaxation (response SNP) was not impaired without Mg2+. Beta2-adrenergic cAMP-mediated relaxation was also impaired in the absence of Mg2+. In the presence of Mg2+, ISO 10(-6) M produced complete relaxation but without Mg2+, only 30% relaxation was produced (P < 0.05). We conclude that Mg2+ is essential for cGMP- and cAMP-mediated mechanisms of pulmonary vasorelaxation. Hypomagnesemia should be avoided to prevent pulmonary vasomotor dysfunction.

Acetylcholine↗