Biomedical subjects

R C McIntyre

Publications and source records attributed to R C McIntyre.

At least 55 records · Page 3Linked to original sources

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

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↗

PubMed1996

Exposure for laparoscopic cholecystectomy dissection adversely alters biliary ductal anatomy.

BACKGROUND: Exposure for open cholecystectomy entails lateral, caudal traction on the gallbladder infundibulum, which results in opening the angle between the cystic and hepatic ducts. Laparoscopic cholecystectomy (LC), as initially described, is done with cephalad traction on the gallbladder. We hypothesized LC exposure technique narrows the angle between the cystic and hepatic ducts, placing them at increased risk of injury. METHODS: Twenty-three patients had routine LC. Cystic duct cholangiography (IOC) was done with a flexible 5-Fr catheter via a percutaneous introducer placed anterior to the gallbladder. Exposure of Calot's triangle was maintained with cephalad traction on the gallbladder fundus. IOC was repeated after allowing the organ to assume the anatomic position. The cholangiograms were inspected for significant differences, and the angle of the cystic to the hepatic duct (CDHD) was measured by a blinded radiologist. RESULTS: The mean angle of the cystic to hepatic duct was 30 degrees +/- 19 degrees in the IOCs taken with cephalad traction on the gallbladder fundus vs 59 degrees +/- 22 degrees, P < 0.001, in the cholangiograms taken without traction. A filling defect at the cystic-hepatic duct junction was present in 39% of IOC taken with traction vs none without traction. The intrahepatic ducts were seen in all films without traction, whereas the intrahepatic ducts were not visualized in 13% of IOCs taken with traction. CONCLUSIONS: From these data we conclude (1) extra-hepatic biliary ducts may be at increased risk of injury during LC because of the exposure technique and (2) imaging bile ducts in the anatomic position may convey misleading information about the relative location of important structures. Optimal exposure for dissection of Calot's triangle should utilize a second clamp on the infundibulum with lateral, caudal traction.

Bile Ducts, Intrahepatic↗

PubMed1996

Impact of respiratory acid-base status in patients with pulmonary hypertension.

BACKGROUND: The perioperative management of patients undergoing mitral valve replacement (MVR) with pulmonary hypertension from mitral stenosis may be complicated by increased pulmonary vascular resistance. The purpose of this study was to examine the influence of respiratory acid-base status on the pulmonary hemodynamic indices of patients with pulmonary hypertension before and after MVR. METHODS: Ten patients with pulmonary hypertension from mitral stenosis (mean preoperative systolic pulmonary artery pressure, 73 +/- 8 mm Hg) undergoing MVR were studied in the operating room before and after MVR. Arterial partial pressure of carbon dioxide was manipulated by the addition of 5% carbon dioxide to the breathing circuit. Hemodynamic data were collected as the partial pressure of carbon dioxide rose from 30 mm Hg to 50 mm Hg and decreased back to 30 mm Hg. RESULTS: There were no differences in mean pulmonary artery pressure or pulmonary vascular resistance before and after MVR. Before MVR, mean pulmonary artery pressure increased from 32 +/- 1 mm Hg to 48 +/- 1 mm Hg as the partial pressure of carbon dioxide rose from 30 mm Hg to 50 mm Hg (p < 0.05), and pulmonary vascular resistance rose from 379 +/- 30 to 735 +/- 40 dynes.second.cm-5 (p < 0.05). These effects on mean pulmonary artery pressure and pulmonary vascular resistance were not different after MVR. CONCLUSION: Respiratory acid-base status has a profound impact upon pulmonary vascular resistance in patients with pulmonary hypertension from mitral stenosis undergoing MVR. This impact persists in the immediate postoperative period. We conclude that respiratory acidemia should be avoided in these patients, whereas respiratory alkalemia may be used to help minimize pulmonary vascular resistance.

Acid-Base Imbalance↗

PubMed1996

Adenosine effectively controls pulmonary hypertension after cardiac operations.

BACKGROUND: Pulmonary hypertension secondary to increased pulmonary vascular resistance may greatly complicate the perioperative management of patients having cardiac operations. Adenosine may have a therapeutic role as a selective pulmonary vasodilator. The purpose of this study was to examine the pulmonary hemodynamic effects of a central venous infusion of adenosine in cardiac operative patients with pulmonary hypertension. METHODS: Ten cardiac patients with pulmonary hypertension (age, 62 +/- 6 years) were studied in the operating room under general anesthesia after weaning from cardiopulmonary bypass. Cardiac output, pulmonary vascular resistance, systemic vascular resistance, mean pulmonary arterial pressure, and mean systemic arterial pressure were determined before, during, and after central venous infusion of adenosine (50 micrograms x kg-1 x min -1) for 15 minutes. Statistical analysis was by analysis of variance, and significance was accepted at p < 0.05. RESULTS: Adenosine produced significant pulmonary vasodilation. Mean pulmonary arterial pressure was lowered from 36 +/- 1 to 28 +/- 2 mm Hg (p < 0.05), and pulmonary vascular resistance was lowered from 560 +/- 30 to 260 +/- 30 dynes x s x cm-5 (p < 0.05) during adenosine administration. At the same time, cardiac output rose from 4.0 +/- 0.6 to 6.2 L/min (p < 0.05). Pulmonary vascular resistance, mean pulmonary arterial pressure, and cardiac output returned to baseline after the adenosine infusion was stopped. There was no change in systemic mean arterial pressure during adenosine infusion. CONCLUSIONS: Adenosine may be used clinically as a selective pulmonary vasodilating agent to optimize pulmonary hemodynamic indices without adverse systemic hemodynamic effects in patients with pulmonary hypertension having cardiac operations. It may be particularly valuable in patients with right heart dysfunction by selectively lowering right ventricular afterload.

Adenosine↗

PubMed1996

Inhaled nitric oxide: therapeutic applications in cardiothoracic surgery.

Hypoxemia and increased pulmonary vascular resistance can greatly complicate the management of cardiothoracic surgical patients. These complications are commonly found in the setting of thoracic organ transplantation, adult and pediatric cardiac surgical procedures, and general thoracic surgical procedures. Inhaled nitric oxide is a new therapy that promises to be extremely valuable to the cardiothoracic surgeon. It has been shown to improve oxygenation in the setting of acute lung injury and to selectively lower pulmonary vascular resistance, without producing unwanted systemic vasodilation. The purpose of this review is to discuss the biochemistry, toxicity, experimental studies, and therapeutic applications of inhaled nitric oxide administration in cardiothoracic surgical patients.

Administration, Inhalation↗

PubMed1996

Effective control of pulmonary vascular resistance with inhaled nitric oxide after cardiac operation.

Increased pulmonary vascular resistance may greatly complicate the perioperative management of cardiac surgical patients. Inhaled nitric oxide may be a promising new therapy to selectively lower pulmonary vascular resistance. The purpose of this study was to examine the effects of inhaled nitric oxide on pulmonary and systemic hemodynamics in cardiac surgical patients. Twenty patients (age 57 +/- 6 years) were studied in the operating room after weaning from cardiopulmonary bypass. Mean pulmonary artery pressure, pulmonary vascular resistance, systemic vascular resistance, and mean aortic pressure were determined at four points of data collection: before nitric oxide, with 20 ppm nitric oxide, with 40 ppm nitric oxide, and after nitric oxide. Statistical analysis was by analysis of variance; significance was accepted for p < 0.05. Inhaled nitric oxide produced selective pulmonary vasorelaxation. Pulmonary vascular resistance was lowered from 343 +/- 30 before nitric oxide to 233 +/- 25 dynes.sec-1.cm-5 with 20 ppm nitric oxide. Pulmonary vascular resistance was not further lowered by 40 ppm nitric oxide (p < 0.05). Mean pulmonary arterial pressure was 29 +/- 1 mm Hg before nitric oxide and was lowered to 22 +/- 1 mm Hg by 20 ppm nitric oxide and 21 +/- 1 mm Hg by 40 ppm nitric oxide (p < 0.05). Both pulmonary vascular resistance and mean pulmonary arterial pressure returned to baseline after withdrawal of inhaled nitric oxide. Inhaled nitric oxide produced no changes in either systemic vascular resistance or mean aortic pressure. We conclude that nitric oxide may be used as an effective pulmonary vasodilator after cardiac operations. It may be particularly valuable for selectively lowering right ventricular afterload in patients with right ventricular dysfunction.

Administration, Inhalation↗

PubMed1996

Pulmonary vasomotor dysfunction is produced with chronically high pulmonary blood flow.

This study examined the hypothesis that chronic high pulmonary blood flow produces dysfunction of the mechanisms of pulmonary vasorelaxation. A 3:1 left-to-right shunt was created in dogs by bilateral femoral artery-femoral vein shunts with use of 6 mm polytetrafluoroethylene grafts. Isolated pulmonary artery rings were studied at the following times: 3 days (n = 2), 2 weeks (n = 4), and 5 months (n = 6). Control animals had no shunt. The following mechanisms of pulmonary vasorelaxation were studied in isolated pulmonary artery rings (4 rings from each dog): (1) endothelium-dependent cyclic guanosine monophosphate-mediated relaxation (response to acetylcholine), (2) endothelium-independent cyclic guanosine monophosphate-mediated relaxation (response to sodium nitroprusside), and (3) beta-adrenergic cyclic adenosine monophosphate-mediated relaxation (response to isoproterenol). Statistical analysis was done by analysis of variance. This model of high pulmonary flow did not produce an increase in pulmonary arterial pressure or transpulmonary gradient. However, chronic high pulmonary flow produced progressive dysfunction of all three of these mechanisms of pulmonary vasorelaxation. By 5 months of high pulmonary flow, acetylcholine produced only 36% +/- 6% relaxation versus 95% +/- 5% in control animals (p < 0.05). Likewise, sodium nitroprusside produced only 69% +/- 6% relaxation versus 100% in control animals (p < 0.05). Finally, isoproterenol produced only 55% +/- 5% relaxation versus 94% +/- 6% in control animals (p < 0.05). We conclude that dysfunction of the mechanisms of pulmonary vasorelaxation may contribute to exaggerated perioperative pulmonary vasoconstriction in the setting of chronic high pulmonary blood flow.

Acetylcholine↗

PubMed1996

Impairment of endothelial-dependent pulmonary vasorelaxation after mesenteric ischemia/reperfusion.

BACKGROUND: A major hemodynamic feature of acute lung injury is pulmonary hypertension caused by pulmonary vasoconstriction. Impairment of the mechanisms of pulmonary vasorelaxation may contribute to this pulmonary vasoconstriction. This study examined the effect of mesenteric ischemia/reperfusion (I/R) on lung neutrophil accumulation and endothelial-dependent and -independent cyclic 3'-5' guanosine monophosphate-mediated pulmonary vasorelaxation in rats. METHODS: Rats were studied after 1 hour of superior mesenteric artery occlusion and 2 hours of reperfusion. Lung neutrophil accumulation was determined by myeloperoxidase assay (MPO). The following mechanisms of pulmonary vasorelaxation were studied in isolated pulmonary artery rings by generating dose response curves (10(-9) to 10(-6)mol/L): (1) receptor-dependent, endothelial-dependent relaxation (response to acetylcholine), (2) receptor-independent, endothelial-dependent relaxation (response to the calcium ionophore, A23187), and (3) endothelial-independent relaxation (response to sodium nitroprusside [SNP]). RESULTS: Lung MPO activity was significantly increased from 2.4 +/- 0.2 units/gm lung weight in controls to 10.3 +/- 0.4 after mesenteric I/R (p < 0.05). The vasorelaxation response to SNP was not different after mesenteric I/R, but vasorelaxation by both acetylcholine and A23187 were significantly impaired. CONCLUSIONS: Endothelial-dependent pulmonary vasorelaxation is significantly impaired after mesenteric I/R. Such impairment of pulmonary vasorelaxation may help tip the net balance of pulmonary vasomotor tone toward vasoconstriction and contribute to the pulmonary hypertension seen in acute lung injury.

Acetylcholine↗

PubMed1996

Mechanistic imbalance of pulmonary vasomotor control in progressive lung injury.

BACKGROUND: Pulmonary hypertension is the major hemodynamic feature of progressive lung injury. We hypothesized that the mechanisms of pulmonary vasorelaxation become progressively impaired in progressive lung injury. The purpose of this study was to examine the following mechanisms of pulmonary vasorelaxation in a rat model of monocrotaline-induced progressive lung injury: endothelial-dependent cyclic guanosine monophosphate-mediated relaxation (response to acetylcholine), endothelial-independent cyclic guanosine monophosphate-mediated relaxation (response to nitroprusside), beta-adrenergic cyclic adenosine monophosphate-mediated relaxation (response to isoproterenol), and hypoxic pulmonary vasoconstriction. METHODS: Rats were studied 2, 7, and 14 days after monocrotaline injection (100 mg/kg intraperitoneally). Pulmonary vasomotor control mechanisms were studied in isolated pulmonary artery rings. Controls were studied 14 days after saline injection. Statistical analysis was by ANOVA; p < 0.05 was considered significant. RESULTS: A progressive impairment of pulmonary vasorelaxation was observed. By 14 days after monocrotaline injection acetylcholine produced only 25% +/- 5% relaxation versus 95% +/- 5% in controls (p < 0.05), nitroprusside produced 46% +/- 5% relaxation versus 100% in controls (p < 0.05), and isoproterenol produced only 18% +/- 5% relaxation versus 94% +/- 4% in controls (p < 0.05). At the same time hypoxic pulmonary vasoconstriction became progressively exaggerated. CONCLUSIONS: Progressive dysfunction of pulmonary vasomotor control may contribute to the pulmonary hypertension seen in progressive lung injury.

Animals↗

PubMed1996

Vinblastine attenuates endotoxin-induced impairment of CGMP-mediated pulmonary vasorelaxation.

We tested the hypothesis that neutrophils contribute to endotoxin-induced impairment of endothelium-dependent and -independent cyclic guanosine monophosphate (cGMP)-mediated pulmonary vascular smooth muscle relaxation. Rats were studied 6 h after endotoxin (20 mg/kg, intraperitoneal) or saline (1 cc, intraperitoneal). Neutrophil-depleted rats were studied 4 days after administration of vinblastine (750 micrograms/kg, intravenous). Concentration-response curves were generated for acetylcholine and sodium nitroprusside in isolated pulmonary arterial rings (10(-9) M to 10(-6) M). The absolute neutrophil count of controls was 1050 +/- 206 neutrophils/mL, and the absolute neutrophil count of vinblastine-treated rats was 100 +/- 41 neutrophils/mL (p < .05 versus controls) and 25 +/- 25 neutrophils/mL in vinblastine-treated rats receiving endotoxin (p < .05 versus control and endotoxin). Endotoxin-induced impairment of endothelium-dependent and -independent cGMP-mediated pulmonary vasorelaxation was significantly attenuated by prior treatment with vinblastine. We conclude that neutrophils contribute to the pathogenesis of endotoxin-induced impairment of cGMP-mediated pulmonary vascular smooth muscle relaxation.

Acetylcholine↗

PubMed1996

Inhaled nitric oxide prevents pulmonary endothelial dysfunction after mesenteric ischemia-reperfusion.

This study examined the effect of inhaled nitric oxide (NO) on lung neutrophil accumulation and endothelial-dependent and -independent guanosine 3',5'-cyclic monophosphate (cGMP)-mediated mechanisms of pulmonary vasorelaxation after mesenteric ischemia-reperfusion (I/R) in mechanically ventilated rats. Inhaled NO (20 ppm) was administered in two protocols: 1) throughout mesenteric I/R and 2) during mesenteric reperfusion alone. Concentration-response curves were generated (10(-9) to 10(-8) M) for acetylcho-line (ACh), A23187, and sodium nitroprusside (SNP) in isolated pulmonary arterial rings preconstricted with phenylephrine. Lung neutrophil accumulation [myeloperoxidase assay (MPO)] was significantly increased from 2.4 +/- 0.2 units/g lung wt in controls to 10.3 +/- 0.4 after 1 h of superior mesenteric artery occlusion and 2 h of reperfusion. Lung MPO activity was not different from controls in rats receiving inhaled NO either 1) during mesenteric I/R or during mesenteric reperfusion alone. The concentration-response curves demonstrated significant impairment of pulmonary vasorelaxation by endothelial-dependent mechanisms (response to ACh and A23187) but not endothelial-independent pulmonary vasorelaxation (response to SNP) after mesenteric I/R. This pulmonary vasomotor dysfunction was prevented by administration of inhaled NO during either mesenteric I/R or during mesenteric reperfusion alone. We conclude that inhaled NO prevents lung neutrophil accumulation and pulmonary vascular endothelial dysfunction after mesenteric I/R.

Administration, Inhalation↗

PubMed1996

Neutrophil depletion attenuates endotoxin-induced dysfunction of cGMP-mediated pulmonary vasorelaxation.

The effect of neutrophil depletion on endotoxin-induced dysfunction of guanosine 3',5'-cyclic monophosphate (cGMP)-mediated pulmonary vasorelaxation was studied in rats. Two mechanisms of neutrophil depletion were used: vinblastine (0.75 mg/kg iv) and rabbit anti-rat neutrophil antiserum (0.15 ml iv). Concentration-response curves were generated (10(-9) to 10(-6) M) for acetylcholine (ACh), A-23187, and sodium nitroprusside (SNP) in isolated pulmonary arterial rings preconstricted with phenylephrine 6 h after endotoxin (20 mg/kg ip). Absolute neutrophil count was significantly lowered from 1,050 +/- 206 (neutrophils/ml; mean +/- SE) in controls to 100 +/- 41 by vinblastine and to 50 +/- 29 by antiserum. Endotoxin produced histological evidence of pulmonary vascular endothelial damage and significantly increased lung neutrophil accumulation (myeloperoxidase assay, 5.1 +/- 0 vs. 1.2 +/- 0.1 in controls; 0.1 +/- 0.1 and 0.8 +/- 0.0 U/g lung wt after endotoxin in neutrophil-depleted rats by vinblastine and antiserum, respectively). Endotoxin produced significant impairment of endothelium-dependent cGMP-mediated pulmonary vasorelaxation by receptor-dependent (ACh) and -independent (A-23187) pathways as well as endothelium-independent relaxation (SNP). Neutrophil depletion significantly attenuated the endotoxin-induced impairment of all three of these mechanisms. We conclude that neutrophils contribute to endotoxin-induced impairment of GMP-mediated pulmonary vasorelaxation.

Acetylcholine↗