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D G McCormack

Publications and source records attributed to D G McCormack.

At least 37 records · Page 2Linked to original sources
PubMed1996

Inducible nitric oxide synthase and vascular reactivity in rat thoracic aorta: effect of aminoguanidine.

We tested the hypothesis that selective inhibition of the inducible form of nitric oxide (NO) synthase with aminoguanidine would prevent the loss of vascular contractility after exposure to endotoxin [lipopolysaccharide (LPS)]. Aortic rings were dissected from Sprague-Dawley rats, suspended in organ baths containing Krebs solution, and tested for vascular reactivity. Vessels incubated with LPS (1 microgram/ml) for 5 h exhibited a significant decrease in the maximal contractile response to phenylephrine. Aminoguanidine (100 microM) restored the maximal contractile response of LPS-treated vessels to the level of the control vessels. Aminoguanidine was approximately 250-fold less potent than NG-nitro-L-arginine methyl ester in inhibiting the constitutive NO synthase in vascular tissue as determined by its ability to further increase tone of submaximally contracted aortic rings. NO synthase activity was determined in vascular tissue incubated with and without LPS. Vessels incubated with LPS exhibited a marked increase in the levels of inducible NO synthase activity compared with control vessels. This increase was restored to control levels when tissue homogenates were incubated with aminoguanidine. We conclude that aminoguanidine is a selective concentration-dependent inhibitor of the inducible form of NO synthase and may be a useful probe to evaluate the role of inducible NO synthase in the abnormal vascular contractility characteristic of endotoxemia and sepsis.

Animals↗
PubMed1996

Nonadrenergic noncholinergic relaxation of human pulmonary arteries is partially mediated by nitric oxide.

Nonadrenergic noncholinergic (NANC) vasodilator mechanisms may contribute to the maintenance of low vascular resistance characteristic of the pulmonary circulation. Previous studies have demonstrated that nitric oxide (NO) is the principal NANC neurotransmitter in guinea pig pulmonary arteries. We examined whether NANC relaxation could be demonstrated in human pulmonary arteries, and the role of NO in this phenomenon. Fresh human pulmonary artery rings, with and without an intact endothelium, were mounted in organ baths containing Krebs' solution and precontracted with U44069 (0.3 microM). Adrenergic and cholinergic neurotransmitter pathways were blocked with guanethidine and atropine, respectively (10 microM each). In both endothelium-intact and -denuded vessels, electrical field stimulation (EFS, 1 to 10 Hz, 100 V) resulted in a frequency-dependent relaxation (maximal relaxation of 25 +/- 4% and 15 +/- 2% in endothelium-intact and -denuded vessels, respectively). Tetrodotoxin (0.3 microM) abolished the EFS-induced relaxation. L-NG-nitro-arginine methyl ester (L-NAME, 10 microM), was used to block enzymatic synthesis of NO. In both endothelium-intact and -denuded vessels, L-NAME reduced NANC relaxation to approximately 50% of control values. This reduction was reversible with the application of L-arginine (100 microM). We conclude that NANC relaxation exists in human pulmonary arteries and that it is partly mediated through NO.

Arginine↗
PubMed1996

Noninvasive assessment of cardiac function during exercise in patients with CHF or COPD: measurement of aortic bloodflow indices by continuous wave Doppler.

OBJECTIVE: To test whether continuous-wave Doppler measurements of aortic bloodflow indices would reliably distinguish patients with congestive heart failure (CHF) from those with chronic obstructive pulmonary disease (COPD) and a similar degree of exertional dyspnea. DESIGN. Parallel group comparison. SETTING: University teaching hospital. PARTICIPANTS: Eighteen out-patients with clinically distinct syndromes of CHF or COPD but of similar age and functional limitation. INTERVENTION: Participants were observed during graded treadmill exercise. The following indices were obtained: heart rate, systolic blood pressure (SBP), earlobe oxygen saturation, and continuous-wave Doppler measurements of aortic bloodflow from the suprasternal notch. MAIN RESULTS: Exercise duration (mean +/- SE): COPD 14.2 +/- 1.2 mins, CHF 14.0 +/- 1.2 mins, not significant. Maximum results during exercise: heart rate, CHF 143 +/- 7 beats/min, COPD 149 +/- 5 beats/min, not significant; peak velocity, CHF 0.60 +/- 0.04 m/s, COPD 0.92 +/- 0.07 m/s, P < 0.005; peak acceleration, CHF 17 +/- 1 m/s2, COPD 37 +/- 3 m/s2, P < 0.001; SBP: CHF 152 +/- 8 mmHg, COPD 207 +/- 5 mmHg, P < 0.001; minimum oxygen saturation: CHF 92 +/- 1%, COPD 88 +/- 2%, not significant. CONCLUSIONS: Aortic bloodflow indices can be measured during exercise in patients with exertional dyspnea due to CHF or COPD and, in CHF, these indices are significantly reduced compared with individuals with COPD measured at similar levels of exercise. These data suggest that measurement of aortic bloodflow indices may have a role as an adjunct to routine tests in the diagnosis of patients with dyspnea. Further studies are indicated in patients with clinical features of both COPD and CHF in whom the etiology of dyspnea is uncertain.

Aged↗
PubMed1995

Vascular reactivity in sepsis: importance of controls and role of nitric oxide.

We have previously reported differential impairment of pulmonary and systemic vascular contractility in hyperdynamic sepsis. The objectives of this study were (1) to determine whether the magnitude of this phenomenon depends on the control group chosen for comparison, and (2) to examine the role of nitric oxide (NO) in this altered vascular contractility. Rats were randomized to sepsis induced by cecal ligation and perforation (CLP) or to one of two control procedures. The Sepsis group had a jugular venous line for fluid administration, laparotomy, and CLP. Control group 1 (Control) had only a jugular venous line inserted, while group 2 (Sham) had a jugular venous line inserted and an abdominal incision. All rats were killed 24 h after surgery. Vascular contractility of small pulmonary arterial and thoracic aortic rings was assessed in vitro by obtaining cumulative dose-response curves to the contractile agonists potassium chloride (KCl), phenylephrine (PE), and prostaglandin F2 alpha (PGF2 alpha). Pulmonary vessels from animals in the Sepsis and Sham groups exhibited significant attenuation of the contractile responses to KCl, PE, and PGF2 alpha compared with the Control group. In contrast, contractility of the aortic rings to KCl, PE, and PGF2 alpha was not significantly different in the three groups studied. Incubation of pulmonary and aortic vessels with NG-nitro-L-argine methyl ester (L-NAME, 10 microM) caused an increase in the response to KCl, PE, and PGF2 alpha in pulmonary vessels in Sepsis and Sham rats but not in Control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Control of vascular reactivity.

The two commonly recognized sequelae of acute lung injury (ALI) are pulmonary hypertension and arterial hypoxemia. The mechanism of the pulmonary hypertension is not precisely known, but undoubtedly is contributed to by both vasoactive mediators and pulmonary parenchymal structural changes. The pulmonary circulation is normally tightly controlled such that there is excellent matching of perfusion to ventilation through attenuation of hypoxic pulmonary vasoconstriction (HPV). In ALI, there is an attenuation of HPV and resulting areas of low ventilation/perfusion or shunt. The mechanism behind this abnormal pulmonary vascular contractility in disease is under investigation, but may involve the release of endogenous vasodilator mediators such as nitric oxide.

Acute Disease↗
PubMed1994

Effect of inhibition of NO synthase on vascular reactivity in a rat model of hyperdynamic sepsis.

To evaluate the role of nitric oxide (NO) in the attenuated vascular reactivity observed in sepsis, we utilized the specific NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). Male Sprague-Dawley rats (n = 16) were randomized to either sepsis induced by cecal ligation and perforation (CLP; n = 8) or sham procedure (Sham; n = 8). Vascular reactivity was assessed by measuring the pulmonary pressor response to hypoxia (HPV) (fractional inspired O2 concentration = 0.08) and the pulmonary and systemic pressor response to an intravenous infusion of phenylephrine (1.5-6.0 micrograms.kg-1.min-1). Twenty-four hours after surgery, CLP animals had significantly attenuated HPV compared with Sham animals. In response to hypoxia the change in total pulmonary vascular resistance during hypoxia was 0.008 +/- 0.004 and 0.021 +/- 0.006 mmHg.min-ml-1 in CLP and Sham animals, respectively (P < 0.05). The pulmonary and systemic blood pressure response to phenylephrine was also attenuated in CLP compared with Sham animals. After L-NAME infusion (15 mg/kg), there was a significant augmentation of the HPV response in Sham animals. In contrast, the HPV response in CLP animals was unchanged after L-NAME. The attenuated pressor response to phenylephrine in neither the pulmonary nor the systemic circulation was changed after the administration of L-NAME. These data suggest that in rats, excess NO is not an important mediator of the attenuated vascular reactivity observed in sepsis.

Amino Acid Oxidoreductases↗
PubMed1994

Accuracy of portable chest radiography in the critical care setting. Diagnosis of pneumonia based on quantitative cultures obtained from protected brush catheter.

Sixty-six supine portable chest radiographs done on the day of bronchoscopy in 62 critical care unit patients suspected of having pneumonia were examined in a blinded fashion by two radiologists. Quantitative culture results obtained from protected brush catheter (PBC) specimens were compared with chest radiograph scores. For one observer, the sensitivity of the chest radiograph for predicting the presence of positive culture results was 0.60, specificity was 0.29, overall agreement was 0.41, positive predictive value was 0.34, and negative predictive value was 0.55. For the second observer, the values were as follows: sensitivity, 0.64; specificity, 0.27; overall agreement, 0.41; positive predictive value, 0.35; and negative predictive value, 0.55. The kappa statistic was calculated at 0.27 indicating marginal interobserver reproducibility. We conclude the portable chest radiograph in the critical care setting is not accurate in predicting the presence of pneumonia when the diagnosis is based on quantitative cultures obtained from protected brush catheter specimens.

Aged↗
PubMed1993

New perspectives in the pulmonary circulation and hypoxic pulmonary vasoconstriction.

In the past few years there has been a reawakening of interest in the systems that underly pulmonary vascular control and an increased awareness of the clinical potential of pharmacological manipulation of the pulmonary circulation. Nevertheless, although so much has been learned about the physiological role of the endothelium, vasoactive substances, and neural modulation of the pulmonary vasculature; how these disparate influences interact to control the matching of ventilation to perfusion remains uncertain. Consequently, even less is known of the way in which lung injury influences these regulatory processes. It is likely that the response to hypoxia may involve a system with many pathways and much redundancy, such that blockade of the production of a single agent has only a minor effect on HPV. We speculate that the products of arachidonic acid metabolism, PAF, adenosine and EDRF, may act in concert with neural pathways in a 'microenvironment' bounded by the alveolus and endothelium to modify pulmonary vascular tone during both normoxic and hypoxic conditions.

Animals↗
PubMed1993

Sensory neuropeptides and hypoxic pulmonary vasoconstriction in the rat.

BACKGROUND: Endogenous vasodilators such as endothelially derived relaxant factor have been shown to modulate hypoxic pulmonary vasoconstriction. Sensory peptides such as substance P (SP) and calcitonin gene related peptide (CGRP) are also potent pulmonary vasodilators in both animals and humans. Their possible role in the modulation of the normal hypoxic pressor response has been examined in an isolated, ventilated, and blood perfused rat lung preparation. METHODS: Animals (n = 7) were pretreated with 50 mg/kg capsaicin administered subcutaneously to deplete nerve endings of sensory neuropeptides. A control group (n = 7) received a subcutaneous dose of capsaicin vehicle. One week later the rats were killed and the rise in pulmonary artery pressure was measured during four successive periods of hypoxic ventilation (FIO2 0.03), and after four injections of angiotensin II (1.0 microgram). RESULTS: A 60% depletion of SP levels was measured in the sciatic nerves of animals treated with capsaicin. The hypoxic pressor response was not significantly altered in capsaicin treated animals compared with controls, except during the fourth hypoxic episode when it was augmented. The angiotensin II pressor response was the same in both groups during each of the injections. CONCLUSION: The sensory neuropeptide SP (and possibly CGRP) does not have a major role in modulating the pulmonary vascular response to hypoxia.

Angiotensin II↗
PubMed1993

Nitric oxide does not mediate the attenuated pulmonary vascular reactivity of chronic pneumonia.

Chronic Pseudomonas pneumonia is associated with decreased acute hypoxic pulmonary vasoconstriction. However, it is not known whether this is a result of a generalized reduction in contractile responsiveness. We therefore examined the effect of chronic Pseudomonas pneumonia on in vitro pulmonary vascular responsiveness to agonists. We then investigated the role of nitric oxide (NO) in the altered pulmonary vascular contractility. Control rats or rats infected with Pseudomonas (pneumonia) were killed, and small intrapulmonary arteries (100-200 microns effective lumen radius) were removed. In the pneumonia group, arteries were harvested from the pneumonic area of the lung. Vascular responsiveness was assessed in vitro by obtaining cumulative dose-response curves to contractile agonists [phenylephrine (PE), 5-hydroxytryptamine (5-HT), prostaglandin F2 alpha (PGF2 alpha), and KCl]. KCL-induced (voltage-operated) contractions were not significantly depressed in small pulmonary arteries from pneumonic lungs, suggesting that the smooth muscle contractile apparatus in these arteries was preserved. Contractile responses to the three receptor-operated agonists (PE, 5-HT, and PGF2 alpha) were significantly depressed in arteries subserving the pneumonic lobe of infected rats. NG-monomethyl-L-arginine, which blocks the synthesis of NO, caused a shift toward the left in the dose-contraction curves to PE, PGF2 alpha, and 5-HT in vessels from the sterile control lungs, but it had little effect on arteries from the pneumonic lungs. Chronic Pseudomonas pneumonia is associated with depressed pulmonary vascular contractility in vitro, particularly affecting the receptor-mediated contractile responses. Excessive NO release does not contribute to this attenuated vascular contractility.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1993

Loss of hypoxic pulmonary vasoconstriction in chronic pneumonia is not mediated by nitric oxide.

In pulmonary inflammatory processes such as pneumonia there is diminished hypoxic pulmonary vasoconstriction (HPV). We investigated whether the attenuated HPV in pneumonia is a due to excess nitric oxide (NO) release. Sprague-Dawley rats were anesthetized, and a slurry (0.06 ml) of infected agar beads (containing 6 x 10(5) Pseudomonas aeruginosa organisms) or control (sterile) beads was then injected into a distal bronchus through a tracheotomy. After the establishment of a chronic P. aeruginosa pneumonia (7-10 days later) animals were instrumented for hemodynamic monitoring, and the response to exposure to hypoxic gas (fraction of inspired O2 = 0.08) was recorded before and after the administration of NG-monomethyl-L-arginine (L-NMMA; 50 mg/kg), an inhibitor of NO synthesis. The hypoxic pressor response, as assessed by the absolute increase in pulmonary arterial pressure (PAP) and total pulmonary resistance (TPR), was reduced in infected animals compared with control animals. The change in PAP and TPR was 8.5 +/- 0.7 and 0.053 +/- 0.007, respectively, in control animals compared with 5.9 +/- 0.5 and 0.041 +/- 0.011 in infected animals. After L-NMMA the increase in PAP and TPR during hypoxia was greater in both control and infected animals. However, treatment with L-NMMA did not affect the difference between control and infected animals. We conclude that excess release of NO does not account for the attenuated hypoxic pressor response in pneumonia.

Animals↗
PubMed1992

Bleomycin-induced lung injury in rats selectively abolishes hypoxic pulmonary vasoconstriction: evidence against a role for platelet-activating factor.

1. The role of platelet-activating factor in the attenuated hypoxic pulmonary vasoconstriction associated with lung injury was evaluated using specific platelet-activating factor antagonists and an isolated perfused lung preparation. 2. Intratracheal bleomycin was administered to rats to produce acute lung injury. Animals received intratracheal saline (control), intratracheal bleomycin or the platelet-activating factor antagonists BN 52021, WEB 2170 or WEB 2086 before and after bleomycin treatment. Forty-eight hours after intratracheal administration of bleomycin or saline the animals were killed. 3. The increases in pulmonary artery pressure during two periods of hypoxic ventilation and in response to 0.2 microgram of angiotensin II were measured. Acetylcholine-induced vasodilatation after pre-constriction with prostaglandin F2 alpha was also measured. To quantify lung injury, the wet/dry ratio of lung weight was determined. 4. Bleomycin treatment attenuated the first and second hypoxic pressor responses by 93% and 77%, respectively, but not the pressor response to angiotensin II nor the vasodilator response to acetylcholine. BN 52021 plus bleomycin augmented the first hypoxic pressor response compared with bleomycin treatment alone, but the structurally unrelated platelet-activating factor antagonists WEB 2170 and WEB 2086 had no significant effect on the bleomycin-induced attenuation of hypoxic pulmonary vasoconstriction. None of the platelet-activating factor antagonists blocked the increase in the wet/dry lung weight ratio induced by bleomycin. 5. Bleomycin-induced lung injury selectively attenuates hypoxic pulmonary vasoconstriction, an effect that does not appear to be mediated by platelet-activating factor. The mechanism remains to be elucidated, but may involve destruction of the hypoxic 'sensor' within the respiratory tract.

Acetylcholine↗
PubMed1992

Bleomycin-induced acute lung injury in the rat does not influence pulmonary vascular responsiveness in vitro.

OBJECTIVE: To investigate the effects of the intratracheal and iv administration of bleomycin on the contraction and endothelially dependent vasodilation of rat pulmonary arteries in vitro. DESIGN: Prospective pharmacologic study. SETTING: National Heart and Lung Institute, London, UK. INTERVENTIONS: Intratracheal saline, intratracheal and iv bleomycin. MEASUREMENTS AND MAIN RESULTS: Rats treated with intratracheal bleomycin developed a significant increase in mean lung wet/dry weight ratio (5.6 +/- 0.4 [SEM] vs. 3.9 +/- 0.1, p less than .05) when compared with saline-treated control animals, confirming the development of pulmonary edema. However, these rats displayed normal relaxant responses to the endothelially dependent vasodilator acetylcholine and a normal contractile response to phenylephrine in vitro. Intravenous bleomycin had no effect on either wet/dry weight ratio or the response to either drug. CONCLUSIONS: Despite evidence for the loss of endothelial integrity that characterizes lung injury after intratracheal bleomycin, isolated pulmonary artery rings in vitro showed no loss of endothelial cell function. The role of the endothelium in modulating pulmonary ventilation/perfusion matching after lung injury is unclear.

Animals↗
PubMed1991

Adenosine as a vasodilator in primary pulmonary hypertension.

BACKGROUND: The acute administration of vasodilator drugs to patients with primary pulmonary hypertension has been advocated to identify those with reversible pulmonary vasoconstriction. Unfortunately, the usefulness of the drugs currently available is limited by accompanying systemic hypotension. A vasodilator with effects confined to the pulmonary circulation would therefore be advantageous in such patients. METHODS AND RESULTS: The purine nucleoside adenosine was infused into the pulmonary artery in seven patients with primary pulmonary hypertension (baseline pulmonary vascular resistance [PVR], 442-1,295 dyne/cm/sec-5) to determine its effect on PVR. In all patients, there was a dose-dependent and significant reduction (mean maximal percent decrease from baseline, 38.9%; p less than 0.001) in PVR mediated through a decrease in pulmonary artery pressure and an increase in cardiac output. Systemic vascular resistance (SVR) also decreased, but the ratio of PVR to SVR decreased (maximal mean percent decrease from baseline) by 10.5% (p less than 0.025), indicating that adenosine has a preferential vasodilator effect on the pulmonary circulation when administered in this manner. CONCLUSIONS: Because of its pharmacokinetic and vasodilator properties, adenosine may have a specific role in the investigation of primary pulmonary hypertension.

Adenosine↗
PubMed1990

Ligustrazine is a vasodilator of human pulmonary and bronchial arteries.

We have investigated the dilator effect of ligustrazine, the semisynthetic principle of a traditional Chinese herbal remedy, on human pulmonary and bronchial arteries in vitro. Ligustrazine caused a concentration-dependent relaxation of human small pulmonary arteries, which was independent of endothelium. Although ligustrazine was equally potent in inducing dilatation of pulmonary and bronchial arteries, it was about 10 times more potent in relaxing small pulmonary arteries (300-500 microns i.d.) compared with lobar pulmonary arteries (7-8 mm i.d.). By contrast, the relaxant responses of small and lobar pulmonary arteries to sodium nitroprusside was not significantly different. Ligustrazine was equally potent in relaxing prostaglandin F2 alpha- or 5-hydroxytryptamine-precontracted pulmonary arteries, suggesting that it is not a prostaglandin F2 alpha or 5-hydroxytryptamine antagonist. Preincubating the vessels with propranolol (1 microM) or indomethacin (10 microM) had no significant effect on the ligustrazine-induced vasodilatation. However, ligustrazine caused concentration-dependent inhibition of calcium-evoked contraction when applied to rat aorta in calcium-free K(+)-depolarizing medium. We conclude that ligustrazine is a dilator of human pulmonary and bronchial arteries, which is endothelium-independent and that ligustrazine preferentially relaxes pulmonary resistance vessels rather than large conduit pulmonary arteries.

Animals↗
PubMed1990

Effects of dopexamine hydrochloride on hypoxic pulmonary vasoconstriction in isolated rat lung.

Dopexamine hydrochloride is a new analog of dopamine that lowers systemic vascular resistance and has positive inotropic and chronotropic properties, but lacks the alpha-adrenoceptor agonist activity of dopamine. The effects of dopexamine on hypoxic pulmonary vasoconstriction (HPV) are not known. We investigated this using an isolated, blood-perfused, and ventilated rat lung model. To study HPV, the ventilating gas was changed from an FIO2 of 0.21 to 0.03 and dopexamine hydrochloride was added. At blood concentrations of 100, 200, and 300 ng/ml, dopexamine caused a significant decrease in HPV of 22 +/- 3%, 31 +/- 4%, and 58 +/- 4% (mean +/- SEM, p less than .05), respectively. This effect was blocked completely by pretreatment of the preparation with propranolol (0.5 mg/kg, p less than .05). Dopexamine also induced significant (p less than .05) vasodilation of the pulmonary circulation preconstricted under normoxic conditions with prostaglandin F2 alpha, suggesting that the effects of the drug were not specific to hypoxia. We conclude that dopexamine inhibits HPV and vasodilates the pulmonary circulation by stimulation of beta 2 adrenoceptors.

Animals↗