Biomedical subjects

D G McCormack

Publications and source records attributed to D G McCormack.

47 records · Page 3Linked to original sources

PubMed1990

Platelet-activating factor: evidence against a role in hypoxic pulmonary vasoconstriction.

The mechanism of hypoxic pulmonary vasoconstriction (HPV) remains unknown. The platelet-activating factor (PAF) antagonist WEB 2086 attenuated HPV in the isolated lung model of the rat. We evaluated the effect of WEB 2086 on HPV in an intact animal. Pigs were anesthetized, mechanically ventilated, and had their hemodynamic variables monitored with a pulmonary artery catheter and arterial line. Cardiac output was measured by thermodilution. Initial studies determined that PAF (0.03 to 1.0 micrograms) injected iv dose-dependently increased pulmonary vascular resistance (PVR) with a 262 +/- 58% increase in PVR 5 min after a dose of 1.0 microgram. WEB 2086 (25 mg/kg iv) completely blocked the increase in PVR caused by iv PAF. Additionally, indomethacin (2 mg/kg followed by 2 mg/kg.h iv) treatment of the animals attenuated the PAF-induced increase in PVR. To evaluate the effect of WEB 2086 on HPV, animals were alternately ventilated with 21% oxygen and 10-min periods of 10% oxygen to induce HPV. After three initial control episodes of hypoxic ventilation, WEB 2086 (25 mg/kg) was injected iv and two more episodes of ventilation with 10% oxygen were given. During the three control HPV episodes the increases in PVR were 80 +/- 10%, 108 +/- 10%, and 107 +/- 22% (n = 5). After WEB 2086, the increase in PVR during two episodes of hypoxia were 96 +/- 28% and 99 +/- 19%, respectively, which was not significantly different from the control response to hypoxia. We conclude that iv PAF dose dependently increases PVR in pigs, and can be blocked by WEB 2086, that its effect is partially mediated through cyclooxygenase products, and that PAF does not appear to mediate HPV in this species.

Animals↗

PubMed1989

Effect of sensory neuropeptides on canine bronchial and pulmonary vessels in vitro.

Sensory neuropeptides may be important in the noncholinergic component of parasympathetic vasodilation in the tracheobronchial circulation. We studied the effects of substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and calcitonin gene-related peptide (CGRP) on the isolated canine bronchial artery and used pulmonary artery and vein of similar size for comparison. CGRP (10pM-300nM) was a potent relaxant of the bronchial and pulmonary arteries, and the pulmonary vein with equal potency in all vessels. SP in low concentrations (10pM-100nM) caused vasodilation of the precontracted bronchial artery and in high concentration (10-100 microM) contracted the vessel from resting tone. SP also relaxed the pulmonary artery and vein. NKA and NKB caused relaxation in all three vessels. All of the vascular effects of the sensory neuropeptides were concentration-dependent. The order of potency of the neuropeptides in the bronchial and pulmonary artery was SP greater than NKA greater than CGRP greater than NKB. In the pulmonary vein NKB caused a much larger relaxation than SP and NKA but it was less potent than either NKA or CGRP. Capsaicin (1 microM) caused a large contraction of the bronchial artery, similar in magnitude to the contraction caused by high dose of SP. Neuropeptide Y was also studied and found to cause no consistent constriction of any of the vessels studied. In conclusion, CGRP is a universal dilator of the bronchial and pulmonary blood vessels. SP and NKA exert their main effect on arterial vasomotor tone, whereas NKB is the only tachykinin producing marked dilation of the pulmonary vein.

Animals↗

PubMed1989

Evidence against a role for platelet-activating factor in hypoxic pulmonary vasoconstriction in the rat.

1. The effect of two structurally different platelet-activating factor (PAF) receptor antagonists, WEB 2086((3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-[1,2,4]- treazolo-[4,3-alpha][1,4]-diazepine-2-yl]-1-(morpholinyl)-1- propanone)) and BN 52021, on hypoxic pulmonary vasoconstriction (HPV) was studied using an isolated rat lung preparation perfused with blood. 2. In lungs treated with WEB 2086 there was a dose-dependent attenuation of HPV, with complete abolition of HPV at the maximum dose. 3. Low doses of WEB 2086 caused only slight diminution of the pressor response to angiotensin II, although higher doses caused increasing attenuation of the angiotensin pressor response. 4. BN 52021 did not affect HPV. 5. Injection of PAF caused an increase in pulmonary artery pressure of 145%, a response abolished by pretreatment of the lungs with either WEB 2086 or BN 52021. 6. These results suggest that PAF does not mediate HPV in the rat.

Animals↗

PubMed1989

Purinoceptors in the pulmonary circulation of the rat and their role in hypoxic vasoconstriction.

1. P2-purinoceptors have been characterized in the systemic circulation of a variety of species but little is known about their nature in the pulmonary vasculature. 2. In the isolated, blood perfused and ventilated lung of the rat the P2x selective analogues alpha,beta-methylene ATP(alpha,beta-meATP) (25 micrograms) and beta,gamma-methylene ATP (400 micrograms) caused a rise in pulmonary artery pressure (127 +/- 32% and 110 +/- 23% increase respectively, n = 6), demonstrating the existence of vasoconstrictor P2 receptors in the pulmonary circulation. 3. Repeated boluses of alpha,beta-meATP resulted in complete desensitization of the constrictor response to beta,gamma-meATP, but a small vasodilator response remained indicating unopposed stimulation of P2y receptors. The desensitization by alpha,beta-meATP had no effect on angiotensin II-induced vasoconstriction. 4. After desensitization of the vasoconstrictor P2 receptors with alpha, beta-meATP, hypoxic pulmonary vasoconstriction remained intact, indicating that these receptors are not involved in this response.

Adenosine Triphosphate↗

PubMed1989

Evidence for two P2-purinoceptor subtypes in human small pulmonary arteries.

1. P2-purinoceptors have not been characterized in human pulmonary vessels and we therefore examined the effects of adenosine 5'-triphosphate (ATP) and its analogues on human isolated small pulmonary arteries (SPA) in vitro. 2. Contractile responses were induced by all of the analogues, with the rank order of potency alpha,beta-methylene-ATP (alpha,beta-meATP) = beta,gamma-methylene-ATP (beta,gamma-meATP) greater than ATP greater than 2-methylthio-ATP, indicating the presence of vasoconstrictor P2x receptors. 3. In precontracted SPA, vasodilator responses were produced by all of the analogues. The rank order of potency for the analogues causing vasodilator responses was: 2-methylthio-ATP much greater than ATP much greater than beta,gamma-meATP = alpha,beta-meATP, indicating a vasodilator P2y receptor. 4. Removal of endothelial cells had no significant effect on either the contractile or relaxant responses to any of the analogues. 5. After pretreatment of the endothelium-denuded vessels with alpha,beta-meATP (to desensitize P2x receptors), the contractile response to beta,gamma-meATP (a potent P2x receptor agonist) was abolished. 6. We conclude that both P2x- and P2y-purinoceptors are present in human SPA and that both receptors reside on the vascular smooth muscle.

Adenosine Triphosphate↗

PubMed1989

Characterization of adenosine receptors in human pulmonary arteries.

We have characterized the effects of adenosine, the A1-receptor agonist N6-(L-2-phenylisopropyl)-adenosine (PIA) and the A2-receptor agonist 5'-(N-ethyl)-carboxamido-adenosine (NECA), in isolated human pulmonary vessels. Fresh human lung tissue was obtained from nine patients, and small pulmonary arteries (200-400 micron ID) were dissected and mounted in an organ bath. The effects of the adenosine antagonist 8-phenyltheophylline (8-PT) and endothelial denudation were also studied. Adenosine, NECA, and PIA (1-300 microM) all caused a dose-dependent vasodilation with log EC30 values of -4.31, -4.31, and -3.53, respectively. 8-PT (10 microM) caused a rightward shift of the adenosine dose-response curve, significantly decreasing the effect of adenosine (pKB = 6.3). Mechanical removal of endothelial cells had no significant effect on adenosine-mediated vasodilation. We also compared the effects of adenosine on eight large (7-10 mm ID) and eight small (200-400 micron ID) arteries and found no significant difference in the sensitivity to adenosine between these vessels. Our findings suggest that the pulmonary vasodilator effects of adenosine in humans are mediated through A2 receptors that are localized to vascular smooth muscle. Adenosine may function as a regulator of pulmonary vascular tone in humans and may have therapeutic potential.

Adenosine↗

PubMed1989

Calcitonin gene-related peptide vasodilation of human pulmonary vessels.

Human calcitonin gene-related peptide (CGRP) is localized to sensory neurons in pulmonary vessels and is a potent vasodilator. We have characterized the effects of CGRP in human pulmonary vessels and localized the receptors for this peptide by autoradiography. Fresh human lung tissue was obtained from eight patients undergoing surgery and small (200-400 microns ID) pulmonary arteries and veins were dissected free of surrounding connective and pulmonary tissue. Pairs of vessels were studied and in one of each pair the endothelium was left intact and from the other of each pair the endothelium was removed by gentle abrasion. For functional studies arteries (n = 9) and veins (n = 9) were suspended in an organ bath, precontracted with 1 microM prostaglandin F2 alpha. CGRP (10 pM to 10 microM) was added in a cumulative manner. CGRP caused a dose-dependent relaxation of endothelium intact human pulmonary arteries and veins with log EC50 values of -8.01 +/- 0.35 and -8.70 +/- 0.40, respectively (not significant). Removal of the endothelium did not diminish the vasodilator potency of CGRP in either vessel. For autoradiographic studies, cryostat sections of the small human pulmonary vessels with or without endothelium were used. 125I-CGRP densely labeled CGRP receptors on vascular smooth muscle and endothelial removal did not have any effect on grain density. We concluded that CGRP is a potent vasodilator of human pulmonary arteries and veins that is not dependent on an intact endothelium. These functional studies correlate with the distribution of CGRP receptors as localized by autoradiography.

Adult↗

PubMed1989

The contrasting influence of two lipoxygenase inhibitors on hypoxic pulmonary vasoconstriction in anesthetized pigs.

Because leukotrienes may mediate hypoxic pulmonary vasoconstriction (HPV), we examined the influence of two lipoxygenase inhibitors on HPV in anesthetized pigs. HPV was induced by ventilation with a hypoxic gas mixture (FIO2 at 0.095), resulting in a fall in PaO2 to 23 +/- 2 mm Hg and a rise in pulmonary vascular resistance from 285 +/- 15 to 595 +/- 30 dyne/s/cm-5. After infusion of either U-60,257B (50 mg/kg, n = 13) or BW 755c (20 mg/kg, n = 8), the responses to repeated hypoxic challenges were recorded. After U-60,257B infusion the hypoxic pressor response was eliminated at 10 and 30 min and remained significantly (p less than 0.01) attenuated at 50 min. The pulmonary pressor response to angiotensin II infusion (0.2 micrograms/kg/min) was also ablated, whereas the systemic response was unchanged. In contrast, after BW 755c infusion there was a modest but sustained augmentation of HPV, maximum at 30 min (pulmonary vascular resistance, 158 +/- 23% control, p less than 0.01), and no alteration of the responses to angiotensin II. BW 755c inhibited the A23187-induced release of leukotrienes, but not histamine, from isolated porcine lung cells (IC50, 6.3 x 10(-5) M), whereas U-60,257B inhibited the release of both leukotriene (IC50, 1.1 x 10(-4) M) and histamine. These findings indicate that reduction of HPV by lipoxygenase inhibitors is not necessarily a consequence of inhibition of leukotriene synthesis.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

PubMed1989

Characterization and distribution of P2-purinoceptor subtypes in rat pulmonary vessels.

To characterize P2-purinoceptors in pulmonary vessels we have examined the effects of ATP analogs on rat isolated pulmonary artery and vein in vitro. The rank order of potency for causing vasoconstriction was: alpha,beta-methylene-ATP (alpha,beta-meATP) greater than beta,gamma-methylene-ATP (beta,gamma-meATP) greater than 2-methylthio-ATP (2m.S.ATP) greater than ATP for arteries; and alpha,beta-meATP much greater than beta,gamma-meATP = 2m.S.ATP greater than ATP for veins, indicating that a P2x receptor was involved. The contractile response to these analogs was virtually abolished after desensitization of P2x-receptors by alpha,beta-meATP. Removal of the endothelial cells enhanced the contractile responses to all of the ATP analogs in both arteries and veins. The rank order of potency for vasodilatation was 2m.S.ATP much greater than ATP = beta,gamma-meATP much greater than alpha,beta-meATP for arteries and 2m.S.ATP much greater than ATP = beta-gamma-meATP, with alpha,beta-meATP being no effect for veins, indicating a P2y receptor. Pretreatment of the pulmonary arteries with the P2y-antagonist reactive blue 2 caused a rightward shift of the dose-response curves to 2m.S.ATP, ATP and beta,gamma-meATP. Reactive blue 2 was only used with the pulmonary arteries. Removal of the endothelium converted the relaxant responses to all the ATP analogs (except to ATP in pulmonary artery) to further contraction. In the pulmonary artery, the small endothelium-independent relaxation induced by ATP was abolished completely by pretreating the vessels with 100 microM theophylline (a P1-purinoceptor antagonist), suggesting that it was due to conversion of ATP to adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1988

Muscarinic receptor subtypes mediating vasodilation in the pulmonary artery.

Binding studies in several species have demonstrated a high proportion of M1 muscarinic receptors in the lung but their localization is uncertain. Using [3H]quinuclidinyl benzylate we have confirmed that binding sites with high affinity for pirenzepine account for 50% of muscarinic receptors in the rat lung. Our functional studies using the muscarinic antagonists 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), methoctramine and pirenzepine have demonstrated that the muscarinic receptor on the rat pulmonary artery endothelium which mediates vasodilation is of the M3 subtype and cannot account for the high proportion of M1 receptors identified in lung homogenates.

Animals↗

PubMed1987

The midclavicular line: a wandering landmark.

Although the midclavicular line (MCL) is the usual reference point for clinical assessment of liver size and localization of the cardiac apex beat, we found substantial interobserver variation in locating the MCL. The distance from the midline to the MCL as estimated by 20 clinicians in three subjects varied by up to 10 cm. More variation was found for estimates in the obese subject than for those in the two subjects of normal build (p = 0.004). No difference in variation was found between consultants and house staff. The limitations of the MCL as a reference point are discussed in light of these findings.

Cardiomegaly↗