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K M McCulloch

Publications and source records attributed to K M McCulloch.

At least 19 recordsLinked to original sources
PubMed2000

Regional distribution of potassium currents in the rabbit pulmonary arterial circulation.

The response of pulmonary arteries to hypoxia varies as a function of vessel diameter. Small intrapulmonary resistance arteries are thought to be the main site of hypoxic pulmonary vasoconstriction (HPV), with hypoxia causing minimal contraction or even dilatation in large, conduit vessels. This has been proposed to reflect a differential distribution of morphologically and electrophysiologically distinct pulmonary artery smooth muscle (PASM) cells. We investigated longitudinal heterogeneity in smooth muscle cells isolated from five regions of the rabbit pulmonary vasculature and could find no evidence of morphological heterogeneity at the level of the light microscope. PASM cells from main (8 mm outer diameter) and branch (5 mm) arteries and large ( 400 m) intrapulmonary arteries (IPA) were similar in shape and size, as indicated by cell capacitance (25 pF). PASM cells from medium (200-400 m) and small ( 200 m) IPA were significantly smaller (15 pF), but had the same classical spindle shape. Cells from all five regions also had similar resting membrane potentials and displayed voltage-activated K+ currents of similar amplitude when recorded in standard physiological solution. Longitudinal heterogeneity in K+ current became apparent when tetraethylammonium ions (TEA; 10 mM) and glibenclamide (10 M) were added. The remaining delayed rectifier current (IK(V)) doubled in amplitude upon moving down the pulmonary arterial tree from the main artery (9 pA pF-1 at 40 mV) to the large IPA (17 pA pF-1), but remained constant throughout the intrapulmonary vasculature. The O2-sensitive, non-inactivating K+ current (IK(N)) showed a similar trend, but was significantly reduced in the smallest IPA, where its amplitude was comparable with the main artery. Thus the IK(N)/IK(V) ratio was relatively constant, at around 0.14, from the main pulmonary artery to medium IPA, but fell by 50% in the smallest vessels. The amplitude of the TEA-sensitive K+ current was similar (16 pA pF-1 at 40 mV) at all levels of the pulmonary arterial tree, except in the medium sized vessels where it was 50% smaller. These variations in K+ current expression correlate with reported variations in sensitivity to hypoxia and may contribute to the regional heterogeneity of HPV in the rabbit lung.

Anaerobiosis↗
PubMed1999

NOS inhibition potentiates norepinephrine but not sympathetic nerve-mediated co-transmission in resistance arteries.

OBJECTIVE: The in vitro interaction between sympathetic nerves and basal nitric oxide release was studied in a resistance artery, since these interact powerfully in large vessels. METHODS: The pharmacological interaction between L-NAME and vasoconstriction to field stimulation of sympathetic nerves or exogenous norepinephrine was studied in rabbit cutaneous resistance arteries in wire myographs. RESULTS: Relaxation of norepinephrine-induced tone by acetylcholine, but not sodium nitroprusside, was blocked by N omega-nitro-L-arginine methyl ester (L-NAME: 100 microM), indicating that the agonist-induced release of nitric oxide could oppose the vasoconstrictor effect of norepinephrine and confirming that L-NAME had no effect on endothelium-independent vasodilatation. L-NAME increased norepinephrine potency indicating basal NO release. With short bursts of electrical field stimulation purinergic transmission was dominant at low frequencies and adrenergic at high frequencies. L-NAME had no effect on nerve-mediated responses, even after blocking the purinergic component with alpha,beta-methylene ATP (3 microM), suggesting that the influence of spontaneously released nitric oxide does not extend to the vascular smooth muscle cells under adrenergic nervous control. CONCLUSION(S): This resistance artery exhibits a highly effective nitric oxide-mediated vasodilatation to acetylcholine. It has basal release of nitric oxide which antagonises exogenous norepinephrine. However, basal nitric oxide did not influence adrenergic nerve transmission, which contrasts with previous studies of larger arteries and veins. We speculate that in small resistance arteries there may be a spatial limitation to the zones of vascular smooth muscle influenced by the adrenergic nerves and by basal nitric oxide from the endothelium, respectively. The role of endogenous nitric oxide in modulating vascular tone may thus be less in resistance arteries than in conducting arteries or capacitance vessels and purinergic transmission appears to be particularly resistant.

Acetylcholine↗
PubMed1999

Oxygen-sensing potassium currents in pulmonary artery.

The pulmonary vasculature is sensitive to the relative components of the respiratory gases and will vasoconstrict in response to decreased oxygen (O2) levels. This hypoxic pulmonary vasoconstriction (HPV) controls pulmonary blood flow in the fetus and serves to maximize ventilation perfusion matching in the adult lung. The exact mechanism of HPV is not fully understood but it appears to involve direct effects on both the endothelium and smooth muscle cells within the vessel wall. There is growing evidence to suggest that hypoxia mediates vasoconstriction, at least in part through the inhibition of outward potassium (K+) current in smooth muscle. A number of K+ currents present in the pulmonary vasculature have been shown to be sensitive to O2, with hypoxia acting to inhibit these currents in the majority of cases. Differences in the expression of these O2-sensitive K+ channels may explain regional and generic variations observed in the HPV response. The mechanism by which these K+ channels sense changes in O2 levels may involve changes in the cellular redox state, oxidative phosphorylation or a direct effect on the channel protein itself.

Animals↗
PubMed1998

Influence of applied tension and nitric oxide on responses to endothelins in rat pulmonary resistance arteries: effect of chronic hypoxia.

1. The effect of basal tension (transmural tensions 235 +/- 29 mg wt (low tension: equivalent to approximately 16 mmHg) and 305 +/- 34 mg wt (high tension: equivalent to 35 mmHg)) on rat pulmonary resistance artery responses to endothelin-1 (ET-1) and the selective ET(B)-receptor agonist sarafotoxin S6c (S6c) were studied. The effects of nitric oxide synthase inhibition with N(omega)-nitro-L-arginine methylester (L-NAME, 100 microM) on ET receptor-induced responses, as well as vasodilator responses to acetylcholine (ACh) and S6c, were also investigated. Changes with development of pulmonary hypertension, induced by two weeks of chronic hypoxia, were determined. 2. Control rat preparations showed greatest sensitivity for ET-1 when put under low tension (pEC50: 8.1 +/- 0.1) compared with at the higher tension (pEC50: 7.7 +/- 0.1) and there were significant increases in maximum contractile responses to S6c (approximately 80%) and noradrenaline (approximately 60%) when put under high tension. 3. In control pulmonary resistance arteries, both ET-1 and S6c produced potent vasoconstrictor responses. S6c was 12 fold more potent than ET-1 in vessels set at low tension (S6c pEC50: 9.2 +/- 0.1) and 200 fold more potent than ET-1 when the vessels were set at high tension (S6c pEC50: 9.0 +/- 0.1). Chronic hypoxia did not change the potencies of ET-1 and S6c but did significantly increase the maximum contractile response to ET-1 by 60% (at low tension) and 130% (at high tension). 4. In control rat vessels, L-NAME itself caused small increases in vascular tone (5-8 mg wt tension) in 33-56% of vessels. In the chronic hypoxic rats, in vessels set at high tension, L-NAME-induced tone was evident in 88% of vessels and had increased to 26.9 +/- 6.6 mg wt tension. Vasodilatation to sodium nitroprusside, in non-preconstricted vessels, was small in control rat vessels (2-6 mg wt tension) but increased significantly to 22.5 +/- 8.0 mg wt tension in chronic hypoxic vessels set at the higher tensions. Together, these results indicate an increase in endogenous tone in the vessels from the chronic hypoxic rats which is normally attenuated by nitric oxide production. 5. L-NAME increased the sensitivity to S6c 10 fold (low tension) and 6 fold (high tension) only in chronic hypoxic rat pulmonary resistance arteries. It had no effect on responses to ET-1 in any vessel studied. 6. Vasodilatation of pre-contracted vessels by ACh was markedly greater in the pulmonary resistance arteries from the chronic hypoxic rats (pIC50: 7.12 +/- 0.19, maximum: 72.1 +/- 0.2.0%) compared to their age-matched controls (pIC50: 5.77 +/- 0.15, maximum: 28.2 +/- 2.0%). There was also a 2.5 fold increase in maximum vasodilatation induced by ACh. 7. These results demonstrate that control rat preparations showed greatest sensitivity for ET-1 when set at the lower tension, equivalent to the pressure expected in vivo (approximately 16 mmHg). Pulmonary hypertension due to chronic hypoxia potentiated the maximum response to ET-1. Pulmonary resistance arteries from control animals exhibited little endogenous tone, but exposure to chronic hypoxia increased endogenous inherent tone which is normally attenuated by nitric oxide. Endogenous nitric oxide production may increase in pulmonary resistance arteries from chronic hypoxic rats and attenuate contractile responses to ET(B2) receptor stimulation. Relaxation to ACh was increased in pulmonary resistance arteries from chronic hypoxic rats.

Animals↗
PubMed1998

Endothelin receptors mediating contraction of rat and human pulmonary resistance arteries: effect of chronic hypoxia in the rat.

1. We examined the endothelin (ET) receptors mediating contractions to ET-1, ET-3 and sarafotoxin S6c (SX6c) in rat pulmonary resistance arteries by use of peptide and non-peptide ET receptor antagonists. Changes induced by pulmonary hypertension were examined in the chronically hypoxic rat. The effect of the mixed ET(A)/ET(B) receptor antagonist SB 209670 on endothelin-mediated contraction was also examined in human pulmonary resistance arteries. 2. In rat vessels, the order of potency for the endothelin agonists was SX6c = ET-3 > ET-1 (pEC50 values in control rats: 9.12+/-0.10, 8.76+/-0.14 and 8.12+/-0.04, respectively). Maximum contractions induced by ET-3 and ET-1 were increased in vessels from chronically hypoxic rats. 3. The ET(A) receptor antagonist FR 139317 (1 microM) had no effect on the potency of ET-1 in any vessel studied but abolished the increased response to ET-1 in the chronically hypoxic vessels. The ET(A) receptor antagonist BMS 182874 (1 microM) increased the potency of ET-1 in control rat vessels without effecting potency in the pulmonary hypertensive rat vessels. 4. Bosentan (non-peptide mixed ET(A)/ET(B) receptor antagonist) increased the potency of ET-1 in control rat vessels but was without effect in the pulmonary hypertensive rat vessels. Bosentan (1 microM) inhibited responses to SX6c in control and chronically hypoxic rat vessels with pKb values of 5.84 and 6.11, respectively. The ET(B) receptor antagonist BQ-788 (1 microM) did not inhibit responses to ET-1 in any vessel tested but did inhibit responses to both SX6c and ET-3 (pKb values in control and chronically hypoxic rat vessels respectively: SX6c 7.15 and 7.22; ET-3: 6.68 and 6.89). BQ-788 (1 microM) added with BMS 182874 (10 microM) did not inhibit responses to ET-1 in control vessels but caused a significant inhibition of responses to ET-1 in chronically hypoxic preparations. 5. SB 209670 inhibited responses to ET-1 in both control and chronically hypoxic vessels with pKb values of 7.36 and 7.39, respectively. SB 209670 (0.1 and 1 microM) virtually abolished responses to ET-1 in the human pulmonary resistance artery. 6. In conclusion, in rat pulmonary resistance arteries, vasoconstrictions induced by ET-1, SX6c and ET-3 are mediated predominantly by activation of an ET(B)-like receptor. However, lack of effect of some antagonists on ET-1 induced vasoconstriction suggests that ET-1 stimulates an atypical ET(B) receptor. The increase in potency of ET-1 in the presence of some antagonists suggests the presence of an inhibitory ET(A)-like receptor. The influence of this is reduced, or absent, in the chronically hypoxic rats. Increased responses to ET-1 are observed in the chronically hypoxic rat and may be mediated by increased activation of ET(A) receptors. SB 209670 is unique in its potency against responses to ET-1 in both control and chronically hypoxic rats, as well as human, isolated pulmonary resistance arteries.

Animals↗
PubMed1996

Hypoxic constrictor response in the isolated pulmonary artery from chronically hypoxic rats.

The aim of this study was to characterise the response to acute hypoxia in pulmonary artery rings isolated from rats exposed to chronic hypoxia for 2 weeks (CH) and following recovery in room air for 24 h (post hypoxic, PH). Large intrapulmonary artery (IPA) rings (internal diameter = 1.5 +/- 0.11 mm; n = 13) from CH and PH rats and age-matched controls were studied. These were precontracted with phenylephrine using standard organ bath procedures at an oxygen tension of 152 mmHg and subjected to an acute hypoxia stimulus (bubbling with 0% O2 giving Po2 = 7 mmHg or 2% O2 giving PO2 = 20 mmHg). Acute hypoxia-induced pulmonary vasoconstriction (HPV) consisted of a transient contraction, a relaxation and a sustained contraction over 30 min. Pulmonary vasoconstriction induced by 0% O2 was significantly reduced in IPA rings from the CH but not PH group compared with the response obtained from the control group. HPV induced by 2% O2 in IPA rings from CH and PH rats was not significantly different from that in control rats not subjected to chronic hypoxia. Mechanical removal of the endothelium or inhibition of nitric oxide (NO) synthase by L-NOARG (300 microM) reduced the contractile phases of HPV in IPA rings from control and CH rats. Carbachol-induced endothelium-dependent relaxation in phenylephrine precontracted IPA rings was significantly attenuated in the CH but not PH group. In conclusion, the present study demonstrates that HPV induced by 0% O2 in rat IPA rings was blunted in CH rats and restored following 24 h in room air, in parallel with changes in endothelium function.

Animals↗
PubMed1996

Vitamin A deficiency and severe bronchopulmonary dysplasia in very low birthweight infants.

Preterm infants often have abnormally low serum vitamin A concentrations. Persistence of vitamin A deficiency for a prolonged postnatal period may contribute to the development of bronchopulmonary dysplasia. We retrospectively analyzed data from 22 infants with birthweight < or = 1250 g who had hyaline membrane disease requiring mechanical ventilation with oxygen and in whom serum vitamin A concentrations had been measured at the onset of enteral feeding and every 2 weeks thereafter. Thirteen infants (low serum vitamin A group) had one or more serum vitamin A concentrations < or = 11 mcg/dL at > 10 days of age. In 9 infants (higher serum vitamin A group) all serum vitamin A concentrations were > 11 mcg/dL at > 10 days of age. Mean birthweight, mean gestational age, sex, race, incidence of antenatal maternal glucocorticoid treatment and ventilatory support on the first day of life were similar for the two groups. Severe bronchopulmonary dysplasia was as defined as characteristic radiographic changes and either discharge from the hospital with supplemental oxygen or death from respiratory failure at > 28 days of age following mechanical ventilation with oxygen since birth. The incidence of severe bronchopulmonary dysplasia was significantly higher in the low serum vitamin A group (11/13, 3 deaths vs. 1/9, no deaths; p=0.001). The incidence of pulmonary air leak, the number of ventilator days, the number of days of postnatal glucocorticoid treatment for chronic lung disease, the number of episodes of suspected sepsis and the number of days of antibiotic treatment also were higher in the low serum vitamin A group. Low serum vitamin A group infants were older at the onset of enteral feeding (21 days vs. 8 days; p = 0.001) and during feeding their average daily enteral intake of vitamin A was lower (713 IU vs. 1255 IU; p = 0.001) when compared with infants in the higher serum vitamin A group. Our retrospective analysis of data from these infants confirms earlier reports from other workers that persistent marked vitamin A deficiency in very low birthweight infants is associated with a high incidence of severe bronchopulmonary dysplasia, delayed onset of enteral feeding and low enteral intake of vitamin A.

Bronchopulmonary Dysplasia↗
PubMed1996

Intravenous morphine attenuates pain induced changes in skin blood flow in newborn infants.

In a previous study we found that pain and discomfort caused a marked increase in skin blood flow in newborn infants, and that skin blood flow decreased after morphine. In this study we tested morphine effect on the skin blood flow response to pain more systematically. Skin blood flow was measured using a laser Doppler technique during 19 percutaneous central venous catheter placements in 18 infants, 10 of whom received intravenous morphine premedication. The mean +/- SD baseline skin blood flow was similar between the two groups: 22.5 +/- 9.5 ml 100 g-1 min-1 in the morphine group, and 23.7 +/- 8.0 ml 100 g-1 min-1 in the no-morphine group, respectively (p = n.s.). During PCVC placement in the morphine treated group, skin blood flow remained low with minimal variability. The mean value was 22.6 +/- 7.7 ml 100 g-1 min-1 (p = n.s. compared to baseline). In 7/9 infants not treated with morphine skin blood flow increased dramatically during PCVC placement, while in two it did not. But the mean skin blood flow in this group of 9 infants during PCVC placement was 45.3 +/- 34 ml 100 g-1 min-1, an overall change of 97% increase from the baseline. This was statistically significant compared with the baseline and the morphine group value during PCVC insertion (p < 0.04). During the 45 min time period after PCVC placement, skin blood flow values between groups again were similar. We conclude that morphine pretreatment for PCVC placement minimizes pain-associated increases in skin blood flow. The issue of whether skin blood flow changes could serve as measures of adequate analgesia needs to be evaluated with further studies.

Analgesics, Opioid↗
PubMed1996

5-Hydroxytryptamine receptors mediating vasoconstriction in pulmonary arteries from control and pulmonary hypertensive rats.

1. We investigated 5-hydroxytryptamine (5-HT)-receptor mediated vasoconstriction in the main, first branch and resistance pulmonary arteries removed from control and pulmonary hypertensive rats. Contractile responses to 5-HT, 5-carboxamidotryptamine (5-CT, non-selective 5-HT1 agonist), and sumatriptan (5-HT1D-like receptor agonist) were studied. The effects of methiothepin (non-selective 5-HT1 + 2-receptor antagonist) and ketanserin (5-HT2A receptor antagonist) and GR55562 (a novel selective 5-HT1D receptor antagonist) on 5-HT-mediated responses were also studied. Basal levels of adenosine 3':5'-cyclic monophosphate ([cyclic AMP]i) and guanosine 3':5'-cyclic monophosphate ([cyclic GMP]i) were determined and we assessed the degree of inherent tone in the vessels under study. 2. 5-HT was most potent in the resistance arteries. pEC50 values were 5.6 +/- 0.1, 5.3 +/- 0.1, 5.0 +/- 0.2 in the resistance arteries, pulmonary branch and main pulmonary artery, respectively (n = at least 5 from 5 animals). The sensitivity to, and maximum response of, 5-HT was increased in all the arteries removed from the chronic hypoxic (CH) rats. In CH rats the pEC50 values were 5.9 +/- 0.2, 6.3 +/- 0.2, 6.4 +/- 0.2 and the increase in the maximum response was 35%, 51% and 41% in the resistance arteries, pulmonary branch and main pulmonary artery, respectively. Sumatriptan did not contract any vessel from the control rats whilst 5-CT did contract the resistance arteries. In the CH rats, however, they both contracted the resistance arteries (responses to sumatriptan were small) (pEC50: 5-CT; 5.4 +/- 0.2) and the pulmonary artery branches (pEC50: sumatriptan, 5.4 +/- 0.2; 5-CT, 5.4 +/- 0.2). 5-CT also caused a contraction in the main pulmonary artery (pEC50: 6.0 +/- 0.3). 3. Ketanserin (1 nM-1 microM) caused a competitive antagonism of the 5-HT response in all vessels tested. In control rats, the estimated pKb values for ketanserin in resistance arteries, pulmonary branches and main pulmonary artery were 8.3, 7.8 and 9.2, respectively. Methiothepin (1 nM-1 microM) inhibited responses to 5-HT in the first branch (estimated pKb value: 7.8) and main pulmonary artery. In CH rats, the estimated pKb values for ketanserin in resistance arteries, pulmonary branches and main pulmonary artery were 7.7, 8.3 and 9.6, respectively. Methiothepin also inhibited contractions to 5-HT in the pulmonary artery branch and main pulmonary artery with estimated pKb values of 7 and 9.5, respectively. In control animals, GR55562 had no effect on responses to 5-HT in any of the vessels tested. In the CH rats the estimated pKb values for GR55562 were 6.5, 7.8 and 7.0 in the pulmonary resistance arteries, first branch and main pulmonary artery, respectively. 4. Large pulmonary arteries from controls demonstrated inherent tone and this was increased three fold in the CH rats. The resistance arteries from controls demonstrated little inherent tone though this was enhanced in those from the CH rats. 5. [Cyclic AMP]i was 259 +/- 23 pmol mg-1 protein in the pulmonary artery branches removed from control rats and decreased to 192 +/- 11 pml mg-1 protein in the CH rats (P < 0.01, n = 8). [Cyclic GMP]i also decreased in the pulmonary artery branches (from 550 +/- 15, control to 462 +/- 31 pmol mg-1 protein in CH vessels, n = 8, P < 0.01) and in the main pulmonary arteries (from 566 +/- 33, control to 370 +/- 25 pmol mg-1 protein in CH vessels, n = 8, P < 0.001). No changes in either [cyclic AMP]i or [cyclic GMP]i were observed in the resistance arteries. 6. The results suggest that the increased vasoconstrictor response to 5-HT in CH rat pulmonary arteries is due to an increase in 5-HT2A-receptor mediated contraction combined with an increase in r5-HT1B-like receptor-mediated contraction. An increase in vascular tone and decreased levels of [cyclic GMP]i in the large pulmonary arteries may contribute to the observed increase in activity of r5-HT1B-like receptor

Animals↗
PubMed1996

EndothelinB receptor-mediated contraction in human pulmonary resistance arteries.

1. Using wire myography, we have examined the endothelin (ET) receptor subtypes mediating vasoconstriction to ET peptides in human pulmonary resistance arteries (150-200 microns, i.d.). 2. Cumulative concentration-response curves to ET-1, sarafotoxin 6c (SX6c) and ET-3 were constructed in the presence and absence of the selective antagonists FR 139317 (ETA-selective), BMS 182874 (ETA-selective) and BQ-788 (ETB-selective). 3. All agonists induced concentration-dependent contractions. However, the response curves to ET-1 were biphasic in nature. The first component demonstrated a shallow slope up to 1 nM ET-1. Above 1 nM ET-1 the response curve was markedly steeper. Maximum responses to ET-3 and SX6c were the same as those to 1 nM ET-1 and 30% of those to 0.1 microM ET-1. The order of potency, taking 0.3 microM as a maximum concentration was SX6c >> ET-3 > ET-1 (pEC50 values of: 10.75 +/- 0.27, 9.05 +/- 0.19, 8.32 +/- 0.08 respectively). Taking 1 nM ET-1 as a maximum, the EC50 for ET-1 was 10.08 +/- 0.13 and therefore ET-1 was equipotent to ET-3 and SX6c over the first component of the response curve. 4. Responses to ET-1 up to 1 nM were resistant to the effects of the ETA receptor antagonists, FR 139317 and BMS 182874 but were inhibited by the ETB receptor antagonist, BQ-788. Conversely, responses to ET-1 over 1 nM were inhibited by the ETA receptor antagonists, FR 139317 and BMS 182874 but unaffected by the ETB receptor antagonist, BQ-788. 5. The results suggest that at concentrations up to 1 nM, responses to ET-1 are mediated via the ETB receptor, whilst the responses to higher concentrations are mediated by ETA receptors.

Endothelins↗
PubMed1995

Skin blood flow changes during routine nursery procedures.

OBJECTIVE: The objective of this study was to establish that changes in skin blood flow could serve as an index of pain and discomfort in newborn infants. METHODS: Skin blood flow changes during intensive care procedures and during morphine administration were measured in a group of newborn infants using a laser Doppler technique. Heart rate, respiratory rate and oxygen saturation were also measured. Changes in skin blood flow and physiologic variables that occurred during procedures were analyzed and compared among procedures. RESULTS: Measurements were made during 145 procedures in 15 infants 2-32 days old with birth weights of 500-2900 g and gestational ages of 23-37 weeks. Ten of the infants were receiving mechanical ventilation. Skin blood flow increased 27-134% during lancet puncture of the heel, physical handling, standard suctioning and chest physiotherapy, and there were no changes during closed system suctioning. Skin blood flow decreased 35% by 20 min after intravenous morphine. Changes seen in heart rate, respiratory rate and oxygen saturation were generally minimal. CONCLUSIONS: We conclude that laser Doppler skin blood flow changes could be an index of neonatal pain and discomfort; even noninvasive handling procedures are associated with increases in skin blood flow; and changes in skin blood flow may be more useful than conventional physiologic variables in assessing the response to intensive care nursery procedure.

Analgesics↗
PubMed1995

Effects of pulmonary hypertension on vasoconstrictor responses to endothelin-1 and sarafotoxin S6C and on inherent tone in rat pulmonary arteries.

Vasoconstrictor responses to endothelin-1 (ET-1) and the ETB receptor agonist sarafotoxin S6c (SXS6c) were investigated in the main pulmonary artery and pulmonary artery branch removed from rats previously exposed to 10% O2 [chronic hypoxic (CH) rats] or room air (control rats) for 2 weeks. The effects of nitric oxide synthase (NOS) inhibition with L-Nomega-nitroarginine methyl ester (L-NAME) (100 microM) on ET receptor-induced responses in these arteries were also investigated. In control rats, in rings of main pulmonary arteries and pulmonary artery branches. ET-1 induced vasoconstrictor responses. These responses were mediated by the ETA receptor as they were antagonized by the ETA receptor antagonist FR 139317 whereas SXS6c did not vasoconstrict. Chronic hypoxia had no effect on the sensitivity of the main pulmonary arteries to ET-1, whereas small vasoconstrictor responses to SCS6c were evident. ET-1 was more potent in the CH rat pulmonary artery branches than in controls. SXS6c also caused vasoconstriction with a maximum response 30% of that to ET-1 in both endothelium-intact and endothelium-denuded vessels. L-NAME increased the sensitivity to ET-1 in the CH rat main pulmonary arteries and increased the responses to low concentrations of ET-1 in the control rat main pulmonary arteries but did not affect any ET-1 responses in any other vessels. It did disclose responses to SXS6c in control rat main pulmonary arteries. L-NAME itself increased vascular tone to a greater extent in CH rat pulmonary arteries than in controls. In preconstricted pulmonary arteries, however, relaxations to acetylcholine (ACh) were diminished in the CH rats as compared with their controls. All pulmonary artery branches, denuded of their vascular endothelium, relaxed to sodium nitroprusside (SNP) and therefore exhibited endogenous vascular tone. This effect was greatest in the pulmonary artery branches from the CH rats. The results suggest that rat large pulmonary artery responses to ET-1 are normally mediated by ETA receptors. Pulmonary hypertension can potentiate ETA receptor-mediated vasoconstriction and facilitate ETB receptor-mediated vasoconstriction. Endogenous NO may normally suppress ETA receptor-mediated responses in rat main pulmonary arteries. Rat pulmonary arteries exhibit endogenous tone, which is increased by exposure to chronic hypoxia.

Animals↗
PubMed1995

EndothelinB receptor-mediated contraction of human and rat pulmonary resistance arteries and the effect of pulmonary hypertension on endothelin responses in the rat.

We investigated the endothelin (ET) receptor subtypes that mediate vasoconstriction in human and rat pulmonary resistance arteries and the effect of pulmonary hypertension on endothelin (ET)-induced contractile responses in rat vessels. In human vessels, sarafotoxin S6c (SXS6c) was more potent than ET-1, but its maximal contractile response was only 20-30% of that to ET-1. Responses to ET-1 were resistant to the ETA antagonist FR 139317, and another, BMS 182874, inhibited responses only to high concentrations of ET-1. In all rat vessels, ET-1, ET-3, and the ETB receptor agonist SXS6c showed the following order of potency: SXS6c = ET-3 > ET-1, and responses to SXS6c were inhibited by the ETB receptor antagonist BQ 788 (1 microM). Maximal responses to ET-1 were greatest in chronic hypoxic (CH) pulmonary-hypertensive rats. In control rats, responses to ET-1 were unaffected by FR 139317 (1 microM) and were potentiated by BMS 182874 (1 microM) and by the mixed ETA/ETB receptor antagonist bosentan (1 microM). A combination of BMS 182874 (10 microM) and the ETB receptor antagonist BQ 788 (1 microM) had no effect on responses to ET-1. In the CH rats, responses to ET-1 were unaffected by FR 139317, BMS 182874, or bosentan. The results suggest the presence of an inhibitory ETA receptor in these vessels that may inhibit ET-1 activation of ETB receptors, and also suggest that the influence of this inhibitory ETA receptor is reduced in CH rat vessels. The results indicate a role for ETB receptors in ET-1-mediated vasoconstriction in both human and rat pulmonary resistance arteries.

Animals↗
PubMed1994

Endothelin ETA- and ETB-receptor-mediated vasoconstriction in rat pulmonary arteries and arterioles.

We investigated the endothelin (ET) receptors involved in the vasoconstrictor responses to ET-1 in rat pulmonary arteries and arterioles and the effect of endothelium removal, nitric oxide (NO) synthase inhibition, and hypoxia on ET-1-induced responses in the arteries. In isolated rat pulmonary artery rings (2-3 mm ID) prepared from the pulmonary artery branch before its entry into the lung, ET-1-induced vasoconstrictor responses. These responses were mediated by the ETA receptor as they were competitively antagonized by the ETA receptor antagonist FR 139317, and the ETB-receptor agonist sarafotoxin S6c (SXS6c) was a very weak vasoconstrictor in these vessels, inducing maximum contractions only 9% of those of ET-1. In contrast, in rat intrapulmonary resistance arteries (100-150 microns ID), SXS6c induced FR 139317-resistant contractions, and these vessels were more sensitive to SXS6c than to ET-1. SXS6c produced maximum contractions 92% those of ET-1, suggesting that ET-1-induced contractions were mediated by the ETB receptor in these resistance vessels. In the larger pulmonary arteries, the NO synthase inhibitor L-N omega nitroarginine methyl ester (L-NAME) (100 microM) potentiated responses to ET-1, an effect that was reversed by FR 139317. Endothelium removal also potentiated response to ET-1, and L-NAME had no effect on ET-1 responses in endothelium-denuded vessels, suggesting that in these vessels the ETA receptor-mediated responses to ET-1 are normally suppressed by endothelium-derived NO.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Assessing adherence to standards for neonatal resuscitation taught throughout the perinatal referral area. A quality assurance activity.

The American Heart Association/American Academy of Pediatrics Neonatal Resuscitation Program provides standards for management of newborn infants in birthing areas. Certification and subsequent evaluation of birthing area personnel at perinatal network hospitals should result in better stabilization of infants prior to transport.

American Heart Association↗
PubMed1993

Alterations in theophylline metabolism during the first year of life.

Maturational changes in theophylline disposition were evaluated in 52 infants (gestational age, 24 to 40 weeks; postnatal age, 2 to 69 weeks) receiving maintenance theophylline therapy. Theophylline and metabolites were measured in serum and urine at steady state, and the influence of clinical parameters on the maturational changes was analyzed by multiple stepwise linear regression. Theophylline clearance and urine metabolite pattern reached adult values at 55 weeks' postconceptional age. Serum caffeine concentrations greater than 1 microgram/ml occurred in infants up to 50 weeks' postconceptional age. Disappearance of serum caffeine concentrations and maturation of theophylline clearance were primarily related (p < 0.001) to development of the demethylation pathway to 3-methylxanthine. Postconceptional age was the major factor (p < 0.001) explaining the interpatient variability in theophylline clearance (r2 = 0.57), serum caffeine to theophylline ratio (r2 = 0.46), and urinary excretion of theophylline (r2 = 0.51), caffeine (r2 = 0.49), 1,3-methyluric acid (r2 = 0.32), 1-methyluric acid (r2 = 0.53), and 3-methylxanthine (r2 = 0.58). Our findings indicate that postconceptional age rather than postnatal age should be used as a maturational marker during theophylline therapy in infancy.

Aging↗
PubMed1993

Influences of the endothelium and hypoxia on neurogenic transmission in the isolated pulmonary artery of the rabbit.

1. The effects of nitric oxide (10(-6) M), N omega-nitro-L-arginine methylester (L-NAME, 10(-4) M, an inhibitor of nitric oxide synthase), endothelium removal, hypoxia and selective alpha-adrenoceptor antagonists on responses to nerve electrical field-stimulation (EFS) were studied in the rabbit isolated pulmonary artery. 2. EFS induced frequency-dependent contractions which were abolished by prazosin (alpha 1-adrenoceptor antagonist) and unaffected by rauwolscine (alpha 2-adrenoceptor antagonist). EFS-induced responses were potentiated by L-NAME and inhibited by nitric oxide. The effect of L-NAME was reversed by the presence of L-arginine (2 x 10(-4) M), which had no effect on its own. In the presence of L-NAME, the EFS-induced responses were reduced by rauwolscine and the residual responses were abolished by prazosin. 3. Removal of the vascular endothelium increased the maximum contractile response to EFS but did not inhibit the ability of L-NAME to potentiate contractile responses to EFS. 4. Hypoxia inhibited the contractile response to EFS. This effect of hypoxia was also seen in the presence of L-NAME and in endothelium rubbed preparations. 5. In conclusion, the endothelium modulates EFS-induced contractions in the rabbit pulmonary artery. The contraction induced by EFS was inhibited by nitric oxide, but potentiated by the nitric oxide-synthase inhibitor, L-NAME. The effect of L-NAME was not mediated solely through the endothelium and revealed involvement of alpha 2-adrenoceptors in EFS-induced contraction. Hypoxia inhibited neurogenic responses in rabbit isolated pulmonary arteries.

Adrenergic alpha-Antagonists↗