Biomedical subjects

D M Rodman

Publications and source records attributed to D M Rodman.

At least 19 recordsLinked to original sources

PubMed1997

Cytosolic Ca2+ and adenylyl cyclase responses in phenotypically distinct pulmonary endothelial cells.

Pulmonary microvascular endothelium forms a tighter barrier than does pulmonary artery endothelium; the mechanism of this important phenotypic difference is uncertain. We examined two regulators of endothelial permeability, cytosolic Ca2+ concentration ([Ca2+]i) and adenosine 3',5'-cyclic monophosphate (cAMP), in microvascular (PMVEC) and pulmonary conduit artery (PAEC) endothelium. Both resting and stimulated [Ca2+]i were lower in PMVEC compared with PAEC (resting [Ca2+]i, 94 +/- 7 vs. 123 +/- 8 nM; ATP-stimulated peak, 1.04 +/- 0.14 vs. 1.98 +/- 0.13 microM). Sustained Ca2+ transients in response to either ATP or thapsigargin were reduced in PMVEC compared with PAEC (ATP, 199 +/- 22 vs. 411 +/- 43 nM; thapsigargin, 195 +/- 13 vs. 527 +/- 65 nM), suggesting reduced Ca2+ influx in PMVEC. Reduced Ca2+ influx in PMVEC was confirmed by Mn2+ quenching and patch-clamp experiments. mRNA for Ca(2+)-inhibitable and protein kinase C-stimulated adenylyl cyclases was detected in both cell types. Whereas ATP caused a [Ca2+]i-mediated decrease in cAMP in PAEC, ATP caused a protein kinase C-mediated increase in cAMP in PMVEC. We conclude that PMVEC express a unique phenotype that favors enhanced barrier function through attenuated Ca2+ influx and preservation of cAMP content.

Adenosine Triphosphate↗

PubMed1996

Inhibition of cyclic 3'-5'-guanosine monophosphate-specific phosphodiesterase selectively vasodilates the pulmonary circulation in chronically hypoxic rats.

While it is known that nitric oxide (NO) is an important modulator of tone in the hypertensive pulmonary circulation, the roles of cyclic 3'-5'-guanosine monophosphate (cGMP) and cGMP-phosphodiesterase (PDE) are uncertain. We found that isolated lung perfusate levels of cGMP were over ninefold elevated in hypertensive vs. normotensive control rats. 98-100% of lung cGMP hydrolytic activity was cGMP-specific PDE5, with no significant decrease in PDE activity in hypertensive lungs, suggesting that the elevation in cGMP was due to accelerated production rather than reduced degradation. In pulmonary hypertensive rat lungs, in vitro, cGMP-PDE inhibition by E4021[1-(6-chloro-4-(3,4-methylbenzyl) amino-quinazolin-2-yl)piperdine-4-carboxylate], increased perfusate cGMP threefold, reduced hypoxic vasoconstriction by 58 +/- 2%, and reduced baseline pulmonary artery pressure by 37 +/- 5%. In conscious, pulmonary hypertensive rats, intravenous administration of E4021 reduced hypoxic vasoconstriction by 68 +/- 8%, pulmonary artery pressure by 12.6 +/- 3.7% and total pulmonary resistance by 13.1 +/- 6.4%, with no significant effect on cardiac output, systemic pressure, and resistance. Comparison of E4021 to inhaled nitric oxide demonstrated that cGMP-PDE inhibition was as selective and as effective as inhaled NO.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed1996

Thapsigargin stimulates increased NO activity in hypoxic hypertensive rat lungs and pulmonary arteries.

This study addressed the controversy of whether endothelium-derived nitric oxide (NO) activity is increased or decreased in the hypertensive pulmonary vasculature of chronically hypoxic rats. Thapsigargin, a receptor-independent Ca2+ agonist and stimulator of endothelial NO production, was used to compare NO-mediated vasodilation in perfused lungs and conduit pulmonary artery rings isolated from adult male rats either kept at Denver's altitude of 5,280 ft (control pulmonary normotensive rats) or exposed for 4-5 wk to the simulated altitude of 17,000 ft (chronically hypoxic pulmonary hypertensive rats). Under baseline conditions, thapsigargin (10(-9)-10(-7) M) caused vasodilation in hypertensive lungs and vasoconstriction in normotensive lungs. Whereas the sustained vasodilation in hypertensive lungs was reversed to vasoconstriction by the inhibitor of NO synthase N(omega)-nitro-L-arginine (L-NNA; 10(-4) M), a transient vasodilation to thapsigargin in acutely vasoconstricted normotensive lungs was potentiated. As measured by a chemiluminescence assay, the recirculated perfusate of hypertensive lungs accumulated considerably higher levels of NO-containing compounds that did normotensive lungs, and thapsigargin-induced stimulation of NO-containing compounds accumulation was greater in hypertensive than in normotensive lungs. Similarly, low concentrations of thapsigargin (10(-10)-10(-9) M) caused greater endothelium-dependent L-NNA-reversible relaxation of hypertensive than of normotensive pulmonary artery rings. The increased sensitivity of hypertensive arteries to thapsigargin-induced relaxation was eliminated in nominally Ca(2+)-free medium and was not mimicked by ryanodine, a releaser of intracellular Ca2+. These results with thapsigargin, which acts on endothelial cells to stimulate Ca2+ influx and a sustained rise in intracellular Ca2+ concentration, support the idea that pulmonary vascular endothelium-derived NO activity is increased rather than decreased in chronic hypoxia-induced pulmonary hypertension in rats.

Animals↗

PubMed1995

Ca(2+)-inhibitable adenylyl cyclase modulates pulmonary artery endothelial cell cAMP content and barrier function.

Maintenance by the endothelium of a semi-permeable barrier is critically important in the exchange of oxygen and carbon dioxide in the lung. Intracellular free Ca2+ ([Ca2+]i) and cAMP are principal determinants of endothelial cell barrier function through their mutually opposing actions on endothelial retraction. However, details of the mechanisms of this antagonism are lacking. The recent discovery that certain adenylyl cyclases (EC 4.6.1.1) could be acutely inhibited by Ca2+ in the intracellular concentration range provided one possible mechanism whereby elevated [Ca2+]i could decrease cAMP content. This possibility was explored in pulmonary artery endothelial cells. The results indicate that a type VI Ca(2+)-inhibitable adenylyl cyclase exists in pulmonary artery endothelial cells and is modulated by physiological changes in [Ca2+]i. Furthermore, the results suggest the inverse relationship between [Ca2+]i and cAMP that is established by Ca(2+)-inhibitable adenylyl cyclase plays a critical role in modulating pulmonary artery endothelial cell permeability. These data provide evidence that susceptibility to inhibition of adenylyl cyclase by Ca2+ can be exploited in modulating a central physiological process.

Adenylyl Cyclases↗

PubMed1994

Reduced PO2 alters the behavior of Fura-2 and Indo-1 in bovine pulmonary artery endothelial cells.

Calcium-sensitive fluorophores are used to estimate cytosolic free Ca2+ in many cell types under various conditions. We tested the effect of reduced PO2 on the behavior of Fura-2 and Indo-1 in cultured bovine pulmonary artery endothelial cells. Reduced PO2 (PO2 25-35 mmHg) caused a significant upward shift of in vivo calibration curves for both fluorophores. The in vivo emission spectrum of Fura-2 indicated that the effect was principally due to attenuated emission at the Ca(2+)-unbound 380 nm wavelength, with no shift in position of the emission maxima for either Ca(2+)-bound or unbound forms of the fluorophore. Reduced PO2 did not directly alter the behavior of the dyes, as no shift of in vitro calibration curves was seen. Neither decreased photobleaching nor altered autofluorescence accounted for the shift. We investigated several potential indirect effects, including cellular acidification, reduced viscosity, inhibition of oxidative energy production and reductive stress. In contrast to lowered PO2, acidification in vitro produced a leftward but not an upward shift. Estimation of intracellular pH with SNAFL-calcein under reduced PO2 showed no apparent acidification in these cells, further strengthening the argument that altered intracellular pH was not causing the shift. Others have shown that decreases in viscosity in vitro may shift the calibration curve for Fura-2 upward, similar to our finding with reduced PO2. However, for Indo-1 we found that decreased viscosity in vitro attenuated fluorescence emission at the Ca(2+)-bound 405 nm wavelength, thus producing the opposite effect on fluorescence ratio and indicating that reduced PO2 was not acting through changes in cellular microviscosity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Acute reductions in PO2 depolarize pulmonary artery endothelial cells and decrease [Ca2+]i.

Whereas pulmonary artery endothelial cells (PAECs) are sensitive to oxygen, neither the effect of an acute reduction in PO2 on PAEC membrane potential nor its effect on intracellular free Ca2+ ([Ca2+]i) is known. We hypothesized that in confluent primary cultures of PAECs, an acute decrease in PO2 would depolarize the cell membrane, inhibit Ca2+ influx, and reduce [Ca2+]i. To test this hypothesis, the membrane-sensitive fluorophore bis (1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC4, 1 microM) and [Ca2+]i-sensitive probe fura 2 (3 microM) were used. A decrease in PO2 from 125 to 35 mmHg caused membrane depolarization and a 60 +/- 8% (data are means +/- SE) reduction in Ca2+ influx, estimated by manganese quenching of fura 2 fluorescence. While basal [Ca2+]i was 79 +/- 5 nM in normoxic cells, it decreased to 31 +/- 2 nM after 15 min of hypoxia. Decreasing the electrochemical gradient for Ca2+ entry with either low extracellular Ca2+, the K+ channel blockers tetraethylammonium or charybdotoxin, or blockade of Ca2+ entry with lanthanum decreased [Ca2+]i by 54-71% of that observed during an acute reduction in PO2. These results demonstrate that an acute reduction in PO2 1) depolarizes PAECs, 2) reduces Ca2+ influx, and 3) decreases [Ca2+]i, and that a similar reduction in [Ca2+]i was observed with interventions designed to reduce the electrochemical driving force for Ca2+ entry.

Animals↗

PubMed1994

Acute hypoxia causes membrane depolarization and calcium influx in fetal pulmonary artery smooth muscle cells.

Changes in oxygen tension in the perinatal period contribute to high pulmonary vascular tone in the fetus and the decline in resistance that occurs at birth. Distal pulmonary artery smooth muscle cells (PASMC) isolated from late-gestation ovine fetuses respond to acute hypoxia with an increase in cytosolic calcium concentration ([Ca2+]i) dependent on Ca2+ entry. The purpose of this study is to determine 1) whether acute hypoxia results in PASMC membrane depolarization, 2) whether Ca2+ entry was through voltage-operated calcium channels (VOCC), 3) the contribution of Ca(2+)-induced Ca2+ release (CICR) to the hypoxic response, and 4) whether a subset of K+ channels might serve as oxygen sensors in fetal PASMC. We used microfluorimetry on subconfluent monolayers of PASMC in primary culture loaded with either a membrane potential-sensitive dye, bis(1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC4; DPASMC), to estimate membrane potential, or the Ca(2+)-sensitive fluorophore, fura 2, to measure [Ca2+]i. Hypoxia increased fluorescence from PASMC loaded with DiBAC4, consistent with membrane depolarization. Verapamil (an inhibitor of VOCC) attenuated, and BAY K 8644 (a VOCC facilitator) potentiated, the hypoxia-induced increase in [Ca2+]i, respectively. The hypoxic response was transient after treatment with ryanodine (10(-7) M), a blocker of calcium release from intracellular stores. Charybdotoxin (10(-7) M), an inhibitor of Ca(2+)-activated K+ channels, almost doubled [Ca2+]i, whereas glibenclamide (10(-5) M), an ATP-sensitive K(+)-channel antagonist, had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1993

EDRF suppresses an unidentified vasoconstrictor mechanism in hypertensive rat lungs.

To test whether endothelium-derived relaxing factor (EDRF) plays a role in regulating the hypertensive pulmonary vascular bed, we compared effects of the inhibitor of EDRF production, N omega-nitro-L-arginine (L-NNA), on resting vascular tone in lungs and conduit pulmonary arteries isolated from control and chronically hypoxic rats. In contrast to no effect on normoxic vascular tone in salt solution-perfused normotensive lungs, 100 microM L-NNA caused a marked, L-arginine-sensitive, precapillary vasoconstriction in unstimulated hypertensive lungs. Bioassay of hypertensive lung perfusate did not detect a circulating vasoconstrictor, and L-NNA vasoconstriction was not inhibited by blockers of cyclooxygenase, 5-lipoxygenase, platelet-activating factor receptors, alpha-adrenoceptors, and serotonin 5-HT2 receptors or by scavengers of superoxide anion and H2O2. Inhibitors of endothelin-1 (ET-1) production and vasoconstriction tended to blunt the response, but accumulation of perfusate ET-1 was not increased in hypertensive lungs. L-NNA vasoconstriction was blocked by Ca(2+)-free plus ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid perfusion but not by nifedipine. Quiescent, endothelium-intact hypertensive but not normotensive conduit pulmonary artery rings were markedly constricted by 200 microM L-NNA. The onset but not the peak of the response was blunted by meclofenamate. The response was reduced slightly by the ETA receptor antagonist, BQ 123. L-NNA had little effect on denuded hypertensive arteries, and treatment with dilators showed they had constricted spontaneously. Both the L-NNA and the spontaneous constrictions were readily inhibited by nifedipine. These results indicate that in rat hypertensive pulmonary arteries, the basal release of EDRF suppresses vasoconstrictor mechanisms which are not expressed in normotensive arteries.

Altitude↗

PubMed1993

Acute hypoxia increases cytosolic calcium in fetal pulmonary artery smooth muscle cells.

We studied the effect of acute hypoxia on the cytosolic calcium concentration ([Ca2+]i) of fetal vascular smooth muscle cells (SMC) from late gestation fetal lambs. We tested the following hypotheses: 1) fetal pulmonary artery (PA) SMC sense hypoxia; 2) hypoxia stimulates transmembrane Ca2+ influx causing increased basal [Ca2+]i and Ca2+ responses to pharmacological vasoconstrictors; and 3) the response is unique to SMC from small (near resistance) PA. Fetal SMC were isolated from the proximal and distal pulmonary (DPA) and carotid arteries of late-gestation ovine fetuses, maintained in culture for 5-14 days prior to study, and studied with dual-excitation microfluorimetry using fura 2. Acute hypoxia caused a 233% increase in [Ca2+]i in distal PA SMC (P < 0.01), which was absent in low extracellular calcium bath. [Ca2+]i increased transiently in normoxic DPA SMC treated with angiotensin II, and oscillations in [Ca2+]i occurred (amplitude > or = 30 nM). In hypoxic DPA SMC the increase in [Ca2+]i was sustained and oscillations were attenuated or absent. [Ca2+]i in proximal PA SMC did not change with exposure to acute hypoxia and carotid artery SMC [Ca2+]i decreased by 13% (P < 0.05). We conclude that fetal SMC isolated from the DPA of late-gestation ovine fetuses directly sense decreased oxygen tension with an increase in [Ca2+]i that is dependent on the entry of extracellular Ca2+.

Acute Disease↗

PubMed1992

Endothelin-1 increases the pulmonary microvascular pressure and causes pulmonary edema in salt solution but not blood-perfused rat lungs.

Endothelin-1 (ET-1) is a potent vasoactive peptide that has been reported to cause lung edema. This study tested if the edemagenic effect of ET-1 is due to preferential venoconstriction and, if so, whether the site of resistance is similar with salt solution (PSS) and more physiologic blood perfusate. ET-1 caused concentration-dependent contraction of pulmonary arterial and venous rings, with an EC50 of 1.3 nM in artery and 0.6 nM in vein (p less than 0.05). In PSS-perfused lungs, 5 nM ET-1 caused a 7.0 +/- 0.8 torr pressor response that was associated with a 5.0 +/- 0.3 torr increase in microvascular pressure and a 530 +/- 20 mg increase in lung weight within 10 min. In contrast, KCl-treated lungs had an equivalent pressor response (7.4 +/- 1.1 torr), yet the microvascular pressure increased by only 2.5 +/- 0.4 torr (p less than 0.05 from ET-1) and the lung weight was unchanged. Meclofenamate did not prevent the effect of ET-1 on microvascular pressure or lung weight. In blood-perfused lungs, ET-1 caused a 7.3 +/- 0.1 torr pressor response but only a 2.0 +/- 0.5 torr increase in microvascular pressure and no increase in lung weight. ET-1 had no effect on permeability either of cultured endothelial cell monolayers or in the pulmonary microvasculature in vivo. We conclude that the edemagenic effect of ET-1 in PSS-perfused lungs is mediated through venoconstriction and an increase in microvascular pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Role of ATP-sensitive potassium channels in ovine fetal pulmonary vascular tone.

To study the potential role of ATP-sensitive K+ (K+ATP) channels in fetal pulmonary vasoregulation, we studied the effect of a K+ATP channel agonist, lemakalim, and antagonist, glibenclamide, on the fetal pulmonary circulation in nine chronically instrumented late-gestation fetal lambs. Left pulmonary artery (LPA) blood flow was measured with an electromagnetic flow transducer. Brief (10 min) infusions of lemakalim at 3, 10, and 30 micrograms/min into the LPA produced dose-dependent increases in flow from 68 +/- 7 to 96 +/- 11, 160 +/- 15, and 204 +/- 34 ml/min, respectively. The duration of pulmonary vasodilation after the 10-min infusions of lemakalim at 3, 10, and 30 micrograms/min was 20 +/- 3, 47 +/- 10, and 55 +/- 15 min, respectively. Pulmonary blood pressure and flow did not change with intrapulmonary infusion of glibenclamide (10 mg), a K+ATP channel antagonist. Lemakalim-induced pulmonary vasodilation was not affected by nitro-L-arginine (10 mg), a competitive inhibitor of endothelium-dependent relaxing factor, but was blocked by glibenclamide. Prolonged (2 h) intrapulmonary infusions of lemakalim (2-6 micrograms/min) increased pulmonary blood flow by 137%. The increase in pulmonary blood flow was sustained throughout the infusion. Systemic and pulmonary arterial pressures decreased during prolonged infusion. We conclude that K+ATP channels are present in the fetal pulmonary circulation, but do not participate in the regulation of basal pulmonary vascular tone. K+ATP channel activation produces sustained vasodilation that is not mediated by endothelium-derived relaxing factor. We speculate that birth-related stimuli activate K+ATP channels to enhance the pulmonary vasodilation that occurs at birth.

Adenosine Triphosphate↗

PubMed1992

Chronic hypoxia selectively augments rat pulmonary artery Ca2+ and K+ channel-mediated relaxation.

The initiating event in hypoxic pulmonary hypertension is felt to be sustained hypoxic vasoconstriction, ultimately leading to vascular remodeling and fixed pulmonary hypertension. During the initial vasospastic phase endogenous vasodilatory pathways may serve to ameliorate the development of pulmonary hypertension. However, various studies in the systemic and pulmonary circulations have shown that chronic hemodynamic stress alters both endothelial and smooth muscle cell function. The effect of chronic hypoxia in rats was therefore tested on three major vasodilatory pathways: 1) endothelium-dependent relaxation (using endothelium-derived relaxing factor agonists and antagonists); 2) smooth muscle cell cyclic nucleotide-mediated relaxation [using guanosine and adenosine 3',5'-cyclic monophosphate (cGMP and cAMP) agonists]; and 3) ion channel-dependent relaxation (using K+ channel agonists and Ca2+ channel antagonists). It was found that short-term exposure (72 h) to hypoxia caused augmentation of K+ and Ca2+ channel-dependent relaxation with no effect on endothelium-dependent or cyclic nucleotide-mediated relaxation. More prolonged exposure (4-5 wk) was additionally associated with inhibition of endothelium-dependent relaxation and smooth muscle cell cGMP-mediated relaxation. There was no effect on either basal modulation of tone by the endothelium, cAMP-mediated relaxation, or systemic vessel relaxation. It is concluded that an early response to hemodynamic stress in the pulmonary circulation is alteration in smooth muscle cell ion channel function and/or Ca2+ homeostasis.

Animals↗

PubMed1991

The cystic fibrosis heterozygote--advantage in surviving cholera?

Cystic fibrosis (CF) is the most common fatal genetic disorder of caucasians. While it has been hypothesized that there is a CF heterozygote advantage which allowed the gene to achieve such high prevalence, the nature of that advantage remains a mystery. The recent identification and sequencing of the CF gene has increased the probability that the CF heterozygote advantage will be discovered. In this hypothesis we review the information which is known about the selection of the CF mutation and its cellular consequences, and present evidence which suggests that resistance to cholera may have been the environmental factor which selected CF heterozygotes over their 'normal' homozygote cohort. Future lines of experimentation and possible clinical applicability to therapy of secretory diarrhea are presented.

Chloride Channels↗

PubMed1991

Paradoxical constriction to platelets by arteries from rats with pulmonary hypertension.

We recently described the early appearance of pulmonary hypertension in the fawn-hooded rat (FHR), an animal with platelet storage pool disease also known to develop systemic hypertension at later ages. Since mediators released from aggregating platelets influence vascular tone, we hypothesized that platelet-mediated pulmonary vascular responses in FHR may be abnormal and potentially linked to the mechanism of pulmonary hypertension. To test this we examined reactivity of isolated pulmonary arteries (PA) and thoracic aortas (Ao) from young FHR with moderately severe pulmonary hypertension but normal systemic pressures. These vessels were compared with PA and Ao from control Sprague-Dawley rat (SDR). Aggregating platelets (1,000-40,000 platelets/mm3) from FHR caused dilation of SDR PA and Ao but constriction of FHR PA and Ao. Qualitatively similar responses were also observed with platelets isolated from SDR implying that abnormal responses were not simply due to the storage pool deficiency in FHR. Response to the platelet-derived endothelium-dependent vasodilator ADP was markedly impaired in FHR PA and mildly impaired in FHR Ao. Endothelium-dependent dilation to acetylcholine, but not to A23187, was mildly impaired in FHR PA while responses to both dilators were normal in FHR Ao. Endothelium-independent dilation to sodium nitroprusside was normal in both FHR PA and Ao. Constrictor sensitivity to serotonin, but not to the thromboxane A2 mimetic U-46619, was increased in FHR PA while responses to both constrictors were normal in FHR Ao. In summary, PAs from FHR with spontaneous pulmonary hypertension exhibit paradoxical constriction to both normal and storage pool deficient platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

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

PubMed1991

Effects of inhibitors of EDRF and EDHF on vasoreactivity of perfused rat lungs.

Recent studies indicate that the endothelium of isolated rat pulmonary arteries releases two different factors, endothelium-derived relaxing factor (EDRF) and hyperpolarizing factor (EDHF), which participate in histamine- and acetylcholine-induced relaxation. There is evidence for EDRF vasoreactivity in perfused lungs, but a role for EDHF, which hyperpolarizes vascular smooth muscle by activating membrane K+ channels, has not been reported. We used the inhibitors of EDRF, 20 microM hemoglobin, 200 microM NG-mono-methyl-L-arginine, and 2 mM L-canavanine, the nonselective blocker of K+ channels, 10 mM tetraethylammonium (TEA), and the inhibitor of ATP-sensitive K+ channels, 20 microM glibenclamide, to compare the roles of EDRF and EDHF in the vasoregulation of meclofenamate-treated, salt solution-perfused rat lungs. The three EDRF inhibitors had little or no effect on baseline perfusion pressure, but each potentiated the peak pressor response to airway hypoxia. Neither of them inhibited the pulmonary vasodilation to 5 microM histamine. TEA, but not glibenclamide, increased baseline pressure and potentiated the peak hypoxic response. Both K+ channel blockers, but not the EDRF inhibitors, also prolonged the hypoxic response by reducing the rate of spontaneous vasodilation. TEA, but not glibenclamide, inhibited histamine vasodilation. These results suggest roles for both EDRF and EDHF in the control of rat pulmonary vascular reactivity. EDRF is apparently not responsible for the low vascular tone of the normoxic lung and does not mediate the vasodilation to histamine, but it does modulate the hypoxic pressor response. The exact role of EDHF is uncertain, but it may also modulate hypoxic vasoconstriction and mediate at least part of the histamine vasodilation.

Analysis of Variance↗

PubMed1991

Maturational changes in endothelium-derived relaxing factor activity of ovine pulmonary arteries in vitro.

To examine mechanisms underlying fetal pulmonary vascular vasodilator responses and maturational changes in endothelial function, we studied effects of endothelium-dependent (acetylcholine, ACh: adenosine diphosphate, ADP; and A23187) and -independent (sodium nitroprusside, SNP) vasodilators on tone of small (third generation) pulmonary artery rings isolated from late-gestation fetal, newborn, and adult sheep. Changes in isometric force of phenylephrine-contracted rings were measured after the cumulative addition of vasodilators in baths aerated with 21% O2 and 5% CO2. Pulmonary artery rings from fetal lambs demonstrated minimal relaxation to ACh, ADP, and A23187, achieving only 17 +/- 3, 14 +/- 5, and 23 +/- 8% relaxation, respectively. In contrast, fetal rings relaxed completely (100%) to SNP. Rings from newborn and adult animals had significantly greater maximal relaxation in response to ACh. ADP, and A23187 than fetal rings (at least P less than 0.05 for each comparison with fetal rings), but responses to SNP were not different. Hemoglobin (10(-5) M), an inhibitor of endothelium-derived relaxing factor, caused less augmentation of phenylephrine contraction in fetal than adult pulmonary artery rings (11 +/- 4% vs. 49 +/- 8%; P less than 0.01). We conclude that in comparison with pulmonary artery rings from postnatal animals, fetal pulmonary artery rings have diminished endothelium-derived relaxation factor activity. We speculate that maturational changes in endothelial cell function contribute to ontogenetic differences in pulmonary vasoreactivity.

Acetylcholine↗

PubMed1991

Effects of K+ channel blockers on vascular tone in the perfused rat lung.

To learn more of the role of K+ channel activity in the regulation of pulmonary vascular tone, we compared the pressor effects of the differential blockers of numerous K+ channels, tetraethylammonium chloride and 4-aminopyridine, and the inhibitor of ATP-sensitive K+ channels glibenclamide in meclofenamate-treated salt solution-perfused rat lungs. Tetraethylammonium (1 to 20 mM) and 4-aminopyridine (1 to 10 mM), but not glibenclamide (1 to 20 microM) caused vasoconstriction in the normoxic lung. The Ca++ channel blocker nifedipine (0.1 microM) and the alpha adrenoceptor antagonist phentolamine (10 microM) inhibited the 4-aminopyridine response by about 50% and reduced slightly the smaller tetraethylammonium response. 4-Aminopyridine and, to a lesser extent, tetraethylammonium, but not glibenclamide, also potentiated peak vasoconstriction to angiotensin II and airway hypoxia. Nifedipine, but not phentolamine, inhibited hypoxic vasoconstriction and prevented the potentiation by 4-aminopyridine. These results suggest that Ca(++)- and/or voltage-activated (not ATP-sensitive) K+ channels may be important in maintaining low pulmonary vascular tone.

Angiotensin II↗

PubMed1991

Difference in effect of inhibitors of energy metabolism on endothelium-dependent relaxation of rat pulmonary artery and aorta.

Previous studies have suggested that systemic artery endothelial cell production of the nitrovasodilator endothelium-derived relaxing factor (EDRF) is dependent upon oxidative energy production. This study was undertaken to test if pulmonary artery (PA) EDRF has a similar requirement for oxidative phosphorylation. The effects of inhibitors of oxidative phosphorylation and glycolysis on endothelium-dependent relaxation were studied in rat aortic and PA rings. In aortic rings, 0.1 microM rotenone and 0.1 microM antimycin A, and, to a lesser extent, 50 mM 2-deoxyglucose, inhibited endothelium-dependent relaxation to acetylcholine and adenosine diphosphate. Relaxation to the receptor-independent calcium ionophore A23187 was less severely affected, and relaxation to the direct smooth muscle dilator sodium nitroprusside was unaffected. The inhibitors had much less effect on PA relaxation, decreasing the potency but not the efficacy of the endothelium-dependent dilators. These results suggest that the dependence on oxidative energy production for endothelium-dependent relaxation may differ between the systemic and pulmonary vascular beds, and that in pulmonary arterial endothelium, oxidative energy production may not be required for receptor-mediated production and/or release of EDRF. The resistance of PA endothelium to decreases in oxidative energy production may contribute to the normally low tone maintained in this circuit in vivo.

Animals↗