Effects of ouabain, low K+, and aldosterone on hypoxic pressor reactivity of rat lungs

1985 ◽  
Vol 248 (1) ◽  
pp. H55-H60 ◽  
Author(s):  
J. Herget ◽  
I. F. McMurtry
Keyword(s):  
Angiotensin Ii ◽  
Energy Metabolism ◽  
Atpase Activity ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Response Curves ◽  
Hypoxic Response ◽  
Rat Lungs ◽  
Hypoxic Vasoconstriction ◽  
Low K

It can be postulated that inhibition of lung tissue Na+-K+-ATPase might potentiate hypoxic pulmonary vasoconstriction by depolarizing some excitable cell or, in contrast, that it might blunt the hypoxic response by reducing cellular metabolic rate and sensitivity to hypoxia. Thus the purpose of this study was to test in isolated rat lungs whether hypoxic pressor reactivity was related inversely or positively to Na+-K+-ATPase activity. Dose-pressor response curves to hypoxia, angiotensin II, or KCl were measured under control conditions and after exposure either to one of two inhibitors of Na+-K+-ATPase, ouabain, and low-K+ solution or to a stimulator of Na+-K+ pumping, aldosterone. Ouabain and low K+ depressed the response to hypoxia but had little effect on that to angiotensin II. The response to KCl was increased by ouabain. Aldosterone potentiated the hypoxic response. These results do not support the idea that membrane depolarization due to inhibition Na+-K+ pumping is a component of hypoxic vasoconstriction. They do suggest a positive relationship between Na+-K+-ATPase activity and hypoxic pressor reactivity and are consistent with the idea that Na+-K+-ATPase activity might influence hypoxic reactivity indirectly by altering cellular energy metabolism. It is also possible that the results were somehow due to changes in intracellular [Na+] or transmembrane Na+ gradient, rather than to changes in energy metabolism.

Effects of intracellular pH on hypoxic vasoconstriction in rat lungs

1987 ◽  
Vol 63 (6) ◽  
pp. 2524-2531 ◽  
Author(s):  
B. Raffestin ◽  
I. F. McMurtry
Keyword(s):  
Intracellular Ph ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Weak Acid ◽  
Hypoxic Response ◽  
Weak Bases ◽  
Rat Lungs ◽  
Hypoxic Vasoconstriction ◽  
Ethanesulfonic Acid ◽  
Vasoactive Mediator ◽  
Isolated Rat

Isolated rat lungs perfused with physiological salt-Ficoll solutions were studied to test whether hypoxic pulmonary vasoconstriction was potentiated by increases in intracellular pH (pHi) and blunted by decreases in pHi. Whereas addition to perfusate of 5 nM phorbol myristate acetate (PMA), a stimulator of exchange of intracellular H+ for extracellular Na+, potentiated hypoxic vasoconstriction, 1 mM amiloride, an inhibitor of Na+-H+ exchange, blunted the hypoxic response. Hypoxic vasoconstriction was also potentiated by the weak bases NH4Cl (20 mM), methylamine (10 mM), and imidazole (5 mM) and was inhibited by the weak acid sodium acetate (40 mM). NH4Cl, imidazole, and acetate had the same effects on KCl-induced vasoconstriction and on the hypoxic response. Hypoxic vasoconstriction was greater in lungs perfused with N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES)-buffered solution than in those perfused with CO2/HCO3--buffered solution. Similarly, lungs perfused with CO2/HCO3--buffered solution containing 1.8 mM Cl- (NaNO3 and KNO3 substituted for NaCl and KCl) had larger hypoxic and angiotensin II pressor responses than those perfused with 122.5 mM Cl-. Because PMA, NH4Cl, methylamine, imidazole, HEPES-buffered solutions, and low-Cl- solutions can cause increases in pHi and amiloride and acetate can cause decreases in pHi, these results suggest that intracellular alkalosis and acidosis, respectively, potentiate and blunt vasoconstrictor responses to hypoxia and other stimuli in isolated rat lungs. These effects could be related to pHi-dependent changes in either the sensitivity of the arterial smooth muscle contractile machinery to Ca2+ or the release of a vasoactive mediator or modulator by some other lung cell.

Leukotriene synthesis and receptor blockers block hypoxic pulmonary vasoconstriction

1984 ◽  
Vol 56 (5) ◽  
pp. 1340-1346 ◽  
Author(s):  
M. L. Morganroth ◽  
J. T. Reeves ◽  
R. C. Murphy ◽  
N. F. Voelkel
Keyword(s):  
Angiotensin Ii ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Calcium Entry ◽  
Calcium Entry Blocker ◽  
Adult Rat ◽  
Pulmonary Vasoconstriction ◽  
Rat Lungs ◽  
Diethylcarbamazine Citrate ◽  
Receptor Blockers

We hypothesized that leukotrienes are involved in hypoxic pulmonary vasoconstriction, since they are pulmonary vasoconstrictors and cells capable of producing leukotrienes are located in the lung near resistance vessels. We investigated in isolated perfused rat lungs whether three structurally unrelated blockers [diethylcarbamazine citrate (DEC), U-60257, and FPL 55712] of leukotriene synthesis or action block hypoxic pulmonary vasoconstriction. DEC blocked ongoing and subsequent hypoxic pressor responses while minimally affecting the angiotensin II pressor response. The inhibition of the hypoxic pressor response by DEC was not affected by cyclooxygenase or H1-receptor blockers. Potassium-induced vasoconstriction, which is dependent on calcium entry, was largely blocked by verapamil but not by DEC, suggesting that DEC was not acting primarily as a calcium-entry blocker. U-60257 blocked the hypoxic pressor response without inhibiting the pressor response to angiotensin II or potassium chloride. FPL 55712, a leukotriene end-organ blocker, in a dose which inhibited vasoconstriction caused by exogenous leukotriene C4, inhibited the pressor response to hypoxia but not to angiotensin II. We conclude that leukotriene inhibitors preferentially inhibit hypoxic pulmonary vasoconstriction in isolated perfused adult rat lungs.

Platelet antiserum inhibits hypoxic pulmonary vasoconstriction in the dog

1976 ◽  
Vol 41 (2) ◽  
pp. 211-215 ◽  
Author(s):  
E. K. Weir ◽  
J. Mlczoch ◽  
J. Seavy ◽  
J. J. Cohen ◽  
R. F. Grover
Keyword(s):  
Platelet Count ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Hypoxic Response ◽  
Pulmonary Vasoconstriction ◽  
Vasoconstrictor Response ◽  
Hypoxic Vasoconstriction ◽  
Prior Administration ◽  
Temporary Inhibition

The literature suggests that platelets might help mediate the pulmonary vascular pressor response to hypoxia. This study evaluated the hypoxic response in dogs rendered acutely thrombocytopenic by the administration of platelet antiserum. Between 30 and 90 min after the antiserum the pulmonary vasoconstrictor response to hypoxia was virtually abolished, but subsequently returned at a time when the number of circulating platelets remained very low. The prior administration of meclofenamate completely preserved the hypoxic response, though the platelet count still fell precipitously. We conclude that circulating platelets are not necessary for hypoxic vasoconstriction. It is possible that the reaction between platelets and antiserum evokes the synthesis of a dilator prostaglandin which might be responsible for the temporary inhibition of the pressor response to hypoxia but this remains to be proven.

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

1991 ◽  
Vol 260 (2) ◽  
pp. L97-L104 ◽  
Author(s):  
K. Hasunuma ◽  
T. Yamaguchi ◽  
D. M. Rodman ◽  
R. F. O'Brien ◽  
I. F. McMurtry
Keyword(s):  
Vascular Reactivity ◽  
Pressor Response ◽  
Pulmonary Arteries ◽  
K Channel ◽  
Channel Blockers ◽  
Hypoxic Response ◽  
K Channels ◽  
Pulmonary Vasodilation ◽  
Rat Lungs ◽  
Hypoxic Vasoconstriction

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.

BAY K 8644 potentiates and A23187 inhibits hypoxic vasoconstriction in rat lungs

1985 ◽  
Vol 249 (4) ◽  
pp. H741-H746 ◽  
Author(s):  
I. F. McMurtry
Keyword(s):  
Angiotensin Ii ◽  
Vascular Tone ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Bay K 8644 ◽  
Physiological Salt Solution ◽  
Pulmonary Vasoconstriction ◽  
Rat Lungs ◽  
Hypoxic Vasoconstriction ◽  
Voltage Dependent ◽  
Ca2 Channels

The susceptibility of hypoxic pulmonary vasoconstriction to inhibition by Ca2+ channel antagonists suggests that membrane depolarization and Ca2+ influx are components of the hypoxic mechanism. Recent characterization of BAY K 8644 as a 1,4-dihydropyridine that facilitates Ca2+ influx through partially activated voltage-dependent Ca2+ channels provides a new pharmacological tool to further test this idea. Effects of BAY K 8644 on normoxic vascular tone and on hypoxic and angiotensin II-induced vasoconstriction were examined in isolated rat lungs perfused with either blood or physiological salt solution (PSS) containing meclofenamate. Parallel experiments were performed with the Ca2+ ionophore A23187 for comparison with a Ca2+-active agent that does not act selectively on the voltage-dependent Ca2+ channel. Addition of BAY K 8644 (10(-7) to 10(-5) M) to the perfusate did not alter base-line vascular tone of the normoxic lung, but it potentiated hypoxic and angiotensin II pressor responses. For example, addition of 10(-7) M BAY K 8644 to five PSS-perfused lungs increased the hypoxic (5% O2) pressor response from 8.7 +/- 2.1 to 19.5 +/- 4.2 Torr and the angiotensin II (0.1 micrograms) response from 2.1 +/- 0.4 to 6.5 +/- 2.0 Torr. In contrast, addition of A23187 (10(-7) to 10(-6) M) to the perfusate increased normoxic perfusion pressure and inhibited hypoxic vasoconstriction. The respective effects of BAY K 8644 and A23187 were essentially the same in both blood- and PSS-perfused lungs. These results indicate that a Ca2+ channel facilitator and a Ca2+ ionophore have diametric effects on pulmonary vasoreactivity. The marked potentiation of hypoxic vasoconstriction by BAY K 8644 supports the idea that activation of voltage-dependent Ca2+ channels is an important component of the mechanism of hypoxic pulmonary vasoconstriction.

NO and reactive oxygen species are involved in biphasic hypoxic vasoconstriction of isolated rabbit lungs

2001 ◽  
Vol 280 (4) ◽  
pp. L638-L645 ◽  
Author(s):  
Norbert Weissmann ◽  
Stefan Winterhalder ◽  
Matthias Nollen ◽  
Robert Voswinckel ◽  
Karin Quanz ◽  
...  
Keyword(s):  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Oxidase Inhibitor ◽  
No Formation ◽  
Vasoconstrictor Response ◽  
Hypoxic Vasoconstriction ◽  
Chronic Pulmonary Hypertension ◽  
Alveolar Hypoxia ◽  
Pulmonary Arterial ◽  
Synthase Inhibitor

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion with ventilation but may also result in chronic pulmonary hypertension. It has not been clarified whether acute HPV and the response to prolonged alveolar hypoxia are triggered by identical mechanisms. We characterized the vascular response to sustained hypoxic ventilation (3% O2for 120–180 min) in isolated rabbit lungs. Hypoxia provoked a biphasic increase in pulmonary arterial pressure (PAP). Persistent PAP elevation was observed after termination of hypoxia. Total blockage of lung nitric oxide (NO) formation by N G-monomethyl-l-arginine caused a two- to threefold amplification of acute HPV, the sustained pressor response, and the loss of posthypoxic relaxation. This amplification was only moderate when NO formation was partially blocked by the inducible NO synthase inhibitor S-methylisothiourea. The superoxide scavenger nitro blue tetrazolium and the superoxide dismutase inhibitor triethylenetetramine reduced the initial vasoconstrictor response, the prolonged PAP increase, and the loss of posthypoxic vasorelaxation to a similar extent. The NAD(P)H oxidase inhibitor diphenyleneiodonium nearly fully blocked the late vascular responses to hypoxia in a dose that effected a decrease to half of the acute HPV. In conclusion, as similarly suggested for acute HPV, lung NO synthesis and the superoxide-hydrogen peroxide axis appear to be implicated in the prolonged pressor response and the posthypoxic loss of vasorelaxation in perfused rabbit lungs undergoing 2–3 h of hypoxic ventilation.

Does leukotriene C4 mediate hypoxic vasoconstriction in isolated ferret lungs?

1990 ◽  
Vol 68 (1) ◽  
pp. 253-259 ◽  
Author(s):  
C. M. Tseng ◽  
M. McGeady ◽  
T. Privett ◽  
A. Dunn ◽  
J. T. Sylvester
Keyword(s):  
Pulmonary Arterial Pressure ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Physiological Salt Solution ◽  
Leukotriene C4 ◽  
Prostaglandin F2 Alpha ◽  
Pulmonary Vasoconstriction ◽  
Vasoconstrictor Response ◽  
Hypoxic Vasoconstriction ◽  
Pulmonary Arterial

To evaluate leukotriene (LT) C4 as a mediator of hypoxic pulmonary vasoconstriction, we examined the effects of FPL55712, a putative LT antagonist, and indomethacin, a cyclooxygenase inhibitor, on vasopressor responses to LTC4 and hypoxia (inspired O2 tension = 25 Torr) in isolated ferret lungs perfused with a constant flow (50 ml.kg-1.min-1). Pulmonary arterial injections of LTC4 caused dose-related increases in pulmonary arterial pressure during perfusion with physiological salt solution containing Ficoll (4 g/dl). FPL55712 caused concentration-related inhibition of the pressor response to LTC4 (0.6 micrograms). Although 10 micrograms/ml FPL55712 inhibited the LTC4 pressor response by 61%, it did not alter the response to hypoxia. At 100 microgram/ml, FPL55712 inhibited the responses to LTC4 and hypoxia by 73 and 71%, respectively, but also attenuated the vasoconstrictor responses to prostaglandin F2 alpha (78% at 8 micrograms), phenylephrine (68% at 100 micrograms), and KCl (51% at 40 mM). At 0.5 microgram/ml, indomethacin significantly attenuated the pressor response to arachidonic acid but did not alter responses to LTC4 or hypoxia. These results suggest that in isolated ferret lungs 1) the vasoconstrictor response to LTC4 did not depend on release of cyclooxygenase products and 2) LTC4 did not mediate hypoxic vasoconstriction.

Prostaglandin synthetase inhibitors do not decrease hypoxic pulmonary vasoconstriction

1976 ◽  
Vol 41 (5) ◽  
pp. 714-718 ◽  
Author(s):  
E. K. Weir ◽  
I. F. McMurtry ◽  
A. Tucker ◽  
J. T. Reeves ◽  
R. F. Grover
Keyword(s):  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Prostaglandin Synthesis ◽  
Pulmonary Vasoconstriction ◽  
Pressor Responses ◽  
Hypoxic Vasoconstriction ◽  
Before And After ◽  
Anesthetized Dogs ◽  
Prostaglandin Antagonists ◽  
The Stability

Prostaglandins are naturally occurring substances with powerful vasoactive effects that are released from tissues during hypoxia or ischemia. Several workers have suggested that a prostaglandin may help to mediate the pulmonary vascular pressor response to alveolar hypoxia. To investigate this possibility, we have measured the pressor responses to hypoxia before and after prostaglandin synthesis antagonism with meclofenamate in eight anesthetized dogs, two groups of awake calves (n=10 and =5), and nine isolated, perfused rat lungs. In addition, synthesis was inhibited by the use of indomethacin in nine additional dogs. The stability of the pulmonary vascular response to repeated hypoxic challenges was demonstrated in nine other dogs. In each species and with both prostaglandin antagonists, the pulmonary pressorresponses to hypoxia were significantly increased rather than reduced. We conclude that prostaglandins do not mediate the pulmonary vasoconstriction caused by hypoxia. The consistent increase observed suggests that hypoxic vasoconstriction stimulates prostaglandin synthesis, the net effect of which is pulmonary vasodilatation which opposes the constriction.

Pressor responses of rats to vasopressin: effect of sodium, angiotensin, and catecholamines

1983 ◽  
Vol 244 (2) ◽  
pp. H253-H258 ◽  
Author(s):  
M. Burnier ◽  
H. R. Brunner
Keyword(s):  
Angiotensin Ii ◽  
Sodium Intake ◽  
Pressor Response ◽  
Response Curves ◽  
Ether Anesthesia ◽  
Spontaneously Hypertensive ◽  
Lysine Vasopressin ◽  
Pressor Responses ◽  
Wistar Kyoto ◽  
The Right

The pressor response to lysine vasopressin was tested in groups of male Wistar, Brattleboro, Wistar-Kyoto, and spontaneously hypertensive rats. Moreover, the influence of sodium intake, angiotensin II, saralasin, captopril, norepinephrine, and isoproterenol on vasopressin pressor responses was evaluated. The right iliac artery and one or both femoral veins of the animals were catheterized under light ether anesthesia. The experiments were carried out following a 2-h stabilization period with the rats awake and semirestrained. Pressor responsiveness was evaluated acutely on the basis of dose-response curves (0.5-4 mU). In the Wistar rats, angiotensin II (10 and 30 ng/min) and isoproterenol (10 ng/min) markedly decreased the response to vasopressin, whereas variations in sodium intake and blood pressure per se did not seem to exert any influence. Norepinephrine (250 ng/min) slightly enhanced the pressor responsiveness to the smaller doses of lysine-vasopressin. Brattleboro rats with congenital diabetes insipidus were less sensitive to vasopressin than the other animals, and neither angiotensin II nor isoproterenol induced any change. In conclusion, the pressor responsiveness to vasopressin can vary considerably depending on several factors. These must be taken into account when evaluating the possible pressor role of vasopressin in experimental and clinical settings.

Pressor Responsiveness to Angiotensin in Renovascular and Steroid Hypertension

1979 ◽  
Vol 57 (s5) ◽  
pp. 47s-50s ◽  
Author(s):  
E. S. Marks ◽  
H. Thurston ◽  
R. F. Bing ◽  
J. D. Swales
Keyword(s):  
Angiotensin Ii ◽  
Pressor Response ◽  
Plasma Renin ◽  
Receptor Occupancy ◽  
Bilateral Nephrectomy ◽  
Hypertensive Rats ◽  
Response Curves ◽  
Pressor Responses ◽  
Salt Hypertension ◽  
Converting Enzyme Inhibition

1. The pressor response to angiotensin II was reduced in rats with early (<6 weeks) and chronic (>4 months) Goldblatt two-kidney, one-clip hypertension and enhanced in DOCA—salt hypertension. 2. Converting enzyme inhibition with captopril brought the angiotensin pressor response curves into closer proximity although the DOCA hypertensive rats were minimally hyper-responsive and rats with early and chronic renovascular hypertension showed slightly reduced responsiveness. 3. After bilateral nephrectomy the pressor responses to angiotensin were similar. 4. The pressor response to angiotensin II in these animals was inversely related to plasma renin concentration and therefore largely dependent upon receptor occupancy by endogenous angiotensin II. There is no evidence for enhanced pressor responsiveness to angiotensin in either renovascular or DOCA hypertension.

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