Biphasic contractile response of pulmonary artery to hypoxia

1991 ◽  
Vol 261 (2) ◽  
pp. L156-L163 ◽  
Author(s):  
R. E. Bennie ◽  
C. S. Packer ◽  
D. R. Powell ◽  
N. Jin ◽  
R. A. Rhoades
Keyword(s):  
Pulmonary Artery ◽  
Contractile Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Phase 1 ◽  
Phase 2 ◽  
Hypoxic Response ◽  
Sustained Contraction ◽  
First Response ◽  
Complete Relaxation ◽  
Pulmonary Arterial

Isolated perfused lungs exposed to low O2 exhibit a hypoxic pulmonary vasoconstriction response that is transient in nature. The purpose of this study was to determine whether the isolated pulmonary artery behaves similarly in response to hypoxia. Rat pulmonary arterial rings were placed in tissue baths (37 degrees C, air-5% CO2, pH = 7.4) and attached to force transducers. Maximum contractile responses (Po) to high K+ were elicited. After washout, arterial rings were submaximally contracted and made hypoxic (PO2 = 33.7 +/- 1.3, pH = 7.38 +/- 0.01). Aortic rings were used to obtain comparative data. The isolated pulmonary arterial hypoxic response was biphasic, displaying an initial rapid contraction of short duration (phase 1) then, before complete relaxation of this first response, a second slow but sustained contraction occurred (phase 2). Aortic rings did not exhibit a biphasic response, but showed only an initial short contraction followed by complete relaxation. The contractile response of the pulmonary artery was diminished when the endothelium was rendered nonfunctional. However, the phase 2 response was not endothelium dependent. Neither inhibitors of the lipoxygenase or cyclooxygenase pathways nor scavengers of extracellular reactive oxygen species had any effect on the biphasic hypoxic response. Pulmonary arterial hypoxic contractions were blunted when glucose was absent and appear to be dependent on glycolytic ATP. Results of this study show that hypoxia causes a biphasic contractile response of pulmonary arterial muscle and that two different mechanisms appear to be involved, since the transient phase 1 response is endothelium dependent, whereas the sustained contraction of phase 2 is endothelium independent.

Pulmonary vein contracts in response to hypoxia

1993 ◽  
Vol 265 (1) ◽  
pp. L87-L92 ◽  
Author(s):  
Y. Zhao ◽  
C. S. Packer ◽  
R. A. Rhoades
Keyword(s):  
Smooth Muscle ◽  
Regional Blood Flow ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Phase 1 ◽  
Pulmonary Veins ◽  
Arterial Phase ◽  
Channel Blockers ◽  
Phase 2 ◽  
Hypoxic Response ◽  
Sustained Contraction

Hypoxic pulmonary vasoconstriction (HPV) is an important regulatory mechanism in matching regional blood flow and ventilation. The HPV response has been well documented on the arterial side, but the response of pulmonary veins to hypoxia has received little attention. The purpose of the present study was to determine whether isolated rat pulmonary veins contract in response to decreased PO2 and, if so, to compare the venous response with that of the pulmonary artery. Rat pulmonary venous and arterial rings were attached to force transducers and precontracted with either a submaximal dose of KCl or norepinephrine under normoxic conditions and then made hypoxic. The pulmonary venous hypoxic response consisted of a single sustained contraction, whereas the arterial response to hypoxia was biphasic, consisting of an initial rapid contraction and then a slowly developed but sustained contraction. The venous hypoxic contraction was significantly greater in magnitude than either phase 1 or phase 2 of the arterial response. Endothelium denudation did not affect the venous hypoxic response. However, the venous hypoxic response was dependent on the level of precontractile tone and also appeared to be dependent on the specific contractile agonist. Unlike the isolated arterial phase 1 hypoxic response (but similar to the arterial phase 2 response) the pulmonary venous hypoxic contraction was inhibited in Ca(2+)-free media or by Ca2+ channel blockers. In summary, pulmonary venous smooth muscle contracts to a relatively greater degree in response to severe hypoxia than does pulmonary arterial smooth muscle. The venous hypoxic response is endothelium independent, as is phase 2 of the arterial response.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoxic contractile response in isolated human pulmonary artery: role of calcium ion

1988 ◽  
Vol 65 (6) ◽  
pp. 2468-2474 ◽  
Author(s):  
Y. Hoshino ◽  
H. Obara ◽  
M. Kusunoki ◽  
Y. Fujii ◽  
S. Iwai
Keyword(s):  
Pulmonary Artery ◽  
Contractile Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Calcium Ionophore ◽  
Calcium Ionophore A23187 ◽  
Ionophore A23187 ◽  
Voltage Dependent ◽  
Pulmonary Arterial ◽  
Intracellular Storage ◽  
Human Pulmonary Artery

The mechanism for hypoxic pulmonary vasoconstriction (HPVC) was investigated in human pulmonary arterial strips. Hypoxia in the presence of histamine (10(-6) M) caused marked pulmonary arterial contraction, which was reversed by O2. The hypoxic contraction in the presence of histamine was inhibited by diphenhydramine, but not by cimetidine. The hypoxic histamine-mediated contraction was attenuated but still present in the absence of extracellular Ca2+, or by the inhibitors of voltage-dependent Ca2+ influx. However, it was inhibited significantly by a further depletion of intracellular Ca2+, or by HA 1004, an intracellular calcium antagonist. A low concentration (10(-7) M) of a calcium ionophore, A23187, enhanced the hypoxic contraction in the presence of histamine, whereas procaine completely inhibited it. W-7, a calmodulin inhibitor, significantly decreased the hypoxic histamine-mediated contraction, but 12-O-tetradecanoylphorbol-13-acetate (TPA), a C-kinase promotor, had no effect. The hypoxic contractile response was also observed in the presence of both A23187 and KCl instead of histamine, but the hypoxia-induced contraction with KCl alone was much smaller than that. These results indicate that hypoxia in the presence of certain other vasoactive agents has a potent contractile effect on the human pulmonary artery and that the response is dependent on Ca2+. Enhancement of both Ca2+ influx and Ca2+ release from intracellular storage sites by hypoxia, which interacts with calmodulin, were suggested to be involved in the mechanism of HPVC.

Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

2010 ◽  
Vol 9 (4) ◽  
pp. 214-219
Author(s):  
Robyn J. Barst
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Drug Development ◽  
Phase 1 ◽  
Preclinical Studies ◽  
Phase 2 ◽  
Phase 3 ◽  
Preclinical Testing ◽  
New Drug ◽  
Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

Mechanisms of hypoxic vasoconstriction in the canine isolated pulmonary artery: role of endothelium and sodium pump

1994 ◽  
Vol 267 (2) ◽  
pp. L120-L127 ◽  
Author(s):  
Y. Hoshino ◽  
K. J. Morrison ◽  
P. M. Vanhoutte
Keyword(s):  
Pulmonary Artery ◽  
Isometric Force ◽  
Phase 1 ◽  
Similar Data ◽  
Free Solution ◽  
Phase 2 ◽  
H2 Receptor Antagonist ◽  
Phase 3 ◽  
Bathing Medium ◽  
Contraction Phase

Contraction of canine pulmonary artery to hypoxia in vitro is both endothelium dependent and independent. The mechanisms which underlie this phenomenon were studied. Rings of canine pulmonary artery were suspended for isometric force recording in tissue baths containing modified Krebs-Ringer bicarbonate solution. Tissues were first contracted with norepinephrine [effective dose at 35% (ED35) concentration]. Subsequent exposure to hypoxia induced a triphasic response: an initial phasic transient contraction (phase 1), a transient reduction in force (phase 2), followed by a sustained tonic contraction (phase 3). In the absence of endothelium, all phases of the hypoxic response were reduced, and phase 2 was reversed from a contraction to a relaxation (with endothelium: 0.68 +/- 0.2 g; without endothelium: -0.34 +/- 0.1 g). Similar data were obtained in the presence of nitro-L-arginine (3 x 10(-5) M). In the absence of endothelium, indomethacin (10(-5) M) abolished the phase 2 relaxation and converted phase 3 from a contraction to a relaxation (control: 0.99 +/- 0.2 g; indomethacin: -0.44 +/- 0.1 g); and ONO-3708 (thromboxane A2/prostaglandin H2 receptor antagonist) diminished phase 3 (control: 0.99 +/- 0.2 g; ONO-3708: 0.3 +/- 0.04 g). In the absence of endothelium, but in the presence of indomethacin (10(-5) M), K(+)-free solution diminished phase 1 (contraction) and converted phase 2 (relaxation) to a contraction (control: -0.74 +/- 0.1 g; K(+)-free solution: 0.1 +/- 0.06 g). Similar results were obtained with ouabain (4 x 10(-7) M), and cooling of the bathing medium (20 degrees C).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoxic release of calcium from the sarcoplasmic reticulum of pulmonary artery smooth muscle

2001 ◽  
Vol 281 (2) ◽  
pp. L318-L325 ◽  
Author(s):  
Michelle Dipp ◽  
Piers C. G. Nye ◽  
A. Mark Evans
Keyword(s):  
Smooth Muscle ◽  
Sarcoplasmic Reticulum ◽  
Phase 1 ◽  
Transient Phase ◽  
Phase 2 ◽  
Hypoxic Response ◽  
Pulmonary Vessels ◽  
Intracellular Ca ◽  
Pulmonary Artery Smooth Muscle ◽  
Phase Phase

The hypoxic constriction of isolated pulmonary vessels is composed of an initial transient phase ( phase 1) followed by a slowly developing increase in tone ( phase 2). We investigated the roles of the endothelium and of intracellular Ca2+ stores in both preconstricted and unpreconstricted intrapulmonary rabbit arteries when challenged with hypoxia (Po 2 16–21 Torr). Removing the endothelium did not affect phase 1, but phase 2 appeared as a steady plateau. Removing extracellular Ca2+ had essentially the same effect as removing the endothelium. Depletion of sarcoplasmic reticulum Ca2+stores with caffeine and ryanodine abolished the hypoxic response. Omitting preconstriction reduced the amplitude of the hypoxic response but did not qualitatively affect any of the above responses. We conclude that hypoxia releases intracellular Ca2+ from ryanodine-sensitive stores by a mechanism intrinsic to pulmonary vascular smooth muscle without the need for Ca2+ influx across the plasmalemma or an endothelial factor. Our results also suggest that extracellular Ca2+ is required for the release of an endothelium-derived vasoconstrictor.

Regional contractile responses in pulmonary artery to α- and β-adrenoceptor agonists

1987 ◽  
Vol 65 (6) ◽  
pp. 1165-1170 ◽  
Author(s):  
Ralph C. Kolbeck ◽  
William A. Speir Jr.
Keyword(s):  
Pulmonary Artery ◽  
Contractile Response ◽  
Pulmonary Arteries ◽  
Regional Heterogeneity ◽  
Receptor Sites ◽  
Arterial Contraction ◽  
Adrenoceptor Agonists ◽  
Vascular Sensitivity ◽  
Pulmonary Arterial ◽  
Arterial Reactivity

Contractile sensitivity and reactivity to α- and β-adrenoceptor stimulation was studied in incubated rabbit pulmonary artery cylindrical segments of differing diameters. Distinct differences were noted between the responses of extra- and intra-pulmonary pulmonary arteries to norepinephrine and isoproterenol. The sensitivity to norepinephrine was largest in the intrapulmonary pulmonary arteries. Arterial reactivity to norepinephrine was greatest in the larger of the intrapulmonary vessel segments, diminishing considerably as the vessels became smaller. Cocaine did not cause substantial alterations in the response of any of the arterial segments to the α-agonist. Phentolamine, however, exerted its influence primarily in the smaller arterial segments. Vascular sensitivity to isoproterenol was least in the intrapulmonary pulmonary arteries. These smaller vessel segments, however, were more reactive to isoproterenol than were the extrapulmonary pulmonary arterial segments. Propranolol, at a concentration of 10−8 M, was an effective antagonist of the β-agonist; at a concentration of 10−7 M, however, this antagonist was related to isoproterenol-induced arterial contraction, apparently by stimulation of α-receptor sites. The results of this study demonstrated a regional heterogeneity in the contractile response of the pulmonary artery to α- and β-stimulation. The extrapulmonary arterial segments were found to be more sensitive to β-stimulation than were the smaller, intrapulmonary, segments. The intrapulmonary arterial segments, on the other hand, were found to be more sensitive to α-stimulation than were the extrapulmonary segments.

Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction

1992 ◽  
Vol 262 (4) ◽  
pp. C882-C890 ◽  
Author(s):  
J. M. Post ◽  
J. R. Hume ◽  
S. L. Archer ◽  
E. K. Weir
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
K Channel ◽  
Pulmonary Vasoconstriction ◽  
Channel Inhibition ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
K Currents

Cellular mechanisms responsible for hypoxic pulmonary vasoconstriction were investigated in pulmonary arterial cells, isolated perfused lung, and pulmonary artery rings. Three K+ channel antagonists, Leiurus quinquestriatus venom, tetraethylammonium, and 4-aminopyridine, mimicked the effects of hypoxia in isolated lung and arterial rings by increasing pulmonary artery pressure and tension and also inhibited whole cell K+ currents in isolated pulmonary arterial cells. Reduction of oxygen tension from normoxic to hypoxic levels directly inhibited K+ currents and caused membrane depolarization in isolated canine pulmonary arterial smooth muscle cells but not in canine renal arterial smooth muscle cells. Nisoldipine or high buffering of intracellular Ca2+ concentration with [1,2-bis(2)aminophenoxy] ethane-N,N,N',N'-tetraacetic acid prevented hypoxic inhibition of K+ current, suggesting that a Ca(2+)-sensitive K+ channel may be responsible for the hypoxic response. These results indicate that K+ channel inhibition may be a key event that links hypoxia to pulmonary vasoconstriction by causing membrane depolarization and subsequent Ca2+ entry.

Pulmonary arterial hypoxic contraction: signal transduction

1992 ◽  
Vol 263 (1) ◽  
pp. L73-L78 ◽  
Author(s):  
N. Jin ◽  
C. S. Packer ◽  
R. A. Rhoades
Keyword(s):  
Adenosine Receptor ◽  
Second Messengers ◽  
Phase 1 ◽  
Acute Hypoxia ◽  
Pulmonary Arteries ◽  
Receptor Activation ◽  
Phase 2 ◽  
Relaxation Phase ◽  
Pulmonary Arterial ◽  
Free Media

The response of isolated rat pulmonary arteries to acute hypoxia has previously been reported to be biphasic, consisting of an initial rapid contraction of short duration, followed by partial relaxation (phase 1) and then a second slowly developed but sustained contraction (phase 2). The purpose of this study was to determine the following: 1) whether products from the endothelium might be required, 2) whether extra- and/or intracellular calcium or protein kinase C might be second messengers in mediating the pulmonary arterial hypoxic contraction, and 3) whether or not guanosine 3',5'-cyclic monophosphate (cGMP), endothelium-derived relaxing factor (EDRF), prostaglandin I2 (PGI2) or A2 adenosine receptor activation is involved in phase 1 relaxation. Neither Ca(2+)-free media nor verapamil (a Ca2+ channel blocker) altered the phase 1 contraction, but the phase 2 contraction was abolished by either of these treatments. Ryanodine (a sarcoplasmic reticulum Ca2+ depleter) had no effect on phase 1 contraction. H-7 (a PKC inhibitor) inhibited the phase 2 contraction, whereas it had no effect on phase 1 contraction. Removal of the endothelium abolished phase 1 contraction in either Ca(2+)-free media or normal Ca2+ media but did not alter phase 2 contraction or phase 1 relaxation. Neither methylene blue (guanylate cyclase inhibitor), N omega-nitro-L-arginine, (EDRF blocker), acetylsalicylic acid (cyclooxygenase inhibitor), xanthine amino congener (adenosine receptor blocker), nor glybenclamide blocked the phase 1 relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of endogenous nitric oxide on pulmonary vascular tone in intact dogs

1994 ◽  
Vol 266 (6) ◽  
pp. H2343-H2347 ◽  
Author(s):  
M. Leeman ◽  
V. Z. de Beyl ◽  
M. Delcroix ◽  
R. Naeije
Keyword(s):  
Nitric Oxide ◽  
Methylene Blue ◽  
Pulmonary Artery ◽  
Vascular Tone ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Balloon Catheter ◽  
Hypoxic Response ◽  
Pulmonary Vasoconstriction ◽  
Endogenous Nitric Oxide ◽  
Anesthetized Dogs

The interaction between inspiratory fraction of O2 (FIO2) and endogenous nitric oxide (NO) regulation of pulmonary vascular tone was examined in intact anesthetized dogs. Stimulus (FIO2 of 1, 0.4, 0.21, 0.12, and 0.1)-response (changes in pulmonary artery pressure minus pulmonary artery occlusion pressure) curves were constructed with cardiac output kept constant (by opening a femoral arteriovenous bypass or inflating an inferior vena cava balloon catheter), before and after administration of compounds acting at different levels of the L-arginine-NO pathway, NG-nitro-L-arginine (L-NNA, 10 mg/kg iv, n = 16), a NO synthase inhibitor, and methylene blue (8 mg/kg iv, n = 16), a guanylate cyclase inhibitor. L-NNA and methylene blue did not influence pulmonary vascular tone in hyperoxic and in normoxic conditions, but they increased it during hypoxia, thus enhancing the vasopressor response to hypoxia (from 4.5 +/- 0.9 to 10.4 +/- 1.2 mmHg and from 4.2 +/- 0.8 to 9 +/- 1.5 mmHg, respectively, both P < 0.01). Hypoxic pulmonary vasoconstriction was augmented in dogs with a baseline hypoxic response (“responders”) and restored in dogs without hypoxic response (“nonresponders”). These results suggest that endogenous NO does not influence hyperoxic and normoxic pulmonary vascular tone, but that it inhibits hypoxic pulmonary vasoconstriction in intact anesthetized dogs.

A dramatic learning curve of extracardiac Fontan operation in the modern era

2019 ◽  
Vol 27 (3) ◽  
pp. 172-179 ◽  
Author(s):  
Oktay Korun ◽  
Murat Çiçek ◽  
Okan Yurdakök ◽  
Emine Hekim Yılmaz ◽  
Ahmet Çelebi ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Extracorporeal Membrane Oxygenation ◽  
Learning Curve ◽  
Phase 1 ◽  
Fontan Procedure ◽  
Phase 2 ◽  
Pulmonary Artery Reconstruction ◽  
Artery Reconstruction ◽  
Extracardiac Fontan ◽  
Fontan Patients

Background This study aimed to describe the learning curve of the extracardiac Fontan procedure in a single center and to analyze the changes in clinical applications and outcomes. Methods A retrospective chart review of all extracardiac Fontan patients in a single tertiary care center was undertaken. Patients with a diagnosis of hypoplastic left heart syndrome and those who had undergone a lateral tunnel modification, intra/extracardiac Fontan, Kawashima procedure, or inferior vena cava-to-azygous vein connection were excluded from the analysis. Results Between May 2004 and February 2018, data of 159 extracardiac Fontan patients were analyzed. The median age was 5.5 years (range 4.5–8.2 years). Based on a cumulative sum analysis, a hinge point was determined to divide the cohort into 2 phases. Phase 1 ( n = 70) represented the first learning phase and phase 2 ( n = 89) represented the later phase. Mortality decreased in phase 2 (2/89; 2%) compared to phase 1 (10/70; 14%; p = 0.004). Two (3%) patients had extracorporeal membrane oxygenation in phase 1, and 5 (6%) in phase 2 ( p = 0.47). More patients in phase 2 underwent a prior bidirectional Glenn procedure (83/89 vs. 57/70; p = 0.02), fenestration (80/89 vs. 9/70; p < 0.001), and pulmonary artery reconstruction (37/89 vs. 2/70; p < 001). Conclusions This study shows that increased use of extracorporeal membrane oxygenation, strict implementation of the three-stage management plan, routine fenestration, and a low threshold for pulmonary artery reconstruction may be associated with decreased mortality in the extracardiac Fontan procedure.

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