Evidence for Distinct Endothelin Receptors in the Pulmonary Vascular Bed in vivo

The present study was undertaken to investigate the effects of endothelin (ET) isopeptides on the pulmonary vascular bed of the intact spontaneously breathing cat under conditions of constant pulmonary blood flow and left atrial pressure. When pulmonary vasomotor tone was actively increased by intralobar infusion of U-46619, intralobar bolus injections of ET-1 (1 microgram), ET-2 (1 microgram), and ET-3 (3 micrograms) produced marked reductions in pulmonary and systemic vascular resistances. The pulmonary vasodilator response to each ET isopeptide was not altered by atropine (1 mg/kg iv), indomethacin (2.5 mg/kg iv), and ICI 118551 (1 mg/kg iv) but was significantly diminished by glybenclamide (5 mg/kg iv). This dose of glybenclamide significantly diminished the decrease in lobar arterial and systemic arterial pressures in response to intralobar injection of pinacidil (30 and 100 micrograms) and cromakalim (10 and 30 micrograms), whereas pulmonary vasodilator responses to acetylcholine (0.03 and 0.1 microgram), prostaglandin I2 (0.1 and 0.3 microgram), and isoproterenol (0.03 and 0.1 microgram) were not altered. The systemic vasodilator response to each ET isopeptide was not changed by glybenclamide or by the other blocking agents studied. The present data comprise the first publication demonstrating that ET-1, ET-2, and ET-3 dilate the pulmonary vascular bed in vivo. The present data further suggest that the pulmonary vasodilator response to ET isopeptides depends, in part, on activation of potassium channels and is mediated differently from the systemic vasodilator response to these substances. Contrary to earlier work, the present data indicate the pulmonary vascular response to ET isopeptides does depend on the preexisting level of pulmonary vasomotor tone.(ABSTRACT TRUNCATED AT 250 WORDS)

Download Full-text

Fate of vasopressin and oxytocin in the pulmonary circulation

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y69-121 ◽

1969 ◽

Vol 47 (8) ◽

pp. 713-717 ◽

Cited By ~ 7

Author(s):

P. Biron ◽

J.-C. Boileau

Keyword(s):

Pulmonary Circulation ◽

Pressure Response ◽

Systemic Pressure ◽

Vascular Bed ◽

Pulmonary Vascular Bed

The pulmonary inactivation of lys-8 vasopressin in anesthetized, normal dogs, cats, rabbits, and rats, and that of Pitressin in rats, was studied by means of the systemic pressure response technique. The pulmonary fate of oxytocin was measured in rats by the same technique and, in addition, by means of an in vivo oxytocic assay. The pulmonary inactivation of these three neurohypophyseal peptides was negligible in all instances. The data reinforce the concept that circulating hormones freely cross the pulmonary vascular bed.

Download Full-text

L-NAME enhances pulmonary vasoconstriction without inhibiting EDRF-dependent vasodilation

Journal of Applied Physiology ◽

10.1152/jappl.1992.73.6.2432 ◽

1992 ◽

Vol 73 (6) ◽

pp. 2432-2439 ◽

Cited By ~ 11

Author(s):

H. L. Lippton ◽

Q. Hao ◽

A. Hyman

Keyword(s):

Arterial Pressure ◽

Receptor Agonist ◽

Bolus Administration ◽

Vasodilator Response ◽

Vascular Bed ◽

Pulmonary Vasodilator ◽

Vasoconstrictor Response ◽

Serotonin2 Receptor ◽

Pulmonary Vascular Bed

The purpose of the present study was to determine the influence of NG-nitro-L-arginine methyl ester (L-NAME) on pulmonary vascular responses to endothelium-dependent relaxing factor- (EDRF) dependent and EDRF-independent substances in the pulmonary vascular bed of the anesthetized cat. Because pulmonary blood flow and left atrial pressure were kept constant, changes in lobar arterial pressure directly reflect changes in pulmonary vascular resistance. When pulmonary vasomotor tone was actively increased by intralobar infusion of U-46619, intralobar bolus injections of acetylcholine, bradykinin, serotonin, and 5-carboxyamidotryptamine (a serotonin1A receptor agonist) decreased lobar arterial pressure in a dose-related manner. The pulmonary vasodilator response to serotonin, but not to 5-carboxyamidotryptamine, acetylcholine, and bradykinin, was significantly decreased by L-NAME (100 mg/kg i.v.). Administration of ritanserin (0.5 mg/kg i.v.), but not L-arginine (1 g/kg i.v. with 60 mg.kg-1 x min-1 i.v. infusion), reversed the inhibitory effects of L-NAME on the pulmonary vasodilator response to serotonin and abolished the enhanced pulmonary vasoconstrictor response to (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoproprane hydrochloride (a serotonin2 receptor agonist) after L-NAME administration. In conclusion, the present experiments suggest that L-NAME inhibits the pulmonary vasodilator response to serotonin by increasing the sensitivity of serotonin2 receptor-mediated vasoconstriction and not by inhibiting EDRF formation. Because the pulmonary vasodilator responses to bolus administration of acetylcholine and bradykinin were not inhibited by L-NAME, these data suggest that L-NAME does not appear to be an adequate probe to study the role of endogenous EDRF in the adult feline pulmonary vascular bed in vivo.

Download Full-text

Pulmonary vascular obstruction in graded tachypneagenic diffuse embolism

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1961.200.2.279 ◽

1961 ◽

Vol 200 (2) ◽

pp. 279-286 ◽

Cited By ~ 12

Author(s):

Theodore Bernthal ◽

Alan D. Horres ◽

Joseph T. Taylor

Keyword(s):

Vascular Tone ◽

Moderate Increase ◽

Lung Lobe ◽

Vascular Bed ◽

Anesthetized Dogs ◽

Flow Pressure ◽

Vascular Obstruction ◽

Pulmonary Vascular Obstruction ◽

Pulmonary Vascular Bed

One group of experiments revealed minimal doses of 75 µ pulmonary emboli required for eliciting increased frequency and decreased amplitude of breathing in anesthetized dogs. Others measured in vivo lung lobe autoperfusion flow rates at several constant perfusion pressures to determine the fractions of the pulmonary vascular bed obstructed by these and other quantities and to determine concurrent changes in flow-pressure relationships. The fraction of the vascular bed obstructed by threshold tachypneagenic quantities averaged 10% but in some instances was as little as 3%—values so small that the expected hemodynamic consequences in intact animals would be within physiological ranges and therefore seemingly not important as a tachypneagenic mechanism. Following embolization, resistance to blood flow increased in the nonoccluded intralobar vascular bed, particularly at lower perfusion pressures, and associated alterations in flow-pressure and resistance-pressure relationships pointed toward moderate increase in vascular tone as the cause. Quantities of emboli apparently required for completely obstructing the pulmonary vascular bed were considered in relation to established anatomical dimensions.

Download Full-text

Endothelin produces pulmonary vasoconstriction and systemic vasodilation

Journal of Applied Physiology ◽

10.1152/jappl.1989.66.2.1008 ◽

1989 ◽

Vol 66 (2) ◽

pp. 1008-1012 ◽

Cited By ~ 92

Author(s):

H. L. Lippton ◽

T. A. Hauth ◽

W. R. Summer ◽

A. L. Hyman

Keyword(s):

Aortic Pressure ◽

Systemic Arterial Pressure ◽

Vasomotor Tone ◽

Vascular Bed ◽

Vasoconstrictor Response ◽

Potent Vasodilator ◽

Beta 2 ◽

The Right ◽

Pulmonary Vascular Bed

Endothelin is a newly described polypeptide derived from endothelial cells. The effects of porcine endothelin on the pulmonary vascular bed and systemic vascular bed were investigated in the anesthetized, intact-chest cat under conditions of constant pulmonary blood flow and left atrial pressure. Intralobar bolus injections of porcine endothelin (100–1000 ng) produced a mild vasoconstrictor response in the pulmonary vascular bed. The pulmonary vasoconstrictor response to endothelin was not altered when pulmonary vasomotor tone was increased by infusion of U46619. In contrast to this mild pulmonary vasoconstrictor response, endothelin decreased systemic arterial pressure. Moreover, injections of porcine endothelin into the right and left atria produced similar reductions in aortic pressure as well as similar increases in cardiac output and decreases in systemic vascular resistance. The systemic vasodilator response to porcine endothelin was not affected by beta 2-adrenoceptor blockade. The present data suggest that endothelin does not undergo significant first-pass pulmonary metabolism. The pulmonary vasoconstrictor response to bolus injections of porcine endothelin is not altered by changes in pulmonary vasomotor tone. In contrast, endothelin markedly dilated the systemic vascular bed independently of activation of beta 2-adrenoceptors. The present study provides the first report of the activity of endothelin on pulmonary and systemic hemodynamics in vivo. Moreover, the potent vasodilator activity of endothelin in the systemic vascular bed and its weak effect on pulmonary vessels suggest that endothelin may be more important in the regulation of peripheral vasomotor tone than the pulmonary vascular bed.

Download Full-text

Mechanisms of signal transduction for adenosine and ATP in pulmonary vascular bed

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1992.262.3.h926 ◽

1992 ◽

Vol 262 (3) ◽

pp. H926-H929 ◽

Cited By ~ 3

Author(s):

H. L. Lippton ◽

Q. Hao ◽

T. Hauth ◽

A. Hyman

Keyword(s):

G Proteins ◽

Purinergic Receptor ◽

Blocking Agent ◽

Dependent Manner ◽

Vascular Bed ◽

Vasoconstrictor Response ◽

Txa2 Receptor Antagonist ◽

Dose Dependent ◽

Pulmonary Vascular Bed

The purpose of the present study was to investigate the contribution of pertussis toxin (PTX)-sensitive guanine nucleotide (G) proteins in the pulmonary vascular response to adenosine and ATP in the intact cat under conditions of controlled pulmonary blood flow and left atrial pressure. Adenosine, ATP, and beta-tau-ATP increased lobar arterial pressure in a dose-dependent manner. The pulmonary vasoconstrictor response to adenosine was abolished by BW 1433U, a specific purinergic receptor (P1) inhibitor, PTX pretreatment, indomethacin, and ONO 3708, a thromboxane A2 (TxA2) receptor antagonist. These data suggest that the pulmonary vasoconstrictor response to adenosine depends on activation of P1 purinergic receptors coupled to PTX-sensitive G proteins and subsequent metabolism of liberated arachidonic acid to form TxA2. Because each blocking agent studied produced similar reductions in the pulmonary vasoconstrictor response to ATP without altering the pulmonary vasoconstrictor response to beta-tau-ATP, the present data suggest that ATP constricts the pulmonary vascular bed, in part, by hydrolysis to adenosine. Moreover, the present study suggests that both A1 purinoceptors that are linked to PTX-sensitive G proteins as well as P2x purinoceptors receptors that are independent of PTX-insensitive G proteins mediate the pulmonary vasoconstrictor response to ATP in vivo.

Download Full-text

Platelet Release from Infused CD34+-Derived Human Megakaryocytes: Lessons from a Natural-Occurring Platelet Bioreactor

Blood ◽

10.1182/blood.v128.22.1375.1375 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1375-1375

Author(s):

Ian Johnston ◽

Vincent M Hayes ◽

Jing Dai ◽

Danuta Jadwiga Jarocha ◽

Paul Kubes ◽

...

Keyword(s):

Conflicts Of Interest ◽

Ex Vivo ◽

Three Dimensional ◽

Blood Stream ◽

Published Data ◽

Vascular Bed ◽

Platelet Release ◽

Pulmonary Vascular Bed

Abstract The release of biologically intact platelets from in vitro-grown megakaryocytes remains one of the challenges in an attempt to replace donor-derived platelets with platelets prepared from in vitro-grown megakaryocytes. Thrombopoiesis, the process by which megakaryocytes release platelets, is thought to occur as megakaryocytes exit from the medullar space and transit into the blood stream. Two-photon fluorescence microscopy studies by several groups have documented megakaryocytes transitioning into the blood stream and extending mostly a single protrusion that appears to release large cytoplasmic fragments downstream. These studies have been widely interpreted to support platelet release in the bone marrow environment. A counter proposal made by Dr. William Howell over 75 years ago is that either whole megakaryocytes or large cytoplasmic fragments circulate to the lungs and release platelets in the lungs. Studies by our group infusing in vitro-grown megakaryocytes (both human and mouse) have shown that infused megakaryocytes do indeed become entrapped in the lungs and release platelets. These in vivo-released platelets have a much longer half-life than in vitro-prepared platelets from static cultures and have the same size distribution and nearly the same functionality as infused donor-derived platelets. Using confocal intravital microscopy, we now directly visualized the lungs of recipient NOD-SCID interferon 2 receptor γ-deficient mice during the infusion of calcein-loaded CD34+-derived megakaryocytes. Infused human megakaryocytes were immediately arrested in the pulmonary bed in vessels ~50 µm in diameter. Each cell then extended several distinct protrusions winding down presumed pulmonary capillaries that are presumably wrapped around alveoli. Some of these protrusions reached 200-300 µm in length and assumed the appearance of beads on a string. Consistent with our recently published data, this thrombopoiesis process appears to take 30 minutes to be near-complete, similar to the timeframe we showed for detecting newly released human platelet-like particles after megakaryocyte infusion. At 30 minutes, remaining bodies of the megakaryocytes are still present and we presume these are mostly the remaining nuclei. To better define whether the pulmonary bed is unique for releasing platelets, we also infused megakaryocytes intra-arteriole rather than intravenously to have the megakaryocytes encounter other organ capillary beds before the lung. These studies showed poor platelet release compared to parallel studies in mice receiving the megakaryocytes intravenously. Many of the intra-arterial infused megakaryocytes were entrapped in the spleen and very few were notable in other organs, including the lungs, liver and kidney. Our studies showed that megakaryocytes can shed platelets in the lungs where they may take advantage of the unique three-dimensional organization of the pulmonary vascular bed, flow conditions, vascular surface receptors and glycocalyx as well as a sudden shift from hypoxic to normoxic conditions. Whether these features of the pulmonary vascular bed can be simulated ex vivo and whether this will enhance true platelet release from megakaryocytes in vitro needs to be examined. Disclosures No relevant conflicts of interest to declare.

Download Full-text