A model of embolic chronic pulmonary hypertension in the dog

1984 ◽  
Vol 56 (3) ◽  
pp. 810-815 ◽  
Author(s):  
I. Shelub ◽  
A. van Grondelle ◽  
R. McCullough ◽  
S. Hofmeister ◽  
J. T. Reeves
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Histological Study ◽  
Systemic Arterial Pressure ◽  
Right Atrial ◽  
Pulmonary Vasodilation ◽  
Reliable Model ◽  
Chronic Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
Wedge Pressure

Despite numerous efforts, a reliable model of chronic embolic pulmonary hypertension has not been established. To develop such a model five conscious mongrel dogs were embolized repeatedly over 16–30 wk with Sephadex microspheres 286 +/- 70 micron in diameter. Hemodynamic and respiratory measurements were obtained just prior to each embolization. Chronic pulmonary hypertension developed in all dogs. Pulmonary hypertension was not accounted for by increased cardiac output, wedge pressure, right atrial pressure, or systemic arterial pressure. Gas exchange was little altered. Lung histological study revealed microspheres clustered within vessels. In three dogs increased pulmonary arterial pressure was sustained despite cessation of embolization for up to 5 mo. Reembolization in one of these caused further pulmonary hypertension. In two dogs acute pulmonary vasodilation by O2 breathing and administration of prostaglandin E1 reduced, but did not abolish, the increased pulmonary vascular resistance, suggesting some vascular tone was present. An embolic model of chronic pulmonary hypertension in awake dogs allows further investigation into the evolution of pulmonary hypertension.

Pulmonary vasodilation with structurally altered pulmonary vessels and pulmonary hypertension

1988 ◽  
Vol 65 (6) ◽  
pp. 2459-2467 ◽  
Author(s):  
E. C. Orton ◽  
J. T. Reeves ◽  
K. R. Stenmark
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Sodium Nitroprusside ◽  
Pulmonary Arteries ◽  
Systemic Arterial Pressure ◽  
Pulmonary Resistance ◽  
Pulmonary Vasodilation ◽  
Pulmonary Arterial ◽  
Neonatal Calves

To evaluate pulmonary vasodilation in a structurally altered pulmonary vascular bed, we gave endothelium-dependent (acetylcholine) and endothelium-independent [sodium nitroprusside, prostaglandin I2 (PGI2)] vasodilators in vivo and to isolated lobar pulmonary arteries from neonatal calves with severe pulmonary hypertension. Acetylcholine, administered by pulmonary artery infusion, decreased pulmonary arterial pressure from 120 +/- 7 to 71 +/- 6 mmHg and total pulmonary resistance from 29.4 +/- 2.6 to 10.4 +/- 0.9 mmHg.l-1.min without changing systemic arterial pressure (90 +/- 5 mmHg). Although both sodium nitroprusside and PGI2 lowered pulmonary arterial pressure to 86 +/- 4 and 96 +/- 4 mmHg, respectively, they also decreased systemic arterial pressure to 65 +/- 4 and 74 +/- 3 mmHg, respectively. Neither sodium nitroprusside nor PGI2 was as effective as acetylcholine at lowering total pulmonary resistance (18.0 +/- 3.6 and 19.1 +/- 2.2 mmHg.l-1.min, respectively). Right-to-left cardiac shunt through the foramen ovale was decreased by acetylcholine from 1.6 +/- 0.4 to 0.1 +/- 0.2 l/min but was not changed by sodium nitroprusside or PGI2. Isolated lobar pulmonary arteries from pulmonary hypertensive calves did not relax in response to acetylcholine, whereas isolated pulmonary arteries from age-matched control calves did relax in response to acetylcholine. Control and pulmonary hypertensive lobar pulmonary arteries relaxed equally well in response to sodium nitroprusside. We concluded that acetylcholine vasodilation was impaired in vitro in isolated lobar pulmonary arteries but was enhanced in vivo in resistance pulmonary arteries in neonatal calves with pulmonary hypertension.

Selective pulmonary vasodilation with ATP-MgCl2 during pulmonary hypertension in lambs

1990 ◽  
Vol 69 (5) ◽  
pp. 1836-1842 ◽  
Author(s):  
J. R. Fineman ◽  
M. R. Crowley ◽  
S. J. Soifer
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Systemic Arterial Pressure ◽  
Pulmonary Vasodilation ◽  
Potent Vasodilator ◽  
Pulmonary Arterial ◽  
Dose Dependent Decrease ◽  
High Doses ◽  
Dose Dependent

We investigated the effects of infusions of ATP-MgCl2 on the circulation in 11 spontaneously breathing newborn lambs during pulmonary hypertension induced either by the infusion of U-46619, a thromboxane A2 mimetic, or by hypoxia. During pulmonary hypertension induced by U-46619, ATP-MgCl2 (0.01-1.0 mg.kg-1.min-1) caused a significant dose-dependent decrease in pulmonary arterial pressure (12.4-40.7%, P less than 0.05), while systemic arterial pressure decreased only at the highest doses (P less than 0.05). Left atrial infusions of ATP-MgCl2 caused systemic hypotension without decreasing pulmonary arterial pressure. During hypoxia-induced pulmonary hypertension, ATP-MgCl2 caused a similar significant dose-dependent decrease in pulmonary arterial pressure (12.0-41.1%, P less than 0.05), while systemic arterial pressure decreased only at high doses (P less than 0.05). Regression analysis showed selectivity of the vasodilating effects of ATP-MgCl2 for the pulmonary circulation during pulmonary hypertension induced either by U-46619 or hypoxia. ATP-MgCl2 is a potent vasodilator with a rapid metabolism that allows for selective vasodilation of the vascular bed first encountered (pulmonary or systemic). We conclude that infusions of ATP-MgCl2 may be clinically useful in the treatment of children with pulmonary hypertension.

L-Arginine, a precursor of EDRF in vitro, produces pulmonary vasodilation in lambs

1991 ◽  
Vol 261 (5) ◽  
pp. H1563-H1569 ◽  
Author(s):  
J. R. Fineman ◽  
R. Chang ◽  
S. J. Soifer
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Phosphodiesterase Inhibitor ◽  
Hemodynamic Effects ◽  
Synthesis Inhibitor ◽  
Pulmonary Vasodilation ◽  
Pulmonary Arterial ◽  
Rate Limiting

There is increasing evidence that resting pulmonary vascular tone is mediated in part by the release of endothelium-derived relaxing factors (EDRF). Because L-arginine may be a precursor for EDRF synthesis, we studied the pulmonary vasodilating effects of L-arginine at rest and during pulmonary hypertension in 16 intact newborn lambs. At rest, the intravenous infusions of L-arginine (150 mg/kg) had no hemodynamic effects. However, during pulmonary hypertension induced by hypoxia or the infusion of U-46619 (a thromboxane A2 mimic), L-arginine decreased pulmonary arterial pressure by 22 and 27%, respectively (P less than 0.05). The decrease in pulmonary arterial pressure produced by L-arginine was blocked by methylene blue, a guanylate cyclase inhibitor, and augmented by Zapranast, a guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor (-17.9 vs. -31.2%, P less than 0.05). In addition, L-arginine partially reversed the pulmonary hypertension induced by N omega-nitro-L-arginine, a competitive EDRF synthesis inhibitor, but D-arginine had no hemodynamic effects. This study suggests that L-arginine produces pulmonary vasodilation by increasing cGMP concentrations, supporting the in vitro hypothesis that L-arginine is a precursor for EDRF synthesis, whose availability may become rate limiting during pulmonary hypertension.

Hemodynamic effects of arginine vasopressin in rats adapted to chronic hypoxia

1989 ◽  
Vol 66 (1) ◽  
pp. 151-160 ◽  
Author(s):  
H. K. Jin ◽  
R. H. Yang ◽  
Y. F. Chen ◽  
R. M. Thornton ◽  
R. M. Jackson ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Cardiac Output ◽  
Arterial Pressure ◽  
Arginine Vasopressin ◽  
Pulmonary Arterial Pressure ◽  
Systemic Arterial Pressure ◽  
Systemic Hemodynamic ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Arterial ◽  
Air Control

Acute and chronic pulmonary and systemic hemodynamic responses to arginine vasopressin (AVP) were examined in 4-wk hypoxia-adapted and air control rats. AVP, administered intravenously as bolus injections or sustained infusions, produced major dose-dependent V1-receptor-mediated reductions in mean pulmonary arterial pressure in hypoxia-adapted rats. These effects were comparable in pentobarbital-anesthetized, thoracotomized animals and in conscious, intact rats. Chronic infusions of AVP induced a sustained reduction in mean pulmonary arterial pressure and partially prevented the development of pulmonary hypertension without changing systemic arterial pressure. AVP induced significant decreases in cardiac output in both groups; the cardiac output response was not significantly different in hypoxia-adapted and air control animals. AVP induced almost no change in MPAP in air control rats. Furthermore the systemic pressor effects of AVP were significantly blunted in hypoxia-adapted rats compared with air controls. We conclude that the pulmonary depressor and blunted systemic pressor effects of AVP observed in hypoxia-adapted rats may be related to release of a vasodilator, such as endothelium-derived relaxing factor, vasodilator prostaglandins, or atrial natriuretic peptides. Further study is needed to elucidate these mechanisms and assess the usefulness of AVP and/or its analogues in the treatment and prevention of hypoxia-induced pulmonary hypertension.

E-4010, a selective phosphodiesterase 5 inhibitor, attenuates hypoxic pulmonary hypertension in rats

1999 ◽  
Vol 277 (2) ◽  
pp. L225-L232 ◽  
Author(s):  
Norihisa Hanasato ◽  
Masahiko Oka ◽  
Masashi Muramatsu ◽  
Mayu Nishino ◽  
Hideyuki Adachi ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Cardiac Output ◽  
Arterial Pressure ◽  
Right Ventricular ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Systemic Arterial Pressure ◽  
Right Ventricular Hypertrophy ◽  
Pulmonary Arterial

The purpose of this study was to determine whether E-4010, a newly synthesized potent and selective orally active phosphodiesterase (PDE) 5 inhibitor, would prevent the development of chronic hypoxia-induced pulmonary hypertension in rats. In conscious, pulmonary hypertensive rats, a single oral administration of E-4010 (1.0 mg/kg) caused an acute, long-lasting reduction in mean pulmonary arterial pressure (PAP), with no significant effects on systemic arterial pressure, cardiac output, and heart rate. In rats that received food containing 0.01 or 0.1% E-4010 during the 3-wk exposure to hypoxia, mean PAP was significantly decreased (mean PAP 24.0 ± 0.9, 16.2 ± 0.8, and 12.8 ± 0.5 mmHg in rats treated with 0, 0.01, and 0.1% E-4010-containing food, respectively), whereas mean systemic arterial pressure was unchanged and cardiac output was slightly increased compared with chronically hypoxic control rats. Right ventricular hypertrophy, medial wall thickness in pulmonary arteries corresponding to the respiratory and terminal bronchioles, and the degree of muscularization of more distal arteries were less severe in E-4010-treated rats. Long-term treatment with E-4010 caused an increase in cGMP levels in lung tissue and plasma but not in aortic tissue and no significant change in cAMP levels in either lung, aorta, or plasma. These results suggest that long-term oral treatment with E-4010 reduced the increase in PAP, right ventricular hypertrophy, and pulmonary arterial remodeling induced by exposure to chronic hypoxia, probably through increasing cGMP levels in the pulmonary vascular smooth muscle.

Repeated inhalation of adrenomedullin ameliorates pulmonary hypertension and survival in monocrotaline rats

2003 ◽  
Vol 285 (5) ◽  
pp. H2125-H2131 ◽  
Author(s):  
Noritoshi Nagaya ◽  
Hiroyuki Okumura ◽  
Masaaki Uematsu ◽  
Wataru Shimizu ◽  
Fumiaki Ono ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Arteries ◽  
Systemic Arterial Pressure ◽  
Inhalation Therapy ◽  
Rank Test ◽  
Pulmonary Resistance ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Arterial

Adrenomedullin (AM) is a potent vasodilator peptide. We investigated whether inhalation of aerosolized AM ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Male Wistar rats given MCT (MCT rats) were assigned to receive repeated inhalation of AM ( n = 8) or 0.9% saline ( n = 8). AM (5 μg/kg) or saline was inhaled as an aerosol using an ultrasonic nebulizer for 30 min four times a day. After 3 wk of inhalation therapy, mean pulmonary arterial pressure and total pulmonary resistance were markedly lower in rats treated with AM than in those given saline [mean pulmonary arterial pressure: 22 ± 2 vs. 35 ± 1 mmHg (–37%); total pulmonary resistance: 0.048 ± 0.004 vs. 0.104 ± 0.006 mmHg · ml–1 · min–1 · kg–1 (–54%), both P < 0.01]. Neither systemic arterial pressure nor heart rate was altered. Inhalation of AM significantly attenuated the increase in medial wall thickness of peripheral pulmonary arteries in MCT rats. Kaplan-Meier survival curves demonstrated that MCT rats treated with aerosolized AM had a significantly higher survival rate than those given saline (70% vs. 10% 6-wk survival, log-rank test, P < 0.01). In conclusion, repeated inhalation of AM inhibited MCT-induced pulmonary hypertension without systemic hypotension and thereby improved survival in MCT rats.

Hemodynamic response to hypoxia in dogs with chronic pulmonary hypertension

1964 ◽  
Vol 207 (3) ◽  
pp. 650-652 ◽  
Author(s):  
Dusan Kentera ◽  
Charles R. Wallace ◽  
William F. Hamilton ◽  
Lois T. Ellison
Keyword(s):  
Pulmonary Hypertension ◽  
Cardiac Output ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Sodium Pentobarbital ◽  
Pulmonary Resistance ◽  
Chronic Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
Clear Increase ◽  
Sodium Pentobarbital Anesthesia

Control dogs showed a clear increase in pulmonary resistance, in cardiac output, and in pulmonary arterial pressure when artifically ventilated with 10% O2 under sodium pentobarbital anesthesia. Dogs with pulmonary hypertension from Dirofilariasis showed the same increase in pulmonary arterial resistance but no statistically significant change in pulmonary arterial pressure or in cardiac output when ventilated in the same manner and under the same anesthesia. The anoxia produced a greater lowering of arterial saturation in the hypertensive dogs but this is not enough to explain the clear differences in the response of cardiac output and pulmonary arterial pressure to the anoxic stimulus. It is hypothesized that failure of blood flow and pressure to increase significantly in the hypertensive animals is due to the inability of the chronically overloaded heart to increase its performance in response to anoxia and the accompanying sympathetic stimulation.

Inhibition of phosphodiesterase 1 augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs with acute pulmonary hypertension

2006 ◽  
Vol 290 (4) ◽  
pp. L723-L729 ◽  
Author(s):  
Oleg V. Evgenov ◽  
Cornelius J. Busch ◽  
Natalia V. Evgenov ◽  
Rong Liu ◽  
Bodil Petersen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Selective Inhibition ◽  
Pulmonary Vasodilation ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Vasodilator ◽  
Pulmonary Arterial ◽  
Inhaled No

Phosphodiesterase 1 (PDE1) modulates vascular tone and the development of tolerance to nitric oxide (NO)-releasing drugs in the systemic circulation. Any role of PDE1 in the pulmonary circulation remains largely uncertain. We measured the expression of genes encoding PDE1 isozymes in the pulmonary vasculature and examined whether or not selective inhibition of PDE1 by vinpocetine attenuates pulmonary hypertension and augments the pulmonary vasodilator response to inhaled NO in lambs. Using RT-PCR, we detected PDE1A, PDE1B, and PDE1C mRNAs in pulmonary arteries and veins isolated from healthy lambs. In 13 lambs, the thromboxane A2 analog U-46619 was infused intravenously to increase mean pulmonary arterial pressure to 35 mmHg. Four animals received an intravenous infusion of vinpocetine at incremental doses of 0.3, 1, and 3 mg·kg−1·h−1. In nine lambs, inhaled NO was administered in a random order at 2, 5, 10, and 20 ppm before and after an intravenous infusion of 1 mg·kg−1·h−1 vinpocetine. Administration of vinpocetine did not alter pulmonary and systemic hemodynamics or transpulmonary cGMP or cAMP release. Inhaled NO selectively reduced mean pulmonary arterial pressure, pulmonary capillary pressure, and pulmonary vascular resistance index, while increasing transpulmonary cGMP release. The addition of vinpocetine enhanced pulmonary vasodilation and transpulmonary cGMP release induced by NO breathing without causing systemic vasodilation but did not prolong the duration of pulmonary vasodilation after NO inhalation was discontinued. Our findings demonstrate that selective inhibition of PDE1 augments the therapeutic efficacy of inhaled NO in an ovine model of acute chemically induced pulmonary hypertension.

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