Inhalation of the BKCa-Opener NS1619 Attenuates Right Ventricular Pressure and Improves Oxygenation in the Rat Monocrotaline Model of Pulmonary Hypertension

Infants with congenital diaphragmatic hernia (CDH) fail to adapt at birth because of persistent pulmonary hypertension (PH), a condition characterized by excessive muscularization and abnormal vasoreactivity of pulmonary vessels. Activation of soluble guanylate cyclase by BAY 41-2272 prevents pulmonary vascular remodeling in neonatal rats with hypoxia-induced PH. By analogy, we hypothesized that prenatal administration of BAY 41-2272 would improve features of PH in the rabbit CDH model. Rabbit fetuses with surgically induced CDH at day 23 of gestation were randomized at day 28 for an intratracheal injection of BAY 41-2272 or vehicle. After term delivery (day 31), lung mechanics, right ventricular pressure, and serum NH2-terminal-pro-brain natriuretic peptide (NT-proBNP) levels were measured. After euthanasia, lungs were processed for biological or histological analyses. Compared with untouched fetuses, the surgical creation of CDH reduced the lung-to-body weight ratio, increased mean terminal bronchial density, and impaired lung mechanics. Typical characteristics of PH were found in the hypoplastic lungs, including increased right ventricular pressure, higher serum NT-proBNP levels, thickened adventitial and medial layers of pulmonary arteries, reduced capillary density, and lower levels of endothelial nitric oxide synthase. A single antenatal instillation of BAY 41-2272 reduced mean right ventricular pressure and medial thickness of small resistive arteries in CDH fetuses. Capillary density, endothelial cell proliferation, and transcripts of endothelial nitric oxide synthase increased, whereas airway morphometry, lung growth, and mechanics remained unchanged. These results suggest that pharmacological activation of soluble guanylate cyclase may provide a new approach to the prenatal treatment of PH associated with CDH.

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Apelin decreases myocardial injury and improves right ventricular function in monocrotaline-induced pulmonary hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00089.2009 ◽

2009 ◽

Vol 296 (6) ◽

pp. H2007-H2014 ◽

Cited By ~ 99

Author(s):

Inês Falcão-Pires ◽

Nádia Gonçalves ◽

Tiago Henriques-Coelho ◽

Daniel Moreira-Gonçalves ◽

Roberto Roncon-Albuquerque ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricular ◽

Systolic Pressure ◽

Pressure Rise ◽

Chronic Administration ◽

Left Ventricular ◽

Ventricular Pressure ◽

Peak Rate ◽

Male Wistar Rats ◽

Neurohumoral Activation

We investigated the endogenous production of apelin and the cardiac and pulmonary effects of its chronic administration in monocrotaline (MCT)-induced pulmonary hypertension (PH). Male Wistar rats were injected with MCT (60 mg/kg sc) or vehicle ( day 0). One week later, these animals were randomly treated during 17 days with pyroglutamylated apelin-13 (Pyr-AP13; 200 μg·kg−1·day−1 ip) or a similar volume of saline, resulting in four groups: sham ( n = 11), sham-AP ( n = 11), MCT ( n = 16), and MCT-AP ( n = 13). On day 25, right ventricular (RV) and left ventricular (LV) hemodynamic and morphometric parameters were assessed. Tissue and plasma samples were collected for histological and molecular analysis. When compared with sham, the MCT group presented a significant increase of RV mass (166 ± 38%), diameter of cardiomyocyte (40 ± 10%), myocardial fibrosis (95 ± 20%), peak systolic pressure (99 ± 22%), peak rate of ventricular pressure rise (dP/d tmax; 74 ± 24%), peak rate of ventricular pressure decline (dP/d tmin; 73 ± 19%), and time constant τ (55 ± 16%). In these animals, RV expression of apelin (−73 ± 10%) and its receptor APJ (−61 ± 20%) was downregulated, whereas mRNA expression of type B natriuretic peptide (9,606 ± 713%), angiotensinogen (191 ± 147%), endothelin-1 (RV, 497 ± 156%; and LV, 799 ± 309%), plasmatic levels of apelin (104 ± 48%), and angiotensin 1-7 (161 ± 151%) were increased. Chronic treatment with Pyr-AP13 significantly attenuated or normalized these changes, preventing apelin-APJ mRNA downregulation and PH-induced neurohumoral activation of several vasoconstrictors, which exacerbates apelin-APJ vasodilator effects. Therefore, apelin delayed the progression of RV hypertrophy and diastolic dysfunction. Together, these observations suggest that the apelin-APJ system may play an important role in the pathophysiology of PH, representing a potential therapeutic target since it significantly attenuates RV overload and PH-induced neurohumoral activation.

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Rosuvastatin, Sildenafil and Their Combination in Monocrotaline-Induced Pulmonary Hypertension in Rat

Acta Pharmaceutica ◽

10.2478/acph-2014-0029 ◽

2014 ◽

Vol 64 (3) ◽

pp. 345-353 ◽

Cited By ~ 6

Author(s):

Magdalena Jasińska-Stroschein ◽

Jacek Owczarek ◽

Anna Wesołowska ◽

Daria Orszulak-Michalak

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricle ◽

Right Ventricular ◽

Density Lipoprotein ◽

Ventricular Pressure ◽

Positive Role ◽

Phosphodiesterase Type 5 Inhibitor ◽

Hypertension Development ◽

Experimental Findings ◽

Hydrophilic Statin

Abstract There is considerable interest in the pleiotropic effects of statins and their potential role in the treatment of pulmonary hypertension. Previous experimental findings indicate that a combination of lipophilic statins with phosphodiesterase type-5 inhibitor, sildenafil, can offer preventive effects on rat monocrotaline-induced pulmonary hypertension. The present study is aimed to assess whether therapeutic regimen provides any benefits. Seven days after pulmonary hypertension induction, hydrophilic rosuvastatin and sildenafil were given for 14 days to male Wistar outbred rats. Right ventricular pressure, right ventricle mass and three biomarkers were evaluated after 21 days: brain natriuretic peptide, high-density lipoprotein cholesterol and vascular endothelial growth factor. The present study demonstrates that administration of hydrophilic statin with sildenafil results in reduction of pulmonary vascular remodeling and right ventricular pressure. The results of biochemical measurements may suggest that statins play a positive role in right ventricle function or the process of angiogenesis in pulmonary hypertension development.

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Assessment of Right Ventricular Pressure-Volume Relationships Using 256-Slice CT in an Experimental Model of Acute Pulmonary Hypertension

The Journal of Heart and Lung Transplantation ◽

10.1016/j.healun.2013.01.861 ◽

2013 ◽

Vol 32 (4) ◽

pp. S301-S302

Author(s):

B. Schmack ◽

A. Weymann ◽

K.U. Klein ◽

S. Boehme ◽

W. Stiller ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricular ◽

Experimental Model ◽

Ventricular Pressure ◽

Acute Pulmonary Hypertension

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Electrocardiographic detection of right ventricular pressure overload in patients with suspected pulmonary hypertension

Journal of Electrocardiology ◽

10.1016/j.jelectrocard.2013.10.010 ◽

2014 ◽

Vol 47 (2) ◽

pp. 175-182 ◽

Cited By ~ 22

Author(s):

Vivian P. Kamphuis ◽

Marlieke L.A. Haeck ◽

Galen S. Wagner ◽

Arie C. Maan ◽

Charles Maynard ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricular ◽

Pressure Overload ◽

Ventricular Pressure

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Impaired Left Ventricular Filling Due to Right Ventricular Pressure Overload in Primary Pulmonary Hypertension

CHEST Journal ◽

10.1378/chest.119.6.1761 ◽

2001 ◽

Vol 119 (6) ◽

pp. 1761-1765 ◽

Cited By ~ 129

Author(s):

J. Tim Marcus ◽

Anton Vonk Noordegraaf ◽

Roald J. Roeleveld ◽

Pieter E. Postmus ◽

Rob M. Heethaar ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricular ◽

Primary Pulmonary Hypertension ◽

Pressure Overload ◽

Left Ventricular ◽

Left Ventricular Filling ◽

Ventricular Pressure ◽

Ventricular Filling

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An antifibrotic agent reduces blood pressure in established pulmonary hypertension in the rat

Journal of Applied Physiology ◽

10.1152/jappl.1990.68.4.1542 ◽

1990 ◽

Vol 68 (4) ◽

pp. 1542-1547 ◽

Cited By ~ 21

Author(s):

G. J. Poiani ◽

C. A. Tozzi ◽

J. K. Choe ◽

S. E. Yohn ◽

D. J. Riley

Keyword(s):

Blood Pressure ◽

Pulmonary Hypertension ◽

Right Ventricular ◽

Rheological Properties ◽

Wall Thickness ◽

Pulmonary Arteries ◽

Collagen Content ◽

Ventricular Pressure ◽

Hydroxyproline Content ◽

Collagen Accumulation

We have shown that administration of the antifibrotic agent cis-4-hydroxy-L-proline (cHyp) to rats at the onset of exposure to hypoxia prevents collagen accumulation in pulmonary arteries and the rise in pulmonary blood pressure. In this experiment, we tested whether cHyp is effective when administered after hypertension was already established. Rats were exposed to hypoxia (10% O2) for 21 days. Groups were hypoxic animals treated with cHyp (200 mg/kg sc twice daily) on days 10-21 (hypoxic cHyp) and saline-injected hypoxic animals (hypoxic). On day 21, we measured mean right ventricular pressure, hematocrit, collagen content of main and intrapulmonary arteries, and wall thickness of arterioles. Treatment reduced right ventricular pressure from 21 +/- 1 to 17 +/- 1 mmHg (P less than 0.05), hematocrit from 66 +/- 1 to 56 +/- 1% (P less than 0.05), hydroxyproline content of intrapulmonary arteries from 30 +/- 3 to 11 +/- 2 micrograms/vessel (P less than 0.05), and wall thickness from 27 +/- 3 to 16 +/- 2 microns (P less than 0.05). These results show that vascular collagen content is increased in established pulmonary hypertension and that cHyp treatment is effective in partially preventing the hemodynamic, structural, and biochemical changes if started after pulmonary hypertension is established. cHyp may also affect the rheological properties of blood.

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