Vasodilatory Action of the Calcium Antagonist Amlodipine on Large and Resistance Pulmonary Arteries from Normoxic and Chronically Hypoxic Rats

1. Isolated rat aorta and pulmonary arteries were maximally precontracted with 100 mmol/l KCl, and the vasorelaxation due to the dihydropyridine calcium antagonist amlodipine was measured. The response of large pulmonary arteries (mean lumen diameter 983 μm) was directly compared with that of isolated pulmonary resistance vessels (mean lumen diameter 259 μm) from both normoxic animals and animals exposed to chronic hypoxia. 2. Amlodipine caused a significant relaxation of aorta (P <0.001). A significant relaxation of large and resistance pulmonary arteries from both normoxic and chronically hypoxic animals was also demonstrated at all doses tested (P <0.05) or less). 3. Amlodipine produced significantly more relaxation in pulmonary resistance vessels than in large pulmonary arteries from both normoxic and chronically hypoxic rats (P <0.02). 4. The action of amlodipine was slow in onset and persistent in all vessels studied. In the pulmonary vessels from normoxic animals both the rate of onset and the magnitude of effect was proportional to the drug concentration (P <0.001). 5. These results demonstrate that amlodipine is a potent inhibitor of KCl-induced contractions in rat pulmonary arteries with a preferential action in pulmonary resistance vessels.

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Distribution of NOS in normoxic vs. hypoxic rat lung: upregulation of NOS by chronic hypoxia

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1994.267.6.l667 ◽

1994 ◽

Vol 267 (6) ◽

pp. L667-L678 ◽

Cited By ~ 26

Author(s):

C. Xue ◽

A. Rengasamy ◽

T. D. Le Cras ◽

P. A. Koberna ◽

G. C. Dailey ◽

...

Keyword(s):

Nitric Oxide ◽

Smooth Muscle ◽

Chronic Hypoxia ◽

De Novo ◽

Rat Lung ◽

Pulmonary Resistance ◽

Pulmonary Vessels ◽

Resistance Vessels ◽

Staining Techniques ◽

Oxide Synthase

Expression and localization of nitric oxide synthase (NOS) in the lungs of chronically hypoxic and normoxic rats were studied using both immunohistochemistry and NADPH diaphorase (NADPH-d) staining techniques. In the normoxic and in the hypoxic rat, NOS was detected by both methods in the endothelium of large pulmonary vessels and in the epithelium of bronchi and bronchioli. NOS expression was not detected in the endothelium of normoxic pulmonary resistance vessels but was prominently expressed in the endothelium of these vessels after 2-4 wk of chronic hypoxia. In contrast to small pulmonary vessels, the endothelium of small bronchial vessels exhibited NOS immunostaining in both normoxic and hypoxic lungs. Hypoxia was also found to induce de novo NOS expression in the smooth muscle of large and small pulmonary vessels and in bronchial smooth muscle. NOS enzyme activity in lung homogenates was assessed by [3H]arginine to [3H]citrulline conversion. The activity of soluble NOS, but not particulate NOS, was increased in the hypoxic lungs. These results demonstrate chronic hypoxia-induced upregulation of NOS protein expression and activity in the rat lung, suggesting a potentially important role of nitric oxide in adaptation of the pulmonary circulation to chronic hypoxia. The lack of immunostaining in small pulmonary resistance vessels is also consistent with physiological studies suggesting that NO may not be involved in the mechanism for maintaining the normally low pulmonary vascular resistance.

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Effect of chronic hypoxia on rat pulmonary resistance vessels: vasodilatation by atrial natriuretic peptide

Clinical Science ◽

10.1042/cs0830723 ◽

1992 ◽

Vol 83 (6) ◽

pp. 723-729 ◽

Cited By ~ 12

Author(s):

T. K. Rogers ◽

A. G. Stewart ◽

A. H. Morice

Keyword(s):

Atrial Natriuretic Peptide ◽

Natriuretic Peptide ◽

Chronic Hypoxia ◽

Prostaglandin F2α ◽

Vessel Diameter ◽

Maximal Response ◽

Pulmonary Resistance ◽

Contractile Responses ◽

Resistance Vessels ◽

Atrial Natriuretic

1. We have investigated the vasoreactivity of isolated pulmonary resistance vessels of rats after acclimatization to chronic hypoxia in a normobaric, hypoxic chamber. Vasoconstriction, in response to KCl and prostaglandin F2α, and vasodilatation, in response to atrial natriuretic peptide, were studied isometrically in a small-vessel myograph. Resting tensions were set to simulate transmural pressures of 17.5 mmHg or 35 mmHg. 2. There were no significant differences between intergroup internal vessel diameters or maximal contractile responses to either agonist. Both control and chronically hypoxic vessels generated significantly greater active contractions at 35 mmHg than at 17.5 mmHg. There were significant positive correlations between vessel diameter and maximum contractility for both control and chronically hypoxic vessels, but when contraction was expressed as equivalent transmural pressure no correlation existed. 3. There was a significant increase in potency (as measured by the concentration necessary to produce 50% of the maximum response) of KCl in chronically hypoxic vessels compared with control vessels at 35 mmHg, but not at 17.5 mmHg. In contrast, the potency of prostaglandin F2α was significantly increased in chronically hypoxic vessels at 17.5 mmHg, but not at 35 mmHg. Thus the change in contractile responses of vessels from chronically hypoxic animals, in terms of maximal response and potency, is dependent on both resting pressure and agonist used. 4. After exposure to chronic hypoxia, atrial natriuretic peptide induced significantly greater maximal relaxation of pulmonary resistance vessels at both resting pressures, but its potency was unaffected.

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Hypercapnia Attenuates the Hypoxia-Induced Blunting of the Reactivity in Chronically Hypoxic Rats

Physiological Research ◽

10.33549/physiolres.932565 ◽

2013 ◽

pp. 585-588

Author(s):

M. ŽALOUDÍKOVÁ ◽

J. HERGET ◽

M. VÍZEK

Keyword(s):

Lung Injury ◽

Biochemical Markers ◽

Vascular Reactivity ◽

Chronic Hypoxia ◽

Pulmonary Arteries ◽

Transmural Pressure ◽

Small Vessel ◽

Vessel Size ◽

Pulmonary Vessels ◽

Maximal Tension

Chronic hypoxia causes oxidative injury of pulmonary vessels and attenuates their reactivity to different stimuli. When combined with hypercapnia, biochemical markers of this injury are reduced but the effect of concomitant hypoxia and hypercapnia on vascular reactivity is not fully understood. This study was therefore designed to test whether hypercapnia can prevent also the hypoxia-induced loss of reactivity of pulmonary vessels. The reactivity of vessels from rats exposed either to hypoxia or hypoxia combined with hypercapnia was tested using a small vessel myograph (M 500A, Linton, Norfolk, GB). The second and third intrapulmonary branches of pulmonary arteries were isolated under a dissecting microscope from lungs of 8 control rats (group N), 6 rats exposed to hypoxia for 5 days (isobaric, 10 % O2, group H) and 7 rats exposed to hypoxia combined with hypercapnia for 5 days (10 % O2, 5 % CO2, group H+CO2). The transmural pressure was set by automatic normalization to 30 mm Hg. The vessel size did not vary among the groups. After stabilization we challenged the vessels twice with KCl (80 mM) and once with PGF2α (0.1 mM). There were no significant differences in KCl induced contractions among the groups. The responses to PGF2α were expressed as a ratio to the maximal tension obtained by the exposure to 80 mM KCl. Contractions induced by PGF2α were markedly reduced in group H (0.07±0.02) and in group H+CO2 (0.26±0.03) in comparison with group N (0.83±0.07). The vessels of group H responded to PGF2α less than those of group H+CO2. However we observed the attenuated reactivity also in group H+CO2 in comparison with N. Hypercapnia therefore partially blunted the hypoxia-induced loss of reactivity in pulmonary arteries. This finding supports the hypothesis that hypercapnia significantly alters the nature of lung injury induced by chronic hypoxia.

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Mechanisms of bradykinin-mediated dilation in newborn piglet pulmonary conducting and resistance vessels

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00032.2002 ◽

2002 ◽

Vol 283 (2) ◽

pp. L373-L382 ◽

Cited By ~ 8

Author(s):

Judy L. Aschner ◽

Thuy K. Smith ◽

Nora Kovacs ◽

Joaquim M. B. Pinheiro ◽

Mamta Fuloria

Keyword(s):

Signaling Pathways ◽

Pulmonary Arteries ◽

Smooth Transition ◽

Resistance Arteries ◽

Pulmonary Resistance ◽

Calcium Dependent ◽

A 23187 ◽

Resistance Vessels ◽

Muscle Calcium ◽

Arteries And Veins

Bradykinin (BK) is a potent dilator of the perinatal pulmonary circulation. We investigated segmental differences in BK-induced dilation in newborn pig large conducting pulmonary artery and vein rings and in pressurized pulmonary resistance arteries (PRA). In conducting pulmonary arteries and veins, BK-induced relaxation is abolished by endothelial disruption and by inhibition of nitric oxide (NO) synthase with nitro-l-arginine (l-NA). In PRA, two-thirds of the dilation response isl-NA insensitive. Charybdotoxin plus apamin and depolarization with KCl abolish the l-NA-insensitive dilations, findings that implicate the release of endothelium-derived hyperpolarizing factor (EDHF). However, endothelium-disrupted PRA retain the ability to dilate to BK but not to ACh or A-23187. In endothelium-disrupted PRA, dilation was inhibited by charybdotoxin. Thus in PRA, BK elicits dilation by multiple and duplicative signaling pathways. Release of NO and EDHF contributes to the response in endothelium-intact PRA; in endothelium-disrupted PRA, dilation occurs by direct activation of vascular smooth muscle calcium-dependent potassium channels. Redundant signaling pathways mediating pulmonary dilation to BK may be required to assure a smooth transition to extrauterine life.

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Effects of Acidosis and CO2 on Vascular Tone in Newborn Piglet Pulmonary Resistance Vessels (PRV)

Pediatric Research ◽

10.1203/00006450-199904020-01832 ◽

1999 ◽

Vol 45 (4, Part 2 of 2) ◽

pp. 308A-308A

Author(s):

Nora Kovacs ◽

Thuy K Smith ◽

Mamta Fuloria ◽

Judy L Aschner

Keyword(s):

Vascular Tone ◽

Newborn Piglet ◽

Pulmonary Resistance ◽

Resistance Vessels

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Linked opening angle and histological and mechanical aspects of the proximal pulmonary arteries of healthy and pulmonary hypertensive rats and calves

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00025.2011 ◽

2011 ◽

Vol 301 (5) ◽

pp. H1810-H1818 ◽

Cited By ~ 11

Author(s):

Lian Tian ◽

Steven R. Lammers ◽

Philip H. Kao ◽

Mark Reusser ◽

Kurt R. Stenmark ◽

...

Keyword(s):

Mechanical Behavior ◽

Wall Thickness ◽

Arterial Wall ◽

Chronic Hypoxia ◽

Pulmonary Arteries ◽

Opening Angle ◽

Histological Structure ◽

Arterial Remodeling ◽

Stiffness Ratio ◽

Arterial Wall Thickness

Understanding how arterial remodeling changes the mechanical behavior of pulmonary arteries (PAs) is important to the evaluation of pulmonary vascular function. Early and current efforts have focused on the arteries' histological changes, their mechanical properties under in vitro mechanical testing, and their zero-stress and no-load states. However, the linkage between the histology and mechanical behavior is still not well understood. To explore this linkage, we investigated the geometry, residual stretch, and histology of proximal PAs in both adult rat and neonatal calf hypoxic models of pulmonary hypertension (PH), compared their changes due to chronic hypoxia across species, and proposed a two-layer mechanical model of artery to relate the opening angle to the stiffness ratio of the PA outer to inner layer. We found that the proximal PA remodeling in calves was quite different from that in rats. In rats, the arterial wall thickness, inner diameter, and outer layer thickness fraction all increased dramatically in PH and the opening angle decreased significantly, whereas in calves, only the arterial wall thickness increased in PH. The proposed model predicted that the stiffness ratio of the calf proximal PAs changed very little from control to hypertensive group, while the decrease of opening angle in rat proximal PAs in response to chronic hypoxia was approximately linear to the increase of the stiffness ratio. We conclude that the arterial remodeling in rat and calf proximal PAs is different and the change of opening angle can be linked to the change of the arterial histological structure and mechanics.

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Lack of synergistic interaction between quercetin and catechin in systemic and pulmonary vascular smooth muscle

British Journal Of Nutrition ◽

10.1017/s0007114510004952 ◽

2010 ◽

Vol 105 (9) ◽

pp. 1287-1293 ◽

Cited By ~ 12

Author(s):

Carmen Menendez ◽

Rosario Jimenez ◽

Laura Moreno ◽

Pilar Galindo ◽

Angel Cogolludo ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Vascular Function ◽

Pulmonary Arteries ◽

Rat Aorta ◽

Relaxant Effect ◽

Isobolographic Analysis ◽

Scavenging Effect ◽

Synergistic Interactions ◽

Pure Compounds ◽

Intermediate Effect

Due to their ubiquitous distribution, flavonoids from different classes are commonly present together in foods. However, little is known about the interactions between them. The flavonol quercetin and the flavan-3-ol (+)-catechin are among the most abundant flavonoids in the diet. In the present study, we have analysed the interactions between these two flavonoids on vascular function using two pure compounds and mixtures of these flavonoids in 1:0·1, 1:1 or 1:10 proportions. Quercetin induced a more potent concentration-dependent relaxant effect than catechin in the isolated rat aorta, and the isobolographic analysis of the mixtures showed no synergistic or antagonistic effects between them, i.e. their effects were additive. Quercetin was more potent in mesenteric than in pulmonary arteries. Catechin had weak effects in these vessels and did not modify the effects of quercetin. Endothelial dysfunction induced by increased oxidative stress by the superoxide dismutase inhibitor diethyldithiocarbamate was prevented by quercetin, whereas catechin showed a weak effect and the 1:1 mixture an intermediate effect compared with the pure compounds. Quercetin but not catechin showed a pro-oxidant and NO-scavenging effect, which was not prevented by catechin. In conclusion, catechin was less potent than quercetin as a vasodilator, pro-oxidant or to prevent endothelial dysfunction, and there were no synergistic interactions between quercetin and catechin.

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Role of Rho kinases in PKG-mediated relaxation of pulmonary arteries of fetal lambs exposed to chronic high altitude hypoxia

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00178.2006 ◽

2007 ◽

Vol 292 (3) ◽

pp. L678-L684 ◽

Cited By ~ 60

Author(s):

Yuansheng Gao ◽

Ada D. Portugal ◽

Sewite Negash ◽

Weilin Zhou ◽

Lawrence D. Longo ◽

...

Keyword(s):

High Altitude ◽

Chronic Hypoxia ◽

Pulmonary Arteries ◽

Regulatory Subunit ◽

Fourth Generation ◽

Minor Effect ◽

Altitude Hypoxia ◽

High Altitude Hypoxia ◽

Rock Activity

An increase in Rho kinase (ROCK) activity is implicated in chronic hypoxia-induced pulmonary hypertension. In the present study, we determined the role of ROCKs in cGMP-dependent protein kinase (PKG)-mediated pulmonary vasodilation of fetal lambs exposed to chronic hypoxia. Fourth generation pulmonary arteries were isolated from near-term fetuses (∼140 days of gestation) delivered from ewes exposed to chronic high altitude hypoxia for ∼110 days and from control ewes. In vessels constricted to endothelin-1, 8-bromoguanosine-cGMP (8-Br-cGMP) caused a smaller relaxation in chronically hypoxic (CH) vessels compared with controls. Rp-8-Br-PET-cGMPS, a PKG inhibitor, attenuated relaxation to 8-Br-cGMP in control vessels to a greater extent than in CH vessels. Y-27632, a ROCK inhibitor, significantly potentiated 8-Br-cGMP-induced relaxation of CH vessels and had only a minor effect in control vessels. The expression of PKG was increased but was not accompanied with an increase in the activity of the enzyme in CH vessels. The expression of type II ROCK and activity of ROCKs were increased in CH vessels. The phosphorylation of threonine (Thr)696 and Thr850 of the regulatory subunit MYPT1 of myosin light chain phosphatase was inhibited by 8-Br-cGMP to a lesser extent in CH vessels than in controls. The difference was eliminated by Y-27632. These results suggest that chronic hypoxia in utero attenuates PKG-mediated relaxation in pulmonary arteries, partly due to inhibition of PKG activity and partly due to enhanced ROCK activity. Increased ROCK activity may inhibit PKG action through increased phosphorylation of MYPT1 at Thr696 and Thr850.

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