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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. We investigated the haemodynamic effects of intravenously administered hydrallazine, diazoxide and nitroprusside and orally administered minoxidil to determine whether vasodilators (such as nitroprusside) which do not increase cardiac output might be better treatment for hypertensive complications associated with, or caused by, myocardial failure than those that do. 2. Hydrallazine and diazoxide caused increases in heart rate, cardiac output, cardiopulmonary blood volume, the ratio of cardiac output to cardiopulmonary volume, and pulmonary artery pressure. Nitroprusside, although decreasing pressure and vascular resistance, caused no significant change in the other functions except for reducing pulmonary artery pressure. Minoxidil, when given orally, had the potential for causing pulmonary hypertension. This seemed explained by increased flow (hyperdynamic type) in some but by congestive cardiac failure in others; the latter condition was probably intensified by the marked fluid retention that the drug can cause. 3. On the basis of these results a classification of vasodilators was constructed which depends on the presence or absence of a venodilating effect. Vasodilators which produce no (or little) venodilatation, increase heart rate, cardiac output, cardiopulmonary blood volume and pulmonary artery pressure. In this class are diazoxide, hydrallazine and minoxidil. Those that cause venodilatation do not stimulate the heart nor do they cause pulmonary hypertension. Nitroprusside and nitroglycerine are drugs of this type. 4. These results suggest that drugs producing both venodilatation and arteriolar dilatation may be more specific therapy for hypertensive complications associated with cardiac failure than those that cause only arteriolar dilatation.
Clin Sci Mol Med Suppl 1976 Dec
PMID:Vasodilating drugs: contrasting haemodynamic effects. 107 83

The remodeling of pulmonary vessels that occurs in association with pulmonary hypertension involves, in part, thickening of the adventitia. The stimulus for this process is not understood. One explanation is that endothelial cells secrete a growth factor that expands the local population of fibroblasts by acting as a chemoattractant and mitogen. Endothelins are a family of potent newly discovered vasoactive peptides. One of these compounds, endothelin-1 (ET-1), is secreted by endothelial cells and is known to constrict pulmonary vessels. Another, endothelin-3 (ET-3), is not secreted by endothelial cells and is less potent as a pulmonary vasoconstrictor. We hypothesized that the endothelins may have the capacity both to constrict these vessels and to initiate fibroblast chemotaxis and replication. Here we investigated the effects of both ET-1 and ET-3 on the chemotaxis and replication of fibroblasts derived from pulmonary vessels. Cells were isolated from rat pulmonary arteries, cultured in medium and 10% newborn calf serum, and used between passages 2 and 5. Chemotaxis was assessed using a modified Boyden chamber with a polycarbonate filter (pore size, 8 microns) separating cells in the upper chambers from endothelin in the lower chambers. Replication was assessed both by direct cell counts and by a colorimetric assay based on uptake and subsequent release of methylene blue. Both ET-1 and ET-3 induced chemotaxis of pulmonary artery fibroblasts and did so in a dose-dependent fashion. The maxima for both peptides occurred at a concentration of about 10(-7) M, when chemotaxis was greatest for ET-1 (22 +/- 1.4 versus 14 +/- 1.8 cells/grid [mean +/- SEM], (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1992 Nov
PMID:Endothelin-1 and endothelin-3 induce chemotaxis and replication of pulmonary artery fibroblasts. 141 25

Chronic pulmonary hypertension is associated with arterial structural remodeling. Insulin-like growth factor I (IGF-I) has been proposed as one of the mediators of vascular change because of its ability to stimulate proliferation in, and elastin production by, cultured vascular smooth muscle cells. We have shown previously that 12 days of continuous air embolization into the pulmonary arterial circulation of sheep results in the functional and structural changes of chronic pulmonary hypertension. In the present study, measurements of IGF-I (by radioimmunoassay) and IGF-I binding protein activity in sheep lung lymph and plasma were made before and during the 12 days of air embolization in six sheep. Two untreated animals served as controls. Baseline lung lymph contained 23.5 +/- 3.6 ng/ml (mean +/- SEM) of IGF-I, and there was a slight increase to 36.7 +/- 9.8 on day 3, but by day 6 levels were back to baseline. The flux of IGF-I from the lung (concentration times lymph flow) increased significantly by day 2 embolization and remained elevated through day 12 (baseline = 37.2 +/- 11.1 ng/15 min; day 2 = 237.7 +/- 55.8; day 5 = 190.2 +/- 53.4; day 6 = 82.6 +/- 21.9; day 12 = 78.7 +/- 12.5). IGF-I binding protein activity was also present in lung lymph at baseline (29.6 +/- 3.0%) and was unchanged during air embolization. Plasma levels of IGF-I and plasma binding protein activity remained at baseline throughout the 12 days of embolization (71.51 +/- 34.48 ng/ml and 36.4 +/- 3.5%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1992 Jan
PMID:Insulin-like growth factor I and pulmonary hypertension induced by continuous air embolization in sheep. 172 99

To examine the role of endogenous proteases in limiting the bronchodilating effects of vasoactive intestinal peptide (VIP) in human airway, we studied precontracted bronchial rings from five nonsmokers undergoing heart-lung transplantation for pulmonary hypertension, either primary or secondary to congenital heart disease. The protease inhibitors aprotinin, leupeptin, phosphoramidon, and soybean trypsin inhibitors significantly potentiated the bronchodilator response to VIP. Even in the presence of the four protease inhibitors, VIP-induced bronchodilation reversed spontaneously in some tissues. These studies show that degradation by endogenous airway proteases is an important determinant of the bronchodilating potency of VIP in isolated human airway.
Am J Respir Cell Mol Biol 1990 May
PMID:Protease inhibitors potentiate smooth muscle relaxation induced by vasoactive intestinal peptide in isolated human bronchi. 218 92

The pathogenesis of monocrotaline-induced pulmonary hypertension is not clear. Progressive pulmonary arteritis leading to vascular sclerosis, narrowing of the lumina, and thrombosis is the suspected sequence. To investigate this, we examined the effect of isosorbide dinitrate (ISDN), prednisolone, indomethacin, and elastase in 100 SD male rats, 4 weeks after the injection of monocrotaline (MCT) by cardiac catheterization, right ventricle-to-left ventricle plus septum weight ratio (RV/LV + S), histology, and electron microscopy. ISDN, a vasodilator, reduced the elevation of right ventricular (RV) pressure, RV/LV + S, and also pulmonary vascular remodeling; the characteristic histological feature was dilatation of small pulmonary arteries. Both prednisolone and indomethacin reduced RV pressure, RV/LV + S, and pulmonary vasculitis. Elastase, a protease which controls the metabolism of elastin in the arterial wall, likewise reduced RV pressure, RV/LV + S, and pulmonary vascular remodeling, with a significant decrease in elastosis of the small pulmonary arteries histologically. We concluded that all of the pathological processes resulting from arteritis are important in the development of MCT-induced pulmonary hypertension. In all experimental groups, decreased histopathologic changes correlated with decrease in the pressure. Elastase, which reduces pulmonary arterial sclerosis, is suggested as a new agent to treat pulmonary hypertension.
Exp Mol Pathol 1989 Jun
PMID:Comparative effects of isosorbide dinitrate, prednisolone, indomethacin, and elastase on the development of monocrotaline-induced pulmonary hypertension. 249 22

Neonatal calves exposed to chronic hypobaric hypoxia develop severe pulmonary hypertension associated with altered vascular reactivity, cellular proliferation, and increased elastin and collagen production. We hypothesized that prostaglandin (PG) production would be decreased in the pulmonary arterial vessel wall of these calves. Further, because of the possibility that the hemodynamic stresses of hypoxic pulmonary hypertension might change along the longitudinal axis of the pulmonary circulation, we measured prostaglandin synthetic capability in tissues isolated from proximal pulmonary artery, distal pulmonary artery, and pulmonary vein. We found that PGI2 production was decreased in both proximal and distal pulmonary artery rings isolated from pulmonary hypertensive calves compared to controls. PGI2 production was greater in distal than in proximal lobar pulmonary artery. In contrast, pulmonary veins from hypertensive calves, which are protected from the hemodynamic stress of pulmonary arterial hypertension, did not demonstrate altered PGI2 production compared to controls. PGE2 production was also decreased in proximal hypertensive pulmonary arterial rings as compared to controls. To determine if this decrease in vessel wall production of prostaglandins was due to changes in cellular prostaglandin production, we studied prostaglandin production by the three major cell types comprising hypertensive and control arteries. Endothelial cells cultured from hypertensive main pulmonary artery produced less PGI2 than did those from control artery, and there appeared to be a shift from PGI2 production to PGE2 production in endothelial cells isolated from hypertensive artery. Explanted advential fibroblasts from hypertensive artery produced less PGE2 than did controls. Smooth muscle cell PGI2 production did not differ between cells isolated from hypertensive and control arteries in these brief 30-min incubations. We conclude that there is a relative deficit in PGI2 and PGE2 production in the pulmonary arteries of calves with hypoxia-induced pulmonary hypertension and speculate that this contributes to altered vascular tone and vessel remodeling.
Am J Respir Cell Mol Biol 1989 Dec
PMID:Decreased arterial wall prostaglandin production in neonatal calves with severe chronic pulmonary hypertension. 251 77

The contractile properties of single rat cardiac myocytes isolated from normal and hypertrophied right ventricles have been investigated and then correlated with the isoenzyme pattern of ventricular myosin. The isoprenaline-stimulated contraction and the beta-adrenoceptor sensitivity were also investigated. Right ventricle hypertrophy was obtained by injecting monocrotaline, an alkaloid which induces severe pulmonary hypertension. The contractile parameters, namely contraction amplitude and speed of shortening, were obtained by means of an inverted microscope TV-system and edge-detection-device. Hypertrophied cells showed a significantly decreased speed of shortening and contraction amplitude when contraction was induced by maximum calcium and maximum isoprenaline. A statistically significant correlation existed between myosin alpha-chain percentage and both contraction parameters. Isoprenaline sensitivity expressed in terms of ED50, p kappa a and Hill coefficient were similar in the control and monocrotaline treated animals. Moreover no correlation between the degree of ventricular hypertrophy and ED50 existed. These results suggest that, in this animal model, the depressed contractile function which characterizes the hypertrophic myocardium depends on changes in isomyosin pattern while beta-adrenoceptor desensitization does not occur.
J Mol Cell Cardiol 1989 Dec
PMID:Contractile abnormalities of single right ventricular myocytes isolated from rats with right ventricular hypertrophy. 253 36

In a model of pulmonary hypertension induced by a single injection of monocrotaline (MCT), we observed a time-dependent right ventricular hypertrophy, which became apparent in treated rats 21 days after administration of MCT and progressed through day 45. Associated with this right ventricular hypertrophy were time-dependent increases in ventricular levels of immunoreactive atrial natriuretic peptide (iANP). Forty-five days after MCT treatment, treated rats exhibited a 72-fold increase in right ventricular iANP levels and a 7-fold increase in left ventricular iANP levels. Hybridization analysis of total RNA extracted from cardiac tissue indicated that both atrial and ventricular ANP mRNA levels were elevated in treated rats. These data suggest that during pulmonary hypertension and cardiac hypertrophy the endocrine activity of the heart expands to include ventricular tissue. ANP binding site autoradiography revealed decreased binding site density in the kidney and hearts of treated rats at 49 days, consistent with the occurrence of desensitization/down-regulation. Enhanced ventricular ANP production may serve as a compensatory response to sustained elevation of pulmonary arterial pressure or may function as an autocrine/paracrine system regulating cardiac function. In either case, the effects of augmented ANP production may be subject to modulation by the status of ANP receptors in target organs and cells.
Mol Cell Endocrinol 1989 Apr
PMID:Enhanced activity of the cardiac endocrine system during right ventricular hypertrophy. 254 90

Lung injury induced in rats by the pyrrolizidine alkaloid monocrotaline is a well-documented model of pulmonary hypertension. To our knowledge, however, monocrotaline-induced cardiopulmonary injury has rarely been described and has never been quantitated in mice. In the present study, adult male mice received 2.4, 4.8, or 24.0 mg monocrotaline/kg body weight/day in the drinking water continuously for 6 weeks. These doses represent 1, 2, and 10 times the severely pneumotoxic regimen in rats. Pulmonary endothelial function was monitored by right lung angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Light and electron microscopy were performed on the left lungs. Cardiac right ventricular hypertrophy was evaluated by the right ventricle to left ventricle plus septum weight ratio (RV/LV + S). Monocrotaline-treated mice exhibited a dose-dependent decrease in lung ACE and PLA activities and an increase in PGI2 and TXA2 production, indicative of endothelial dysfunction. However, these responses were significant only after the highest monocrotaline dose. Light and electron microscopy revealed dose-dependent pulmonary inflammatory and exudative reactions. Unlike previous studies in rats, however, monocrotaline-treated mice developed relatively little lung fibrosis, cardiomegaly, or right ventricular hypertrophy, and no occlusive medial thickening of the pulmonary arteries, even at the highest dose level. These and previous data indicate that there are quantitative biochemical and qualitative morphological differences between mice and rats with respect to monocrotaline pneumotoxicity. Furthermore, in monocrotaline-treated mice (but not in rats) there appears to be a dissociation between lung endothelial dysfunction and inflammation on the one hand, and pulmonary hypertension and fibrosis on the other.
Virchows Arch B Cell Pathol Incl Mol Pathol 1989
PMID:Monocrotaline pneumotoxicity in mice. 257 Apr 81

Pulmonary hypertension and foreign body granulomas are complications of the chronic intravenous injection of crushed, suspended pentazocine (Talwin) tablets. To evaluate the early cellular mechanisms underlying the response of the lung to foreign body microemboli, we examined lung histopathology and bronchoalveolar lavage (BAL) fluid in dogs for accumulation of inflammatory cells shortly after the injection of crushed, suspended pentazocine tablets. We found that the injection of suspended pentazocine tablets is associated with the rapid accumulation of neutrophils around intravascular talc crystals but not within the alveolar airspaces. To determine the cause of the observed neutrophil accumulation, we assayed plasma and lavage fluid for neutrophil chemoattractant activity (NCA). NCA appeared in pulmonary arterial (PA) and left ventricular (LV) plasma within 60 s of injection of the suspended tablets. However, there was no evidence of NCA in BAL. To determine whether appearance of chemoattractant activity found in plasma was modified by inhibitors of arachidonic acid metabolism, we infused dogs with indomethacin, diethylcarbamazine (DEC), or FPL 55712 and assayed plasma for NCA after the injection of suspended pentazocine tablets. We found that the appearance of NCA is prevented by the infusion of either DEC or FPL 55712 but not by the infusion of indomethacin. We found that cultured pulmonary arterial or aortic endothelial cells also release NCA when incubated with either the suspended pentazocine tablets or talc. Extraction with acidified diethyl ether partitioned all the NCA into the organic phase. The release of NCA from cultured endothelial cells was likewise prevented by coincubation with DEC or FPL 55712 but not by coincubation with indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1989 Jul
PMID:Pulmonary response to foreign body microemboli in dogs: release of neutrophil chemoattractant activity by vascular endothelial cells. 262 57


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