Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adjunctive use of intravenous captopril with tissue plasminogen activator early during acute myocardial infarction offers theoretic advantages of diminishing left ventricular volume, preventing ventricular dilation and improving patient survival. To test the safety and efficacy of combined early administration of intravenous captopril and recombinant tissue-type plasminogen activator (rt-PA), 38 patients treated with rt-PA 3 +/- 0.3 h (mean +/- SE) after the onset of myocardial infarction were randomized to intravenous followed by oral captopril or placebo therapy. They underwent cardiac catheterization with measurement of hemodynamic variables and left ventricular function and determination of serum renin, angiotensin and aldosterone levels on days 1 and 7. Oral administration of the selected agent was continued for 3 months along with other antianginal medications, including nonangiotensin-converting enzyme inhibitor vasodilators. Repeat measurements of left ventricular function were obtained before hospital discharge and at 3 months. There were no significant differences in baseline clinical characteristics between groups. One patient in the captopril-treated group became hypotensive during intravenous therapy, requiring discontinuation of treatment. Compared with the placebo-treated group, the captopril-treated group had significant reductions at day 7 in left ventricular end-diastolic pressure (22.5 +/- 1.5 versus 16.3 +/- 1.6 mm Hg, p less than 0.01) and mean systemic arterial pressure (93.6 +/- 3.3 versus 86.2 +/- 2.7 mm Hg, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A randomized placebo-controlled trial of combined early intravenous captopril and recombinant tissue-type plasminogen activator therapy in acute myocardial infarction. 182 97

Pulmonary endothelial cells and the renin-angiotensin-aldosterone (RAA) system respond to different types of injury (direct or indirect) with variations in their functions. These variations influence the regulatory mechanisms of pulmonary and systemic blood pressure, electrolyte balance and fibrinolysis. Concentration changes of some components of the RAA system and lung plasminogen activator were observed following NdYag laser application to the brain surface in rats. These changes were similar to those observed in cutaneous burn and haemorrhagic hypotension. CO2 laser application did not cause the same changes.
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PMID:Brain surface exposure to CO2 and NdYag laser application: effect on pulmonary endothelium response in the rat. 303 May 14

A highly active angiotensin-producing enzyme (enzyme II) was obtained from dog serum by acid treatment and fractionation to remove angiotensinase and converting enzyme, separate an inhibitor, and convert an inactive precursor (proenzyme II) to enzyme II. Proenzyme II was found to be converted to enzyme II by an endogenous activating enzyme identified as plasmin. Conversion was also caused by the interaction of bacterial streptokinase with human proactivator, by trypsin, and by an activator formed from liver tissue extract and dog serum. Neither plasma kallikrein nor the labile, human extrinsic tissue-type plasminogen activator induced activation. The inhibitor, which normally blocks the activation of proenzyme II, was unusually stable against high temperatures and extremes of pH, and it was not identical to any of the six known protease inhibitors of serum. Enzyme II was not identical to other angiotensin-producing enzymes such as enzyme I, renin, cathepsin D, pepsin, plasmin, tonin, or cathepsin G. Enzyme II reacted maximally at pH 4.7 and produced up to 2250 ng of angiotensin I/ml serum/hr from the substrate of dog serum (i.e., amounts 3200-fold higher than that produced by endogenous renin of normal dog serum). Since at pH 7.2, angiotensin I formation is still about 30 times higher than that of renin, enzyme II may be physiologically active under some conditions.
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PMID:Angiotensin-producing serum enzyme II. Formation by inhibitor removal and proenzyme activation. 390 15

The concept of classical endocrine control of ovarian function has now been extended to a more complex regulator system, including paracrine and autocrine modulating mechanisms. Among many factors, locally produced intraovarian insulin-like growth factors (IGFs) and the binding proteins (IGFBPs) and renin-angiotensin system (RAS) have been shown to play an important role in the control of folliculogenesis and ovulation. Growth hormone (GH) amplified gonadotropin actions in the process of follicular development and ovulation, at least in part, stimulating ovarian IGF-I production. IGF-I as well as IGFBPs were produced by ovarian granulosa cells. IGF-I acted synergistically with gonadotropins in the stimulation of a variety of granulosa cell functions, including estradiol (E2) and progesterone production and plasminogen activator (PA) activity. Furthermore, rabbit ovarian cells and rat granulosa cells possessed specific IGF type I receptors. The biological effects of IGF-I, including intrafollicular PA activities and ovarian steroidogenesis, were modulated by a family of IGFBPs in a complex manner. In the ovary IGFBP-3 appeared to neutralize the actions of gonadotropin and IGF-I, probably via its ability to sequester IGF-I, in the process of follicular growth, oocyte maturation, and ovulation. A functional local RAS is also known to exist in the ovary. Angiotensin II (Ang II) at 2-h intervals induced oocyte maturation, ovulation, and the production of E2 and prostaglandins (PGs) in the in vitro perfused rabbit ovaries in the absence of gonadotropin. In addition, the intrafollicular Ang II content and renin-like activity were enhanced during the ovulatory process by exposure to hCG, and the concomitant addition of saralasin inhibited hCG-induced ovulation in a dose-dependent manner. Captopril, an inhibitor of angiotensin converting enzyme, significantly inhibited the resumption of meiosis in the ovulated ova and follicular oocytes stimulated by hCG. Autoradiographic study revealed that AT2 receptors were predominantly located in granulosa cells, whereas AT1 receptors were more concentrated in the stroma and the thecal layers. Ang II-stimulated production of E2 and PGs and ovulation were significantly blocked by PD123319, a selective nonpeptide antagonist for AT2 receptors. The increase in ovarian IGF-I synthesis by exposure to hCG or GH induced the stimulation of intrafollicular PA activities. IGFBP-3 blocked the stimulatory effects of gonadotropin in the ovulatory process by neutralizing endogenously produced IGF-I, resulting in reduced intrafollicular PA activities. The increase in intrafollicular PA activities significantly stimulated the generation of Ang II in the preovulatory follicles by an activation of prorenin to renin and/or by the direct cleavage of angiotensinogen.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Regulatory system and physiological significance of local factors in the ovary during follicular development and maturation]. 759 85

In healthy subjects, intravenous infusion of the selective V2-vasopressin receptor agonist 1-desamino-8-D-arginine vasopressin (DDAVP, 400 ng/kg in 10 min) causes a marked increase in heart rate with a slight decrease in diastolic blood pressure. These haemodynamic responses are associated with increments in the plasma levels of renin, noradrenaline (NA), clotting factor VIII (FVIII:C), von Willebrand factor (vWF:ag), and tissue-type plasminogen activator (t-PA), and a fall in the plasma level of plasminogen activator inhibitor (PAI). None of these changes was observed in 3 patients with congenital nephrogenic diabetes insipidus (NDI), who had a genetic defect of the V2-receptor. Plasma AVP levels in these patients were normal or slightly elevated, which makes it unlikely that the lack of DDAVP responsiveness was caused by down-regulation of vasopressin V1-receptors. In one NDI patient, arginine vasopressin (AVP) was given in incremental doses (62.5-4000 pg/kg/min). The heart rate and blood pressure responses to AVP were normal, indicating the absence of a V1-receptor defect. The responses of vWF:ag and t-PA to venous occlusion in the patients with NDI were similar to those in 5 healthy volunteers, which indicates that in NDI the endothelial release of both vWF:ag and t-PA is normal. We conclude that DDAVP causes its effects on heart rate and blood pressure, and on the plasma levels of renin, noradrenaline, FVIII:C, vWF:ag, and t-PA through V2-receptor stimulation.
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PMID:1-Desamino-8-D-arginine vasopressin (DDAVP) in patients with congenital nephrogenic diabetes insipidus. 823 94

Plasma levels of tissue type plasminogen activator (tPA), plasminogen activator inhibitor (PAI), fibrinogen (Fg), thromboxane B2 (TXB2), 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), renin activity (PRA) and angiotensin II (ANGII) were assayed in 18 patients with coronary heart disease and 11 healthy subjects before and after submaximal treadmill exercise test according to "Bruce programme". All patients showed significant (> or = 50%) stenosis of at least one branch of the coronary arteries in coronary angiography and normal levels of serum trinitroglycerin. Drugs of dipyridamole, heparin, warfarin and aspirin were not administered to the patients two weeks before the test. The results were as follows: (1) Plasma PAI activity and Fg levels in 12 patients with positive test were remarkablly higher than in the remaining 6 subjects with negative test in the CHD group and in the control before and after exercise. Plasma tPA antigen changed in a reverse way. (2) Plasma levels of TXB2, PRA and ANGII in the positive test subgroup of CHD were higher than in the negative test subgroup and in the control after exercise, but differences of the parameters among the three groups were insignificant before exercise. The study suggests that defectiveness of fibrinolytic system in CHD patients was shown mainly as disorder of tPA-PAI equilibrium and that decreased fibrinolytic activity and increased PAI in exercise-induced myocardial ischemia have relations with activation of platelets and renin-angiotensin system.
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PMID:[Clinical significance of fibrinolytic system defectiveness in exercise induced myocardial ischemia and its mechanism]. 856 12

Neuronal cells in primary culture from the hypothalamus-brain stem areas of normotensive [Wistar-Kyoto (WKY)] and spontaneously hypertensive (SH) rat brains have been used in the present study to investigate an interaction between the brain renin-angiotensin II system and the plasminogen activator system. This is an attempt to further our understanding of the role of brain Ang II in the control of neuronal development and differentiation through its regulation of the extracellular matrix. Ang II caused a 10-fold stimulation of plasminogen activator inhibitor-1 (PAI-1) messenger RNA (mRNA) in WKY rat brain neuronal cultures. The stimulation was mediated by the AT1 receptor subtype and was accompanied by an increase in PAI-1 gene transcription and the synthesis of cellular PAI-1 protein. The stimulation involved activation of protein kinase C, and alterations in the intracellular Ca2+ pool caused a significant inhibition of Ang II stimulation of PAI mRNA. Ang II stimulation of PAI-1 mRNA succeeded its action on c-fos mRNA and was attenuated by c-fos antisense oligonucleotide. Although PAI-1 gene expression was also stimulated by Ang II in neuronal cultures of SH rat brain, two differences between WKY and SH rat brain neurons were observed: 1) the level of Ang II stimulation in SH rat neurons was 50% of that in WKY rat neurons; and 2) Ang II stimulation of c-fos was 2.4-fold higher in SH neurons than in WKY neurons, but c-fos antisense oligonucleotide did not attenuate the stimulatory action of Ang II on PAI-1 mRNA in SH neurons. These observations suggest that the changes in the Ang II-mediated signaling pathways and/or the regulatory region(s) of the PAI-1 gene may contribute to the differential actions of Ang II in WKY and SH rat brain neurons.
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PMID:Angiotensin II regulation of plasminogen activator inhibitor-1 gene expression in neurons of normotensive and spontaneously hypertensive rat brains. 864 Dec 4

Although rapid growth of the heart during early postnatal development ceases with maturation of the organism, the potential for cardiomyocyte growth is not lost and may be observed even in senescent hearts. Rapid developmental heart growth is accompanied by a proportional growth of capillaries but not always of larger vessels, and thus coronary vascular resistance gradually increases. Growth of adult hearts can be enhanced by thyroid hormones, catecholamines and the renin-angiotensin system hormones, but these do not always stimulate growth of coronary vessels. Likewise, chronic exposure to hypoxia leads to growth, mainly of the right ventricle and its vessels but without vascular growth elsewhere in the heart. On the other hand, ischaemia is a potent stimulus for the release of various growth factors involved in the development of collateral circulation. Heart hypertrophy develops in response to training, pressure or volume overload. Training usually leads to growth of larger coronary vessels but little growth of capillaries, except in young animals. However, growth of the capillary bed, but not the resistance vasculature capacity, can be induced by either increased coronary blood flow, bradycardia (electrically or pharmacologically induced) or increased inotropism, all of which are involved in the training stimulus. Thus, what actually promotes growth of larger vessels as opposed to capillaries in training is unclear. Pressure overload hypertrophy is mediated by both the renin-angiotensin system and the response of cardiomyocytes to stretch; both lead to activation of early oncogenes (c-fos, c-jun, c-myc) and angiotensin II activates several protein kinases involved in cell growth. In this condition, growth of larger vessels is inadequate, although some capillary growth may occur. Volume overload leads to cardiomyocyte hypertrophy and hyperplasia and some increase in vascular supply. Deficits in capillary supply in pressure or volume overload hypertrophy can be reversed by chronic administration of ACE inhibitors, dipyridamole, the bradycardic drug alinidine or pacing-induced bradycardia respectively, but in neither case is training effective. Mechanical and humoral factors are involved in growth of cardiomyocytes and vessels. For cardiomyocytes, stretch is most important, activating oncogenes, protein kinases and possibly the inositol phosphate pathway, but not ion channels, with regulation by the balance of angiotensin II, TGF-beta 1 and IGF-1, but not FGFs. For vessels, growth is stimulated by stretch and shear stress, possibly with involvement of VEGF. Increased shear stress disrupts the glycocalyx on the luminal side of vessels and releases plasminogen activator and metalloproteinases which disrupt the basement membrane and enable endothelial cell migration and proliferation. It also causes rearrangement of the endothelial cytoskeleton and transmission of mechanical signals to the abluminal side disturbing extracellular matrix and causing distortion of capillary basement membrane. Stretch acting from the abluminal side has a similar effect resulting also in basement membrane disruption and endothelial cell proliferation.
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PMID:Postnatal growth of the heart and its blood vessels. 869 52

The interactions between insulin-like growth factor-I (IGF-I) and the renin-angiotensin system (RAS) in follicular growth and ovulation were studied with the use of an isolated perfused rabbit ovary preparation. Ovulation failed to occur in either control ovaries or the experimental ovaries perfused with IGF-I in a concentration of 1, 10, or 100 ng/ml in the absence of gonadotropin. Exposure to IGF-I stimulated the secretion rate of angiotensin II-like immunoreactivity (Ang II-IR) in perfused rabbit ovaries in a dose-dependent manner. The percent increase in follicle diameter in ovaries perfused with IGF-I for 12 h was significantly correlated with the secretion rate of Ang II-IR at 12 h after exposure to IGF-I. The addition of IGFBP-3 to the perfusate did not induce ovulation in the absence of gonadotropin, but exposure to IGFBP-3 inhibited hCG-induced ovulation in a dose-dependent manner. In addition, IGFBP-3 significantly reduced the ovarian secretion rate of Ang II-IR and prostaglandins stimulated by hCG administration. Intrafollicular plasminogen activator (PA) activity significantly increased within 4 h after exposure to 100 ng/ml of IGF-I, compared with that in control ovaries perfused with medium alone. The concomitant addition of IGFBP-3 to the perfusate significantly reduced the IGF-I-stimulated PA activity in the preovulatory follicles at 4, 6, and 8 h after exposure to IGF-I. However, IGFBP-3 alone affected neither the ovarian secretion rate of Ang II-IR nor intrafollicular PA activity. Exposure to streptokinase, an exogenous PA, in vitro stimulated both follicular growth and the intrafollicular Ang II-IR content. In conclusion, IGF-I enhances both ovarian Ang II production and follicular development by stimulating intrafollicular PA activity.
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PMID:Interactions between insulin-like growth factor-I (IGF-I) and the renin-angiotensin system in follicular growth and ovulation. 875 39

We examined the potential of in vivo linkage of plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) in the setting of endothelial injury and sclerosis following radiation injury in the rat. PAI-1 is a major physiological inhibitor of the plasminogen activator (PA)/plasmin system, a key regulator of fibrinolysis and extracellular matrix (ECM) turnover. PAI-1 mRNA expression in the kidney was markedly increased (9-fold) at 12 weeks after irradiation (P < 1.001 vs. normal control). In situ hybridization revealed significant association of PAI-1 expression with sites of glomerular injury (signal intensity in injured vs. intact glomeruli, P < 0.001). Angiotensin converting enzyme inhibitors (ACEI, captopril or enalapril) or angiotensin II receptor antagonist (AIIRA, L158,809) markedly reduced glomerular lesions (thrombosis, mesangiolysis, and sclerosis; sclerosis index, 0 to 4+ scale, 0.49 +/- 0.20 in untreated vs. 0.05 +/- 0.02, 0.02 +/- 0.01, 0.04 +/- 0.02 in captopril, enalapril and AIIRA, respectively, all P < 0.01 vs untreated). Further, ACEI and AIIRA markedly attenuated increased PAI-1 mRNA expression in the irradiated kidney (36, 19 and 20% expression, respectively, for captopril, enalapril and AIIRA, compared to untreated irradiated kidney, P < 0.05, < 0.01, < 0.01). This effect was selective in that neither tissue-type nor urokinase-type PA mRNA expression was affected by these interventions. Thus, we speculate that inhibition of the renin-angiotensin system may ameliorate injury following radiation by accelerating fibrinolysis and ECM degradation, at least in part, via suppression of PAI-1 expression. In summary, inhibition of Ang II, in addition to its known effects on vascular sclerosis, may also by its novel effect to inhibit PAI-1, lessen fibrosis following endothelial/thrombotic injury.
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PMID:Modulation of plasminogen activator inhibitor-1 in vivo: a new mechanism for the anti-fibrotic effect of renin-angiotensin inhibition. 899 30


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