Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical course of 76 patients with aortic aneurysmal disease undergoing 107 coincidental surgical procedures was analysed in order to examine the relationship between aortic aneurysmal rupture and coincidental treatment. Additionally the incidence of aneurysmal rupture was assessed following 82 endoscopic procedures in 42 patients with aortic aneurysms. Two patients ruptured an aortic aneurysm after operation, one after colonoscopy (maximal transverse diameter 7 cm) and one after coronary artery bypass grafting (maximal transverse diameter 5.6 cm). The mean maximal transverse diameter of aneurysms in 76 patients was 5.08 cm (95% confidence interval 4.7-5.4 cm). Both patients with ruptured aortic aneurysm were outside these confidence limits and were known hypertensives whose perioperative control of hypertension was questionable. The present series of patients is discussed with reference to induction of collagenase activity as a precipitating cause for postoperative rupture of aortic aneurysms, perioperative control of hypertension, transverse aneurysm diameter as a predictor of postoperative rupture and conduct of coincidental procedures in the presence of aneurysmal disease.
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PMID:Incidence of rupture of aortic aneurysms after coincidental operation. 778 Jul 5

Myocardial fibrosis is associated with an activated renin-angiotensin-aldosterone system (RAAS). In renovascular hypertension, this presents as a reactive perivascular and interstitial fibrosis in not only the pressure overloaded, hypertrophied left ventricle but also the normotensive, nonhypertrophied right ventricle. It therefore would appear that circulating hormonal and not hemodynamic factors are responsible for this adverse fibrous tissue response. To ascertain whether the RAAS effector hormones angiotensin II (AII) or aldosterone (ALDO) directly stimulate collagen synthesis or inhibit collagenase production we used cell culture. Adult rat cardiac fibroblasts (Fb) were cultured since these cells express mRNA for types I and III collagens, the major fibrillar collagens in the heart, and collagenase or matrix metalloproteinase 1 (MMP 1), the key enzyme for interstitial collagen degradation. Collagen synthesis, determined by 3H-proline incorporation, and collagenase activity were measured in confluent, quiescent Fb after 24 h incubation with various concentrations of AII or ALDO (10(-11)-10(-6)M) in the presence or absence of either 10(-5)M type 1 (DuP 753) and type 2 (PD 123177) AII or 10(-9)-3 x 10(-6)M ALDO (spironolactone) receptor antagonists, respectively. Collagen synthesis, normalized per total protein synthesis, increased significantly (P < 0.005) after incubation with either 10(-9)M ALDO (5.9 +/- 1.0%) or 10(-7)M AII (5.3 +/- 1.2%) compared with untreated control cells (2.9 +/- 0.5%) of the same passage (p6-p10). This increase in collagen synthesis could be completely abolished by either types 1 or 2 AII receptor antagonists in AII stimulated Fb or the competitive ALDO receptor antagonist, spironolactone, at equimolar concentration in ALDO stimulated Fb. AII significantly decreased collagenase activity which could be completely abolished by PD 123177, but not DuP 753, while ALDO had no effect on collagenase activity. The mineralocorticoid, ALDO, stimulates collagen synthesis in cultured adult rat cardiac Fb in concentrations similar to those found in plasma in renovascular hypertension and this response appears to occur via type I corticoid receptors. AII appears to stimulate collagen synthesis by both type 1 and 2 AII receptors, but only in high concentrations that could be generated locally within the myocardium. In addition, AII unlike ALDO inhibits collagenase activity that could be attenuated only by type 2 receptor blockade. These findings suggest a direct interaction between ALDO, AII and cardiac Fb in mediating myocardial fibrosis in hypertensive heart disease.
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PMID:Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. 796 49

The interstitial space of the myocardium is composed of nonmyocyte cells and a highly organized collagen network which serves to maintain the architecture and mechanical behavior of the myocardial walls. It is the myocardial collagen matrix that determines myocardial stiffness in the normal and structurally remodeled myocardium. In hypertensive heart disease, the heterogeneity in myocardial structure, created by the altered behavior of nonmyocyte cells, particularly cardiac fibroblasts which are responsible for collagen synthesis and degradation, explains the appearance of diastolic and/or systolic dysfunction of the left ventricle that leads to symptomatic heart failure. Several lines of evidence suggest that circulating and myocardial renin-angiotensin systems (RAS) are involved in the regulation of the structural remodeling of the nonmyocyte compartment, including the cardioprotective effects of angiotensin converting enzyme (ACE) inhibition that was found to prevent myocardial fibrosis in the rat with renovascular hypertension. In cultured adult rat cardiac fibroblasts angiotensin II was shown to directly stimulate collagen synthesis and to inhibit collagenase activity, which is the key enzyme for collagen degradation, that would lead to collagen accumulation. In the spontaneously hypertensive rat, an appropriate experimental model for primary hypertension in man, left ventricular hypertrophy could be regressed and abnormal myocardial diastolic stiffness due to interstitial fibrosis could be restored to normal by inhibition of the myocardial RAS. These antifibrotic or cardioreparative effects of ACE inhibition that occurred irrespective of blood pressure normalization may be valuable in reversing left ventricular diastolic dysfunction in hypertensive heart disease.
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PMID:Renin-angiotensin system and myocardial collagen matrix remodeling in hypertensive heart disease: in vivo and in vitro studies on collagen matrix regulation. 851 39

Cardiac fibroblasts appear to be important in producing and maintaining the extracellular matrix (ECM) of the heart. The abnormal proliferation of cardiac fibroblasts and deposition of the ECM protein, collagen, associated with hypertension and myocardial infarction, may adversely affect the performance of the heart. Several groups of factors affect collagen gene expression and/or growth of cardiac fibroblasts. Angiotensin II, aldosterone and endothelins play a central role in the remodeling of the ECM in hypertension, and decrease collagenase activity and/or increase collagen synthesis in cultured cells. Regulatory peptides that are generally elevated at sites of injury, such as TGF-beta 1 and PDGF, increase collagen synthesis and/or stimulate mitogenesis. Mechanical stretch enhances collagen expression and cell proliferation, responses which could in part be due to integrin activation. Cytokines may stimulate or inhibit cell growth, the latter through prostaglandin formation. Angiotensin II is a principal determinant in vivo of cardiac fibroplasia and synthesis of the ECM proteins, collagen and fibronectin. Cardiac fibroblasts possess G-protein-coupled AT1 receptors for angiotensin II that couple to activation of multiple signalling pathways, including: phospholipase C-beta, with the subsequent release of Ca2+ from intracellular stores and activation of protein kinase C, mitogen-activated protein kinases, tyrosine kinases, phospholipase D, phosphatidic acid formation, and the STAT family of transcription factors. Cardiac fibroblasts respond to angiotensin II with hyperplastic/hypertrophic growth, and increased expression of collagen, fibronectin, and integrins. The mechanisms by which the AT1 receptor activates multiple signalling pathways are not known, although the receptor might interact at some level with both integrins and cytokine receptors. Different signalling pathways of the AT1 receptor may subserve different cellular responses, such as mitogenesis, ECM synthesis, or an inflammatory/stress response. Crosstalk among the signalling pathways of the AT1 receptor, and those of G-protein, cytokine, and growth-factor receptors, may determine the ultimate response of the cell.
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PMID:Molecular signalling mechanisms controlling growth and function of cardiac fibroblasts. 857 2

Increased elastin production and accumulation is a rapid and sensitive response to elevated vascular wall stress in both systemic and pulmonary hypertension. While initially protecting the vessel wall, these structural changes may in the longer term result in reinforcement of the hypertensive state and contribute to the persistence of the pathology of hypertension. Rapid responses apparently uncorrelated with increased elastin mRNA, at least in the case of systemic vessels, suggest novel mechanisms perhaps including increased efficiency of message translation or matrix accumulation of the protein. Investigations using in vitro organ and cell culture models have indicated a role for phospholipases and protein kinases, including protein kinase C, in stretch-induced elastin synthesis. In addition, tyrosine phosphorylation of membrane/sub-membrane/cytoskeletal sensors, including focal adhesion kinase and members of the lipocortin family, have been shown to be important in this transduction mechanism. Because its turnover is normally very slow, additional vascular elastin accumulated during hypertensive episodes, together with its consequences for the physical properties of the vessel wall, may persist long after blood pressure is restored to normal levels. Thus, recent interest has been drawn to the possibility of achieving regression of accumulated matrix elastin by promoting turnover of this protein through activation of endogenous vascular elastase and collagenase activities.
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PMID:Elastin in systemic and pulmonary hypertension. 857 61

Angiotensin II (Ang II) has growth-stimulatory properties on different renal cell types. However, possible growth effects of this vasoactive peptide on endothelial cells isolated from the glomerular microvasculature have not been formally investigated. Therefore, we isolated and characterized primary cultures of rat glomerular endothelial cells. We used a simple technique in which collagenase-treated glomeruli were sparsely plated in several 96-well culture plates and microscopically screened for cobblestone-like outgrowth. After two limiting dilutions, homogeneous cultures were obtained. Cells were characterized by positive staining for the endothelial markers factor VIII, CD 31, endothelial leukocyte adhesion molecule-1, and the lectin Bandeiraea simplificifolia. Ang II stimulated the synthesis and release of endothelin-1 in culture supernatants. Moreover, in contrast to syngeneic mesangial cells, glomerular endothelial cells expressed angiotensin-converting enzyme. Ang II stimulated a mild but significant proliferation of quiescent cells, as measured by [3H]thymidine incorporation and direct cell counting. This mitogenesis was transduced by losartan-blockade angiotensin type 1 receptors. Moreover, Ang II mediated phosphorylation of mitogen-activated protein kinase 2 and induction of transcripts for the immediate early gene Egr-1. Our results indicate that Ang II is a moderate mitogen for primary cultures of rat glomerular endothelial cells and activation of these metabolically active cells may play a role in the pathophysiology of several types of glomerulonephritis. Moreover, remodeling of glomerular endothelial cells by Ang II may be important in the progression of structural renal damage during the course of hypertensive injury.
Hypertension 1996 Apr
PMID:Angiotensin II is mitogenic for cultured rat glomerular endothelial cells. 861 66

The effect of methylmercury (CH3HgCl) on the production of endothelium-derived relaxing factor (EDRF) by cultured human umbilical vascular endothelial cells (HUVECs) based on its anti-aggregatory effect on human platelets was examined. HUVECs were harvested from umbilical veins by collagenase treatment. The platelet aggregation test was performed with cuvettes lined with HUVECs. Platelet aggregation induced by 0.05 units thrombin/ml was inhibited in the presence of HUVECs. This HUVEC-dependent anti-platelet aggregatory effect was enhanced by the addition of bradykinin (10 nmol/L), which stimulates the production of EDRF. Indomethacin (IND, 1 mumol/L) reduced the HUVEC-dependent anti-platelet aggregatory effect. The effect of NG-monomethyl-L-arginine L-NMMA, 100 mumol/L), an inhibitor of nitric oxide synthase (NOS) in endothelial cells, on HUVECs pretreated with IND showed almost complete platelet aggregation similar to results without HUVECs. The anti-platelet aggregatory effect of HUVECs pretreated with IND seemed to depend mainly on EDRF. Methylmercury (MeHg) (20-50 mumol/L) induced dose-dependent platelet aggregation in cuvettes, without HUVECs. Methylmercury (30 mumol/L) induced less platelet aggregation in the presence of HUVECs than in their absence. The degree of inhibitory effect by HUVECs on MeHg-induced platelet aggregation was reduced dose-dependently (30-50 mumol/L MeHg). Methylmercury-induced platelet aggregation at 50 mumol/L MeHg with or without HUVECs was similar. These findings suggest that this simple new experimental system is useful for assessing the production of EDRF by HUVECs, and show that MeHg inhibits the production of EDRF by HUVECs, which may be involved in the etiology of cardiovascular diseases such as hypertension and arteriosclerosis.
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PMID:The effect of methylmercury (CH3HgCl) on the production of endothelium-derived relaxing factor (EDRF) by cultured human umbilical vascular endothelial cells based on its anti-aggregatory effect on human platelets. 878 7

Altered function of smooth muscle cell K+ channels have been reported in hypertension, but the contribution of various K+ channel types to these changes has not been completely determined. The purpose of this study was to compare the contribution of K+ channel types to whole cell K+ currents recorded from isolated thoracic aorta myocytes of 13 to 15 week old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Cells were isolated by collagenase and elastase digestion, and K+ currents recorded using whole cell voltage clamp methods at room temperature. Cells were superfused with a solution containing (in mmol/ L) 140 NaCl, 5 KCl, 2 CaCl2, 1 MgCl2, 10 HEPES, and 10 glucose. Pipettes were filled with a solution containing (in mmol/L) 120 KCl, 5 NaCl, 5 MgATP, 20 HEPES, and 10 BAPTA. The K+ currents (IK) recorded from a holding potential (HP) of -80 mV were smaller in the SHR compared to those in WKY (for example, at 20 mV: WKY = 6.1 +/- 0.6 pA/pF and SHR = 3.7 +/- 0.2 pA/pF). Values of cell capacitance were not different between the two groups (WKY = 25.2 +/- 3.2 pF and SHR = 26.6 +/- 1.9 pF). A component of IK inhibited by voltage (Kv) over the range from -80 to -20 mV was smaller in SHR. The voltage dependence of Kv availability and activation were not significantly different between the two groups. IK recorded from a HP = -20 mV (KCa) was not different between the two groups. Difference currents calculated from IK measured at HP of -80 and -20 mV (that is, Kv) were smaller in SHR as was the fraction of IK inhibited by 4-aminopyridine. These results suggest that under conditions of low intracellular [Ca2+] there are no differences in KCa currents, but the Kv currents are smaller in SHR. Inhibition of Kv by 4-aminopyridine (0.1 to 10 mmol/L) caused larger increases in basal tone in WKY aorta. These results suggest that Kv channels contribute to resting K+ conductance in both WKY and SHR aorta, but with a relatively larger contribution in the WKY.
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PMID:Comparison of K+ channel properties in freshly isolated myocytes from thoracic aorta of WKY and SHR. 887 45

Glomerulosclerosis and tubulointerstitial fibrosis are common morphological correlates of many end-stage kidneys. There is ample evidence that transforming growth factor-beta (TGF-beta) plays a major role in these alterations by directly stimulating synthesis of many extracellular matrix components and reducing collagenase production, finally leading to renal scarring. Although many factors may induce TGF-beta expression in the kidney, one very interesting aspect is the link between angiotensin II (ANG II) and TGF-beta. Originating from observations in vascular smooth muscle cells, there are now several additional studies showing that ANG II stimulates TGF-beta expression in the kidney. Although cell culture studies have convincingly demonstrated that the vasoactive peptide directly stimulates transcription as well as bioactivation of TGF-beta, the in vivo evidence is more indirect. Nevertheless, there are several pathophysiological situations including unilateral ureteral obstruction, chronic cyclosporin A nephrotoxicity, various models of hypertension, and probably diabetic nephropathy in which ANG II-mediated TGF-beta induction has been demonstrated to play an important role in the progression of the disease. The fascinating aspect of this relationship between ANG II and TGF-beta is the fact that hemodynamic changes as well as structural changes are linked together generating a unifying model of progression of chronic renal failure with ANG II as the key player. Angiotensin-converting enzyme (ACE) inhibitor and the more recently introduced AT1-receptor blocker may be potential drugs to interfere with this ANG II-mediated TGF-beta expression. Therefore, these drugs should not only be considered as antihypertensive medications, but should rather be viewed as renoprotective substances influencing renal remodeling by preventing local TGF-beta expression.
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PMID:Link between angiotensin II and TGF-beta in the kidney. 952 2

Experiments were conducted to gain insight into mechanisms responsible for exaggerated renal vascular reactivity to ANG II and vasopressin (AVP) in spontaneously hypertensive rats (SHR) during the development of hypertension. Cytosolic calcium concentration ([Ca2+]i) was measured by ratiometric fura 2 fluorescence and a microscope-based photometer. Vascular smooth muscle cells (SMC) from preglomerular arterioles were isolated and dispersed using an iron oxide-sieving method plus collagenase treatment. ANG II and AVP produced rapid and sustained increases in [Ca2+]i. ANG II elicited similar dose-dependent increases in [Ca2+]i in SMC from SHR and Wistar-Kyoto rats (WKY). In contrast, AVP caused almost twofold larger responses in afferent arteriolar SMC from SHR. ANG II effects were inhibited by the AT1 receptor antagonist losartan. AVP action was blocked by the V1 receptor antagonist [d(CH2)5,Tyr(NH2)9]AVP. In SMC pretreated with nifedipine, neither ANG II nor AVP elicited [Ca2+]i responses. Poststimulation nifedipine reversed elevated [Ca2+]i to basal levels. Short-term reductions in external [Ca2+]i (EGTA) mimicked the nifedipine effects. Our study shows that AT1 and V1 receptors stimulate [Ca2+]i by a common mechanism characterized by preferential action on voltage-gated L-type channels sensitive to dihydropyridines. Calcium signaling elicited by AT1 receptors does not differ between SHR and WKY; thus the in vivo exaggerated reactivity may be dependent on interactions with other cell types, e. g., endothelium. In contrast, AVP produced larger changes in [Ca2+]i in arteriolar SMC from SHR, and such direct effects can account for the exaggerated renal blood flow responses.
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PMID:Exaggerated Ca2+ signaling in preglomerular arteriolar smooth muscle cells of genetically hypertensive rats. 995 Sep 57


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