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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The arterial wall is structurally and functionally compartmentalized. Each compartment is characterized by a specific cell type and by specific interactions. The endothelial compartment interacts with circulating blood, and the adventitial compartment with the surrounding tissue. The media, which contains the effector smooth muscle cells, perceives centrifugal messages from the endothelium and centripetal messages from metabolically active tissues, from adventitial nerve endings, and from peptides produced in the interstitium. The degree of contraction or relaxation of the vascular smooth muscle cells characterizes the general vasomotor tone, which governs the local blood pressure level and distributes the flow according to metabolic needs. The main physiologic vasoactive agent is nitric oxide (NO) and is produced by the endothelium. In disease states, other agents can become predominant in centrifugal parietal messages. NO is produced by type 3 NO synthase, an enzyme that is constitutively expressed by endothelial cells. The activity of this enzyme on its substrate, arginine, is regulated by the concentration of free calcium and by intracellular phosphorylations. Several peptides, including receptors, are coupled to the phospholipase C pathway in the endothelial cell; endothelial growth factors such as FGF and VEGF, enhance the activity of endothelial NO synthase. However, the main physiologic factor responsible for endothelial NO synthase activation is the shearing stress produced by friction of the flowing blood against the immobile vessel wall. This shearing stress constantly adjusts the diameter of conductance vessels to peripheral metabolic needs. Expression of endothelial NO synthase is modulated by the chronic effects of the same agents. NO has a vasodilating effect that is mediated by the generation of cyclic GMP. Cyclic GMP and cyclic AMP are the main second messengers in smooth muscle cell relaxation. NO binds to a heme-protein, soluble guanylate cyclase, that converts GMP to cyclic GMP. Kinase-G is the main target for cyclic GMP in the smooth muscle cell. Kinase-G phosphorylates phospholambans and releases the repumping activity of calcium ATPase. More importantly, kinase-G phosphorylates the protein G that links seven-domain membrane-spanning receptors to phospholipases, thus inhibiting coupling between the ligand-receptors interaction and the intracellular signaling process that leads to contraction. NO can relax the smooth muscle cell only in the presence of a preexisting contractile tone. Conversely, absence of NO enhances the preexisting contractile tone. All these notions can be analyzed via the experimental model of L-NAME-induced chronic NO synthase blockade in rats. The decrease in parietal cyclic GMP seen in this model is associated with an increase in contractile tone that translates into systemic arterial hypertension. The increase in contractile tone can be blocked by renin-angiotensin system inhibitors. Chronic blockade of NO production rapidly induces vascular wall phenotype changes that lead to renal failure, ischemic stroke, and fibrosis of target organs. These phenotype changes may be related to the increase in the oxidative potential of the various types of parietal cells, as suggested by the abnormal presence of inflammatory cells and by the increased expression of inflammation mediators including cyclooxygenase II, inducible NO synthase, and adhesion molecules such as ICAM and VCAM. This model therefore holds promise for elucidating interactions between NO and arteriosclerosis. NO system dysfunction is also seen in other cardiovascular disorders, including congestive heart failure.
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PMID:[Role of endothelial nitric oxide in the regulation of the vasomotor system]. 976 14

Angiotensin (Ang) II-induced organ damage has fascinated students of hypertension since the work of Wilson and Byrom. We are investigating a double transgenic rat (dTGR) model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7. The heart shows necrosis and fibrosis, whereas the kidneys resemble the hemolytic-uremic syndrome vasculopathy. Surface adhesion molecules (ICAM-1 and VCAM-1) are expressed early on the endothelium, while the corresponding ligands are found on circulating leukocytes. Leukocyte infiltration in the vascular wall accompanies PAI-1, MCP-1, and VEGF expression. The expression of TGF-beta and deposition of extracellular matrix proteins follows, which is accompanied by fibrinoid vasculitis in small vessels of the heart and kidneys. Angiotensin-converting enzyme inhibitors and AT1 receptor blockers each lowered blood pressure and shifted pressure natriuresis partially leftward by different mechanisms. When combined, they normalized blood pressure, pressure natriuresis, and protected from vasculopathy completely. Renin inhibition lowered blood pressure partially, but protected from vasculopathy completely. Endothelin receptor blockade had no influence on blood pressure but protected from vasculopathy and improved survival. We show evidence that Ang II stimulates oxidative stress directly or indirectly via endothelin 1 and that NFkappaB is upregulated in this model. We speculate that the transcription factors NFkappaB and AP-1 are involved with initiating chemokine and cytokine expression, leading to the above cascade. The unique model and our pharmacological probes will enable us to test these hypotheses.
Hypertension 1999 Jan
PMID:Hypertension-induced end-organ damage : A new transgenic approach to an old problem. 993 Nov 7

The aim of the study was to investigate the influence of long-term ACE inhibition with ramipril on myocardial hypertrophy and its molecular background in spontaneously hypertensive stroke-prone rats (SHR-SP). Therefore, 1-month-old pre-hypertensive SHR-SP were randomized into three groups and exposed lifelong via drinking water to 1 mg/kg/day ramipril (anti-hypertensive dose, RHI), 10 micrograms/kg/day ramipril (non-anti-hypertensive dose, RLO) or placebo. After 15 months cardiac tissue was collected from ten rats each for immunohistochemistry and Northern blot analysis of structural proteins, proteins of the extracellular matrix and several growth factors. Results showed that RHI, but not RLO, treatment prevented development of myocyte hypertrophy (ANP). Furthermore, unlike placebo-treated rats, the ramipril-treated animals had no evidence of degeneration and loss of structural proteins (alpha -actinin), inflammatory infiltrates (CD45) and deposition of extracellular matrix proteins (collagen, fibronectin, vimentin). Only in RHI-treated animals, mRNA levels for TGF- beta(1)as well as of collagen alpha(1)(I) and fibronectin were downregulated compared to placebo-treated animals. In contrast, VEGF mRNA levels increased significantly in both groups of ramipril-treated animals v. placebo-treated SHR-SP. Thus, the reported life prolonging effect of high doses of ramipril which is associated with prevention of hypertension and hypertrophy is accompanied by prevention of the development of necrosis and fibrosis. The role of VEGF, however, seems to be independent of this effect.
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PMID:Effect of long-term ACE inhibition on myocardial tissue in hypertensive stroke-prone rats. 1042 43

The vasodilatory effect of VEGF has not been characterized in the setting of hypertension. This study investigated the in vitro vasorelaxant effects of VEGF in organ chambers in the aorta of the adult (12-week-old) spontaneously hypertensive rats (SHR), young (4-week-old) SHR without hypertension, and age-matched Wistar-Kyoto (WKY) rats compared with acetylcholine (ACh). Cumulative concentration-relaxation curves were established for VEGF (approximately 10(-12)-10(-8.5) M) and ACh (approximately 10(-10)-10(-5) M) in U46619 (10(-8) M)-induced contraction. VEGF induced endothelium-dependent relaxation that was significantly reduced in the adult SHR compared with the age-matched WKY control (87.8 +/- 2.8 versus 61.4 +/- 8.6%, P = 0.01). These responses were significantly attenuated by pretreatment with N(omega)-nitro-L-arginine (L-NNA, 300 microM) alone (SHR: 25.1 +/- 1.9%; WKY: 21.0 +/- 2.6%; P = 0.01) or indomethacin (7 microM) + L-NNA (SHR: 30.2 +/- 2.1%; WKY: 35.0 +/- 2.9%; P = 0.01). Further addition of oxyhemoglobin (20 microM) abolished the residual relaxation and reduced the relaxation induced by nitroglycerin. ACh induced similar responses to VEGF. In contrast, pretreatment with indomethacin alone enhanced VEGF- or ACh-induced relaxations and the effect was greater in the adult SHR than in WKY rats. In contrast to the adult SHR versus WKY rats, there were no significant differences of VEGF- or ACh-induced relaxations between young SHR and WKY rats. The results demonstrate that VEGF induces endothelium- or nitric oxide-dependent relaxation, which is blunted in the adult SHR. The mechanism of this impairment may be related to decreased release of NO although increased release of contracting factors from the dysfunctional endothelium may also be involved.
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PMID:Vascular endothelial growth factor-mediated endothelium-dependent relaxation is blunted in spontaneously hypertensive rats. 1116 Jun 33

Recent studies have demonstrated a role for microvascular and tubulointerstitial injury in some models of salt-sensitive hypertension. We utilized a model of post-cyclosporin A (CsA) nephropathy and hypertension to test the hypothesis that treatment with an angiogenic factor aimed at ameliorating the microvascular and renal injury would prevent the development of hypertension. CsA was administered with a low-salt diet for 45 days, resulting in a renal lesion characterized by afferent arteriolopathy, focal peritubular capillary loss, and tubulointerstitial fibrosis. Rats were then placed on a high-salt diet and randomized to receive either vascular endothelial growth factor (VEGF(121)) or vehicle for 14 days. Placement of rats with established CsA nephropathy on a high-salt diet results in the rapid development of salt-sensitive hypertension. VEGF(121) treatment resulted in lower blood pressure, and this persisted on discontinuing the VEGF. VEGF(121) treatment was also associated with a decrease in osteopontin expression, macrophage infiltration, and collagen III deposition and markedly stimulated resolution of the arteriolopathy (20.9 +/- 7.8 vs. 36.9 +/- 6.1%, VEGF vs. vehicle, P < 0.05). In conclusion, CsA-associated renal microvascular and tubulointerstitial injury results in the development of salt-sensitive hypertension. Treatment of animals with established CsA nephropathy with VEGF reduces the hypertensive response and accelerates histological recovery. The vascular protective effect of VEGF may be due to the improvement of arteriolopathy. Angiogenic growth factors may represent a novel strategy for treating CsA-associated hypertension and renal disease.
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PMID:Post-cyclosporine-mediated hypertension and nephropathy: amelioration by vascular endothelial growth factor. 1124 64

The authors present the results of experimental and clinical trials of recombinant genes coding the synthesis of endothelial growth factors VEGF, bFGF. Single transendocardial administration of these genes' DNA into the zone of hybernating myocardium in some patients with CHD caused in 3-6 months significant increase in perfusion, left ventricular ejection fraction, decrease in stenocardic pang rate, increase in exercise tolerance. The marked clinical effect was achieved when these drugs were introduced into ischemized tissue in patients with obliterating atherosclerosis of lower extremity arteries. Development of the methods for studying endothelial function available for wide clinical practice will permit to raise the efficiency of initial and secondary prophylaxis of arterial hypertension, CHD. Today the evaluation and correction of endothelial dysfunction is the new and the most perspective direction in cardiology development.
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PMID:[Endothelial dysfunction and its clinical significance (new trend in cardiology)]. 1155 Mar 27

We assessed the role of angiotensin (Ang) II in ischemia-induced angiogenesis and analyzed the molecular pathways involved in such an effect. Ischemia was produced by unilateral artery femoral occlusion in control, in valsartan-treated (Ang II receptor type I antagonist, 20 mg/kg per day), in Ang II-treated (5 ng/kg per min), and in Ang II and valsartan-treated rats. After 28 days, angiogenesis was assessed by microangiography and capillary density measurement in hindlimbs. The ischemic/nonischemic leg ratio for angiographic score and capillary number increased by 2.6- and 2-fold, respectively, in Ang II-treated rats compared with controls (P<0.01). This was associated with an increase in vascular endothelial growth factor (VEGF; 1.6-fold) and endothelial NO synthase (eNOS; 1.8-fold) protein content within the ischemic leg, assessed by Western blot. Angiotensin type 1 receptor blockade and administration of VEGF neutralizing antibody (2.5 microg IP, twice a week) in Ang II-treated rats completely prevented such Ang II angiogenic effects. The key role of eNOS was then emphasized by using mice deficient in gene encoding for eNOS. In wild-type mice, Ang II (0.3 mg/kg per min) treatment increased by 1.7- and 1.6-fold the ischemic/nonischemic leg for angiographic score and blood perfusion (assessed by laser Doppler perfusion imaging) ratios, respectively (P<0.01). Conversely, no significant changes were observed in Ang II-treated mice deficient in gene encoding for eNOS. Subhypertensive dose of Ang II enhanced angiogenesis associated with tissue ischemia through angiotensin type 1 receptor activation that involved the VEGF/eNOS-dependent pathway.
Hypertension 2002 Mar 01
PMID:Endothelial nitric oxide synthase lies downstream from angiotensin II-induced angiogenesis in ischemic hindlimb. 1189 73

Gap junction channels provide the basis for the electrical syncytial properties of the heart as a communicating electrical network. Cardiac gap junction channels are predominantly composed of connexin 40 or connexin 43. The conductance of these channels (g(j)) can be regulated pharmacologically: substances which activate protein kinase C, protein kinase A or protein kinase G may alter Cx43 gap junction conductance. However, for PKC, this seems to be subtype specific. Thus, antiarrhythmic peptides can enhance g(j) via activation of PKCepsilon, while FGF-2 reduces g(j) via PKCepsilon. Lipophilic drugs can uncouple the channels. Besides an acute regulation of g(j), the expression of the cardiac connexins can also be regulated. A decrease in Cx43 with a concomitant increase in Cx40 has been found in end-stage failing hearts, while in renovascular hypertension, an increase in Cx43 has been described. Mediators like endothelin-1, angiotensin-II, TGF-beta, VEGF, and cAMP have been shown to increase Cx43. Interestingly, endothelin-1 and angiotensin-II increased Cx43 but did not affect Cx40 expression. In contrast, in humans suffering from atrial fibrillation (AF), the content in Cx40 can be enhanced while Cx43 was unaltered, although in several other studies, other changes of the cardiac connexins were found, which might be related to the type of AF. Regarding the role of calcium, the content in both Cx40 and Cx43 was decreased in cultured neonatal rat cardiomyocytes after 24 h administration of 100 nM verapamil. Thus, gap junctional channels can be affected pharmacologically either acutely by modulating gap junction conductance or chronically by altering gap junction protein expression. Interestingly, it appears that the expression of Cx43 and Cx40 can be differentially regulated.
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PMID:Pharmacological modulation and differential regulation of the cardiac gap junction proteins connexin 43 and connexin 40. 1256 16

Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF. Additionally, VEGF and PlGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia.
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PMID:Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. 1261 13

The roots of Angelica keiskei Koizumi have traditionally been used as a health food, with diuretic, laxative, analeptic and galactagogic effects. It has been thought that the roots and leaves of A. keiskei have preventive effects against coronary heart disease, hypertension and cancer. In the present study, we examined the antitumor and antimetastatic activities of various fractions isolated from a 50% ethanol extract of A. keiskei roots. The ethyl acetate-soluble fraction of the 50% ethanol extract inhibited tumor growth in LLC-bearing mice at a daily dose of 100 mg/kg prolonged survival time and inhibited metastasis to the lung after surgical removal of primary tumors. Two active substances were isolated from fractions 1 and 2: compound 1 was identified as xanthoangelol based on the data of the (1)H- and (13)C-NMR spectra. Xanthoangelol inhibited tumor growth in LLC-bearing mice as well as lung metastasis and prolonged survival time in carcinectomized mice at a daily dose of 50 mg per kg. Furthermore, xanthoangelol (50 or 100 mg per kg daily) inhibited liver metastasis and the growth of metastasized tumor cells in the livers of mice with intrasplenically implanted LLC. Xanthoangelol inhibited DNA synthesis in LLC cells at concentrations of 10 and 100 microM, but it had no effect on DNA synthesis in HUVECs or on the adherence of LLC cells to HUVECs. Xanthoangelol inhibited tumor-induced neovascularization (in vivo) at doses of 10 and 20 mg per kg, and it inhibited the Matrigel-induced formation of capillary-like tubes by HUVECs at concentrations of 1-100 microM. Furthermore, xanthoangelol inhibited the binding of VEGF to HUVECs at concentrations of 1-100 microM. These results indicate that the antitumor and/or antimetastatic activities of xanthoangelol may be due to inhibition of DNA synthesis in LLC cells and of tumor-induced neovascularization through inhibition of the formation of capillary-like tubes by vascular endothelial cells and inhibition of the binding of VEGF to vascular endothelial cells.
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PMID:Antitumor and antimetastatic activities of Angelica keiskei roots, part 1: Isolation of an active substance, xanthoangelol. 1284 85


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