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

A rat aortic explant culture system was developed for the investigation of the effects of hydrocortisone (HC) and the glucocorticoid antagonist, RU486, on prostacyclin (PGI2 synthesis. HC, but not aldosterone, progesterone, 17 beta-estradiol, or testosterone, inhibited spontaneous, epinephrine-stimulated and U46619 (an analog of thromboxane A2)-stimulated PGI2 synthesis by cultured aortic explants in a concentration- and time-dependent manner. Adequate inhibition of aortic explant PGI2 synthesis by physiological concentrations of HC was achieved after an 18-h culture. An 18-h time course was employed in subsequent experiments. In contrast, HC had no effect on arachidonic acid-stimulated PGI2 synthesis. Protein synthesis inhibitors, actinomycin D and cycloheximide, had no effect on the inhibitory action of HC on epinephrine- and U46619-induced release of PGI2. They exerted a direct inhibitory effect on aortic PGI2 synthesis. Arachidonic acid stimulated PGI2 release by the explants and was unaffected either by HC or by treatment with cycloheximide or actinomycin D. RU486 blocked the inhibitory action of HC on aortic PGI2 synthesis in a dose-dependent manner. Thus, the inhibitory effect of HC on vascular PGI2 synthesis is probably mediated through an inhibition of phospholipase A2 and not cyclooxygenase or other PGI2 synthase systems; furthermore, this inhibitory effect is not dependent upon de novo protein synthesis. RU486 antagonizes the inhibitory effect of HC. The inhibition of vascular PGI2 by hydrocortisone has implications in the pathogenesis of steroid-related hypertension and atherosclerosis and the antiinflammatory effect of steroids.
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PMID:Inhibition by hydrocortisone of prostacyclin synthesis by rat aorta and its reversal with RU486. 308 61

The fatty acid pattern of serum triglycerides and cholesterol esters has been estimated in spontaneously hypertensive rats (SHR) and normotensive Wistar rats (WR) at 4, 5, 6, 7, and 8 weeks of age. The percentage of linoleic acid (LA) was lower in SHR when compared with WR, but increased with age in both strains. Arachidonic acid (AA) showed an abrupt fall in SHR and WR at 5 weeks of age in comparison to 4 week old rats. The fall was more pronounced in serum triglycerides of the former and in cholesterol esters of the latter. The changes in AA occurred prior to the onset of hypertension in SHR. From the data it can be concluded that the formation of AA from LA might be dependent on age being quantitatively different in SHR and WR. Furthermore, eicosapentaenoic acid (EPA) appeared lower in SHR than in age-related WR. Docosapentaenoic and docosahexaenoic acids also revealed a marked decrease in rats between 4 and 5 weeks of age indicating that individual polyunsaturated fatty acids (PUFA) change in a different manner which might be relevant to the development of high blood pressure in SHR.
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PMID:Changes of polyunsaturated fatty acids in serum lipids of spontaneously hypertensive rats during the onset of high blood pressure. 632 4

Arachidonic acid (AA)-induced pressor response and production of thromboxane YXB2, the stable metabolite of TXA2, prostaglandin (PG)-like substance (PLS) and 6-keto-PGF1 alpha the stable metabolite of prostacyclin (PGIs), were studied using isolated, perfused kidneys of 6- and 18-week old spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY), two-kidney, one clip hypertensive rats (RHR) and DOCA/salt hypertensive rats (DOCA/salt HR). The AA-induced pressor response and release of TXB2 were highest in the 6-week old SHR, whereas, the release of PLS and 6-keto-PGF 1 alpha was marked in the 18-wek old SHR and the established hypertensive stages of both RHR and DOCA/salt HR. In the kidneys of SHR and WKy, exogenous TXA2 induced a severe vasoconstriction and there was a positive correlation between the AA-induced pressor response and the release of TXB2 or PLS. Thus, the initiation of hypertension in SHR may follow an accelerated synthesis of TXA2 against PGI2 in response to stimuli which induce a release of AA.
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PMID:Enhanced thromboxane A2 biosynthesis in the kidney of spontaneously hypertensive rats during development of hypertension. 722 52

This study was designed to examine the impairment of endothelium-dependent relaxation in spontaneously hypertensive rats (SHR), to determine whether endothelial cell function is normalized by in vivo treatment with a thromboxane A2-prostaglandin endoperoxide (TP)-receptor blocker, and to establish whether endothelial dysfunction contributes to the elevated blood pressure. In isolated aortic rings from SHR, endothelium-dependent relaxations caused by acetylcholine, adenosine diphosphate, and alpha-thrombin were markedly impaired compared with those from Wistar-Kyoto (WKY) normotensive rats. Arachidonic acid-induced contractions were significantly enhanced in aorta from SHR. In contrast, relaxations caused by direct smooth muscle vasodilators, nitroprusside and cromakalim, and contractions caused by U-46619 were not different between SHR and WKY rats. Treatment of SHR with the oral TP-receptor antagonist, ifetroban, at 20 and 50 mg.kg-1.day-1 fully restored endothelium-dependent relaxation toward normal. However, ifetroban produced no effect on blood pressure in SHR. In vitro incubation of aortic rings from SHR with ifetroban also normalized relaxations to acetylcholine but had no effect in aorta from WKY. In contrast, the thromboxane A synthase inhibitor, dazoxiben, only partially improved abnormal acetylcholine-induced relaxations in aorta from SHR. The results demonstrate that endothelial cell dysfunction in hypertension can be restored to normal by selective TP-receptor blockade. Furthermore, endothelial cell dysfunction and TP-receptor activation may not significantly contribute to elevated systemic blood pressure in SHR.
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PMID:Dissociation of endothelial cell dysfunction and blood pressure in SHR. 763 48

Alterations in vascular tone are well documented in hypercholesterolemia, yet little is known about the role of dietary cholesterol in endothelium-dependent contractions of pulmonary arteries. Methacholine and arachidonic acid cause endothelium-dependent contractions in normal rabbit pulmonary artery that are mediated by thromboxane A2. We tested the effect of these agonists on pulmonary arteries from rabbits fed standard rabbit chow or chow supplemented with 2% cholesterol for 2 weeks. Arachidonic acid-induced contractions did not differ in the groups. However, methacholine-induced contractions were significantly depressed in cholesterol-fed rabbits. Vascular thromboxane A2 production was similar in normal and cholesterol-fed rabbits. Pretreatment with the nitric oxide synthase inhibitor nitro-L-arginine had no effect on contractions observed with methacholine in normal rabbits but enhanced methacholine-induced contractions in cholesterol-fed rabbits. In norepinephrine-precontracted vessels, methacholine caused a small relaxation response in normal rabbits. In contrast, in cholesterol-fed rabbits, methacholine produced enhanced relaxations, suggesting that cholesterol feeding augments relaxations and decreases contractions by increasing nitric oxide. However, nitric oxide synthase activity in pulmonary arteries from cholesterol-fed and normal rabbits was not different between the two groups. In an additional experiment, the calcium-dependent potassium channel blocker charybdotoxin had little effect on methacholine-induced contractions in cholesterol-fed rabbits. In summary, the present study demonstrates that hypercholesterolemia alters pulmonary artery vascular contractions and relaxations to methacholine. This effect is not mediated by a decreased production of thromboxane A2 or by an increased production of nitric oxide. Although the mechanisms mediating the altered vascular responses is still unknown, the results from this study clearly indicate that the regulation of vascular tone is different in normal and hypercholesterolemic vessels.
Hypertension 1996 Mar
PMID:Reduced pulmonary artery vasoconstriction in methacholine in cholesterol-fed rabbits. 861 44

Arachidonic acid metabolism through the cytochrome P450-dependent monooxygenase system has been the subject of considerable research interest over the last several years. This article reviews the biological actions of the metabolites generated through this pathway and explores their role in the regulation of renal function and systemic blood pressure. Arachidonic acid is metabolized by the cytochrome P450-dependent monooxygenase system in three ways: epoxidation, resulting in the formation of 5,6-, 8,9-, 11,12-, 14,15-epoxyeicosatrienoic acids; allylic oxidation, resulting in the formation of 5,8,9,11,12,15-hydroxyeicosatetraenoic acids (HETE); and hydroxylation, resulting in the formation of 19,20-HETEs and 20-carboxyl arachidonic acid. Elements of this pathway have been localized in the kidney and several extrarenal sites. Vasodilation, vasoconstriction, inhibition of Na+,K+-ATPase, inhibition of ion transport and modulation of cell growth have been some of the diverse physiological actions demonstrated by metabolites produced by this pathway. As a physiological correlate of these properties, considerable evidence has accumulated regarding the role of the cytochrome P450-dependent metabolites of arachidonic acid in the pathogenesis of hypertension in the spontaneously hypertensive rat. Data in humans are limited, but in small studies increased production of these metabolites has been shown in hypertensive persons. In summary, several properties of products of this "third" pathway of arachidonic acid metabolism suggest a role in cardiovascular and renal function. Additional studies are needed to precisely define the role of this pathway in human hypertension.
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PMID:The role of the cytochrome P450-dependent metabolites of arachidonic acid in blood pressure regulation and renal function: a review. 905 95

Arachidonic acid- and methacholine-induced contractions of rabbit pulmonary arteries are mediated by thromboxane (TX) A2. Although removal of the endothelium abolishes the contractions, endothelial cells isolated from pulmonary arteries do not synthesize TXA2. Further studies described here showed that the expression of TX synthase was evident in platelets and intact pulmonary artery but not in endothelial cells. These studies examined the role of platelet TXA2 production in the vasoconstrictor response to methacholine. Endothelial cells were incubated with platelets in the presence or absence of methacholine. Methacholine caused an increase in TXB2 production. Pretreatment of endothelial cells with aspirin (100 micromol/L) before the addition of platelets did not impair the ability of methacholine to increase TXB2 synthesis. Conversely, if platelets were pretreated with aspirin, methacholine failed to stimulate TXB2. Using endothelial cells with their cellular lipids labeled with [3H]arachidonic acid, methacholine did not stimulate the production of [3H]TXB2. When the endothelial cells were incubated with methacholine and control platelets, [3H]TXB2 was detected. If aspirin-treated platelets were incubated with endothelial cells, methacholine did not increase the production of [3H]TXB2. However, pretreatment of the endothelial cells with aspirin did not affect the ability of methacholine to induce [3H]TXB2 release. This suggests that methacholine stimulated the endothelial cell to release arachidonic acid, which was transferred to the platelets and metabolized to TXA2. To test whether this cell-cell interaction is necessary for methacholine-induced contractions, rabbits were administered aspirin (20 mg/kg) for 2 days. On day 4, methacholine-induced contractions of pulmonary arteries were depressed in aspirin-treated compared with control subjects. Control arteries synthesized 6-keto-prostaglandin F1alpha and TXB2. Aspirin treatment inhibited both pulmonary artery and platelet TXB2 production but had no effect on vessel 6-keto-prostaglandin F1alpha. These studies implicate platelets as a vascular source of TXA2 and indicate that both endothelial cells and platelets may be required for methacholine-induced TXA2 synthesis and vasoconstriction.
Hypertension 1998 Jan
PMID:Methacholine-induced contraction of rabbit pulmonary artery: role of platelet-endothelial transcellular thromboxane synthesis. 945 4

Arachidonic acid metabolites contribute to the endothelin-1 (ET-1)-induced decrease in renal blood flow, but the vascular sites of action are unknown. Experiments performed in vitro used the rat juxtamedullary nephron preparation combined with videomicroscopy. The response of afferent arterioles to ET-1 was determined before and after cytochrome P450 (CYP450) or cyclooxygenase (COX) inhibition. Afferent arteriolar diameter averaged 20+/-1 microm (n=17) at a renal perfusion pressure of 100 mm Hg. Superfusion with 0.001 to 10 nmol/L ET-1 caused a graded decrease in diameter of the afferent arteriole. Vessel diameter decreased by 30+/-2% and 41+/-2% in response to 1 and 10 nmol/L ET-1, respectively. The afferent arteriolar response to ET-1 was significantly attenuated during administration of the CYP450 hydroxylase inhibitor N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), such that afferent arteriolar diameter decreased by 19+/-3% and 22+/-3% in response to 1 and 10 nmol/L ET-1, respectively. COX inhibition also greatly attenuated the vasoconstriction elicited by ET-1, whereas the CYP450 epoxygenase inhibitor N-methylsulfonyl-6-(2-proparglyoxyphenyl) hexanamide enhanced the ET-1-mediated vascular response. Additional studies were performed using freshly isolated smooth muscle cells prepared from preglomerular microvessels. Renal microvascular smooth muscle cells were loaded with the calcium-sensitive dye fura 2 and studied by use of single-cell fluorescence microscopy. Basal renal microvascular smooth muscle cell [Ca(2+)](i) averaged 95+/-3 nmol/L (n=42). ET-1 (10 nmol/L) increased microvascular smooth muscle cell [Ca(2+)](i) to a peak value of 731+/-75 nmol/L before stabilizing at 136+/-8 nmol/L. Administration of DDMS or the COX inhibitor indomethacin significantly attenuated the renal microvascular smooth muscle cell calcium response to ET-1. These data demonstrate that CYP450 hydroxylase and COX arachidonic acid metabolites contribute importantly to the afferent arteriolar diameter and renal microvascular smooth muscle cell calcium responses elicited by ET-1.
Hypertension 2000 Jan
PMID:Cytochrome P450 and cyclooxygenase metabolites contribute to the endothelin-1 afferent arteriolar vasoconstrictor and calcium responses. 1064 16

The nitric oxide-mediated portion of shear stress-induced dilation of rat gracilis muscle arterioles was shown to be impaired in spontaneously hypertensive rats (SHR). Because shear stress-induced dilation is primarily mediated by endothelium-derived prostaglandins in rat cremasteric arterioles, we hypothesized that in the cremasteric vascular bed the mediation of shear stress-induced dilation by prostaglandins is altered in hypertension. At a constant intraluminal pressure of 80 mm Hg, the active diameters of isolated rat cremasteric arterioles of normotensive 30-week-old Wistar-Kyoto rats (WKY) and SHR were 58.0+/-3.1 and 51.7+/-3.6 microm, respectively, whereas their passive diameters were 109.4+/-4.4 and 101.9+/-6.7 microm, respectively. Dilations to increases in shear stress elicited by increases in intraluminal flow (from 0 to 25 microL/min) were significantly less (P<0.05) in cremasteric arterioles isolated from SHR than from WKY. Arachidonic acid (10(-5) mol/L) elicited constrictions in SHR arterioles but dilations in WKY arterioles. The prostaglandin H(2)/thromboxane A(2) (PGH(2)/TxA(2)) receptor antagonist SQ 29,548 (10(-6) mol/L) significantly increased basal diameter by 11% and normalized the attenuated shear stress-induced dilation in SHR, whereas it did not affect basal diameter and arteriolar responses of WKY. Furegrelate, a specific inhibitor of TxA(2) synthase, did not affect the response in SHR. Also, SQ 29,548 reversed the arachidonic acid-induced constriction to dilation in SHR arterioles, whereas it did not affect the dilator response in WKY arterioles. Constrictions of arterioles of WKY and SHR to U46,619 (a PGH(2)/TxA(2) receptor agonist) were not different. These results demonstrate that in cremasteric arterioles of hypertensive rats, shear stress elicits an enhanced release of PGH(2), resulting in a reduced shear stress-dependent dilation. Thus, augmented hemodynamic forces can alter the shear stress-induced synthesis of prostaglandins, which may contribute to the elevated vascular resistance in hypertension.
Hypertension 2000 Apr
PMID:Shear stress-induced release of prostaglandin H(2) in arterioles of hypertensive rats. 1077 63

Angiotensin I-converting enzyme (ACE, kininase II) has 2 active domains (N and C) in a single peptide chain. Because we found its N-domain more stable than its C-domain, we investigated the effect of the amino-terminus of human ACE on the C-domain with a molecular construct expressed in Chinese hamster ovary cells (CHO) cells and transiently in HEK293 cells. This active N-deleted ACE contained only the first 141 amino acids of the human N-domain but not its active center and was linked to the active C-domain containing the transmembrane and cytosolic portions of ACE. The CHO cells were also transfected with human B(2) bradykinin receptor. ACE inhibitors (5 nmol/L or 1 micromol/L) augmented bradykinin (100 nmol/L) effects, elevated B(2) receptor numbers, and resensitized the receptor desensitized by agonist as measured by arachidonic acid release or [Ca(2+)](i) mobilization. Arachidonic acid release was mediated by pertussis toxin-sensitive G alpha(i), and [Ca(2+)](i) mobilization was mediated by pertussis-insensitive G alpha(q) protein receptor complex. The properties of the construct were compared with wild-type ACE and separate N- and C-domains. The N-deleted ACE differed from wild-type in activation by Cl(-) and [SO(4)](2-) ions, hydrolysis ratios of substrates (both short synthetic and endogenous peptides) and heat stability. Thus, the N-terminal peptide of ACE affected the characteristics of the C-domain active center. ACE inhibitors acting on N-deleted ACE, which had only a single C-domain active center anchored to plasma membrane, induced cross-talk between the enzyme and the B(2) receptor (eg, the inhibitors resensitized the receptor) independent of blocking bradykinin inactivation.
Hypertension 2000 Jul
PMID:Effects of the N-terminal sequence of ACE on the properties of its C-domain. 1090 22


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