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)

2-Hydroxylation is one of the major metabolic pathways of estrogens and is believed to be catalyzed by a form of cytochrome P450. Recently it has been reported that estrogen 2-hydroxylase activity in human placenta is catalyzed by aromatase. Some investigators suggested the effect of catechol estrogen on human placental steroidogenesis which may be related to pregnancy-induced hypertension (PIH) through the inhibition of catechol-O-methyltransferase (COMT) activity. In order to better understand the interrelationship between placental aromatase and estrogen 2-hydroxylase activities in PIH patients, both activities were evaluated in the PIH placentas. Human placental microsomes obtained from PIH patients were incubated with [1 beta-3H]androstenedione or [2-3H]estradiol in the presence of NADPH. Aromatase and estrogen 2-hydroxylase activities were assessed by the tritium water method. The immunosuppression patterns of both activities due to monoclonal antiaromatase cytochrome P450 antibody (MAb3-2C2) were studied. Estrogen 2-hydroxylase activity was significantly higher in PIH placentas (4.7 +/- 0.9 pmol/min/mg protein, n = 7) than in normal placentas (3.0 +/- 0.7 pmol/min/mg protein, n = 7). When the PIH placental microsomes were subjected to immunosuppression by 1 to 100 micrograms IgG of MAb3-2C2, estrogen 2-hydroxylase activity was suppressed by 94 to 65% whereas aromatase activity was strongly suppressed by 72 to 17%, respectively. From our results of high estrogen 2-hydroxylase activity in PIH placentas, it is assumed that there is a different estrogen catalyzing mechanism in PIH placentas.
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PMID:Aromatase and estrogen 2-hydroxylase activities of human placental microsomes in pregnancy-induced hypertension. 893 May 23

As a participant of the endogenous arachidonic acid metabolic cascade, microsomal cytochrome P450 metabolizes the fatty acid to biologically active hydroxyeicosatetraenoic and epoxyeicosatrienoic acids. Studies from several laboratories have documented the powerful vasoactive properties of these P450-derived eicosanoids. Associated changes in cell membrane ion permeability and fluxes may provide the molecular basis underlining their vasoactivity. Furthermore, a role for the P450 arachidonic acid monooxygenase in renal physiology and pathophysiology has been suggested by: 1) an association between the activities of the arachidonic acid omega/omega-1 oxygenase and the development of hypertension in spontaneously hypertensive rats, and 2) a relationship between acquired or inherited abnormalities in the renal epoxygenase activities and/or regulation and salt-sensitive hypertension in Dahl rats. These studies provide significant evidence to indicate that microsomal P450, in addition to its recognized traditional toxicological and pharmacological roles, may also play an important physiological role in the control of tissue and body homeostasis.
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PMID:Cytochrome P450, the arachidonic acid cascade, and hypertension: new vistas for an old enzyme system. 894 Feb 91

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

Increased relaxant response to acetylcholine during pregnancy is proposed to be due to an estrogen-mediated increase in nitric oxide release. We studied acetylcholine-induced pathways of relaxation in the thoracic and abdominal aortic rings from pregnant and nonpregnant Wistar-Kyoto rats and measured basal and stimulated release of nitrites in these vessels. Endothelium-dependent relaxation was significantly greater in pregnant than in nonpregnant rats. Acetylcholine provoked a concentration-dependent relaxation on thoracic and abdominal aortic rings from nonpregnant and pregnant rats. After N118-nitro-L-arginine methyl ester pretreatment, the relaxation was significantly inhibited in the two preparations of nonpregnant and pregnant rodents. The relaxation was not inhibited by indomethacin in any of the aortic segments from pregnant and nonpregnant rats. After cytochrome P450 arachidonic acid metabolism inhibitor clotrimazole, a nonsignificant decrease in the Emax to acetylcholine-induced relaxation was observed in the thoracic segments of pregnant and nonpregnant rats. On the other hand, in abdominal aorta, clotrimazole decreased maximal relaxation in rings from pregnant rats (P<.05) but did not change the acetylcholine-induced relaxation from nonpregnant rats. Our results show an increase in the acetylcholine-stimulated release of nitrites in thoracic aortic rings from pregnant rats compared with rings from nonpregnant rats, which cannot be evidenced in abdominal aortic rings. These results suggest that acetylcholine-induced vasodilation in the abdominal segment from pregnant rats is mediated only in part by nitric oxide, the remainder apparently due to an endothelium-derived vasodilator, cytochrome P450-dependent, which may be endothelium-derived hyperpolarizing factor/epoxyeicosatrienoic acid.
Hypertension 1997 Sep
PMID:Possible involvement of endothelium-derived hyperpolarizing factor in vascular responses of abdominal aorta from pregnant rats. 932 88

The present study tested two hypotheses: (1) that a receptor for extracellular Ca2+ (Ca2+ receptor [CaR]) is located in the perivascular sensory nerve system and (2) that activation of this receptor by physiological concentrations of extracellular Ca2+ results in the release of vasodilator substance that mediates Ca2+-induced relaxation. Reverse transcription-polymerase chain reaction using primers derived from rat kidney CaR cDNA sequence showed that mRNA encoding a CaR is present in dorsal root ganglia but not the mesenteric resistance artery. Western blot analysis using monoclonal anti-CaR showed that a 140-kD protein that comigrates with the parathyroid CaR is present in both the dorsal root ganglia and intact mesenteric resistance artery. Immunocytochemical analysis of whole mount preparations of mesenteric resistance arteries showed that the anti-CaR-stained perivascular nerves restricted to the adventitial layer. Biophysical analysis of mesenteric resistance arteries showed that cumulatively raising Ca2+ from 1 to 1.25 mol/L and above relaxes precontracted arteries with an ED50 value of 2.47+/-0.17 mmol/L (n=12). The relaxation is endothelium independent and is unaffected by blockade of nitric oxide synthase but is completely antagonized by acute and subacute phenolic destruction of perivascular nerves. A bioassay showed further that superfusion of Ca2+ across the adventitial surface of resistance arteries releases a diffusible vasodilator substance. Pharmacological analysis indicates that the relaxing substance is not a common sensory nerve peptide transmitter but is a phospholipase A2/cytochrome P450-derived hyperpolarizing factor that we have classified as nerve-derived hyperpolarizing factor. These data demonstrate that a CaR is expressed in the perivascular nerve network, show that raising Ca2+ from 1 to 1.25 mol/L and above causes nerve-dependent relaxation of resistance arteries, and suggest that activation of the CaR induces the release of a diffusible hyperpolarizing vasodilator. We propose that this system could serve as a molecular link between whole-animal Ca2+ balance and arterial tone.
Hypertension 1997 Dec
PMID:Perivascular sensory nerve Ca2+ receptor and Ca2+-induced relaxation of isolated arteries. 940 64

The subcellular localization of the enzymes synthesizing endothelium-derived vasodilator autacoids has been proposed to play a role in determining the ability of endothelial cells to enhance autacoid production in response to stimulation. We therefore investigated the effects of brefeldin A-induced disruption of the Golgi apparatus and Golgi-plasma membrane trafficking on the production of nitric oxide (NO), prostacyclin, and the endothelium-derived hyperpolarizing factor (EDHF) by native and cultured endothelial cells. In porcine coronary artery segments, brefeldin A (35 micromol/L, 90 minutes) did not affect relaxations to sodium nitroprusside or the K+ channel opener cromakalim but elicited a rightward shift in the concentration-response curve to bradykinin without altering the maximum vasodilator response (Rmax). Brefeldin A failed to attenuate the bradykinin-induced, NO-mediated relaxation under depolarizing conditions but inhibited the bradykinin response under conditions of combined cyclooxygenase/NO synthase blockade, suggesting that this agent selectively interferes with the production of EDHF. Indeed, incubation of porcine coronary arteries with brefeldin A, which did not affect the bradykinin-induced accumulation of either cyclic GMP or 6-keto-prostaglandin F1alpha, markedly and reversibly attenuated the EDHF-mediated hyperpolarization of detector smooth muscle cells in a patch-clamp bioassay system. The microtubule destabilizer nocodazole also affected both the EC50 and Rmax to bradykinin in porcine coronary arteries. Since EDHF is thought to be a cytochrome P450-derived metabolite of arachidonic acid and both brefeldin A and nocodazole are known to interfere with the targeting of cytochrome P450 from the Golgi apparatus to the plasma membrane, it is conceivable that brefeldin A inhibits EDHF formation by preventing the targeting of the EDHF-synthesizing enzymes to the plasma membrane.
Hypertension 1997 Dec
PMID:Endothelium-derived hyperpolarizing factor, but not nitric oxide, is reversibly inhibited by brefeldin A. 940 89

Neutrophils respond to ischemic injury by infiltrating the myocardium via the vascular wall. During this process, neutrophils are activated and release inflammatory mediators. Some of these mediators are metabolites of arachidonic acid. We have reported that neutrophils metabolize arachidonic acid to 20-HETE, a cytochrome P450 metabolite. We investigated the effects of 20-HETE on coronary vascular tone by examining 20-HETE-induced changes in isometric tension in bovine coronary artery rings precontracted with the thromboxane-mimetic, U46619. 20-HETE relaxed precontracted coronary rings in a concentration-dependent manner (EC50 of 3 x 10(-7) mol/L). Pretreatment with indomethacin, a cyclooxygenase inhibitor, shifted the concentration-response curve to the right (EC50 of 1 x 10(-6) mol/L); maximal relaxations were not affected. This suggested that 20-HETE-induced relaxations were, in part, dependent on the cyclooxygenase pathway. Relaxations to 20-HETE were not significantly changed in endothelium-denuded rings. To determine whether metabolism of 20-HETE to a vasoactive compound might explain the relaxations caused by 20-HETE, rings of coronary artery were incubated with [3H] 20-HETE. The incubation buffer was extracted and the [3H] products resolved on reverse-phase HPLC. Both denuded and intact arteries failed to metabolize [3H] 20-HETE. To investigate whether 20-HETE-induced relaxations were related to release of prostacyclin, we measured the release of 6-keto PGF1alpha, the stable metabolite of prostacyclin, from bovine coronary arteries. 20-HETE (1 x 10(-6) mol/L) stimulated an increase in 6-keto PGF1alpha in intact vessels (908 +/- 138 pg/mL versus 1402 +/- 157 pg/mL, basal versus stimulated). Thus, 20-HETE-induced relaxations are due, in part, to the stimulation of the release of the dilatory prostanoid, prostacyclin.
Hypertension 1998 Jan
PMID:20-HETE relaxes bovine coronary arteries through the release of prostacyclin. 945 9

Hypertension has been linked to an impaired dilator function of the coronary microvascular endothelium in vivo. However, the profile and mechanism of this dysfunction remain obscure. Thus, this study compared diameter responses to acetylcholine (ACH), bradykinin (BKN), and substance P (SP) between coronary microvessels (i.d.=106+/-4 microm) dissected from left ventricles of normotensive and hypertensive Dahl rats (Dahl-NT and Dahl-HT, respectively). Vessels were cannulated and pressurized on glass pipettes at 80 mm Hg, and internal diameters were monitored by videomicroscopy. Coronary microvessels from Dahl-NT and Dahl-HT showed similar dilator responses to ACH (100 pmol/L to 10 micromol/L), with maximal diameter increases of 63+/-5 microm and 63+/-7 microm, respectively (n=31,17). However, only vessels from Dahl-NT showed dilator responses to SP (10 fmol/L to 1 nmol/L) and BKN (100 fmol/L to 10 nmol/L). All dilator responses persisted after N-nitro-L-arginine (10 micromol/L) or indomethacin (10 micromol/L), but were blunted after inhibition of cytochrome P450 by 10 micromol/L octadecynoic acid (n=6-8). These results suggest that: (1) coronary microvessels from Dahl-HT show a unique pattern of endothelial impairment, whereby ACH-induced relaxations persist at a time when dilator responses to SP and BKN are severely blunted, and (2) a cytochrome P450 product, rather than nitric oxide or prostacyclin, may partly mediate the vasodilator responses to ACH, SP and BKN.
Hypertension 1998 Jan
PMID:Distinct endothelial impairment in coronary microvessels from hypertensive Dahl rats. 945 24

Recently, we reported that primary cultures of inner medullary collecting duct cells from Dahl salt-sensitive (S) rats absorb more Na+ than do cells cultured from Dahl salt-resistant (R) rats. To begin to evaluate the molecular basis for this difference, we selected four candidate gene products that on the basis of their physiology and genetics could participate in regulation of Na+ transport by these cells. During 24-hour exposure, inhibitors of the cytochrome P450 enzymes had no effect on Na+ transport by either S or R monolayers. Twenty-four-hour exposure to NG-monomethyl-L-arginine (0.5 mmol/L), a nonspecific inhibitor of NO synthase, also had no effect on Na+ transport by either S or R monolayers. Neither atrial natriuretic peptide 1-28 (100 nmol/L) nor 8-Br-cyclic GMP (100 micromol/L) had any short-term effect on Na+ transport by either S or R monolayers. 18-Hydroxy-11-deoxycorticosterone (100 nmol/L), an adrenocorticoid hormone that is produced in greater amounts in S rats, stimulated Na+ transport by both S and R monolayers via the mineralocorticoid receptor; however, its effect was less potent than aldosterone. Congenic rats in which the R isoform of the 11beta-hydroxylase gene was bred onto the S background had monolayers that transported Na+ at a rate similar to the S rats. These results demonstrate that neither cytochrome P450 genes, NO synthase genes, the atrial natriuretic peptide receptor gene, nor the 11beta-hydroxylase gene is a likely candidate to explain the difference in Na+ transport between S and R inner medullary collecting duct monolayers in primary culture.
Hypertension 1998 Feb
PMID:Candidate genes in the regulation of Na+ transport by inner medullary collecting duct cells from Dahl rats. 946 Dec 29

There is now overwhelming evidence for factors, other than nitric oxide (NO), that mediate endothelium-dependent vasodilation by hyperpolarizing the underlying smooth muscle via activation of Ca2+-activated K+ channels. Although the identity of endothelium-derived hyperpolarizing factor (EDHF) remains to be established, cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA), namely, the epoxides, fulfill several of the criteria required for consideration as putative mediators of endothelium-dependent hyperpolarization. They are produced by the endothelium, released in response to vasoactive hormones, and elicit vasorelaxation via stimulation of Ca2+-activated K+ channels. Our studies in the rat indicate that, of the epoxides, 5,6-epoxyeicosatrienoic acid (5,6-EET) is the most likely mediator of NO-independent, but CYP-dependent coronary vasodilation in response to bradykinin. Studies in the rat kidney, however, support the existence of additional EDHFs as acetylcholine also exhibits NO-independent vasodilation that is unaffected by CYP inhibitors in concentrations that attenuate responses to bradykinin. In some blood vessels, NO may tonically suppress the expression of CYP-dependent EDHF. In the event of impaired NO synthesis, therefore, a CYP-dependent vasodilator mechanism may serve as a backup to a primary NO-dependent mechanism, although they may act in concert. In other vessels, particularly microvessels, an EDHF may constitute the major vasodilator mechanism for hormones and other physiological stimuli. EDHFs appear to be important regulators of vascular tone; alterations in this system can be demonstrated in hypertension and diabetes, conditions associated with altered endothelium-dependent vasodilator responsiveness.
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PMID:Hyperpolarizing factors. 946 48


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