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

The effects of endothelin-1 (ET-1) on the cardiovascular and bronchial systems were examined in a heart/lung preparation of guinea pig. The role of arachidonic acid metabolites through cyclo-oxygease (COX) and lipoxygenase (LOX) pathways was investigated. Bolus injection of ET-1 (25-400 ng) caused dose-related bronchoconstriction, pulmonary vascular hypertension, and cardiac output reduction. When indomethacin (30 microM) or the thromboxane receptor antagonist Bay u 3405 (1 microM) were added to the perfusing blood, the cardiopulmonary effects of ET-1 were almost completely abolished. Conversely, the presence of the LOX inhibitor Bay x 1005 (10 microM) did not affect the ET-1 produced actions. We concluded that ET-1 exerts both bronchial and pulmonary vascular effects through an indirect mechanism. COX products, most likely thromboxane A2 but not arachidonic acid metabolites via the LOX pathway, make the major contribution to the bronchoconstrictor and pulmonary vascular hypertensive effects of ET-1.
 ...
PMID:Cardiopulmonary effects of endothelin-1 in the guinea pig: role of thromboxane A2. 858 37

Previous studies reported sex differences in production of endothelium-derived substances and suggested that these compounds may be involved in regulation of vascular tone under both normal and pathological conditions. The present study was designed to compare the effects of endothelium-dependent contractions in pulmonary artery vessels obtained from male and female rabbits. Rings of intrapulmonary arteries were suspended under isometric tension in oxygenated Krebs' buffer. In male rabbit pulmonary artery, arachidonic acid and methacholine elicited endothelium-dependent, concentration-related contractions (maximal contraction, 79 +/- 4% and 54 +/- 4% of the KCl contractions, respectively). In contrast, endothelium-dependent arachidonic acid- and methacholine-induced contractions were greater in female pulmonary arteries (maximal response, 113 +/- 7% and 101 +/- 6% of the KCl contractions, respectively). There was no difference in KCl-induced contractions in female and male pulmonary arteries (1.2 +/- 0.1 versus 1.3 +/- 0.1 g, respectively). In male rabbits, the vasoconstrictor responses to arachidonic acid and methacholine were inhibited by the cyclooxygenase inhibitor indomethacin. We have previously identified thromboxane A2 as the endothelium-dependent contracting factor in male rabbits. However, indomethacin only partially inhibited arachidonic acid-induced contractions in female pulmonary arteries (maximal inhibition, 46% of the control response) suggesting that a noncyclooxygenase metabolite of arachidonic acid mediates contraction in female rabbits. Likewise, indomethacin only partially inhibited methacholine-induced contractions of female pulmonary arteries. The combined cyclooxygenase/lipoxygenase inhibitor BW 755C and the lipoxygenase inhibitor nordihydroguaiaretic acid completely blocked arachidonic acid-induced contractions in females. Furthermore, both basal and stimulated production of thromboxane B2, as measured by radioimmunoassay, were similar in female and male pulmonary arteries. When segments of pulmonary arteries obtained from female and male rabbits were incubated with 14C-arachidonic acid and the extracted metabolites were resolved by reverse-phase high-performance liquid chromatography, there was an enhanced production of metabolites in females. Pretreatment with indomethacin attenuated metabolism of all products in the males but enhanced production of some compounds in vessels from the females. These observations suggest that the enhanced vasoconstrictor response to arachidonic acid in female pulmonary arteries is due to a lipoxygenase metabolite of arachidonic acid.
Hypertension 1996 Jan
PMID:Role of endothelium-derived metabolites of arachidonic acid in enhanced pulmonary artery contractions in female rabbits. 859 86

We have previously reported that the nonselective lipoxygenase inhibitor phenidone is a potent hypotensive agent in the spontaneously hypertensive rat (SHR). In the present study, we examined the relationship between production of platelet 12-hydroxyeicosatetraenoic acid (12-HETE) and intra-arterial blood pressure in SHR and Wistar-Kyoto rats (WKY) using both a cross-sectional analysis and an acute pharmacological intervention. Basal generation rate of 12-HETE by platelets collected from the SHR was approximately 3.7-fold higher than in the WKY (0.86 +/- 0.24 versus 0.23 +/- 0.05 nmol/mL per 10 minutes, respectively; P < .01). Systolic arterial pressure was positively related to platelet 12-HETE formation rate when the entire rat population was considered (r = .70, P < .001). The specific 12-lipoxygenase inhibitor cinnamyl-3,4-dihydroxycyanocinnamate induced lowering of both arterial blood pressure and platelet 12-lipoxygenase activity in SHR. At 15 mg/kg, cinnamyl-3,4-dihydroxycyanocinnamate elicited a marked hypotensive effect in SHR but not in WKY. This reduction in arterial pressure was accompanied by an approximate 70% inhibition in platelet 12-HETE production rate. The return of high blood pressure to basal levels was associated with a significant rise in the production of platelet 12-HETE toward control values (baseline, 0.97 +/- 0.33 nmol/mL per 10 minutes; nadir of blood pressure, 0.19 +/- 0.03; resumption of basal pressure, 0.42 +/- 0.14). In contrast, captopril (15 mg/kg) induced a quantitatively similar decrease in blood pressure but had no effect on platelet 12-HETE generation rate. Thus, hypertension in SHR is linked to increased production rate of platelet 12-HETE. Acute blood pressure reduction attained during lipoxygenase inhibition but not by angiotensin converting enzyme inhibition leads to a concomitant reduction in the production of platelet 12-HETE. We speculate that since rat arterial tissue produces 12-HETE, increased 12-lipoxygenase activity in SHR may contribute to the maintenance of elevated arterial pressure in this strain.
Hypertension 1996 May
PMID:Platelet lipoxygenase in spontaneously hypertensive rats. 862 Dec 9

The important role of eicosanoids in pregnancy-induced hypertension is generally accepted. Because of the lack of innervation of the uteroplacental vessels, humoral vasoactive factors are important for the regulation of vascular tone. Until now, mainly the balance of vasodilatative and vasoconstrictive prostaglandins has been studied. We were able to confirm their intrauterine imbalance in hypertensive pregnancies. In addition, the placental production of less known lipoxygenase metabolites has been analyzed in this study. Intrauterine tissues (30-100mg wet weight) were examined for their release of eicosanoids. Short term tissue cultures were performed in Hanks balanced salts solution (HBSS) at 37 degrees C in an atmosphere of 95% air/5% CO2 with and without incorporation of tritiated arachidonic acid. The arachidonate metabolites in culture media were analyzed by High Performance Liquid Chromatography (HPLC) with radioactivity detection or by enzyme immunoassays or radioimmunoassays, respectively. All intrauterine tissues released more lipoxygenase metabolites than cyclooxygenase metabolites with 12-hydroxy-eicosatetraenic acid (12-HETE) as their main metabolite. The placental release of 12-HETE was significantly decreased in hypertensive pregnancies. In hypertensive pregnancies the ratio TXB2/6-keto-PGF1 alpha synthesis was increased. Lipoxygenase metabolites, especially 12-HETE, seem to have important physiological and pathophysiological functions in the intrauterine compartment. Their biological role in this context needs further investigation.
 ...
PMID:Alterations of intrauterine eicosanoid production in pregnancy-induced hypertension: decreased production of 12-hydroxyeicosatetraenoic acid in the placenta. 871 Nov 34

Recently, heme oxygenase-1 (HO-1) has been shown to be present in vascular smooth muscle cells. In the present study, we examined the effect of angiotensin II (Ang II) on HO-1 in rat vascular smooth muscle cells. After treatment with 100 nmol/L Ang II, HO-1 mRNA levels were decreased, with a nadir at 2 hours (39+/-9% of the control level, P<.01). This downregulation was completely blocked by the Ang II type I receptor antagonist losartan. Western blot analysis showed that HO-1 protein is also significantly downregulated, with a nadir at 4 hours (52+/-6% of the control level, P<.01). Heme oxygenase activity was also significantly decreased at 4 hours (control, 0.35+/-0.86 nmol bilirubin/mg per hour; Ang II, 0.10+/-0.06). This downregulation was observed in serum-starved cells to a similar extent as in serum-supplemented cells. Inhibitors of protein kinase C, lipoxygenase, cyclooxygenase, cytochrome P450 monooxygenase, and phospholipase A2 did not block this downregulation. However, this effect was not observed in the absence of calcium and presence of EGTA (2 mmol/L). Furthermore, a 2-hour incubation with calcium ionophore or arginine vasopressin decreased HO-1 mRNA levels, suggesting that an increase of intracellular calcium mediates the downregulation. In conclusion, Ang II decreases HO-1 mRNA in a calcium-dependent manner in vascular smooth muscle cells, which may provide a novel mechanism for the modulation of vascular tone and oxidative stress.
Hypertension 1997 Mar
PMID:Heme oxygenase-1 is regulated by angiotensin II in rat vascular smooth muscle cells. 905 97

We have previously shown that the vasopressor effect of angiotensin II (Ang II) is inhibited by lipoxygenase (LO) blockers. To elucidate the specific mechanism involved, we studied the relationship between the contractile effect of Ang II and LO products in a human placental preparation. In perfused placental cotyledons, Ang II (boluses of 1 to 10 microg) increased perfusion pressure and 12-hydroxyeicosatetraenoic acid (12-HETE) release. The LO blockers phenidone and n-propyl gallate reduced the maximal Ang II-induced increment in pressure from 26+/-3 to 16+/-3 and 18+/-4 mm Hg, respectively (P<.05 for both). Ang II alone (10 microg) increased 12-HETE release from 8.9+/-3.6 to 37.6+/-0.4 ng/min, and this rise was entirely blocked by both phenidone and n-propyl gallate. Pressure increase generated by an increase in flow rate had no effect on 12-HETE formation. In deendothelialized umbilical artery segments, Ang II (10(-7) mol/L) increased 12-HETE formation by 47+/-5% (n=20). In cultured umbilical artery smooth muscle cells, Ang II increased 12-HETE formation from 48.1+/-7.2 to 75.1+/-15.3 ng/mg protein, and this effect was also blocked by the specific LO inhibitor baicalein (10(-6) mol/L). These results provide evidence that the vasopressor effect of Ang II is functionally coupled to 12-LO activation, which apparently takes place in arterial smooth muscle cells.
Hypertension 1997 Mar
PMID:Role of the lipoxygenase pathway in angiotensin II-induced vasoconstriction in the human placenta. 905 98

In recent years, the pathophysiology of renovascular hypertension has been reviewed, and the classic concept that activation of the renin-angiotensin system is solely responsible for the development and maintenance of renovascular hypertension has been challenged. In fact, experimental evidence indicates that other systems, such as the lipoxygenase pathway, may have a more critical role in the long-term maintenance of high blood pressure after renal artery stenosis. Herein we discuss the intrarenal mechanisms that control pressure-induced natriuresis under physiologic conditions and the role of the kidney in the pathophysiology of renovascular hypertension.
 ...
PMID:New insights into the pathophysiology of renovascular hypertension. 907 Feb 2

We have previously demonstrated that administration of inhibitors of the lipoxygenase (LO) pathway of arachidonic acid metabolism lowers blood pressure in hypertensive rats. In addition, we have shown that LO inhibition attenuates pressor agonist-induced vascular reactivity in vitro and calcium mobilization in cultured vascular smooth muscle cells (VSMC). To further elucidate the relationship between elevated LO activity and hypertension, 4, 8, and 12 week old hypertensive SHR were compared with age-matched Wistar-Kyoto (WKY) rats for plasma 12(S)-hydroxyeicosatetraenoic acid (12-HETE) concentration. 12-HETE levels were significantly elevated in the SHR compared to the WKY (SHR elevated by 154%, 159%, and 272% compared to WKY at 4, 8, and 12 weeks, respectively, P < .01 for all ages). There were no differences in plasma potassium levels between SHR and WKY at any of the ages tested. Plasma aldosterone levels and plasma renin activity were in the normal range at the three ages. At 12 weeks of age, both serum (4.72 +/- 0.23 v 2.18 +/- 0.33 microg/mL, P < .01), and aortic smooth muscle 12-HETE levels (0.94 +/- 0.09 v 0.66 +/- 0.08 microg/mg protein, P < .05) were elevated in SHR compared with WKY. The 12 week old SHR were given a bolus of the LO inhibitor 5,8,11-eicosatriynoic acid (ETI, 7 mg/kg, intravenously) and blood pressure measured after 20 min. ETI reduced mean systolic blood pressure from 175.8 +/- 4.2 to 141.6 +/- 5.9 mm Hg (P < .05). To investigate these effects of HETEs, cultured vascular smooth muscle cells were pretreated for 1 min with 12(S)HETE and then challenged with angiotensin II (AngII). The addition of 12(S)HETE increased AngII-induced intracellular calcium levels in normal cultured rat vascular smooth muscle cells by 78% compared to vehicle (P < .05). Thus, LO products, which are high in SHR, may contribute to vascular tone through alterations in the intracellular calcium signal by potentiating calcium responses to pressors such as Ang II.
 ...
PMID:Elevated 12-lipoxygenase activity in the spontaneously hypertensive rat. 912 2

Increasing evidence suggests that cytokines such as interleukin-1beta (IL-1), IL-4, and IL-8 may play an important role in the chronic inflammation and cellular growth observed in cardiovascular diseases. The lipoxygenase (LO) pathway of arachidonate metabolism has also been related to the pathology of hypertension and atherosclerosis. LO products have chemotactic, hypertrophic, and mitogenic effects in vascular cells, and the LO enzyme has been implicated in the oxidation of LDL. Furthermore, earlier studies have shown that vascular smooth muscle cell (VSMC) growth factors such as angiotensin II and platelet-derived growth factor can increase LO activity and expression in VSMCs. In the present study, we have examined whether vasoactive and inflammatory cytokines such as IL-1, IL-4, and IL-8 can modulate 12-LO activity and expression in porcine VSMCs and also whether they have growth-promoting effects in these cells. Treatment of porcine VSMCs with these cytokines led to significant increases in the levels of a cell-associated 12-LO product, 12-hydroxyeicosatetraenoic acid, as well as intracellular 12-LO enzyme activity. Furthermore, each of these cytokines led to a dose-dependent increase in 12-LO mRNA expression (333-base pair PCR product) as well as 12-LO protein expression (72 kD). In addition, all three interleukins could induce significant increases in VSMC DNA synthesis as well as proliferation. These results suggest that these cytokines have mitogenic effects in VSMCs and are also potent positive regulators of the 12-LO pathway. Thus, enhanced 12-LO activity and expression may be a key mechanism for cytokine-induced VSMC migration and proliferation.
Hypertension 1997 Oct
PMID:Regulation of 12-lipoxygenase by cytokines in vascular smooth muscle cells. 933 87

Many eicosanoids produced in vascular and renal structures are endowed with the ability to influence vascular and renal mechanisms of blood pressure regulation. Eicosanoids subserve both prohypertensive and antihypertensive mechanisms. The development of angiotensin-dependent hypertension in rats is accompanied by increased vascular production of thromboxane A2 (TXA2) and of lipoxygenase-derived products with the ability to inhibit prostacyclin synthase. As a result of these abnormalities, the activity of pressor mechanisms mediated by TXA2 and/or prostaglandin (PG) H2 is increased. The cancellation of TXA2- and/or of PGH2-mediated pressor mechanisms, after treatment with thromboxane synthase inhibitors or TXA2/PGH2 receptor blockers, lowers blood pressure in rats with angiotensin-dependent hypertension. Inhibitors of lipoxygenase also lower blood pressure in such animals, in part by decreasing the synthesis of lipoxygenase-derived inhibitors of prostacyclin synthase. Thus, the vasodepressor effect of these agents is accompanied by increased vascular formation of PGI2 and can be prevented by cyclooxygenase inhibitors. Cyclooxygenase-derived eicosanoids, PGE2 and PGI2, also subserve antihypertensive mechanisms in angiotensin-dependent models of hypertension. The level of blood pressure in such models of hypertension reflects, in part, the interplay among prohypertensive and antihypertensive functions subserved by cyclooxygenase- and lipoxygenase-derived eicosanoids.
Hypertension 1998 Jan
PMID:Arthur C. Corcoran Memorial Lecture. The role of eicosanoids in angiotensin-dependent hypertension. 945 2


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>