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 great discovery by Furchgott of the relaxing factor released from the endothelium (EDRF) awakened us to the necessity to reevaluate the functional importance of endothelial cells that have been chemically or physically stimulated. EDRF was first demonstrated to be released by acetylcholine, substance P, bradykinin and calcium ionophore A23187; thereafter, many substances have been found to release EDRF. This factor is quite unstable, is not produced by cyclooxygenase, and is an activator of soluble guanylate cyclase that synthesizes cyclic GMP; its action is suppressed by antioxidants via the superoxide anions produced, potentiated by superoxide dismutase and abolished by methylene blue and oxyhemoglobin. Recently, the role of lipoxygenase products in the production of EDRF was evaluated with new 5-lipoxygenase inhibitors without antioxidant activity. During the last couple of years, the actions and chemical properties of EDRF were verified to be quite similar to those of nitric oxide (NO); therefore, the hypothesis of "EDRF = NO" is widely being accepted. NO is produced from L-arginine via catalysis by an enzyme that is activated by Ca2+. The enzyme activity is inhibited by L-monomethyl arginine and other L-arginine analogs. Chemical and physical stimulations increase intracellular Ca2+ in endothelial cells that seems to be associated with K(+)-channel opening and hyperpolarization. Current interests are directed to the possible roles of NO in the regulation of nerve function. There are evidences suggesting that NO modulates adrenergic nerve function in blood vessels and some brain cell functions regulated by cellular cyclic GMP. Particularly, NO may be a transmitter substance in non-adrenergic, non-cholinergic vasodilator nerves innervating the cerebral arteries. Future investigations will determine the physiological roles of EDRF or NO and its relationships to pathophysiology of vascular dysfunctions, such as vasospasm and those related to hypertension, diabetes, aging, etc., and the extended roles of NO in nerve function, inflammation, immune reactions, etc. would be clarified more extensively by accelerated progress in this field of research.
 ...
PMID:[Endothelium-derived relaxing factor (EDRF)]. 216 93

Previous investigations have shown that brain prostaglandin levels are transiently elevated following experimental fluid percussion brain injury. Associated with these increased prostaglandin levels there is free radical production and abnormalities in cerebral arteriolar function. The purpose of this study was to determine whether experimental fluid percussion brain injury in cats is associated with increased systemic levels of prostaglandins and the lipoxygenase product, 12-HETE. Blood samples were collected before and at various periods of time after 2.7 atm of fluid percussion brain injury was produced in adult cats. Prostaglandin and 12-HETE analysis was performed by radioimmunoassay after extraction of the plasma samples. The control levels for 6-keto-PGF1 alpha, PGE2, and 12-HETE were 477 +/- 42, 2,372 +/- 431, and 13,328 +/- 1,769 pg/ml, respectively. Following injury all three eicosanoids reached peak plasma levels by 1-5 min after injury. The percentile increases for all eicosanoids were similar and increased from 70 to 110%. The increases were sustained at up to 30 min postinjury and by 1 h after injury were at control levels. As in previous studies, hypertension following injury was maximal by 1 min postinjury and blood pressure had returned to near normal levels by 5 min postinjury. These studies demonstrate prolonged systemic increases in eicosanoids following injury. Since free radical production and vascular damage occur concomitantly with eicosanoid production, the prolonged increases in these products suggest that there is an attainable therapeutic window following injury during which administration of free radical scavengers may decrease radical damage and reduce the consequences of injury.
 ...
PMID:Increased plasma PGE2, 6-keto-PGF1 alpha, and 12-HETE levels following experimental concussive brain injury. 250 34

This study examined the role of the lipoxygenase (LO) pathway in the maintenance of hypertension in rats with two-kidney, one clip (2K,1C) Goldblatt hypertension. A single dose of the lipoxygenase blocker phenidone was injected intraperitoneally to 2K,1C rats during the early phase (14 days) of the development of hypertension (mean intraarterial blood pressure 137 +/- 3.9 mm Hg). Phenidone (60 mg/kg) markedly decreased arterial pressure to nadir levels of 58.9% of resting blood pressure. The maximal changes were observed 15 min after injection and the hypotensive response was sustained for at least 2 h. Plasma renin concentration (PRC) increased from 74.3 +/- 18.9 to 281.0 +/- 6.5 ng/mL/h after injection (P less than .05). Thus, the hypotensive effect of phenidone was not due to suppression of renin secretion but presumably due to inhibition of its effects. It is suggested that arachidonate metabolites of the LO pathway at the vascular bed may be involved in maintenance of high arterial pressure in 2K,1C renovascular hypertension in rat.
 ...
PMID:Hypotensive effects of the lipoxygenase inhibitor phenidone in two-kidney, one clip Goldblatt hypertension. 251

Intravenous injection of the complement activator, cobra venom factor (CVF), produces acute lung injury that is neutrophil-dependent and oxygen radical mediated. Using the ex vivo model of lung perfusion, the current studies were designed to measure the appearance of eicosanoids in relation to the development of pulmonary arterial hypertension and vascular permeability. Inhibitors of the cyclooxygenase and lipoxygenase pathways were also employed to assess the possible role of eicosanoids in these two functional responses. Ten minutes after infusion of CVF, when the pulmonary hypertensive changes were maximal, no increases in eicosanoids could be detected in whole lung lavage fluid (TXB2, 6-keto-PGF1 alpha, LTB4, LTC4) or plasma (TXB2, 6-keto-PGF1 alpha) and the inhibitors failed to affect the pressor response. In contrast, lung injury as defined by increased vascular permeability was temporally associated with the appearance in whole lung lavage fluid of TXB2, LTB4 and LTC4, the presence of which was blocked by the relevant inhibitors. Lung injury was attenuated by both cyclooxygenase and lipoxygenase inhibitors. This effect was not peculiar to the isolated lung model since cyclooxygenase (ibuprofen, indomethacin) and lipoxygenase (nafazatrom, U66,855) inhibitors also attenuated the CVF-induced increased vascular permeability in intact rats. These data suggest that in the model system employed eicosanoid production is linked to increases in lung vascular permeability but not to pulmonary artery hypertension.
 ...
PMID:Eicosanoids are involved in the permeability changes but not the pulmonary hypertension after systemic activation of complement. 283 33

Recent epidemiologic studies have shown that rates of cardiovascular disease are lower in populations such as the Greenland Eskimos than in those that do not eat seafood, even though the levels of dietary fat intake are often similar. Dietary fish oils are rich in eicosapentaenoic acid (EPA), a polyunsaturated fatty acid of the omega-3 series. EPA has been shown to prolong bleeding time and to decrease platelet aggregation and blood viscosity. EPA inhibits the production of prostaglandins from endogenous arachidonic acid, which is associated with the formation of thromboxane A2 and may also dampen cyclo-oxygenase and lipoxygenase metabolites involved in mediating endothelial cell proliferation. Dietary fish oils are now available in the form of EPA-enriched capsules. Short-term trials in humans have shown that EPA significantly reduces the levels of plasma triglycerides and may increase the levels of high-density lipoproteins; however, no consistent effect on serum cholesterol levels has been shown. The results of evaluations of EPA's use in patients with renal disorders, mild hypertension, inflammatory disorders or hyperlipidemia have been promising. On the basis of the epidemiologic and biologic evidence dietary fish oils warrant further study in extensive clinical trials.
 ...
PMID:Dietary fish oils containing eicosapentaenoic acid and the prevention of atherosclerosis and thrombosis. 284 22

Drugs that inhibit endothelium-dependent relaxation were tested to determine their effect on soluble guanylate cyclase purified from dog aorta. Basal, arachidonic acid (10(-5) M)-stimulated, and nitroprusside (5 X 10(-5) M)-stimulated guanylate cyclase activities were inhibited by methylene blue and the lipoxygenase inhibitors nordihydroguaiaretic acid and eicosatetraynoic acid. The effective inhibitory doses were in the range of those that have been reported to inhibit endothelium-dependent relaxation. Other compounds known to inhibit endothelium-dependent relaxation had little or no effect on guanylate cyclase activity. Basal guanylate cyclase activity was more resistant to inhibition than were activated states of the enzyme. The data suggest that reported inhibition of endothelium-dependent relaxation by some lipoxygenase inhibitors may be the result, at least in part, of their direct effect on guanylate cyclase activity.
Hypertension 1986 Oct
PMID:Modulation of guanylate cyclase by lipoxygenase inhibitors. 287 47

We have previously reported that des-Arg9-bradykinin can relax the phenylephrine-precontracted rabbit mesenteric artery through B1 kinin receptor stimulation and the subsequent release of prostaglandins. In the present study, we have found that this relaxant response can be converted to a contractile response by the cyclooxygenase inhibitor indomethacin. Contraction was dose-dependent and was blocked by the B1 receptor antagonist [Leu8]des-Arg9-bradykinin, with a pA2 value obtained by Schild regression similar to that reported for relaxation in the absence of indomethacin. Des-Arg10-kallidin (ED50 = 5.0 +/- 0.9 X 10(-9) M) was 16 times more potent than des-Arg9-bradykinin (ED50 = 8.1 +/- 0.8 X 10(-8) M) in contracting the indomethacin-treated artery and was also blocked by [Leu8]des-Arg9-bradykinin. In contrast, only 13 out of 24 indomethacin-treated vessels contracted in response to bradykinin, which had only one tenth and one 160th the potency (ED50 = 9.9 +/- 1.8 X 10(-7) M) of des-Arg9-bradykinin and des-Arg10-kallidin, respectively. B1 kinin receptor-mediated contraction in the presence of indomethacin was unaffected by the dual cyclooxygenase-lipoxygenase inhibitor BW 755c. These results indicate that des-Arg-kinins can stimulate both relaxation and contraction of the phenylephrine-precontracted rabbit mesenteric artery through stimulation of B1 kinin receptors. The relaxation is dependent on the release of prostaglandins, while the contraction may represent a direct effect.
Hypertension 1987 Jun
PMID:Conversion of B1 kinin receptor-mediated vascular relaxation to contraction. 288 69

The effect of PAF has been examined in anaesthetized guinea-pigs. Intravenous (i.v.) administration of PAF (10 ng kg-1) did not modify the respiratory response but decreased the arterial blood pressure. A high dose of PAF (200 ng kg-1) caused marked bronchoconstriction and concomitant hypertension. The cyclooxygenase inhibitors aspirin (5 mg kg-1) and indomethacin (5 mg kg-1) and the thromboxane A2 (TXA2) receptor antagonist BM-13.177 (1 mg kg-1) failed to inhibit the peak bronchoconstrictive response but significantly inhibited the prolonged response following peak response. These inhibitors also attenuated PAF-induced hypertension. On the other hand, the lipoxygenase inhibitors phenidone (10 mg kg-1) and NDGA (5 mg kg-1) and the leukotriene (LT) receptor antagonist FPL-55712 (2 mg kg-1) affected neither bronchoconstriction nor hypertension induced by PAF. However, when aspirin was given in combination with NDGA, phenidone or FPL-55712, the peak and the following prolonged bronchoconstriction were significantly inhibited. The suppression of PAF-induced hypertension by aspirin was not further inhibited by the combination of these inhibitors. These results indicate that in anaesthetized guinea-pigs PAF-induced bronchoconstriction is composed of a dual response, a direct action (peak response) and an indirect action (prolonged response). The latter may be produced by the generation of TXA2 and lipoxygenase products, while PAF-induced hypertension is indirectly mediated by the generation of TXA2.
 ...
PMID:Pharmacological modulation of platelet activating factor (PAF)-induced bronchoconstriction and hypertension in anaesthetized guinea-pigs. 290 7

The effects of selectively inhibiting synthesis of thromboxane A2 (TXA2) with dazoxiben and of all cyclooxygenase products with indomethacin were studied in goats after infusion of 5 X 10(8) live Escherichia coli bacteria/kg. Pulmonary and systemic pressures, cardiac output, and double indicator dilution extravascular lung water (EVLW) were measured at 15-min intervals. EVLW was determined gravimetrically at 6 hr to confirm the final double indicator dilution values. Plasma levels of TXA2 and prostacyclin (PGI2) were measured as their stable metabolites, TXB2 and 6-keto-PGF1 alpha, respectively. Dazoxiben blocked the increase in plasma TXB2, prevented pulmonary hypertension, and attenuated the increase in EVLW after E. coli. Mean gravimetric EVLW was 8.7 ml/kg in the dazoxiben-treated group compared to 11.3 ml/kg in the untreated control group. Indomethacin blocked the increased plasma TXB2 and 6-keto-PGF1 alpha, attenuated pulmonary hypertension, and prevented almost all increases in EVLW. Mean gravimetric EVLW was 8.2 ml/kg after indomethacin. We conclude that in acute bacteremia, the early pulmonary hypertension is mediated largely by TXA2 (however, a second phase of hypertension results from non-cyclooxygenase products), either production of cyclooxygenase products (perhaps PGI2) inhibits part of the action of pulmonary vasoconstrictors, or indomethacin stimulates the production of other vasoconstrictors (such as lipoxygenase products), and indomethacin prevents the accumulation of EVLW by blocking formation of cyclooxygenase products or by other nonspecific actions.
 ...
PMID:Indomethacin, dazoxiben and extravascular lung water after Escherichia coli infusion. 309 72

The cyclooxygenase and lipoxygenase pathways of the arachidonate cascade are investigated in vitro in the mesenteric arteries and in the platelets of Wistar normotensive and Okamoto spontaneously hypertensive (SH) rats, using 1-14C arachidonic acid as substrate. The arachidonate cascade in the mesenteric arteries of both Wistar and Okamoto rats showed a sexual dependence. The lipoxygenase dominance in the mesenteric arteries increased almost in parallel with the blood pressure in female SH rats. The activities of cyclooxygenase and lipoxygenase were 4-12 times higher in female animals than in males. The lipoxygenase pathway dominated the arachidonate cascade in the platelets of both normotensive and hypertensive rats. The lipoxygenase pathway was more active in the platelets of SH animals than in the controls. Both in the mesenteric arteries and in the platelets, the arachidonate cascade might play some role in the pathogenesis of hypertension.
 ...
PMID:Arachidonate cascade in mesenteric blood vessels and platelets of spontaneously hypertensive rats. 312 56


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