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

Vascular smooth muscle from stroke-prone spontaneously hypertensive rats has an increased responsiveness to the vasoconstrictors angiotensin II and serotonin. This abnormality is postulated to contribute to the hypertension characteristic of this strain of rats. We hypothesized that a portion of the increased responsiveness may be due to altered function of G proteins. This hypothesis was tested using mastoparan, a peptide that mimics ligand-bound receptors to stimulate G proteins directly. In addition, we investigated the mechanism of mastoparan-induced contraction of vascular smooth muscle. Changes in isometric tension were recorded in denuded carotid artery strips from hypertensive and normotensive (Wistar-Kyoto) rats. Vascular strips from the hypertensive rats had a significantly greater response to mastoparan at all concentrations between 10(-8) and 10(-5) mol/L. A G protein inhibitor, N-ethylmaleimide (10(-3) mol/L), attenuated the response to mastoparan (10(-7) mol/L) (67 +/- 4% of control response), whereas pertussis toxin treatment did not. Inhibition of phospholipase C also significantly decreased the mastoparan-induced response (23 +/- 12% of control), and nifedipine (10(-3) mol/L), a calcium channel blocker, completely blocked the mastoparan-induced contraction. Indomethacin treatment did not affect the mastoparan contraction even though mastoparan has been shown to stimulate phospholipase A2 in other cell types. In conclusion, we observed an increased response in carotid arteries from genetically hypertensive rats to a pharmacological intervention that appears to act via G protein-linked phospholipase C stimulation and L-type calcium channel activation, suggesting that the increased vascular reactivity in stroke-prone spontaneously hypertensive rats is due in part to altered function of G proteins.
Hypertension 1994 Jun
PMID:Enhanced vascular reactivity to mastoparan, a G protein activator, in genetically hypertensive rats. 820 33

We designed experiments to characterize the role of superoxide anions in the mediation of endothelium-dependent contractions in isolated canine basilar arteries. Rings with and without endothelium were suspended for isometric tension recording in Krebs-Ringer bicarbonate solution bubbled with 94% O2-6% CO2 (37 degrees C, pH 7.4). Radioimmunoassay was used to determine the levels of cyclic GMP and cyclic AMP. Calcium ionophore A23187 (10(-9) to 10(-6) mol/L) caused concentration-dependent contractions. The removal of endothelium abolished the effect of A23187. Contractions to A23187 were reversed into relaxations in the presence of superoxide dismutase (150 U/mL) or the prostaglandin H2/thromboxane A2 receptor antagonist SQ29548 (10(-6) mol/L). NG-nitro-L-arginine methyl ester (3 x 10(-4) mol/L) augmented contractions to A23187. In rings with endothelium, A23187 (3 x 10(-7) mol/L) significantly increased levels of both cyclic AMP and cyclic GMP. Indomethacin (10(-5) mol/L) inhibited stimulatory effects of A23187 on cyclic AMP production. In contrast, indomethacin augmented A23187-induced production of cyclic GMP. Selective augmentation of cyclic GMP production by indomethacin appears to be due to protection of nitric oxide or a closely related molecule released following translocation of calcium into endothelial cells. Our findings suggest that (1) an increased concentration of calcium in endothelial cells may activate both cyclooxygenase and the L-arginine/nitric oxide pathway, (2) arachidonic acid metabolism via cyclooxygenase is a source of superoxide anions, and (3) superoxide anions may be responsible for impairment of balance between relaxing and contracting factors leading to contraction of underlying smooth muscle cells.
Hypertension 1994 Feb
PMID:Role of superoxide anions in the mediation of endothelium-dependent contractions. 830 34

The role of endothelium-derived contracting factor or factors in modulating relaxations and contractions to adenine nucleotides was examined in aortas from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) and Wistar rats. During contractions to phenylephrine, the relaxations to ATP were impaired significantly in SHR compared with WKY aortas with endothelium. In rings treated with NG-nitro-L-arginine (to inhibit nitric oxide synthase), the endothelium significantly augmented contractions evoked by ATP; this enhancement was greater in SHR compared with WKY aortas. Indomethacin (inhibitor of cyclooxygenase) and SQ 29,458 (antagonist of thromboxane/prostaglandin endoperoxide receptors) but not dazoxiben (inhibitor of thromboxane synthase) significantly augmented the maximal relaxation in WKY rats, abolished the impairment of the relaxation in SHR, and prevented the potentiation by the endothelium of the contractions evoked by ATP. In older animals (10 to 12 months old), the endothelium-dependent concentration-relaxation curves to ATP in SHR and WKY aortas treated with indomethacin were superimposable, as were the concentration-contraction curves (with NG-nitro-L-arginine present). Endothelium-dependent concentration-relaxation and -contraction curves to ADP obtained in these preparations overlapped also. In Wistar rats, the magnitude of the endothelium-dependent relaxations to either ATP or ADP were significantly smaller compared with the other strains, and the endothelium-dependent contractions were even smaller. Results show that adenine nucleotides stimulate the production of both endothelium-derived relaxing and contracting factors. Although there is no obvious age-related alteration in the capacity of aortas to release endothelium-derived relaxing factor, aging enhances endothelium-derived contracting factor activity in WKY rats.
Hypertension 1993 Oct
PMID:Purinergic endothelium-dependent and -independent contractions in rat aorta. 840 63

We hypothesized that 5-lipoxygenase and cyclooxygenase products might be mediators of cardiopulmonary and systemic vascular effects induced by a 4 h continuous infusion of platelet-activating factor (PAF, 10 ng/kg/min) in anesthetized pigs. Indomethacin (cyclooxygenase inhibitor) potentiated and CGS 8515 (5-lipoxygenase inhibitor) attenuated PAF-induced increases in total peripheral resistance (TPR) from 2.5 to 4 h. However, the 5-lipoxygenase inhibitor failed to modify pulmonary vasoconstriction and hypertension caused by PAF. Except for a delay in onset (approximately 44 s) and rate of development of pulmonary hypertension during the initial 10 min of PAF infusion, the pulmonary hemodynamic changes were also not attenuated by indomethacin. On the other hand, at 4 h, the PAF-induced pulmonary hypertension and systemic vasoconstriction were completely or partially reversed, respectively, by WEB 2086 (PAF receptor antagonist). The PAF-induced increases in plasma thromboxane B2 (TXB2) were blocked by indomethacin but not by CGS 8515, and at 4 h the 5-lipoxygenase inhibitor potentiated the levels of TXB2 in pigs treated with PAF. The plasma concentrations of 6-keto-PGF1 alpha and leukotriene B4 (LTB4) were not modified by PAF or CGS 8515 + PAF. We conclude that PAF-induced increases in TPR (2.5-4 h) are potentiated by indomethacin and are dependent on 5-lipoxygenase products other than LTB4. Although the early pulmonary vascular response (< 10 min) to PAF is dependent on cyclooxygenase products, the sustained response (after 10 min) cannot be explained by either 5-lipoxygenase or cyclooxygenase products but may be mediated directly by PAF receptors.
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PMID:Effect of 5-lipoxygenase and cyclooxygenase blockade on porcine hemodynamics during continuous infusion of platelet-activating factor. 841 4

We designed experiments to determine the role of endothelium-derived contracting factor or factors in the response to endothelin-1 and endothelin-3 in the aorta of normotensive and hypertensive rats. Rings of thoracic aortas, with and without endothelium, from normotensive and spontaneously hypertensive rats were suspended in organ chambers for recording of isometric tension in the presence of nitro-L-arginine, an inhibitor of nitric oxide synthase. The removal of endothelium decreased the contractions evoked by both endothelins in the aorta of spontaneously hypertensive but not of normotensive rats. Indomethacin (inhibitor of cyclooxygenase), dazoxiben (inhibitor of thromboxane synthase), and SQ-29,548 (antagonist of thromboxane A2 receptors) reduced, in aortic rings of spontaneously hypertensive rats, the contractions to endothelins in rings with but not in those without endothelium, whereas their effect was not endothelium-dependent in tissues of normotensive rats. BQ-123, a selective endothelin-A receptor antagonist, shifted the concentration-response curve to endothelin-1 to the right in a concentration-dependent manner and abolished the endothelium-dependent component of the contractions evoked by the peptide. The presence of the endothelium increased the basal and endothelin-stimulated release of thromboxane B2, the stable metabolite of thromboxane A2, in aortas of spontaneously hypertensive rats but not in those of normotensive rats. These data suggest that endothelium-derived thromboxane A2 contributes to contractions evoked by endothelin-1 and endothelin-3 in the aorta of the spontaneously hypertensive rat but not in that of the normotensive rat. Both the receptors on the endothelial cells (mediating the release of thromboxane A2) and those on vascular smooth muscle belong to the endothelin-A subtype.
Hypertension 1993 Jan
PMID:Role of endothelium in endothelin-evoked contractions in the rat aorta. 841 29

The prevalence and incidence of adverse drug interactions involving nonsteroidal anti-inflammatory drugs (NSAIDs) remains unknown. To identify those proposed drug interactions of greatest clinical significance, it is appropriate to focus on interactions between commonly used and/or commonly coprescribed drugs, interactions for which there are numerous well documented case reports in reputable journals, interactions validated by well designed in vivo human studies and those affecting high-risk drugs and/or high-risk patients. While most interactions between NSAIDs and other drugs are pharmacokinetic, NSAID-related pharmacodynamic interactions may be considerably more important in the clinical context, and prescriber ignorance is likely to be a major determinant of many adverse drug interactions. Prescribing NSAIDs is relatively contraindicated for patients on oral anticoagulants due to the risk of haemorrhage, and for patients taking high-dose methotrexate due to the dangers of bone marrow toxicity, renal failure and hepatic dysfunction. Combination NSAID therapy cannot be justified as toxicity may be increased without any improvement in efficacy. Where lithium or anti-hypertensives are coprescribed with NSAIDs, close monitoring is mandatory for lithium toxicity and hypertension, respectively, and aspirin (acetylsalicylic acid) or sulindac are preferred. Phenytoin or oral hypoglycaemic agents may be administered with NSAIDs other than pyrazoles and salicylates provided that patients are monitored carefully at the initiation and cessation of NSAID treatment. Digoxin, aminoglycosides and probenecid may be coprescribed with NSAIDs, but close monitoring is required, particularly for high-risk patients such as the elderly. Indomethacin and triamterene should be avoided due to the risk of renal failure. High dose aspirin should be replaced by naproxen in patients on valproic acid (sodium valproate) and care is required when corticosteroids are administered to patients taking salicylates long term in high dosage. Interactions between NSAIDs and antacids or cholestyramine are generally avoidable. Adverse drug interactions involving NSAIDs may be limited by rational prescribing and by careful monitoring, particularly for high-risk patients, drugs and therapy periods.
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PMID:Adverse drug interactions with nonsteroidal anti-inflammatory drugs (NSAIDs). Recognition, management and avoidance. 845 60

Cyclosporine and in particular oxidatively modified low density lipoproteins can both exert direct vasoconstricting effects. We hypothesized that coincubation of arteries with low density lipoproteins and cyclosporine would enhance their respective influence on vascular tone. Therefore, we investigated vascular reactivity of isolated intact rabbit renal arteries preincubated with cyclosporine in the presence of native and oxidized low density lipoproteins. After preincubation of the arteries with cyclosporine (10 micrograms/ml, 90 minutes), unstimulated vascular tone as well as norepinephrine-induced vasoconstrictions remained unchanged compared with controls preincubated with the cyclosporine solvent dimethyl sulfoxide. Oxidized low density lipoproteins (100 micrograms/ml) in the absence of cyclosporine significantly enhanced vasoconstrictions to threshold concentrations of norepinephrine (78 +/- 10 microns at 30 nM). However, after cyclosporine treatment, the oxidized low density lipoprotein-induced potentiation of contractile responses to norepinephrine was further enhanced (157 +/- 19 versus 71 +/- 11 microns). Native low density lipoproteins had no influence on vascular tone. Potentiation of norepinephrine-induced vasoconstriction by oxidized low density lipoproteins took place in either endothelium-denuded or endothelium-intact arteries, whereas the further enhancement of vascular tone after cyclosporine treatment was seen only in endothelium-intact segments. Endothelium-dependent dilations to acetylcholine were fully preserved after treatment with oxidized low density lipoproteins and cyclosporine. Indomethacin, saralasin, and the thromboxane A2 antagonist daltroban had no influence, but the Ca2+ antagonist verapamil prevented the potentiation of vasoconstrictions by cyclosporine and oxidized low density lipoproteins.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1993 Mar
PMID:Cyclosporine and oxidized lipoproteins affect vascular reactivity. Influence of the endothelium. 847 41

Bovine coronary arteries relax in response to bradykinin, methacholine, sodium nitroprusside, isoproterenol, and arachidonic acid in a concentration-dependent manner. The relaxations to methacholine, bradykinin, and arachidonic acid are lost when endothelium is removed. Indomethacin, a cyclooxygenase inhibitor, attenuated the relaxations to methacholine, bradykinin, and arachidonic acid and shifted the EC50 (control versus indomethacin) to each (1 x 10(-7) versus 3 x 10(-7) mo1/L, 3 x 10(-10) versus 2 x 10(-9) mo1/L, and 3 x 10(-7) versus 2 x 10(-6) mo1/L, respectively). Nitro-L-arginine, a nitric oxide synthase inhibitor, also attenuated the relaxations to methacholine, bradykinin, and arachidonic acid and shifted the EC50 (control versus nitro-L-arginine) to each (1 x 10(-7) versus 3 x 10(-7) mo1/L, 3 x 10(-10) versus > 10(-9) mo1/L, and 3 x 10(-7) versus > 10(-6) mo1/L, respectively). The combination of indomethacin and nitro-L-arginine blunted the relaxations to these agents and also shifted the EC50 values (control versus indomethacin plus nitro-L-arginine) to each (1 x 10(-7) versus 5 x 10(-7) mo1/L, 3 x 10(-10) versus > 10(-9) mo1/L, and 3 x 10(-7) versus > 10(-6) mo1/L, respectively). Methacholine, bradykinin, and arachidonic acid stimulated the release of prostaglandin I2, measured as 6-keto-PGF1 alpha. Indomethacin, but not nitro-L-arginine, inhibited arachidonic acid-induced release of 6-keto-PGF1 alpha. Vascular cGMP content was unchanged by arachidonic acid but was significantly elevated by bradykinin. Relaxations to prostaglandin I2 and sodium nitroprusside, but not 8,9-epoxyeicosatrienoic acid or isoproterenol, were inhibited by nitro-L-arginine. We conclude that the endothelium-dependent relaxations to methacholine, bradykinin, and arachidonic acid are partly due to prostaglandin I2 release. The remainder of the responses to these agents is due to the release of other relaxing factor or factors. Since bradykinin increased cGMP and nitro-L-arginine partially inhibited its relaxant effects, nitric oxide also appears to participate in the bradykinin-induced effect. Since the combination of indomethacin and nitro-L-arginine failed to completely block the relaxations to methacholine, bradykinin, and arachidonic acid, another endothelial factor must contribute to their vascular effects. Surprisingly, nitro-L-arginine attenuated the relaxations to arachidonic acid; however, L-arginine failed to reverse the effects of nitro-L-arginine on arachidonic acid-induced relaxations. In addition, arachidonic acid failed to increase cGMP. Nitro-L-arginine also reduced the responses to prostaglandin I2 and sodium nitroprusside. These data indicate that these arginine analogues may have effects other than competitive inhibition of nitric oxide synthase.
Hypertension 1996 Jul
PMID:Mediators of arachidonic acid-induced relaxation of bovine coronary artery. 867 67

To determine whether endothelin-1 (ET-1) contributes to hypertension associated with non-steroidal anti-inflammatory drug (NSAID) usage in healthy, elderly, normotensive individuals a randomised, double-blind, placebo-controlled, crossover trial of indomethacin was undertaken in 41 healthy, elderly individuals with stable normotension or controlled hypertension (blood pressure (BP) < or = 160/90 mm Hg). The main outcome measures were systolic and diastolic BP, heart rate, cardiac output, weight, creatinine clearance, plasma renin activity, aldosterone, endothelin-1 and arginine vasopressin concentrations and 24 h urinary endothelin-1 and 6 keto prostaglandin F1 alpha outputs. Analysis of covariance was used to evaluate the effect of indomethacin on BP and related parameters. Indomethacin treatment for 1 month increased systolic (+/- s.e.m.: 4.1 +/- 2.2 mm Hg; 95% confidence interval 0 to 8.3 mm Hg) and diastolic BP (2.7 +/- 1.1 mm Hg; 0.4 to 4.9 mm Hg) without altering cardiac output (P = 0.59), implying an increase in total peripheral resistance. Indomethacin treatment produced a small increase in weight (1.4 +/- 0.4 kg; 0.6 to 2.2 kg), a small reduction in renal function (creatinine clearance: 6.8 +/- 1.8 mis/min; 3.3 to 10.3 mis/min) but a significant (83%) increase in daily urinary endothelin-1 production (13.1 +/- 3.4 ng/ml; 6.4 to 19.8 ng/ml) without altering plasma ET-1 concentration, suggesting increased renal synthesis. In conclusion, renal paracrine effects of ET-1 may contribute to NSAID-induced blood pressure elevation in humans.
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PMID:Potential mechanisms by which nonsteroidal anti-inflammatory drugs elevate blood pressure: the role of endothelin-1. 873 58

The effect of methylmercury (CH3HgCl) on the production of endothelium-derived relaxing factor (EDRF) by cultured human umbilical vascular endothelial cells (HUVECs) based on its anti-aggregatory effect on human platelets was examined. HUVECs were harvested from umbilical veins by collagenase treatment. The platelet aggregation test was performed with cuvettes lined with HUVECs. Platelet aggregation induced by 0.05 units thrombin/ml was inhibited in the presence of HUVECs. This HUVEC-dependent anti-platelet aggregatory effect was enhanced by the addition of bradykinin (10 nmol/L), which stimulates the production of EDRF. Indomethacin (IND, 1 mumol/L) reduced the HUVEC-dependent anti-platelet aggregatory effect. The effect of NG-monomethyl-L-arginine L-NMMA, 100 mumol/L), an inhibitor of nitric oxide synthase (NOS) in endothelial cells, on HUVECs pretreated with IND showed almost complete platelet aggregation similar to results without HUVECs. The anti-platelet aggregatory effect of HUVECs pretreated with IND seemed to depend mainly on EDRF. Methylmercury (MeHg) (20-50 mumol/L) induced dose-dependent platelet aggregation in cuvettes, without HUVECs. Methylmercury (30 mumol/L) induced less platelet aggregation in the presence of HUVECs than in their absence. The degree of inhibitory effect by HUVECs on MeHg-induced platelet aggregation was reduced dose-dependently (30-50 mumol/L MeHg). Methylmercury-induced platelet aggregation at 50 mumol/L MeHg with or without HUVECs was similar. These findings suggest that this simple new experimental system is useful for assessing the production of EDRF by HUVECs, and show that MeHg inhibits the production of EDRF by HUVECs, which may be involved in the etiology of cardiovascular diseases such as hypertension and arteriosclerosis.
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PMID:The effect of methylmercury (CH3HgCl) on the production of endothelium-derived relaxing factor (EDRF) by cultured human umbilical vascular endothelial cells based on its anti-aggregatory effect on human platelets. 878 7


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