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)

The role of platelets in lung injury has not been well defined. In the present study of isolated perfused rat lungs, phorbol myristate acetate (PMA; 0.15 microgram/ml) or platelets (6.7 X 10(4)/ml) alone did not discernibly change the pulmonary arterial pressure (PAP) or lung weight (LW). However, the combination of platelets and PMA drastically increased the PAP and LW (delta PAP 26.2 +/- 1.0 mmHg, delta LW 2.7 +/- 0.4 g). delta PAP was positively correlated with the increase in thromboxane B2 produced by infusion of platelets and PMA (thromboxane B2 = 35.6 + 0.97 delta PAP, r = 0.67, P less than 0.01). The hypertension and edema formation induced by PMA and platelets were strongly attenuated by indomethacin, an inhibitor of platelet cyclooxygenase (delta PAP 5.6 +/- 2.0 mmHg, P less than 0.001; delta LW 0.0 +/- 0.1 g, P less than 0.001), and by imidazole, an inhibitor of thromboxane A2 synthase (PAP 8.0 +/- 2.5 mmHg, P less than 0.001; LW 0.0 +/- 0.3 g, P less than 0.01). Inactivation of platelet lipoxygenase with nordihydroguaiaretic acid mildly depressed pulmonary pressure but did not affect delta LW (delta PAP 18.9 +/- 1.6 mmHg, P less than 0.05; delta LW 3.1 +/- 0.3 g, P greater than 0.05). In vitro experiments showed that the capacity of platelets to release oxygen radicals was only 2.6% of that found for granulocytes. These results suggest that platelets may be activated by PMA to increase PAP and vascular permeability.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclooxygenase pathway mediates lung injury induced by phorbol and platelets. 190 12

Previous studies have demonstrated that inhibition of thromboxane A2-dependent platelet aggregation by the thromboxane A2 synthase inhibitor, OKY 1581, ameliorated the progressive kidney disease of rats with subtotal renal ablation. OKY 1581 also decreased the excessive renal thromboxane A2 synthesis and lowered systemic blood pressure. In the same model, a low dose aspirin and a specific thromboxane A2 receptor antagonist failed to influence proteinuria, glomerulosclerosis, and hypertension, thus excluding a role for either platelet or renal thromboxane A2 in renal disease progression. The aims of this study were to establish (1) whether a thromboxane A2 synthase inhibitor different from OKY 1581 could retard the progression of glomerular disease in rats with remnant kidney and (2) whether this effect was associated with an increase in renal synthesis of the vasodilatory prostacyclin. Treatment of rats with renal mass ablation with FCE 22178 (100 mg/kg by gavage and 200 mg/kg in the drinking water) for 35 days starting 10 days after surgical ablation was associated with an improvement in renal function in comparison with rats receiving the vehicle alone. Proteinuria was significantly lower, and rats were partially protected from the development of glomerulosclerosis. Systolic blood pressure was significantly lower than in animals given the vehicle. Urinary thromboxane B2 excretion was significantly decreased, and urinary 6-keto-prostaglandin F1 alpha increased in respect to vehicle-treated rats. We conclude that FCE 22178 limits glomerular injury in rats with remnant kidney.
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PMID:Thromboxane synthesis inhibition increases renal prostacyclin and prevents renal disease progression in rats with remnant kidney. 213 29

Arterial blood pressure, serum fibrin/fibrinogen degratory products, plasma thromboxane B2, in vitro platelet aggregation, and platelet ultrastructure were studied in ten gravid ewes during fast-triggered ovine pregnancy-induced hypertension and subsequent administration of the thromboxane synthetase inhibitors CGS13080 and CGS12970. During the hypertensive period, blood pressure (p less than 0.005) and plasma thromboxane B2 levels (p less than 0.005) were significantly altered. Collagen-induced in vitro platelet aggregation lag times increased (p less than 0.01), and percent aggregation (p less than 0.05), primary (p less than 0.01), and secondary (p less than 0.005) aggregatory slopes decreased. Collagen also failed to induce aggregation in some ewes. Primary slopes of ADP-induced in vitro platelet aggregation decreased (p less than 0.01) during hypertension. Degranulation and open canalicular tubule system swelling were observed in platelets which produced abnormal or no aggregation response. However, these ultrastructural abnormalities did not necessarily correspond to hypertensive periods. Thromboxane synthetase inhibitor administration lowered blood pressure (p less than 0.005) and plasma thromboxane B2 levels (p less than 0.005). Abnormalities in collagen and ADP-induced platelet aggregation curves were also corrected, and ultrastructural abnormalities were not detected. Marked elevations in plasma thromboxane levels during ovine pregnancy-induced hypertension may have had an "exhaustive" effect on thrombocytes which was reversed by thromboxane synthetase inhibition.
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PMID:Effect of thromboxane synthetase inhibition on platelet function and morphology during ovine pregnancy-induced hypertension. 323 44

Neonatal group B streptococcal (GBS) sepsis produces pulmonary arterial hypertension and hypoxemia that are preventable by pretreatment with the selective thromboxane A2 synthase inhibitor, dazmegrel. In the present experiment we administered dazmegrel (8 mg/kg) 2 h after the initiation of a 2 1/2 h infusion of 5 X 10(8) GBS/kg/h in ten 2- to 3-wk-old piglets. The multiple inert gas elimination technique was used to measure intrapulmonary shunt and alveolar ventilation to pulmonary perfusion mismatching. Thromboxane B2, the stable metabolite of thromboxane A2, and 6-keto-prostaglandin F1 alpha, the stable metabolite of prostacyclin, were assayed in arterial blood. Pulmonary arterial pressure increased immediately after initiation of the GBS infusion, rising from 12 +/- 2 to 34 +/- 4 torr (p less than 0.02); pulmonary vascular resistance increased by 400% (p less than 0.01). Arterial hypoxemia developed (p less than 0.02) in association with an increase in the low ventilation-perfusion ratio index but without a significant increase in intrapulmonary shunt. Thromboxane B2 levels increased 10-fold. Infusion of the carrier substance for dazmegrel after 2 h of GBS infusion produced no change in any variables. In contrast, infusion of the drug resulted in the return to pre-GBS infusion baseline values for both pulmonary arterial pressure and pulmonary vascular resistance. However, no improvement in arterial pO2 or in the low ventilation-perfusion ratio index occurred. Both pulmonary vascular resistance and pulmonary arterial pressure remained normal for 0.5 h after dazmegrel administration despite continued GBS infusion. Thromboxane B2 levels were decreased 30 min after dazmegrel (p less than 0.02), but remained greater than pre-GBS levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neonatal group B streptococcal sepsis: effects of late treatment with dazmegrel. 328 20

Thromboxane A2 is a prostanoid having potent platelet aggregatory and vasoconstrictor properties. To determine a possible role for thromboxane A2 in the development of severe hypertension and stroke, we chronically administered the selective thromboxane A2 synthase inhibitor UK-38,485 (Dazmegrel) to stroke-prone spontaneously hypertensive rats (SHRSP). Serum thromboxane B2 (the stable hydrolysis product of thromboxane A2) generation was significantly greater in incubates of whole blood from SHRSP than in those from normotensive control Wistar-Kyoto rats and was inhibited greater than 89% by UK-38,485 administered in vivo. In 10 male SHRSP fed a Japanese-style rat chow and given 1% NaCl in drinking water to accelerate the occurrence of stroke, treatment with 100 mg/kg/day UK-38,485 by gavage starting at 8.6 weeks of age diminished systolic blood pressure elevation at 10 (205 +/- 2 vs. 220 +/- 4 mm Hg, p less than 0.01) and 11 weeks of age (210 +/- 4 vs. 239 +/- 7 mm Hg, p less than 0.01) compared with 10 untreated SHRSP. The ultimate establishment of severe hypertension was not prevented by UK-38,485. Stroke-related mortality was 70% in both UK-38,485-treated and control SHRSP at 14 weeks of age. Histologic examination revealed cerebrovascular lesions consistent with the occurrence of stroke in both control and UK-38,485-treated SHRSP. Our results support a possible role for thromboxane A2 in the elevation of blood pressure in SHRSP but do not support a possible role for the prevention of stroke by thromboxane A2 synthase inhibition in these rats.
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PMID:Thromboxane A2 in severe hypertension and stroke in stroke-prone spontaneously hypertensive rats. 341 13

Although lipids have received most attention in relation to atherosclerosis, vessel injury also has a role in the development of atherosclerotic lesions. Thrombi that form at sites of injury can be incorporated into the wall, causing thickening, and platelets that adhere to damaged vessel walls release a growth factor (PDGF) that stimulates smooth muscle cell proliferation. The early lesions of atherosclerosis are focal and develop around vessel orifices and branches in relation to the patterns of blood flow and areas of increased permeability and endothelial cell damage. Platelets also contribute to the complications of advanced atherosclerosis caused by occlusive thrombi, thromboembolism, and spasm. The causes of vessel wall injury are not established, although there is evidence pointing to disturbed blood flow, hypertension, antigen--antibody complexes, complement, materials originating from platelets and white blood cells, bacteria, endotoxin, viruses, smoking, dietary lipids, homocystinemia, diabetes, other metabolic disorders, and stress. Platelets do not adhere to intact endothelium, but they adhere to the constituents of the subendothelium, release the contents of their granules (including PDGF), and form thromboxanes. If blood flow is disturbed, platelet--fibrin thrombi can form at sites of injury. Platelet adherence to a damaged wall does not require von Willebrand factor except under conditions of high wall shear. Repeated injury of a vessel wall leads to the development of lipid-rich atherosclerotic lesions, even in normocholesterolemic animals, but these lesions do not form if the experimental animals are made thrombocytopenic before injury is induced. Measurable changes in platelets that are associated with the clinical complications of atherosclerosis include shortened survival, release of granule contents (platelet factor 4, beta-thromboglobulin, thrombospondin), formation of thromboxanes, and decreased buoyant density. "Antiplatelet drugs" such as aspirin are proving to be beneficial in selected groups of patients, such as those with unstable angina. Thromboxane synthetase inhibitors and agents that block the thromboxane receptor on platelets are under investigation. Long term administration of "antiplatelet drugs" to affect the rate of development of atherosclerosis seems neither feasible nor desirable. Modification of dietary and smoking habits and control of hypertension are more likely to be beneficial for most individuals.
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PMID:The role of platelets in the development and complications of atherosclerosis. 351 36

We designed the present study to clarify whether the intracellular pH change by ammonium chloride influences endothelium-dependent relaxation in thoracic aorta of 9-week-old Sprague-Dawley rats. Intracellular alkalinization with 3 mmol/L ammonium chloride, which did not affect resting vascular tone, attenuated acetylcholine-induced relaxation but not nitroglycerin vasodilation. Acetylcholine relaxation was more inhibited by a shorter duration of treatment. Thus, change in intracellular pH may be important in the effect because the alkalinizing effect of ammonium chloride disappears gradually. In support of this, the proton ionophore nigericin abolished the effect. Also, amiloride shortened the effect of ammonium chloride, suggesting that intracellular pH plays a role: sodium-proton antiport antagonizes the disappearance of ammonium chloride-induced intracellular alkalinization. The synthesis of vasoconstrictor prostaglandins, such as thromboxane A2, may be stimulated during acetylcholine treatment, resulting in the attenuation of acetylcholine relaxation, because the relaxation was abolished by treatment with the phospholipase A2 inhibitor quinacrine, cyclooxygenase inhibitor indomethacin, prostaglandin H2/thromboxane A2 receptor antagonist S1452, and thromboxane A2 synthase inhibitor dazmegrel. Phospholipase A2 may contribute to the effect of intracellular alkalinization, which is compatible with the fact that the optimal pH of phospholipase A2 is neutral to alkaline. In addition, superoxide dismutase attenuated the effect of ammonium chloride. In conclusion, intracellular alkalinization by ammonium chloride attenuated acetylcholine-induced relaxation, possibly through the interrelated production of both thromboxane A2 and superoxide radicals.
Hypertension 1994 Aug
PMID:Inhibitory effect of ammonium chloride on acetylcholine-induced relaxation. 803 43

To investigate the nature of the arachidonic acid metabolite involved in the altered reactivity of microvessels of two-kidney, one-clip hypertensive rats and the possible contribution of this product to the elevated blood pressure levels found in two-kidney, one-clip hypertension, mesenteric arterioles either perfused in vitro or studied in vivo were used along with blood pressure determinations. The decreased response to acetylcholine observed was normalized by ridogrel, a thromboxane A2 receptor antagonist, and dazoxiben, a thromboxane A2 synthase inhibitor. The smooth muscle response to nitric oxide, tested with sodium nitroprusside, was unaltered in two-kidney, one-clip hypertensive microvessels. Neither ridogrel nor dazoxiben modified the response to this vasodilator. In contrast, the potentiated response to noradrenaline was corrected by ridogrel and dazoxiben in vitro but not in vivo. Noradrenaline and acetylcholine increased the release of thromboxane A2 from the mesenteric microvessels of two-kidney, one-clip hypertensive rats. Ridogrel and dazoxiben decreased but did not normalize the elevated blood pressure of hypertensive rats. Based on these results, we concluded that: 1) the decreased responsiveness of smooth muscle to acetylcholine resulted from an increase in thromboxane A2 formation rather than a decrease in sensitivity to nitric oxide; 2) thromboxane A2 contributes to the increased noradrenaline response in mesenteric microvessels perfused in vitro while in in vivo other blood borne vasoactive agents may also be involved since the potentiated noradrenaline response was not corrected by inhibiting thromboxane A2 synthesis or receptors; 3) in addition to thromboxane A2, another as yet unidentified factor, may contribute to the elevated blood pressure in two-kidney, one-clip hypertension.
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PMID:The role of thromboxane A2 in the altered microvascular reactivity in two-kidney, one-clip hypertension. 927 80

20-HETE is a potent constrictor of small blood vessels and has been suggested to play a crucial role in the generation of myogenic tone and the development of hypertension. In the present study, we investigated the mechanisms by which exogenously applied 20-HETE modulates vascular tone in small porcine coronary arteries. In organ chamber experiments, 20-HETE elicited a concentration-dependent contraction of small porcine coronary artery rings that was partially inhibited by the cyclooxygenase inhibitor diclofenac, the thromboxane and endoperoxide receptor antagonist SQ29548, and the thromboxane A2 synthase inhibitor furegrelate. Removal of endothelium attenuated the response to 20-HETE, whereas preconstriction of endothelium-denuded vessels to 25% of the maximum response with KCl markedly enhanced the response to 20-HETE. This 20-HETE-induced contraction was not associated with a significant increase in the intracellular concentration of Ca2+. 20-HETE-induced contraction was also observed in beta-escin-permeabilized arteries precontracted with a submaximal concentration of Ca2+ and was abolished by the Rho-kinase inhibitor Y27632, but was insensitive to the PKC inhibitor RO 31-8220. 20-HETE elicited the phosphorylation of the myosin light chain (MLC20) in coronary artery rings, an effect that was sensitive to Y27632 and mimicked by the thromboxane analog U46619. These data suggest that in small porcine coronary arteries, 20-HETE can induce contraction by 2 mechanisms, one endothelium-dependent involving the cyclooxygenase-dependent generation of vasoconstrictor prostanoids, and the other endothelium-independent. The latter response is associated with the activation of Rho-kinase, phosphorylation of MLC20, and sensitization of the contractile apparatus to Ca2+.
Hypertension 2003 Mar
PMID:20-HETE-induced contraction of small coronary arteries depends on the activation of Rho-kinase. 1262 99

Hesperidin (HES) and glucosyl hesperidin (GHES) have antihypertensive effects. In the present study, to clarify the antihypertensive mechanisms, we compared the effects of continuous ingestion of HES and GHES in spontaneously hypertensive rats (SHRs). HES and GHES ingestion for 8 wk significantly prevented hypertension and suppressed the mRNA expression of NADPH oxidase subunits and thromboxane A2 synthase in SHR aortas. Further, hesperetin, a common metabolite of HES and GHES, reduced thromboxane B2 release from SHR aortas. These findings indicate that continuous ingestion of HES and GHES prevents hypertension via regulating the gene expression related to the modulation of vascular tone.
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PMID:Effects of continuous ingestion of hesperidin and glucosyl hesperidin on vascular gene expression in spontaneously hypertensive rats. 2441 82


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