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)

We recently identified a subgroup of rabbits (called nonresponders) that were deficient in vascular thromboxane A2 receptors. Thromboxane A2-mediated platelet aggregation was not different between responders and nonresponders. In the present study, we utilized these nonresponders as a model to study the relative contribution of the platelet and vascular thromboxane A2 receptors to the observed hemodynamic responses associated with arachidonic acid-induced sudden death. Mean arterial pressure was slightly but not significantly lower in the nonresponders compared with the responders. However, nonresponders were protected from arachidonic acid-induced sudden death. While 100% of the responders died at the 2.0 mg dose of arachidonic acid, only 27% of nonresponders died at this same dose. Administration of the thromboxane A2 mimetic U46619 (5 micrograms/kg IV) decreased blood pressure by 41 +/- 6 mm Hg in responders but had no effect in the nonresponders. The affinity and density of thromboxane A2 receptors in cultured aortic vascular smooth muscle cells obtained from both responders and nonresponders were assessed using radioligand binding. The Kd values were not different (4.4 +/- 1.0 versus 2.4 +/- 0.6 nmol/L, responder versus nonresponder). However, there was a significant decrease in the density of receptors from vascular smooth muscle cells of nonresponders (Bmax = 397 +/- 59 versus 157 +/- 59 fmol/10(6) cells, responder versus nonresponder, P < .01). U46619 produced a concentration-dependent increase in [3H]-thymidine incorporation into responder vascular smooth muscle cells but had no effect in the nonresponder cells. Using an anti-thromboxane A2 receptor antibody, we compared the amount of receptor expressed in aortic tissue obtained from responders and nonresponders. Consistent with the results observed with [3H]-thymidine uptake and radioligand binding assays, the expression of thromboxane A2 receptor protein was decreased in nonresponder compared with responder vascular tissue. Platelet thromboxane A2 receptor expression was not different. These studies demonstrate that the vascular smooth muscle cells of nonresponder rabbits are deficient in the thromboxane A2 receptor. Furthermore, the reduction in arachidonic acid-induced sudden death in nonresponders indicates that the vascular smooth muscle thromboxane A2 receptor mediates this effect.
Hypertension 1997 Jan
PMID:Vascular smooth muscle thromboxane A2 receptors mediate arachidonic acid-induced sudden death in rabbits. 903 19

Arachidonic acid- and methacholine-induced contractions of rabbit pulmonary arteries are mediated by thromboxane (TX) A2. Although removal of the endothelium abolishes the contractions, endothelial cells isolated from pulmonary arteries do not synthesize TXA2. Further studies described here showed that the expression of TX synthase was evident in platelets and intact pulmonary artery but not in endothelial cells. These studies examined the role of platelet TXA2 production in the vasoconstrictor response to methacholine. Endothelial cells were incubated with platelets in the presence or absence of methacholine. Methacholine caused an increase in TXB2 production. Pretreatment of endothelial cells with aspirin (100 micromol/L) before the addition of platelets did not impair the ability of methacholine to increase TXB2 synthesis. Conversely, if platelets were pretreated with aspirin, methacholine failed to stimulate TXB2. Using endothelial cells with their cellular lipids labeled with [3H]arachidonic acid, methacholine did not stimulate the production of [3H]TXB2. When the endothelial cells were incubated with methacholine and control platelets, [3H]TXB2 was detected. If aspirin-treated platelets were incubated with endothelial cells, methacholine did not increase the production of [3H]TXB2. However, pretreatment of the endothelial cells with aspirin did not affect the ability of methacholine to induce [3H]TXB2 release. This suggests that methacholine stimulated the endothelial cell to release arachidonic acid, which was transferred to the platelets and metabolized to TXA2. To test whether this cell-cell interaction is necessary for methacholine-induced contractions, rabbits were administered aspirin (20 mg/kg) for 2 days. On day 4, methacholine-induced contractions of pulmonary arteries were depressed in aspirin-treated compared with control subjects. Control arteries synthesized 6-keto-prostaglandin F1alpha and TXB2. Aspirin treatment inhibited both pulmonary artery and platelet TXB2 production but had no effect on vessel 6-keto-prostaglandin F1alpha. These studies implicate platelets as a vascular source of TXA2 and indicate that both endothelial cells and platelets may be required for methacholine-induced TXA2 synthesis and vasoconstriction.
Hypertension 1998 Jan
PMID:Methacholine-induced contraction of rabbit pulmonary artery: role of platelet-endothelial transcellular thromboxane synthesis. 945 4

Losartan is a potent non-peptide, selective angiotensin II (AngII) type 1 (AT1) receptor antagonist. Losartan has been worldwide marketed as the first orally active AT1 receptor antagonist with once-daily dosing for treatment of hypertension. In a study of patients with heart failure, the mortality appeared to be lower with losartan than with the ACE inhibitor captopril. In healthy subjects, losartan produced a dose-dependent reduction in serum uric acid. The mechanism of action is considered to be the inhibition of reabsorption of uric acid in the proximal tubules of the kidney. Furthermore, it was recently reported that losartan has moderate affinity for the thromboxane (TX) A2 receptor in a competitive-inhibition manner in the platelets and vascular smooth muscle. The efficacy of losartan with regard to not only AT1 receptor blockade, but also the reduction of serum uric acid and the blockade of TXA2 receptors, may be advantageous to patients with hypertension having these cardiovascular risk factors.
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PMID:[Pharmacological properties and its significance in clinical practice]. 1036 45

The purpose of this study was to assess whether regimen comprehension deteriorates in the elderly without obvious mental disability. Eligible patients were elderly who could visit hospitals by themselves. We recruited 138 patients (age: 43-89, 75 males and 63 females, underlying diseases: hypertension, hyperlipidemia, arrhythmia etc.) from our outpatient clinic. The participants were tested with a regimen comprehension scale (RCS: Jpn J Geriat 1997; 34:209-214). The differences in scores among individuals increased with age. Scores of 5 or less were recorded in 10 of 69 patients aged 65 or more, but in non of 69 patients aged less than 65 (p < 0.01). The 60 patients who could not get full marks were classified into 2 groups: the tutored group (T) who were tutored by pharmacists about taking drugs, and the non-tutored group (N). Both group were tested again with RCS to evaluate the effect of tutorial. In T-group (n = 28), the second scores increased significantly (from 7.2 +/- 0.9 to 8.6 +/- 2.0 (m +/- SD); p < 0.01). Although the second scores showed a tendency to increase in N-group (n = 29), there was no statistical significance. In 7 patients who obtained less than a score of 5 on the RCS and age- and gender-matched controls who received full marks on the RCS, the HDS-R test failed to show any differences between the two groups. Thus, we concluded that even in the self-attending elderly patients, the regimen comprehension deteriorated with age, and tutorials were considered to be effective.
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PMID:[The deterioration of regimen comprehension in self-attending elderly patients and the effect of tutorials by pharmacists]. 1065 35

We investigated whether regimen comprehension deteriorated in the elderly patients who did not suffer from obvious dementia. Eligible patients were ambulatory elderly patients who did not show any signs of dementia and could visit our outpatient clinic by themselves. 138 patients (age: 43-89, 75 males and 63 females, underlying diseases: hypertension, hyperlipidemia, arrhythmia etc.) were tested with a regimen comprehension scale (RCS: Jpn J Geriat 1997; 34: 209-214). The differences in scores among individuals increased with age. Scores of 5 or less in the RCS were recorded in 10 out of 69 patients aged 65 or more, but no such scores were recorded in younger patients (p < 0.01). The 60 patients who scored less than full marks were classified into two groups, the T-group (tutored by pharmacists), and a Non Tutored group. RCS was tested again in both groups. Only in the T-group (n = 28), did the second scores increase significantly (from 7.2 +/- 0.9 to 8.6 +/- 2.0 (m +/- SD); p < 0.01) after tutorial by pharmacists. Comparing the 7 patients who obtained an RCS score of 5 or less and age- and gender-matched controls who got full marks, there was no difference in the HDS-R test. These results suggest that even in elderly patients who did not show any signs of dementia, the regimen comprehension deteriorated with age, and tutorials in medication protocols were considered to be effective.
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PMID:Medication management skill and regimen compliance are deteriorated in the elderly even without obvious dementia. 1121 34

This review presents a comprehensive discussion on the chemistry, pharmacokinetics, and pharmacodynamics of ifetroban sodium, a new thomboxane A2/prostaglandin H2 receptor antagonist. Thromboxane A2 is an arachidonic acid product, formed by the enzyme cyclooxygenase. In contrast to other cyclooxygenase products, thromboxane A2 has been shown to be involved in vascular contraction and has been implicated in platelet activation. In general, results of clinical studies and animal experiments indicate that hypertension is associated with hyperaggregability of platelets and increased thomboxane A2 levels in blood, urine, and tissues. The precursors to thromboxane A2, prostaglandin G2, and prostaglandin H2, also bind and activate the same receptors. Thus, a receptor antagonist was thought to be an improved strategy for reversing the actions of thromboxane A2/prostaglandin H2, rather than a thromboxane synthesis inhibitor. This review describes new methods for the synthesis and analysis of ifetroban, its tissue distribution, and its actions in a variety of animal models and disease states. We describe studies on the mechanisms of how ifetroban relaxes experimentally contracted isolated vascular tissue, and on the effects of ifetroban on myocardial ischemia, hypertension, stroke, thrombosis, and its effects on platelets. These experiments were conducted on several animal models, including dog, ferret, and rat, as well as on humans. Clinical studies are also described. These investigations show that ifetroban sodium is effective at reversing the effects of thromboxane A2- and prostaglandin H2-mediated processes.
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PMID:Ifetroban sodium: an effective TxA2/PGH2 receptor antagonist. 1148 65

The influence of the endothelium on aortic contractility to KCl 100 mM was studied during maturation and aging in normotensive Wistar and spontaneously hypertensive rats (SHR). In Wistar rats, there was no significant difference in maximal responses in the course of aging whether the endothelium was present (E+) or not (E-). A similar result was obtained in SHR E- rings. However, contraction was significantly higher in E+ rings of young (9 weeks) compared to adult and old SHR (18, 25, 36 and 72 weeks) (in mN/mm2: 34.8 +/- 3.1 versus 24.8 +/- 1.8, 16.0 +/- 2.5, 17.4 +/- 2.0 and 12.9 +/- 1.8, p<0.01). This increase remained significant in 18- compared to that of 25-, 36- and 72-week-old rats (p<0.01). No change appeared with age in noradrenaline-induced contractions of E+ rings neither in Wistar nor in SHR. A dose-dependent decrease in response to KCl was observed after an in vivo pretreatment of the young SHR with acetylsalicylic acid. Finally, blocking the TXA2/PGH2 receptor by addition of GR 32191B or ONO-3708 led to a decrease in the response of young SHR aortic rings to KCl. This study points out a decrease in the response of SHR aortic rings to a depolarizing agent during maturation. The enhanced contraction observed in young SHR seems to be the result of an increased participation of an endothelium-derived, cyclooxygenase-dependent contracting factor(s), most likely either TXA2 or PGH2. This factor might play a key role in the onset of hypertension in the spontaneously hypertensive strain.
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PMID:Maturation reveals a decrease in endothelium-dependent contraction induced by depolarization in the aorta of spontaneously hypertensive rats. 1166 41

Have studied action of chronic urea--an arginase inhibitor--introduction (40 mg/kg, 28 days) on blood pressure, endothelium-dependent reactions of aorta smooth muscle cells (SMC) and nonenzymatic (contents of diene conjugates and H2O2) and enzymatic (contents of free arachidonic acid and vasoconstrictic eicosanoids LTC4 and TXA2) oxidizing lipid metabolism of heart, aorta, plasma and erythrocytes of spontaneously hypertensive rats. Have shown, that urea down regulate blood pressure without any normalization of endothelium-dependent reactions of SMC of aorta and down regulate both enzymatic and nonenzymatic oxidizing lipid metabolism. Down regulation of two alternative (by cyclooxygenase and by lipoxygenase) enzymatic pathways of free arachidonic acid oxidizing metabolism by urea can be one of mechanisms of its antihypertensive action. The possibility of urea use at hypertension and various pathophysiological conditions are discussed.
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PMID:[Inhibitors of arginase in the L-arginine metabolic pathway as a new class of antihypertensive drugs: effect of carbamide on lipid oxidative metabolism and on vessel tonus during arterial hypertension]. 1175 64

Angiotensin II (Ang II) type 1 receptor (AT(1)) antagonists such as losartan (LOS) are widely used for the treatment of hypertension and elicit antiinflammatory and antiaggregatory in vitro and in patients, although the underlying mechanism are unclear. Following computer-based molecule similarity, we proposed that on cytochrome-P450 degradation, the LOS metabolite EXP3179 is generated, which shows molecule homology to indomethacin, a cyclooxygenase inhibitor with antiinflammatory and antiaggregatory properties. Subsequently, serum-levels of EXP3179 were determined for 8 hours in patients receiving a single oral dose of 100 mg LOS. High-performance liquid chromatography followed by liquid chromatography-mass spectrometry (GC-MS) [corrected] from serum samples revealed a maximum of 10(-7) mol/L for EXP3179 peaking between 3 to 4 hours. The increase in serum-EXP3179 levels was associated with a significant reduction in platelet aggregation in vivo (-35+/-4%, P<0.001 versus control). EXP3179 generation was investigated in a chemical reaction mimicking the liver cytochrome-P450-dependent LOS-degradation and human endothelial cells were exposed to Ang II or lipopolysaccharides (LPS) in the presence of EXP3179 (10(-7) mol/L). LPS- and Ang II-induced COX-2 transcription was abolished by EXP3179. Moreover, EXP3179 significantly reduced Ang II- and LPS-induced formation of prostaglandin F2alpha as determined by GC-MS [corrected]. Thus, antiinflammatory properties of LOS are mediated via its EXP3179 metabolite by abolishing COX-2 mRNA upregulation and COX-dependent TXA2 and PGF2alpha generation. Serum levels of EXP3179 are detectable in patients in concentrations that exhibit antiinflammatory and antiaggregatory properties in vitro.
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PMID:Angiotensin II receptor-independent antiinflammatory and antiaggregatory properties of losartan: role of the active metabolite EXP3179. 1196 66

Hyperuricemia is associated with renal disease, but it is usually considered a marker of renal dysfunction rather than a risk factor for progression. Recent studies have reported that mild hyperuricemia in normal rats induced by the uricase inhibitor, oxonic acid (OA), results in hypertension, intrarenal vascular disease, and renal injury. This led to the hypothesis that uric acid may contribute to progressive renal disease. To examine the effect of hyperuricemia on renal disease progression, rats were fed 2% OA for 6 wk after 5/6 remnant kidney (RK) surgery with or without the xanthine oxidase inhibitor, allopurinol, or the uricosuric agent, benziodarone. Renal function and histologic studies were performed at 6 wk. Given observations that uric acid induces vascular disease, the effect of uric acid on vascular smooth muscle cells in culture was also examined. RK rats developed transient hyperuricemia (2.7 mg/dl at week 2), but then levels returned to baseline by week 6 (1.4 mg/dl). In contrast, RK+OA rats developed higher and more persistent hyperuricemia (6 wk, 3.2 mg/dl). Hyperuricemic rats demonstrated higher BP, greater proteinuria, and higher serum creatinine than RK rats. Hyperuricemic RK rats had more renal hypertrophy and greater glomerulosclerosis (24.2 +/- 2.5 versus 17.5 +/- 3.4%; P < 0.05) and interstitial fibrosis (1.89 +/- 0.45 versus 1.52 +/- 0.47; P < 0.05). Hyperuricemic rats developed vascular disease consisting of thickening of the preglomerular arteries with smooth muscle cell proliferation; these changes were significantly more severe than a historical RK group with similar BP. Allopurinol significantly reduced uric acid levels and blocked the renal functional and histologic changes. Benziodarone reduced uric acid levels less effectively and only partially improved BP and renal function, with minimal effect on the vascular changes. To better understand the mechanism for the vascular disease, the expression of COX-2 and renin were examined. Hyperuricemic rats showed increased renal renin and COX-2 expression, the latter especially in preglomerular arterial vessels. In in vitro studies, cultured vascular smooth muscle cells incubated with uric acid also generated COX-2 with time-dependent proliferation, which was prevented by either a COX-2 or TXA-2 receptor inhibitor. Hyperuricemia accelerates renal progression in the RK model via a mechanism linked to high systemic BP and COX-2-mediated, thromboxane-induced vascular disease. These studies provide direct evidence that uric acid may be a true mediator of renal disease and progression.
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PMID:A role for uric acid in the progression of renal disease. 1244 7


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