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 immunosuppressive drug cyclosporin A (CsA) frequently induces hypertension, but the mechanism(s) is unknown. Thus, we examined the mechanism(s) by which CsA increases arterial blood pressure (MAP) in the normotensive rat. Three different treatment modalities were used. First, chronic CsA treatment (20 mg/kg/day, s.c., for 1 week) significantly increased MAP from 109.6 +/- 2.3 mm Hg to 125.8 +/- 2.9 mm Hg (P less than .05). Second, subacute i.v. infusion of CsA (20 mg/kg daily for 3 days) increased MAP to even higher values (140.5 +/- 2.3 mm Hg), which correlated significantly with the highest circulating values of the drug. The pressor effect after i.v. infusion appears to be unrelated to endogenous release of catecholamines, because phentolamine, which abolishes the response to exogenous norepinephrine, failed to prevent the CsA-induced pressor response. Third, i.v. bolus injections of CsA (10-20 mg/kg) evoked immediate, dose-dependent and short-lasting increases in MAP (+15-25 mm Hg) in both anesthetized and conscious rats. Ganglionic blockade did not prevent this effect, rather, a 2- to 3-fold increase in amplitude (+40-60 mm Hg) and duration (+30-45 min) of the CsA-induced pressor response was observed in anesthetized rats. Heart rate was not increased significantly by either acute or chronic administration of CsA. Our results suggest that both CsA-induced pressor responses and hypertension are due to a peripheral action unrelated to sympathetic outflow. Furthermore, CsA's hypertensive effect is accompanied by severe morphological changes in the vascular endothelium and smooth muscle cells. In addition, CsA-treated rats showed significantly attenuated vasodilatory responses to prostacyclin and sodium nitroprusside, and increased pressor responses to norepinephrine. Thus, a direct vascular action of CsA is likely to contribute to the alterations on systemic vascular responsiveness, as well as to the hypertensive effect of the drug.
 ...
PMID:Systemic vascular effects of cyclosporin A treatment in normotensive rats. 194 35

Pregnancy-induced hypertension is associated with a reduction in prostacyclin synthesis that is relative to normotensive pregnancy, whereas thromboxane A2 synthesis is unchanged or increased. The net effect is a decreased prostacyclin/thromboxane ratio that may result in the reduced fetal-placental blood flow seen in pregnancy-induced hypertension because thromboxane is known to constrict this circulation. Low-dose aspirin (acetylsalicylic acid), which is used to treat pregnancy-induced hypertension, selectively inhibits thromboxane synthesis and therefore may alter fetal-placental blood flow. We have investigated the transfer of acetylsalicylic acid in the perfused human placental cotyledon and its effects on fetal-placental perfusion pressure. Human placental cotyledons were perfused with tissue culture medium 199 plus 5% polyvinylpyrrolidone that was gassed with 95% oxygen/5% carbon dioxide at flow rates of 10 ml/min (maternal) and 4 ml/min (fetal). Acetylsalicylic acid (10(-5) mol/L) was added to the maternal circuit, and cotyledons were perfused for 1 hour with aliquots taken from a closed fetal circuit every 5 minutes. Acetylsalicylic acid was assayed by spectrofluorometry at 306/412 nm. Our data indicate an initial rapid transfer of acetylsalicylic acid during the first 5 minutes into the fetal-placental circulation, the concentration then decreased to a steady state at 0.4 x 10(-5) mol/L. Resting perfusion pressure of both maternal and fetal circulation did not change after the addition of acetylsalicylic acid to maternal perfusate and transfer to the fetal circulation.
 ...
PMID:Transfer of aspirin across the perfused human placental cotyledon. 195 59

As a source of several vasoactive factors, the endothelium takes part in the regulation of vascular tone. The most important endothelium-derived vasoactive substances are nitric oxide, prostacyclin, endothelin-1 and contracting factors requiring the activity of cyclooxygenase. The endothelium is an obvious target organ of cardiovascular risk factors. Accordingly, functional alterations do occur with aging, hypertension, and lipids. All three conditions are associated with a decreased basal and stimulated release of endothelium-derived nitric oxide. On the other hand, the release of endothelin-1 appears to increase with age, while the sensitivity to the peptide markedly decreases under the same conditions. In the spontaneously hypertensive rat, acetylcholine and stretch evoke the release of cyclooxygenase-dependent endothelium-derived contracting factor, most likely prostaglandin H2. The sensitivity and circulating levels of endothelin-1, on the other hand, are reduced in this experimental model of hypertension. In the porcine coronary circulation, oxidized low-density lipoproteins selectively reduce endothelium-dependent relaxations to aggregating platelets, serotonin, and thrombin which are mediated by nitric oxide. The alterations of endothelial function occurring with aging, hypertension, and hyperlipidemia may have important clinical implications for the pathogenesis of cardiovascular disease.
 ...
PMID:Endothelium-dependent control of vascular tone: effects of age, hypertension and lipids. 195 6

Production of some lipoxygenase and cyclooxygenase derivatives of arachidonic acid was measured in placental tissue obtained from women with gestational hypertension and with normal pregnancies. The levels of leukotriene B4 were about five times higher in placentas from hypertensive women and also raised thromboxane A2 and reduced prostaglandin E2 levels were observed. Prostacyclin production was lowered only in women with more severe hypertension, in association with the highest measured levels of leukotriene B4 and thromboxane A2. It is suggested that increased placental levels of leukotriene B4 and thromboxane A2 appear already in mild gestational hypertension, while depression of prostacyclin may occur only at more severe stages of gestational hypertensive disease.
 ...
PMID:Increased placental production of leukotriene B4 in gestational hypertension. 196 52

Adrenoceptor antagonists are being used increasingly for the treatment of pregnancy-induced hypertension (PIH). Previous studies have shown that these drugs can inhibit platelet aggregation and thromboxane production. The aims of this study were to determine (i) whether adrenoceptor antagonists had any effect on vascular prostacyclin (PGI2) production and (ii) whether these drugs acted synergistically with PGI2 and the PGI2-like activity derived from umbilical artery to inhibit platelet aggregation in vitro. The adrenoceptor antagonists labetalol, pindolol and propranolol were found to have no effect on PGI2 production from the umbilical artery at low drug concentrations. These agents were also found to act synergistically with both pure PGI2 and PGI2-like activity derived from umbilical artery to inhibit platelet aggregation. This synergistic effect may be beneficial in the treatment of disorders which are associated with reduced PGI2 production, such as PIH where such synergy may help compensate for PGI2 deficiency.
 ...
PMID:Synergistic inhibitory effects of adrenoceptor antagonists and prostacyclin, and umbilical artery-derived prostacyclin-like activity on platelet aggregation. 197 Jul 89

The effects of specific renin inhibitors, angiotensin converting enzyme inhibitors, indomethacin, and prostaglandin I2 analogue on the release of angiotensins from isolated and Krebs-Ringer-perfused rabbit mesenteric arteries were examined. Three different renin inhibitors suppressed release of angiotensins in dose-dependent manners. At the highest concentration (10(-7) M), the inhibitors EMD 52,620, EMD 54,388, and EMD 52,742 induced 46%, 52%, and 48% decreases, respectively, in the basal rate of immunoreactive angiotensin II release. These results provide clear evidence that released angiotensins are produced by the specific action of vascular renin and that the renin inhibitors suppress the vascular renin-angiotensin system as well as the circulating renin-angiotensin system and appear to provide a useful mode for the treatment of hypertension. Nonsulfhydryl angiotensin converting enzyme inhibitors cilazapril and delapril were more effective than captopril, and ramipril was equipotent to captopril, suggesting that the effectiveness of angiotensin converting enzyme inhibitors on the vascular renin-angiotensin system cannot be explained only by its inhibitory effect on angiotensin converting enzyme. Indomethacin, which was reported to suppress angiotensin II release from rat hind limbs, elicited a dose-dependent increase of angiotensin release from rabbit mesenteric arteries. These results suggest that a difference exists in the regulatory mechanisms in the release of angiotensins from diverse vascular beds.
Hypertension 1991 Mar
PMID:Significance of vascular renin for local generation of angiotensins. 199 57

Placental blood flow is reduced in pregnancies complicated by hypertension, intrauterine growth retardation, maternal smoking, or diabetes. Umbilical-placental production of the potent vasodilator prostacyclin is also reduced in these pathologic states and this deficiency may contribute to an associated increase in the incidence of low infant birthweight by affecting a reduction in placental nutrient transfer. We have studied the effects of the prostacyclin analogue carbacyclin on diffusional transfer in the human placenta perfused in vitro. We have found that carbacyclin crosses the human placenta and can significantly increase diffusional transfer in placenta from pregnancies complicated by hypertension or maternal smoking and in the normal term placenta in which prostacyclin production has first been reduced through the administration of ibuprofen. Carbacyclin had no effect, however, in untreated placenta from normal pregnancies or in placenta from diabetic pregnancies. These results suggest that the prostacyclin-deficient perfused placenta may serve as a model for several placental insufficiency syndromes and that the possibility that prostacyclin analogues may improve deficient nutrient transfer in some pathologic pregnancies warrants further investigation.
 ...
PMID:A prostacyclin analogue crosses the in vitro perfused human placenta and improves transfer in some pathologic states. 202 77

More than a decade has passed since the introduction of the concept that inhibition of platelet function may be helpful in preventing the initiation of thrombus formation. Aspirin has been recognized as inhibiting normal platelet function and the mechanism has been clearly delineated. Legions of patients have been studied to answer the question of whether aspirin is efficacious in the primary prevention of acute myocardial infarction. At the present time, however, a solid, clear answer is not available and firm recommendations cannot be made. A large number of studies evaluating aspirin and other antiplatelet agents in the prevention or delay of recurrent myocardial infarction (secondary prevention) have been completed and those studies reporting a favorable beneficial effect are in the minority. In these secondary prevention studies reporting success, the doses of aspirin employed were large enough to inhibit both the cyclo-oxygenase system and thromboxane A2 production as well as the synthesis of prostacyclin. Thus, in these studies if aspirin is effective in reducing adverse cardiovascular events, its efficacy is being mediated by an unknown mechanism. If the reader of the few studies that report positive results is convinced of the benefit of aspirin, it must be emphasized that thoughtful, cautious patient selection based upon the individual's cardiovascular risk profile must be exercised. Individual variation may exist with respect to aspirin's beneficial effect. It must be absolutely recognized that aspirin or any antiplatelet agent does not in any way substitute for the removal or treatment of coexisting risk factors such as tobacco, obesity, hypercholesterolemia, hyperlipidemia, hypertension, and metabolic disease. In contrast to aspirin, control of the above risk factors has been established as beneficial. Aspirin is not free of undesirable side-effects; fatalities secondary to hemorrhage have been reported, and these must be known in detail and understood by both physician and patient before this agent is prescribed in the prophylactic treatment of cardiovascular disease.
 ...
PMID:Aspirin in the prevention of thrombosis. 203 Jun 40

Arterial wall injury either by balloon catheter, drying, or scraping results in a denudation of endothelial cells (EC) and a subsequent proliferation of smooth-muscle cells (SMC). The degree of SMC proliferation appears to be dependent on the degree of initial injury and not to the loss of the overlying endothelium. Successful reendothelialization of denuded areas depends on the size of the denuded segment as well as SMC-EC interactions. Prolonged exposure of SMC to serum substances results in inhibition of EC regrowth, the production of prostacyclin by SMC, and the development of a thromboresistant surface. Heparin appears to inhibit SMC proliferation in vivo (as well as in vitro), an effect that is independent of platelet SMC interaction. EC-derived heparin in vivo may also result in inhibition of SMC proliferation. Platelets may play an important role in the early response to arterial injury and development of myointimal hyperplasia (MIH), but their long-term role appears to be minor. Antiplatelet agents have widely varying species-dependent effects on platelets and platelet-vessel wall interactions, but in specific circumstances they may inhibit MIH. The precise role of steroid drugs and immunosuppression on MIH in arterial injury models awaits further study. The role of lipoproteins in MIH is unclear; however, the inhibition of MIH by omega-3 fatty acids in vivo as well as their inhibition of platelet-derived growth factor production by EC in vitro implies a regulatory role. Acute hypertension results in a marked proliferation of EC and SMC in vivo and enhances the proliferative response to injury as well. Low wall shear stress, turbulence, and boundary layer separation all increase EC turnover, a likely influence on EC growth factor production. The compliance mismatch resulting from graft-artery anastomoses, injury, and endarterectomy results in locally increased cyclical stretch, which may predispose to SMC proliferation.
 ...
PMID:Myointimal hyperplasia: pathogenesis and implications. 2. Animal injury models and mechanical factors. 203 59

We have identified two distinct cellular responses that occur in human astrocytes in the presence of angiotensin (Ang) peptides and are linked to specific receptor subtypes. Ang II and the N-terminal heptapeptide Ang-(1-7) stimulated release of prostaglandin (PG) E2 and PGI2 (measured as the stable metabolite 6-keto-PGF1 alpha). In contrast, only Ang II but not Ang-(1-7) activated phosphoinositide-specific phospholipase C, leading to mobilization of intracellular calcium. The Ang II-induced PGE2 and PGI2 syntheses were attenuated by [Sar1,Ile8]Ang II but not by [Sar1,Thr8]Ang II. Ang-(1-7)-induced PGE2 and PGI2 syntheses were not inhibited by either of these two classical antagonists. DuP 753, a subtype 1-selective Ang receptor antagonist, blocked the Ang II-induced release of PGE2 but not PGI2. In contrast, CGP 42112A, the subtype 2-selective antagonist, totally blocked the Ang II-induced PGI2 release and partially attenuated the PGE2 release. Ang-(1-7)-induced PGE2 and PGI2 release was not altered by DuP 753; however, CGP 42112A totally blocked the effects of Ang-(1-7) on PG stimulation. Calcium mobilization in response to Ang II was blocked by [Sar1,Thr8]Ang II, [Sar1,Ile8]Ang II, and DuP 753 but not by CGP 42112A. These data suggest that human astrocytes contain both Ang receptor subtypes. The subtype 1 Ang receptor participates both in the release of PGs and in the mobilization of calcium, whereas the subtype 2 receptor is coupled to the release of PGs only. In addition, PG release coupled to subtype 2 Ang II receptors occurs through a calcium-independent mechanism and responds uniquely to Ang-(1-7).
Hypertension 1991 Jun
PMID:Subtype 2 angiotensin receptors mediate prostaglandin synthesis in human astrocytes. 204 58


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