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 have previously shown that pretreatment of A-10 smooth muscle cells (SMC) with angiotensin II (Ang II) attenuated atrial natriuretic peptide (ANP) receptor-C (ANP-C)-mediated inhibition of adenylyl cyclase without altering (125)I-ANP binding. In the present studies, we have investigated the modulation of ANP-C receptor signaling by endothelin-1 (ET-1). Pretreatment of A-10 SMC with ET-1 for 24 h attenuated the expression of ANP-C receptor by about 60% as determined by immunoblotting which was reflected in attenuation of ANP-C-receptor-mediated inhibition of adenylyl cyclase. C-ANP(4-23) [des(Gln(18),Ser(19),Gln(20),Leu(21),Gly(22))ANP(4-23)-NH(2)], a ring-deleted peptide of ANP that interacts specifically with ANP-C receptor, inhibited adenylyl cyclase activity in a concentration-dependent manner with an apparent K(i) of about 1 nM in control cells. The maximal inhibition observed was about 30% which was almost completely attenuated in ET-1-treated cells. In addition, Ang II- and oxotremorine-mediated inhibitions of adenylyl cyclase were also attenuated by ET-1 treatment; however, the expression of Gialpha-2 and Gialpha-3 proteins and not of Gsalpha and Gbeta proteins was augmented by such treatment. The increased expression of Gialpha-2 and Gialpha-3 proteins by ET-1 treatment was inhibited by actinomycin D treatment (RNA synthesis inhibitor). On the other hand, the Gsalpha-mediated effects of some agonists on adenylyl cyclase activity were significantly decreased by ET-1 treatment. These results suggest that ET-1-induced downregulation of ANP-C receptor and not the overexpression of Gi proteins may be responsible for the attenuation of C-ANP(4-23)-mediated inhibition of adenylyl cyclase activity. From these studies it may be suggested that the downregulation of ANP-C receptors by increased levels of endothelin in vivo may be one of the possible mechanisms for the pathophysiology of hypertension.
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PMID:Modulation of ANP-C receptor signaling by endothelin-1 in A-10 smooth muscle cells. 1205 68

Increased fibrinogen concentration and erythrocyte aggregation are significant risk factors during various cardiovascular diseases and cerebrovascular disorders. Currently, fibrinogen-induced erythrocyte aggregation is thought to be caused by a non-specific binding mechanism. However, the published data on changes in erythrocyte aggregation during hypertension point to the possible existence of other mechanism(s). Therefore, we tested the hypothesis that specific binding of fibrinogen is involved in erythrocyte aggregation. It was found that Oregon Green 488-labeled human fibrinogen specifically binds rat erythrocyte membranes with a Kd of 1.3 microM. Further experiments showed that the peptide Arg-Gly-Asp-Ser blocked both fibrinogen-induced aggregation of intact erythrocytes and specific binding of fibrinogen to the erythrocyte membranes. These results suggest that in addition to non-specific binding, a specific binding mechanism is also involved in fibrinogen-induced erythrocyte aggregation.
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PMID:Involvement of fibrinogen specific binding in erythrocyte aggregation. 1206 6

beta-Adrenoceptor antagonists play an important role in the treatment of cardiovascular disease and have been used for three decades in the treatment of hypertension and ischemic heart disease. More recently they have been demonstrated to improve survival in patients with mild to moderate congestive heart failure. The beneficial effects of beta-adrenoceptor antagonists stems from their ability to limit the deleterious effects of adrenergic stimulation, which in the cardiovascular system is primarily transmitted through two subclasses of receptor, beta(1) and beta(2). The advances of the Human Genome Project have led to an increased appreciation that variations in genetic background may underlie a substantial portion of the clinical heterogeneity apparent in cardiovascular disease. This review examines the molecular, functional, and clinical significance of the most common polymorphisms of the beta(1 and beta(2)-adrenoceptors. Initial research in adrenoceptor variation focused on the beta(2)-adrenoceptor. Three common polymorphisms appear to influence receptor function: Arg16-->Gly, Glu(27)-->Gln, and Thr(164)-->Ile. In in vitro studies of agonist stimulation, Gly(16) receptors demonstrate enhanced downregulation, while Glu(27) variants are resistant to downregulation. There is much controversy and conflict among various clinical studies regarding the effect of these variants on vasoreactivity and hypertensive risk. The Ile(164) variant demonstrates decreased responsiveness to agonist activity both in vitro and in animal models. In studies of patients with congestive heart failure, this variant has been associated with poor functional capacity and decreased survival. More recent investigations have focused on the two common polymorphisms of the beta(1)-adrenoceptor: Ser(49)-->Gly, and Arg(389)-->Gly. In vitro studies of Arg(389) receptors demonstrate a gain of function, as agonist stimulation results in significantly higher intracellular levels of cyclic adenosine monophosphate when compared with the Gly(389) variant. Consistent with the in vitro data, clinical studies demonstrate increased responsiveness to beta-agonist stimulation, and an increased risk of hypertension among Arg(389) homozygotes. Further investigation of the clinical implications of these common variants of beta(1)- and beta2)-adrenoceptors are needed. Importantly, the pharmacogenetic impact of these variants on the effectiveness of beta-adrenergic blockade remains unknown.
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PMID:Clinical importance of beta-adrenoceptor polymorphisms in cardiovascular disease. 1208 43

alpha-lactorphin (Tyr-Gly-Leu-Phe) lowers blood pressure in conscious adult SHR. This tetrapeptide is originally released from milk protein alpha-lactalbumin by enzymatic hydrolysis. In order to evaluate the antihypertensive mechanisms of alpha-lactorphin, the effects of the tetrapeptide on vascular function were investigated in (30-35 weeks old) spontaneously hypertensive rats (SHR) with established hypertension and age-matched normotensive Wistar-Kyoto (WKY) rats in vitro. In addition, we studied the vascular effects of another structurally related tetrapeptide, beta-lactorphin (Tyr-Leu-Leu-Phe), which originates from milk protein beta-lactoglobulin. Endothelium-dependent relaxation to acetylcholine (ACh) was reduced in mesenteric arterial preparations of SHR as compared to those of WKY. In SHR, the ACh-induced relaxation was augmented by alpha-lactorphin or beta-lactorphin. The role of nitric oxide (NO) is suggested, since this improvement was abolished by the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Simultaneous potassium channel inhibitor tetraethylammonium (TEA) elicited no additional effect on the ACh-induced relaxation. The cyclooxygenase inhibitor diclofenac did not attenuate the augmented ACh relaxation induced by alpha-lactorphin or beta-lactorphin, suggesting that endothelial vasodilatory prostanoids were not involved in the effect of the tetrapeptides. Endothelium-independent relaxation to the NO donor sodium nitroprusside (SNP) was augmented in mesenteric arterial preparations of SHR by simultaneous beta-lactorphin. The tetrapeptides did not alter vascular responses in mesenteric arteries from WKY. In conclusion, both alpha-lactorphin and beta-lactorphin improved vascular relaxation in adult SHR in vitro. The beneficial effect of alpha-lactorphin was directed towards endothelial function, whereas beta-lactorphin also enhanced endothelium-independent relaxation.
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PMID:Alpha-lactorphin and beta-lactorphin improve arterial function in spontaneously hypertensive rats. 1210 90

Human adrenomedullin (hAM) is a 52-amino-acid regulatory peptide containing a six-membered ring structure and an amidated C-terminus, features that are essential for its biological activity. Here, we describe a simple and effective protocol for producing large quantities of highly pure, functional recombinant hAM. A peptide precursor (hAM-Gly) was expressed in Escherichia coli as a fusion protein with thioredoxin and collected as inclusion bodies. The fusion protein was then digested with BLase, a glutamate-specific endopeptidase, to prepare hAM-Gly. The essential ring structure formed spontaneously, while the terminal amide was generated by conversion of the added glycine residue using peptidylglycine alpha-amidating enzyme. The low solubility of hAM-Gly enabled the use of a selective precipitation/extraction method to generate a product that was 80-90% pure, which was sufficient to proceed with the alpha-amidating enzyme reaction. The resultant hAM was then purified further by column chromatography. The final yield was about 82 mg/L of bacterial culture, and the purity, determined by reverse phase HPLC, was >99.5%. The recombinant hAM was biologically active, eliciting concentration-dependent increases in cAMP in CHO-K1 cells expressing a specific hAM receptor and hypotensive responses when intravenously injected into rats. This new approach to the synthesis of hAM is simpler and more cost-effective for large-scale production than chemical synthesis. It therefore represents a new powerful tool that has the potential to facilitate analysis of the structure and function of hAM, as well as the development of new therapeutic protocols for the treatment of ailments such as hypertension.
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PMID:Large-scale production of functional human adrenomedullin: expression, cleavage, amidation, and purification. 1218 25

Dioscorin, the tuber storage protein of yam (Dioscorea alata cv. Tainong No. 1), was purified to homogeneity by DE-52 ion-exchange chromatography. This purified dioscorin was shown by spectrophotometric methods to inhibit angiotensin converting enzyme (ACE) in a dose-dependent manner (12.5-750 microg, respectively, 20.83-62.5% inhibitions) using N-[3-(2-furyl)acryloyl]-Phe-Gly-Gly (FAPGG) as substrates. The 50% inhibition (IC(50)) of ACE activity was 6.404 microM dioscorin (250 microg corresponding to 7.81 nmol) compared to that of 0.00781 microM (0.0095 nmol) for captopril. The commercial bovine serum albumin and casein (bovine milk) showed less ACE inhibitory activity. The use of qualitative TLC also showed dioscorin as ACE inhibitors. Dioscorin showed mixed noncompetitive inhibitions against ACE; when 31.25 microg of dioscorin (0.8 microM) was added, the apparent inhibition constant (K(i)) was 2.738 microM. Pepsin was used for dioscorin hydrolysis at 37 degrees C for different times. It was found that the ACE inhibitory activity was increased from 51.32% to about 75% during 32 h hydrolysis. The smaller peptides were increased with increasing pepsin hydrolytic times. Dioscorin and its hydrolysates might be a potential for hypertension control when people consume yam tuber.
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PMID:Both dioscorin, the tuber storage protein of yam (Dioscorea alata cv. Tainong No. 1), and its peptic hydrolysates exhibited angiotensin converting enzyme inhibitory activities. 1235 88

When rat dams consume a diet low in protein during pregnancy, their offspring develop high blood pressure. On a low-protein diet, the endogenous formation of the amino acid glycine is thought to become constrained. Glycine may become conditionally essential, as its rate of endogenous formation is inadequate to meet metabolic needs, and may be limiting for the normal development of the fetus. In the present study, five groups of Wistar rats were provided during pregnancy with one of five diets: a control diet containing 18% (w/w) casein (CON), a low-protein diet containing 9% casein (MLP), or the low-protein diet supplemented with 3% glycine (MLPG), alanine (MLPA) or urea (MLPU). The offspring were weaned on to standard laboratory chow, and blood pressure was measured at 4 weeks of age. Blood pressure was significantly increased in the MLP, MLPA and MLPU groups compared with the CON group, but for the MLPG group blood pressure was not significantly different from CON. Compared with the CON group, body weight was significantly reduced for the MLP, MLPA and MLPG groups, but for the MLPU group body weight was not different from CON. These data show that different forms of non-essential dietary nitrogen, when consumed during pregnancy, exert different effects upon the growth and function of the offspring. The availability of glycine appears to be of critical importance for normal cardiovascular development.
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PMID:Increased systolic blood pressure in rats induced by a maternal low-protein diet is reversed by dietary supplementation with glycine. 1244 17

Polymorphisms in the gene encoding the beta(2)-adrenoceptor have been associated with interindividual differences in blood pressure and the diagnosis of hypertension. A common polymorphism resulting in a change from arginine to glycine at amino acid 16 (Arg16-->Gly) enhances agonist-promoted downregulation of receptor expression in vitro. It is unknown whether genotype-dependent differences in nitric oxide generation contribute to differences in vasodilator responses to beta(2)-agonists in vivo. To address this question, venous occlusion plethysmography was used to measure forearm blood flow responses to graded brachial artery infusions of the beta-agonist isoproterenol in 41 healthy normotensive Caucasian adults (mean age (+/- S.D.) = 29 +/- 6 years), who were either Arg16 (n = 18) or Gly16 (n = 23) homozygotes. Compared to Arg16 homozygotes, Gly16 homozygotes demonstrated significantly greater blood flow responses to isoproterenol (P = 0.02). After inhibition of nitric oxide synthase by N(gamma)-monomethyl-L-arginine, blood flow responses did not differ significantly between genotype groups (P = 0.27). Consequently, effects of the Arg16 Gly polymorphism on forearm blood flow responses to isoproterenol appear to be dependent on differences in endothelial generation of nitric oxide. In contrast to previous reports based on systemic infusions of beta(2)-agonists, our findings indicate that regional blood flow responses to locally infused isoproterenol are significantly greater in Gly16 than in Arg16 homozygotes.
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PMID:Beta(2)-adrenergic receptor polymorphism and nitric oxide-dependent forearm blood flow responses to isoproterenol in humans. 1252 44

In this study, we investigated the cardiovascular responses mediated by rostral ventrolateral medulla neurons (RVLM) in the Goldblatt hypertension model (2K-1C) treated or not treated with captopril. The actions of glutamate into the RVLM were tested, injecting glutamate (0.1 mol/L, 100 nL) and its antagonist kynurenic acid (0.02 mol/L, 100 nL). Glycine (0.5 mol/L, 100 nL) was also microinjected. Experiments were performed in male Wistar rats (weight, 250 to 300 g); 5 groups were studied: (1) 2K-1C nontreated (H, n=6); (2) 2K-1C treated with captopril, 10 mg/kg per day (Ht10, n=10); (3) 2K-1C treated with captopril, 50 mg/kg per day (Ht50, n=7); (4) control normotensive rats (N, n=7); and (5) normotensive rats treated with captopril, 50 mg/kg per day (Nt50, n=8). All experiments in 2K-1C were performed 6 weeks after renal surgery; captopril treatment lasted for the last 2 weeks. In urethane-anesthetized rats (1.2 g/kg IV), bilateral microinjection of glycine into the RVLM caused a depressor response; there was no difference between groups in relation to the change of variation (N: 54+/-2; H: 46+/-12; Ht10: 50+/-3, and Ht50: 42+/-7 mm Hg). Only in the H group, kynurenic acid microinjection into the RVLM caused a depressor response (H: 158+/-8 to 132+/-8 mm Hg). Glutamate response was larger in hypertensive than in normotensive rats (N: 38+/-2.6 and H: 55+/-6); no difference was observed between hypertensive groups. The data suggest that glutamate acts tonically to drive the RVLM in 2K-1C rats, and this action is modulated by endogenous angiotensin II. The increase in the glutamate actions within the RVLM may contribute to the pathogenesis of renovascular hypertension.
Hypertension 2003 Oct
PMID:Role of endogenous angiotensin II on glutamatergic actions in the rostral ventrolateral medulla in Goldblatt hypertensive rats. 1291 58

The initial element in the causation of venous ulceration is a disturbance of venous blood flow that leads to an increase in venous pressure. Eventually, however, it is the microcirculatory consequences of venous hypertension that lead to trophic skin changes and finally to ulceration. A reduction in blood viscosity results in an improvement at the microcirculatory level. The elimination of fibrinogen from plasma improves blood viscosity. This case report concerns a 75-year-old woman with venous ulcers of both legs (left lower leg: deep ulceration with a surface area of 3 x 5 cm; right lower leg: superficial, confluent ulceration with a total surface area of 5 x 10 cm). The patient underwent 20 sessions of fibrinogen adsorption, while simultaneously continuing with a regimen of conservative measures (activated charcoal cloth dressing with silver, calcium alginate dressings and short-stretch compression bandages). Following binding to a peptide (Gly-Pro-Arg-Pro-Lys), fibrinogen and fibrin were specifically removed from the patient's plasma: her fibrinogen concentration was lowered from an original mean level of 310 mg/dl (SD +/- 104 mg/dl) to 136 mg/dl (SD +/- 54 mg/dl), and there was no return to the baseline concentration by the time of the next fibrinogen adsorption session. In response to this treatment the patient's ulcers healed rapidly within 9 weeks. Dizziness and hematomas at the vascular access sites in both antecubital fossae were reported as adverse effects. A fall in hematocrit was also noted (before treatment 37% +/- 1%; after treatment 35% +/- 2%). This may have been caused by hemodilution due to the procedure and to cell losses during blood-plasma separation, a phenomenon that is known to occur during apheresis. This case report suggests that fibrinogen adsorption is low in adverse effects and is a useful addition to the range of treatments available for ulcers of venous etiology.
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PMID:Fibrinogen adsorption--a new treatment option for venous leg ulcers? 1452 41


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