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)

Lisinopril, the lysine analogue of enalaprilat, is a long-acting angiotensin converting enzyme (ACE) inhibitor which is administered once daily by mouth. The efficacy of lisinopril in reducing blood pressure is well established in younger populations, and many trials now show it to be effective in lowering blood pressure in elderly patients with hypertension. In comparative and non-comparative clinical trials, 68.2 to 89.1% of elderly patients responded (diastolic pressure < or = 90 mm Hg) to > or = 8 weeks' lisinopril treatment. Age-related differences in antihypertensive efficacy do not appear to be clinically significant, and dosages effective in elderly patients tend to range from 2.5 to 40 mg/day. Dosages usually need to be lower in patients with significant renal impairment. In congestive heart failure, lisinopril 2.5 to 20 mg/day increases exercise duration, improves left ventricular ejection fraction and has no significant effect on ventricular ectopic beats. It is similar in efficacy to enalapril and digoxin and similar or superior to captopril on most end-points. Data from the GISSI-3 post-myocardial infarction trial show that lisinopril reduced mortality and left ventricular dysfunction when given for 42 days starting within 24 hours of the onset of infarction symptoms. Results at 6 weeks and 6 months were similar in elderly and younger patients. Elderly patients, however, among other subgroups, exhibited a strong reduction in risk of low ejection fraction after treatment (-25.5%). Economic studies suggest that lisinopril is cost saving compared with other ACE inhibitors in some markets. When given according to the GISSI-3 protocol, lisinopril appears to be one of the less expensive of the successful ACE inhibitor regimens for acute myocardial infarction. In other trials, patients with diabetic nephropathy and hypertension improved or did not deteriorate during lisinopril treatment. Blood pressure was controlled and reductions or trends towards reductions in albuminuria were observed. These reductions were similar to those in diltiazem, nifedipine and verapamil recipients, and greater than those in patients receiving atenolol. Lisinopril appears to reduce mortality in diabetic patients after myocardial infarction and may also improve neuropathy associated with diabetes. Lisinopril is well tolerated and the profile of adverse events seen is typical of ACE inhibitors as a class. There is a tendency for more elderly than younger patients to discontinue treatment, but this trend is not clearly related to the incidence of adverse events in these age groups. Drug interactions occur with few other agents and are usually clinically significant only between lisinopril and either diuretics or lithium. Lisinopril is, thus, an effective treatment for elderly patients with hypertension, congestive heart failure and acute myocardial infarction and has shown promising benefits in patients with diabetic nephropathy.
 ...
PMID:Lisinopril. A review of its pharmacology and clinical efficacy in elderly patients. 906 Dec 70

One of the complications of steroid therapy is the hypothalamic-pituitary-adrenal (HPA) axis' suppression, particularly in children where this can lead to growth suppression and other well known complications. Although there are a large number of studies on suppression of the HPA axis with the use of topical steroids, the subject is still controversial. We measured the HPA axis function in 3 groups of allergic children treated with: 1) intranasal beclomethasone dipropionate (BDP) 400 micrograms/day for 4 weeks or 2) BDP 800 micrograms/day for 4 weeks and 3) oral prednisone, 1 mg/kg/day for 2 weeks. The HPA response was obtained after lysine-vasopressin (LVP) stimulation. LVP acts on the pituitary or hypothalamus level, stimulating the whole axis. Peripheral blood samples through an intravenous line were obtained for serum cortisol measurement at zero, 30, 60, and 90 minutes after the intravenous injection of LVP, before and after the treatment period. Our results showed no suppression of the HPA axis in children medicated with BDP at either 400 micrograms/day or 800 micrograms/day. On the other hand, there was a suppression of the HPA axis after prednisone treatment (p < 0.05). During the LVP test some side effects, possibly due to systemic vasoconstriction, were noted such as abdominal pain, nausea and vomiting, and transient hypertension. In conclusion, intranasal BDP at the dose of 400 or 800 micrograms/day during 4 weeks did not induce HPA axis suppression. The LVP test is efficient to demonstrate HPA hypofunction or suppression and it produced only mild to moderate transient side effects. However, due to the side effects observed, a safer test such as urinary free cortisol (24 hours), should be used in the investigation of the HPA axis.
 ...
PMID:Lysine-vasopressin in the evaluation of the hypothalamic-pituitary-adrenal axis in children with allergic rhinitis treated with intranasal beclomethasone dipropionate or oral prednisone. 909 35

1 In spontaneously hypertensive rat (SHR) we examined over a 4-week period the influence of control low sodium diet, common salt-enriched diet (sodium chloride 6% of the dry weight of the chow) and a novel mineral salt-enriched diet (potassium-, magnesium-, and l-lysine-enriched mineral salt added at a 75% higher level of 10.5% to produce the same sodium chloride concentration of 6%) on the cardiovascular effects produced by a low-dose combination of an angiotensin converting enzyme inhibitor ramipril (0.25 mg kg(-1) day(-1) in the food) and a calcium channel blocker felodipine (0.4 mg kg(-1) day(-1) subcutaneously via an osmotic minipump). 2 Common salt, but not the mineral salt, accelerated the development of hypertension and induced left ventricular and renal hypertrophy in SHR. Neither common salt nor mineral salt significantly affected heart rate. 3 The combination of ramipril and felodipine decreased systolic blood pressure and prevented the development of left ventricular hypertrophy effectively during the common salt diet without any significant effect on the heart rate. The cardiovascular effects of the drug combination were improved by the low sodium diet or by replacement of high common salt in the diet by mineral salt. 4 Responses of endothelium-intact mesenteric arterial rings in vitro were examined at the end of the four-week study. The combination of ramipril and felodipine markedly improved the endothelium-dependent vascular relaxation responses to acetylcholine and enhanced the endothelium-independent vascular relaxation responses to sodium nitroprusside in SHR on control and common salt diets. Replacement of common salt in the diet by mineral salt improved the endothelium-dependent vascular relaxation responses to acetylcholine. The drug combination attenuated the alpha-adrenoceptor-mediated vascular contractile responses to noradrenaline during the common salt diet. 5 Ramipril and felodipine in combination increased plasma renin activity by 1.9-3.2 fold without affecting serum aldosterone levels. 6 Our findings suggest that the cardiovascular effect of the low-dose combination of ramipril and felodipine was maintained during high salt intake. However, salt restriction or replacement of common salt in the diet by the potassium- and magnesium-enriched mineral salt improved the cardiovascular effects of the drug combination. In the face of a high intake of sodium, a part of the beneficial cardiovascular effects of the drug combination is apparently mediated by improved endothelium-dependent and endothelium-independent vascular relaxation responses and attenuated alpha-adrenoceptor-mediated vascular contractile responses.
 ...
PMID:Influence of dietary salts on the cardiovascular effects of low-dose combination of ramipril and felodipine in spontaneously hypertensive rats. 948 6

Taste preferences are altered to reflect physiological needs and to support the recovery from nutritional disorders. The central mechanism both recognition for and adaptation to a deficient essential nutrient, i.e. L-lysine, have been unveiled that the feeding center in the hypothalamus is a primary center nucleus to induce a neuronal plasticity responding to dietary intake of deficient nutrient in the brain and peripherally, such as sense of taste and its concentration change. Changing preferences may act as an alarm, signaling protein malnutrition or metabolic adult disease, such as hypertension for saltiness, diabetes for sweetness, etc. In addition, our consumption of alcohol beverage is still increasing despite of one of candidate to induce the hepatic disorders, because pharmacological function of alcohol in the brain is welcome for people enjoying meal or being relieved from stresses. Preference for both L-alanine and L-glutamine was observed when alcoholic rats fell in the hepatic disorder. Acute alcohol loading induced suppression of motor activity and the hepatic dysfunction, but both amino acids did obviously protect these alcoholic symptoms. People should have to require a little bit more specific L-amino acid physiologically and pharmacologically depending upon different states among aging, lifestyle, metabolic diseases and various stresses.
 ...
PMID:[A new pharmacological and physiological aspects of L-amino acids]. 950 1

The decision to use any pharmacologic intervention inevitably rests on balancing the efficacy and safety of the intervention. The advent of the acquired immunodeficiency syndrome epidemic greatly increased awareness of transfusion-related illnesses and focused attention on methods to prevent the need for blood and blood products. This has led, especially in the last decade, to increased use of drugs to help reduce perioperative bleeding. This chapter focuses on the lysine analogues and aprotinin as the serine protease inhibitor currently available in clinical practice. Both groups of compounds have recently shown promise in reducing surgical bleeding. However, the reader will notice that none of these agents are new; they have all been available for more than 30 years. What is new is their use in preventing bleeding. We therefore have considerable knowledge regarding the safety of these compounds. The first part of this review will compare the actions of these two types of agents on the processes related to thrombosis, hemostasis, and fibrinolysis. This is followed by a comparison of the efficacy of each intervention and any dose-response relationship. This section highlights the reported reduction in postoperative bleeding with both classes of agent. There is, however, no obvious or consistent reduction in the transfusion of blood and blood products in patients given lysine analogues. In contrast, there is a consistent reduction in the need for blood transfusions in patients given aprotinin therapy. The next major section will discuss the evidence to suggest that these drugs may, because of their known effects on the processes related to inflammation, hemostasis, and cellular repair, contribute to an improvement or worsening of outcome after cardiac operations. In particular, this section focuses on the antiinflammatory actions and modifications in vascular tone associated with aprotinin therapy. These effects may be related to improved outcome in patients by reducing the incidence of permanent neurologic deficit or stroke after heart operations, as well as inhibiting pulmonary vascular hyperreactivity and hypertension in susceptible individuals. Finally, this brief review discusses the safety issues that have been raised in regard to each of these classes of agents, specifically problems associated with abnormal renal function, hypersensitivity reactions, and thrombotic complications.
 ...
PMID:Aprotinin versus lysine analogues: the debate continues. 956 97

Bombesin (Bn) receptor subtype 3 (BRS-3) is an orphan receptor that is a predicted member of the heptahelical G-protein receptor family and so named because it shares a 50% amino acid homology with receptors for the mammalian bombesin-like peptides neuromedin B (NMB) and gastrin-releasing peptide. In a recent targeted disruption study, in which BRS-3-deficient mice were generated, the mice developed obesity, diabetes, and hypertension. To date, BRS-3's natural ligand remains unknown, its pharmacology unclear, and cellular basis of action undetermined. Furthermore, there are few tissues or cell lines found that express sufficient levels of BRS-3 protein for study. To define the intracellular signaling properties of BRS-3, we examined the ability of [D-Phe6,beta-Ala11,Phe13, Nle14]Bn-(6-14), a newly discovered peptide with high affinity for BRS-3, and various Bn receptor agonists and antagonists to alter cellular function in hBRS-3-transfected BALB 3T3 cells and hBRS-3-transfected NCI-H1299 non-small cell lung cancer cells, which natively express very low levels of hBRS-3. This ligand stimulated a 4-9-fold increase in [3H]inositol phosphate formation in both cell lines under conditions where it caused no stimulation in untransfected cells and also stimulated an increase in [3H]IP1, [3H]IP2, and 3H]IP3. The elevation of [3H]IP was concentration-dependent, with an EC50 of 20-35 nM in both cell lines. [D-Phe6,beta-Ala11,Phe13,Nle14]Bn-(6-14) stimulated a 2-3-fold increase in [Ca2+]i, a 3-fold increase in tyrosine phosphorylation of p125(FAK) with an EC50 of 0.2-0.7 nM, but failed to either stimulate increases in cyclic AMP or inhibit forskolin-stimulated increases. None of nine naturally occurring Bn peptides or three synthetic Bn analogues reported to activate hBRS-3 did so with high affinity. No high affinity Bn receptor antagonists had high affinity for the hBRS-3 receptor, although two low affinity antagonists for gastrin-releasing peptide and NMB receptors, [D-Arg1,D-Trp7,9, Leu11]substance P and [D-Pro4,D-Trp7,9,10]substance P-(4-11), inhibited hBRS-3 receptor activation. The NMB receptor-specific antagonist D-Nal,Cys,Tyr,D-Trp,Lys,Val, Cys,Nal-NH2 inhibited hBRS-3 receptor activation in a competitive fashion (Ki = 0.5 microM). Stimulation of p125(FAK) tyrosine phosphorylation by hBRS-3 activation was not inhibited by the protein kinase C inhibitor, GF109203X, or thapsigargin, alone or in combination. These results show that hBRS-3 receptor activation increases phospholipase C activity, which causes generation of inositol phosphates and changes in [Ca2+]i and is also coupled to tyrosine kinase activation, but is not coupled to adenylate cyclase activation or inhibition. hBRS-3 receptor activation results in tyrosine phosphorylation of p125(FAK), and it is not dependent on activation of either limb of the phospholipase C cascade. Although the natural ligand is not a known bombesin-related peptide, the availability of [D-Phe6,beta-Ala11, Phe13,Nle14]Bn-(6-14), which functions as a high affinity agonist in conjunction with hBRS-3-transfected cell lines and the recognition of three classes of receptor antagonists including one with affinity of 0.5 microM, should provide important tools to assist in the identification of its natural ligand, the development of more potent selective receptor antagonists and agonists, and further exploration of the signaling properties of the hBRS-3 receptor.
 ...
PMID:Ability of various bombesin receptor agonists and antagonists to alter intracellular signaling of the human orphan receptor BRS-3. 959 99

The functional protein that binds to human hemoglobin (hemoglobin-binding protein; HBP) was purified from Porphyromonas gingivalis cells. The analyses of the amino-terminal sequence and amino acid composition revealed that HBP is identical to lysine-specific cysteine proteinase (51 kDa Lys-gingipain; KGP) of P. gingivalis 381. It is a novel finding that KGP has binding affinity to hemoglobin. The binding activity of HBP was enhanced by acidic or anaerobic conditions. Arg-gingipain, a member of the gingipain family, of P. gingivalis exhibited no ability to bind to hemoglobin. The recombinant protein of KGP (r-KGP) generated in Escherichia coli showed both hemoglobin-binding and proteolytic activities. The treatment of r-KGP by protein disulfide isomerase effectively enhanced binding to hemoglobin, whereas the proteinase activity was decreased. The treated r-KGP significantly inhibited the binding of hemoglobin to the whole cell extracts in a dose-dependent manner. These results suggest that the hemoglobin binding of P. gingivalis is mediated by KGP through active domain(s) distinct from that for proteinase activity.
 ...
PMID:Hemoglobin-binding protein purified from Porphyromonas gingivalis is identical to lysine-specific cysteine proteinase (Lys-gingipain). 970 27

The influence of isosorbide-5-mononitrate (IS-5-MN) on the cardiovascular effects of high dietary salt intake (NaCl, 6.6% of dry weight of food) and that of a potassium, magnesium and l-lysine-enriched salt alternative (Pansalt 10.5%, producing a 6.6% content of NaCl) was studied in spontaneously hypertensive rats in an 8-week experiment. Common salt produced a marked rise in blood pressure and induced cardiac and renal hypertrophy, while the salt alternative, although containing the same amount of NaCl, neither increased blood pressure nor caused any significant cardiac hypertrophy. IS-5-MN treatment at a daily dose of approximately 60-70 mg/kg (mixed with food) attenuated the rise in blood pressure induced by common salt, but did not prevent the cardiac or renal hypertrophy. IS-5-MN did not offer any additional benefit to the use of the salt alternative diet alone in treatment of high blood pressure. Mesenteric arterial responses in vitro were examined at the end of the study. IS-5-MN treatment during the moderately low-salt (NaCl 0.7%) control diet tended to decrease the contractile response to noradrenaline and increase the relaxation to acetylcholine. Common salt, but not the salt alternative, induced a 50% increase in the 24-h urinary excretion of cyclic GMP. Both salt supplements induced an 8-9-fold increase in the excretion of calcium, and about a 2-fold increase in the excretion of phosphorus. Common salt also increased the excretion of magnesium by 50%. IS-5-MN treatment had no significant effect on the excretion of the mineral elements. Our findings show that increased intake of potassium and magnesium reduces the harmful effects of common salt. Pressure-independent mechanisms are involved in salt-induced left ventricular and renal hypertrophy, since they remained unaffected despite the prevention of the salt-induced rise in blood pressure by IS-5-MN treatment.
 ...
PMID:Cardiovascular effects of dietary salts and isosorbide-5-mononitrate in spontaneously hypertensive rats. 975 89

-To protect from metabolism and to improve potency of the AcLys-[D-betaNal7,Ile8]desArg9-bradykinin (BK) (R 715), we prepared and tested 3 analogues containing alpha-methyl-L-Phe ([alphaMe]Phe) in position 5: these are the AcLys-[(alphaMe)Phe5,D-betaNal7, Ile8]desArg9BK (R 892), Lys-Lys-[(alphaMe)Phe5,D-betaNal7, Ile8]desArg9BK (R 913), and AcLys-Lys-[(alphaMe)Phe5,D-betaNal7, Ile8]desArg9BK (R 914). The new compounds were tested against the contractile effect induced by desArg9BK on 2 B1 receptor bioassays, the human umbilical vein, and the rabbit aorta. Their antagonistic activities were compared with those of the early prototypes (Lys-[Leu8]desArg9BK and [Leu8]desArg9BK) and with other recently described peptide antagonists. The 3 (alphaMe)Phe analogues showed high antagonistic potencies (pA2) at both the human (8.8, 7.7, and 8. 7, respectively) and rabbit (8.6, 7.8, and 8.6, respectively) B1 receptors. No antagonistic effects (pA2<5) were observed on the B2 receptors that mediate the contractile effects of BK on the human umbilical vein, the rabbit jugular vein, and the guinea pig ileum. Moreover, these new B1 antagonists were found to be resistant to in vitro degradation by purified angiotensin-converting enzyme from rabbit lung. The Nalpha-acetylated forms, R 892 and R 914, were resistant to aminopeptidases from human plasma. In vivo antagonistic potencies (ID50) of B1 receptor antagonists were evaluated in anesthetized lipopolysaccharide-treated (for B1 receptor) and nontreated (for B2 receptor) rabbits against the hypotensive effects of exogenous desArg9BK and BK. R 892 efficiently inhibited (ID50 2.8 nmol/kg IV) hypotension induced by desArg9BK without affecting that evoked by BK (ID50 >600 nmol/kg IV). Conversely, the peptide antagonists Lys-Lys-[Hyp3,Igl5,D-Igl7,Oic8]desArg9BK (B 9858) and DArg-[Hyp3,Thi5,D-Tic7,Oic8] desArg9BK (S 0765) showed dual B1/B2 receptor antagonism in vitro and in vivo. It is concluded that R 892 and congeners provide selective, highly potent, and metabolically stable B1 kinin receptor antagonists that can be useful for the assessment of the physiological and pathological roles of kinin B1 receptors.
Hypertension 1999 Mar
PMID:Kinin B1 receptor antagonists containing alpha-methyl-L-phenylalanine: in vitro and in vivo antagonistic activities. 1008 94

Wilms' tumor is a childhood kidney tumor that is a striking example of the way that cancer may arise through development gone awry. A proportion of these tumors develop as a result of the loss of function mutations in the Wilms' tumor suppressor gene, WT1. Inherited mutations in the WT1 gene can lead to childhood kidney cancer, severe gonadal dysplasia, and life-threatening hypertension. Knockouts show that the gene is essential for the early stages of kidney and gonad formation. These tissues are completely absent in null mice. The WT1 gene encodes numerous protein isoforms, all of which share four zinc fingers. There is a large body of evidence supporting the notion that WT1 is a transcription factor, particularly a transcriptional repressor. Recently, however, we obtained evidence that WT1 colocalizes and is physically associated with splice factors. What is more, one alternative splice isoform of WT1 containing three amino acids, Lys-Thr-Ser (KTS; inserted between zinc fingers 3 and 4) is preferentially associated with splice factors, whereas the other alternative splice version, lacking these three amino acids, preferentially associates with the transcriptional apparatus. Both genetic and evolutionary considerations suggest that these two different forms of the protein have different functions. We will discuss recent evidence to further implicate WT1 in splicing. Our results raise the possibility that regulation of splicing is a crucial factor in the development of the genitourinary system, and that tumors may arise through aberrant splicing. To pursue the regulation and function of WT1 in whole animals, we have been introducing the human gene and large flanking regions cloned in yeast artificial chromosomes directly into mice. These studies have allowed us to dissect the function of WT1 at late as well as at early stages in organogenesis and to identify new sites and surprising new potential functions for the gene.
 ...
PMID:Multiple roles for the Wilms' tumor suppressor, WT1. 1019 91


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