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)

Bombesin is a tetradecapeptide extracted from the side of discoglossid frogs Bombina bombina and Bombina variegata variegata. In anaesthetized dogs bombesin causes mainly systemic hypertension, bradycardia and constriction of the renal, mesenteric and coeliac arterial vessels. The other vascular beds studied (carotid, femoral and coronaric) passively follow the blood pressure. Tachyphylaxis may occur. Dibenzyline and hexamethonium do not antagonize the hypertensive property of bombesin, while the occlusion either of the renal vessels or of the mesenteric, coeliac arteries and portal vein reduces the intensity and the duration of the hypertensive response. The simultaneous occlusion of all the above mentioned vessels further reduces the duration of the hypertensive response evoked by bombesin and reverses its effect on the heart from mainly bradycardic to pure tachycardic. In these condition bombesin causes carotid and peripheral vasoconstriction. The increase of heart rate and of blood pressure, while occurs after ligation of aplanchnic vessels, is completely or partly antagonized by propranolol. In normal conscious dogs bombesin is at least 10 times more potent and less tachyphylactic than in anesthetized dogs.
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PMID:Cardiovascular pharmacology of bombesin, a new polypeptide from amphibian skin. 120 36

Stimulation of somatic or visceral nociceptors causes changes in gastrointestinal motor activity and blood pressure. The present study examined the possible participation of capsaicin-sensitive afferent and noradrenergic efferent neurons in the blood pressure and gastric motor responses to laparotomy and intraperitoneal injection of capsaicin or hydrochloric acid in the rat. Gastric motor activity was measured by recording the intragastric pressure of phenobarbital-anaesthetized rats via an oesophageal catheter. Laparotomy as well as intraperitoneal injection of capsaicin (33 and 330 microM) or hydrochloric acid (30 mM) caused a transient reduction of gastric motor activity stimulated by intravenous infusion of bombesin (200 pmol/min) and a brief fall of blood pressure (depressor effect). The depressor effect of laparotomy was followed by prolonged hypertension. Defunctionalization of capsaicin-sensitive afferent neurons by systemic pretreatment of rats with capsaicin (0.4 mmol/kg) prevented the depressor effect and gastric motor inhibition elicited by laparotomy, intraperitoneal capsaicin (33 microM) or intraperitoneal hydrochloric acid (30 mM). However, the effects of 330 microM capsaicin on blood pressure and gastric motility were only partially reduced by capsaicin pretreatment. Blockade of noradrenergic sympathetic neurons by pretreating rats with guanethidine (0.225 mmol/kg) prevented the gastric motor inhibition and depressor effects of laparotomy and intraperitoneal injection of hydrochloric acid (30 mM). The inhibition of gastric motility caused by capsaicin (33 and 330 microM) was only partially reduced by guanethidine pretreatment. The secondary hypertension following the depressor effect of intraperitoneal capsaicin or hydrochloric acid was enhanced in guanethidine-pretreated rats whereas the prolonged hypertension induced by laparotomy was left unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Participation of capsaicin-sensitive afferent neurons in gastric motor inhibition caused by laparotomy and intraperitoneal acid. 160 37

2-n-Butyl-4-chloro-5-hydroxy-methyl-1-[(2'-(1H)-tetrazol-5-yl)biph enyl-4- yl)methyl]imidazol potassium salt (DuP 753) is a nonpeptide angiotensin II receptor antagonist that inhibits the contractile effects of angiotensin II competitively and shows pA2 values of 8.27 on the rabbit aorta and jugular vein, 8.66 on the rat portal vein and stomach, 8.19 on the rat urinary bladder, and 8.36 on human colon, ileum, and urinary bladder. This agent (more than 10(-5) M) exhibits no agonistic activity and does not affect the contractile effects of norepinephrine, acetylcholine, bradykinin, desArg9-bradykinin, substance P, neurokinin A, neurokinin B, or bombesin in the various tissues. The present results demonstrate that DuP 753 is a potent nonpeptide antagonist with high affinity, specificity, and selectivity for the angiotensin receptor.
Hypertension 1991 Apr
PMID:DuP 753 is a specific antagonist for the angiotensin receptor. 167 62

If we consider the chemical messengers in the central nervous system, there are about ten classic transmitters--the catecholamines, biogenic amines and amino acids--as opposed to over 50 different neuropeptides. These include previously well-established circulating hormones such as angiotensin, atrial natriuretic peptide, vasopressin and oxytocin, calcitonin and calcitonin gene related peptide (CGRP), the opioid family of peptides, gastrointestinal peptides, pituitary peptides and their releasing factors, and miscellaneous peptides such as the kinins, bombesin, gallanin, and others; all occur as neuropeptides in the brain. There is evidence supporting a role in central cardiovascular control for angiotensin, opioid peptides, substance P, neuropeptide Y, vasopressin, atrial natriuretic peptide, kinins, corticotropin releasing factor, bombesin, somatostatin, and some other peptides. They have been localized in brain areas known to be important for blood pressure regulation, and specific high-affinity peptide receptors have also been discovered. Upon central administration, these peptides produce cardiovascular effects, partly by interacting with other blood pressure-controlling neuroregulators, e.g. catecholamines and GABA. Central inhibition of brain peptide synthesis or interaction with competitive antagonists at the receptor site results in marked cardiovascular effects. Altered peptide levels and activity of synthesizing enzymes, as well as supersensitivity to the pressor action of some brain peptides, have been described in experimental models of hypertension. We are using angiotensin as a model peptide to study the peptidergic control of cardiovascular function.
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PMID:Peptidergic control of cardiovascular function: the angiotensin paradigm. 219 11

1. The changes in blood pressure in response to parenteral administration of bombesin, the active tetradecapeptide of the skin of the European discoglossid frogs Bombina bombina and Bombina variegata variegata have been investigated in some experimental animals.2. In most species, the polypeptide elicited hypertension which was usually gradual in onset and slow to disappear. Blood pressure increases rarely exceeded 40-50 mmHg. At the beginning of an experiment some dose-response relationship could often be observed, but later tachyphylaxis developed. During an intravenous infusion of bombesin the rise in blood pressure could sometimes be maintained at a steady level as long as the infusion was continued, but at other times, the rise of pressure slowly subsided with continued administration of the polypeptide. In the rat and the chicken hypertension elicited by high doses of bombesin was often followed by secondary hypotension.3. Bombesin-induced hypertension was apparently not affected by pretreatment with either alpha- or beta-adrenergic blocking agents. Similarly secondary hypotension was not abolished by atropine. Thus, the effect of bombesin on vascular smooth muscle seems to be predominantly a direct one.4. Angiotensin was usually more potent than bombesin, and its effect on blood pressure was more rapid and of shorter duration. Tachyphylaxis to angiotensin was lacking or moderate.5. In sharp contrast to the other species, the monkey responded to bombesin with frank hypotension, which was usually proportional to the dose. In the monkey the hypotensive effect of bombesin was equal to, or greater than that of eledoisin or physalaemin and bombesin-induced hypotension was of longer duration than that of the other polypeptides. Tachyphylaxis was moderate for low and adequately spaced doses of the polypeptide, but prompt and intense for high doses. Long-lasting hypotension was obtained by intravenous infusion of bombesin, but repeated infusions caused tachyphylaxis. Bombesin-induced hypotension was not affected by pretreatment with atropine.6. Bombesin may be easily distinguished from all other known peptides active on vascular and extravascular smooth muscle by its effects on blood pressure. This does not apply to bombesin-like peptides, such as alytesin and ranatensin.
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PMID:The action of bombesin on the systemic arterial blood pressure of some experimental animals. 434 29

Mammalian bombesin-like peptides are widely distributed in the central nervous system as well as in the gastrointestinal tract, where they modulate smooth-muscle contraction, exocrine and endocrine processes, metabolism and behaviour. They bind to G-protein-coupled receptors on the cell surface to elicit their effects. Bombesin-like peptide receptors cloned so far include, gastrin-releasing peptide receptor (GRP-R), neuromedin B receptor (NMB-R), and bombesin receptor subtype-3 (BRS-3). However, despite the molecular characterization of BRS-3, determination of its function has been difficult as a result of its low affinity for bombesin and its lack of an identified natural ligand. We have generated BRS-3-deficient mice in an attempt to determine the in vivo function of the receptor. Mice lacking functional BRS-3 developed a mild obesity, associated with hypertension and impairment of glucose metabolism. They also exhibited reduced metabolic rate, increased feeding efficiency and subsequent hyperphagia. Our data suggest that BRS-3 is required for the regulation of endocrine processes and metabolism responsible for energy balance and adiposity. BRS-3-deficient mice provide a useful new model for the investigation of human obesity and associated diseases.
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PMID:Mice lacking bombesin receptor subtype-3 develop metabolic defects and obesity. 936 52

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.
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PMID:Ability of various bombesin receptor agonists and antagonists to alter intracellular signaling of the human orphan receptor BRS-3. 959 99

Membrane metalloendopeptidase EC 3.4.24.11 (Enkephalinase, neutral endopeptidase, NEP) is a cellular ectoenzyme, immunophenotypically identified as the leukocyte cluster of differentiation CD10 or CALLA (common acute lymphoblastic leukemia antigen). Immunological, biochemical and molecular biology techniques have identified tis cell membrane feature in various organs: brain, cardiovascular system, lung, placenta, kidney etc. The CD10 immunophenotype is a common feature of lymphoblasts in acute lymphoid leukemia not expressing the T- or B-markers. The enzymatic activity of CD10/NEP possibly influences normal lymphocyte ontogeny by proteolytic cleavage of the regulatory peptides. The substrates of CD10/NEP in the kidneys are (see the list of abbreviations) ANP, adrenomedullin and PAMP; in the brain, the substrates are enkephalins and oxytocin; in the lung, bombesin, BLP, GRP, neuromedin C, substance P and neurokinin A; in the cardiovascular system, angiotenisin II, bradykinin and CGRP; in the gut, VIP; on the neutrophil membrane, fMLP etc. Some substrates are not strictly tissue-specific, e.g. substance P. Preclinical and clinical trials explore possibilities of therapeutic application of the inhibitors of neutral endopeptidase, such as thiorphan in the management of pain, diarrhoea, depression, arterial hypertension and asthma. Other possibilities of application include the treatment of hyalinomembranous disease and prevention of neurotoxicosis in tetanus and botulism.
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PMID:[Membrane metalloendopeptidase (CD10/CALLA): distribution, physiologic and pathophysiologic functions and its inhibitors]. 974 92

The orphan receptor, bombesin (Bn) receptor subtype 3 (BRS-3), shares high homology with bombesin receptors (neuromedin B receptor (NMB-R) and gastrin-releasing peptide receptor (GRP-R)). This receptor is widely distributed in the central nervous system and gastrointestinal tract; target disruption leads to obesity, diabetes, and hypertension, however, its role in physiological and pathological processes remain unknown due to lack of selective ligands or identification of its natural ligand. We have recently discovered (Mantey, S. A., Weber, H. C., Sainz, E., Akeson, M., Ryan, R. R. Pradhan, T. K., Searles, R. P., Spindel, E. R., Battey, J. F., Coy, D. H., and Jensen, R. T. (1997) J. Biol. Chem. 272, 26062-26071) that [d-Tyr(6),beta-Ala(11),Phe(13),Nle(14)]Bn-(6-14) has high affinity for BRS-3 and using this ligand showed BRS-3 has a unique pharmacology with high affinity for no known natural Bn peptides. However, use of this ligand is limited because it has high affinity for all known Bn receptors. In the present study we have attempted to identify BRS-3 selective ligands using a strategy of rational peptide design with the substitution of conformationally restricted amino acids into the prototype ligand [d-Tyr(6),beta-Ala(11),Phe(13),Nle(14)]Bn-(6-14) or its d-Phe(6) analogue. Each of the 22 peptides synthesized had binding affinities determined for hBRS-3, hGRPR, and hNMBR, and hBRS-3 selective ligands were tested for their ability to activate phospholipase C and increase inositol phosphates ([(3)H]inositol phosphate). Using this approach we have identified a number of BRS-3 selective ligands. These ligands functioned as receptor agonists and their binding affinities were reflected in their potencies for altering [(3)H]inositol phosphate. Two peptides with an (R)- or (S)-amino-3-phenylpropionic acid substitution for beta-Ala(11) in the prototype ligand had the highest selectivity for the hBRS-3 over the mammalian Bn receptors and did not interact with receptors for other gastrointestinal hormones/neurotransmitters. Molecular modeling demonstrated these two selective BRS-3 ligands had a unique conformation of the position 11 beta-amino acid. This selectivity was of sufficient magnitude that these should be useful in explaining the role of hBRS-3 activation in obesity, glucose homeostasis, hypertension, and other physiological or pathological processes.
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PMID:Rational design of a peptide agonist that interacts selectively with the orphan receptor, bombesin receptor subtype 3. 1111 77

Transcutaneous allotransplantation of embryonic tissues from the anterior hypothalamus and amygdaloid complex and administration of potentiated antibodies to bombesin normalized blood pressure and parameters of ECG in rats with emotional hypertension.
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PMID:Effect of allotransplantation of embryonic brain tissues and administration of potentiated antibodies to bombesin on hemodynamics in rats with emotional hypertension. 1294 52


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