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)

Calcitonin receptor-like receptor/receptor activity-modifying protein 2 (CRLR/RAMP2) and CRLR/RAMP3 complexes have been reported to be specific adrenomedullin (AM) receptors. In the present study, we evaluated the pathophysiological significance of renal AM and its receptor system in aortocaval shunt (ACS) rats. Renal AM levels were measured serially during 5 weeks after the operation. Renal gene expressions of AM, CRLR, RAMP2, and RAMP3 were measured at 2 weeks (decompensated phase) and 5 weeks (compensated phase) after the operation. Immunohistochemical localizations of renal AM were also evaluated. Furthermore, the relations between urinary sodium excretion (UNaV) and renal AM levels were evaluated. Renal AM levels were higher in ACS than in control animals only at 1, 2, and 3 weeks after the operation. At 2 weeks after the operation, renal AM mRNA expression was also higher in ACS than in control animals. CRLR, RAMP2, and RAMP3 mRNAs were expressed in the kidney, but there were no differences between the 2 groups. Immunohistochemistry revealed the positive AM immunostaining within the renal tubular cells, and it was more intense in ACS than in control animals. There were significant correlations between UNaV and renal AM levels. At 5 weeks after the operation, there were no differences in mRNA levels of AM, CRLR, RAMP2, and RAMP3 between the 2 groups. There was a significant correlation between UNaV and medullary AM levels. The present findings suggest that increased renal AM levels in decompensated heart failure, presumably due to increased AM production in renal tubules, in part, are involved in the regulation of sodium excretion.
Hypertension 2001 Feb
PMID:Alterations of intrarenal adrenomedullin and its receptor system in heart failure rats. 1123 Feb 74

Adrenomedullin (AM), identified from pheochromocytoma and having 52 amino acids, elicits a long-lasting vasodilatation and diuresis. AM is mainly mediated by the intracellular adenylate cyclase coupled with cyclic adenosine monophosphate (cAMP) and nitric oxide (NO) -cyclic guanosine monophosphate (cGMP) pathway through its specific receptor. The calcitonin receptor-like receptor (CLCR) and receptor-activity modifying protein (RAMP) 2 or RAMP3 models have been proposed as the candidate receptor. AM is produced mainly in cardiovascular tissues in response to stimuli such as shear stress and stretch, hormonal factors and cytokines. Recently established AM knockout mice lines revealed that AM is essential for development of vitelline vessels of embryo. Plasma AM levels elevate in cardiovascular diseases such as heart failure, hypertension and septic shock, where AM may play protective roles through its characteristic biological activities. Human AM gene delivery improves hypertension, renal function, cardiac hypertrophy and nephrosclerosis in the hypertensive rats. AM decreases cardiac preload and afterload and improves cardiac contractility and diuresis in patients with heart failure and hypertension. Advances in gene engineering and receptor studies may contribute to further understandings of biological implication and therapeutic availability of AM.
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PMID:A review of the biological properties and clinical implications of adrenomedullin and proadrenomedullin N-terminal 20 peptide (PAMP), hypotensive and vasodilating peptides. 1175 55

We investigated whether adrenomedullin (AM) participates in the pathophysiology during the transition from left ventricular hypertrophy (LVH) to heart failure (HF). We used the Dahl salt-sensitive (DS) rat model, in which systemic hypertension causes LVH at the age of 11 weeks, followed by HF at the age of 18 weeks. Two molecular forms of AM levels in the plasma and myocardium at the LVH stage were significantly elevated compared with those in controls, and they were further increased at the HF stage. Interestingly, the LV tissue AM-mature/AM-total ratio was higher only in the HF group than in controls and LVH. The LV tissue AM-mature/AM-total ratio, AM-mature, and AM-total concentrations had close relations with the LV weight/body weight (r=0.72, r=0.79, and r=0.70, respectively; all P<0.001). AM gene expression was significantly increased at the LVH stage and was further increased at the HF stage. Furthermore, gene expression of AM receptor system components such as calcitonin receptor-like receptor (CRLR), receptor activity-modified protein 2 (RAMP2), and RAMP3 were significantly increased at the stage of LVH and HF. Regarding other neurohumoral factors, plasma renin and aldosterone levels were not increased at the LVH stage but were increased at the HF stage, whereas atrial natriuretic peptide was increased in both the plasma and myocardium at the LVH stage and was further increased at the HF stage. These results suggest that induction of the cardiac AM system, including the ligand, receptor, and amidating activity, may modulate pathophysiology during the transition from LVH to HF in this model.
Hypertension 2003 Mar
PMID:Ventricular adrenomedullin system in the transition from LVH to heart failure in rats. 1262 52

To test the hypothesis that activation of the vanilloid receptor (VR1) contributes to the anandamide-induced depressor effect in spontaneously hypertensive rats (SHR), we used a selective VR1 antagonist capsazepine (CAPZ) and a selective cannabinoid type 1 receptor antagonist SR141716A in conjunction with a VR1 agonist capsaicin in both SHR and Wistar-Kyoto rats (WKY). Mean arterial pressure was increased in SHR compared with WKY (P<0.05). Intravenous administration of capsaicin caused a greater depressor response in SHR compared with WKY (P<0.05), which was blocked by approximately 60% by CAPZ (P<0.05) in SHR only. Methanandamide caused a similar greater depressor response (P<0.05), which was blocked by approximately 50% and 60% by CAPZ and SR141716A, respectively, in SHR (P<0.05) but not in WKY. Radioimmunoassay showed that methanandamide increased plasma calcitonin gene-related peptide (CGRP) levels from baseline in both SHR and WKY (P<0.05), with no difference between 2 strains. Western blot showed that protein expression for the calcitonin receptor-like receptor-but not receptor activity modifying protein 1, VR1, and cannabinoid type 1 receptors-was increased in mesenteric resistance arteries in SHR compared with WKY (P<0.05). These data indicate that in addition to activation of cannabinoid type 1, anandamide may serve as an endogenous compound to stimulate VR1, leading to a decrease in blood pressure via CGRP release from sensory nerve terminals. Increased mesenteric CGRP receptor expression in SHR may account for increased sensitivity of blood pressure to anandamide and may serve as a compensatory response to buffer the increase in blood pressure in SHR.
Hypertension 2003 Mar
PMID:Anandamide-induced depressor effect in spontaneously hypertensive rats: role of the vanilloid receptor. 1262 92

To investigate the pathophysiological role of adrenomedullin (AM) in left ventricular hypertrophy (LVH) in hypertension, we measured the plasma level, left ventricle (LV) tissue level, and mRNA abundance of AM and the mRNA abundance of the AM receptor system in the LV. We also analyzed the molecular forms of AM in the plasma and LV tissue and investigated the relationships between AM and the degree of LVH. We studied the following three groups: control Wistar Kyoto rats (WKY), control spontaneously hypertensive rats (SHR), and deoxycorticosterone acetate (DOCA)-salt SHR (D-SHR). We measured AM-mature, active form, and AM-total (active form+inactive form) in plasma and the LV by a newly developed immunoradiometric assay. Gene expression of AM was measured by Northern blot analysis and gene expression of AM receptor system components, such as calcitonin receptor-like receptor (CRLR), receptor activity modifying protein 2 (RAMP2), and RAMP3 was measured by the reverse transcription polymerase chain reaction method. After 3 weeks of DOCA treatment, D-SHR was characterized by higher blood pressure, LV weight, and plasma atrial natriuretic peptide levels compared with those in the other two groups. Plasma AM-mature and AM-total levels were significantly higher in D-SHR than in the other two groups, whereas there were no significant differences in the AM-mature/AM-total ratio among the three groups. On the other hand, LV tissue AM-mature and AM-total levels were also significantly higher in D-SHR than in the other two groups, and the AM-mature/AM-total ratio was significantly higher in LV tissues than in plasma. Furthermore, the LV tissue AM-mature/AM-total ratio was significantly higher in D-SHR compared with the other two groups. The LV tissue AM-mature/AM-total ratio was significantly correlated with LV weight/body weight (r=0.92, p<0.001). The gene expression levels of AM, CRLR, RAMP2, and RAMP3 in the LV were significantly higher in D-SHR than in the other two groups. These results suggest that the AM amidating enzyme activity, ligand, and receptor system are all upregulated in the LV hypertrophy in this malignant hypertensive rat model. Considering that AM serves as a local antihypertrophic autocrine and/or paracrine factor, the induction of AM system observed here may modulate the pathophysiology of LV hypertrophy in certain forms of malignant hypertension.
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PMID:Altered gene expression of adrenomedullin and its receptor system and molecular forms of tissue adrenomedullin in left ventricular hypertrophy induced by malignant hypertension. 1266 27

The neuropeptide, adrenomedullin, acts in the central nervous system (CNS) to regulate blood pressure, at least partly through an adrenomedullin receptor which is composed of receptor activity modifying protein 2 (RAMP-2) and calcitonin receptor-like receptor (CRLR). We used in situ hybridization to localize RAMP-2 mRNA throughout the brain, and we performed reverse transcription-polymerase chain reaction to detect CRLR mRNA in the brain. We found that RAMP-2 mRNA is expressed in numerous areas, including autonomic nuclei such as the paraventricular, supraoptic, arcuate and ventromedial nuclei, as well as the nucleus of the solitary tract (NTS), area postrema and dorsal motor nucleus of the vagus. Many regions expressing RAMP-2 mRNA also express low levels of CRLR mRNA. We examined changes in the mRNA expression of RAMP-2 and preproadrenomedullin in the brain in response to blood pressure manipulations. Rats received intravenous infusions of nitroprusside or phenylephrine to decrease or increase blood pressure, respectively. Decreased blood pressure elicited an increase in RAMP-2 mRNA expression in the NTS and a decrease in preproadrenomedullin mRNA expression in the paraventricular nucleus (PVN). Increased blood pressure elicited a decrease in RAMP-2 mRNA expression in the PVN and NTS. The CNS distribution and modulation of adrenomedullin signalling components by changes in blood pressure provide anatomical and physiological evidence for a homeostatic role for adrenomedullin in the brain.
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PMID:Receptor activity modifying protein 2 distribution in the rat central nervous system and regulation by changes in blood pressure. 1289 78

The vasodilator peptide adrenomedullin (AM) elicits diuresis and natriuresis and inhibits aldosterone secretion. The aim of this study was to better understand the role of AM in maintaining water and electrolyte balance during chronic salt loading. Male Wistar rats were divided into a high salt (HS) group that received a diet containing 8% sodium chloride (NaCl) and a normal salt group that received a diet containing 0.4% NaCl. Plasma AM concentrations as well as expression of AM mRNA in the adrenal gland and kidney were then measured after 3, 7, 14, and 28 days. After 28 days, sodium and water excretion were significantly higher in HS rats than in control, although blood pressure and fluid volume were not significantly affected. Moreover, although plasma AM remained unchanged for up to 14 days, it was increased 2.5-fold in HS rats after 28 days on a high salt diet, and there were corresponding 3-fold and 1.5-fold increases in the levels of AM mRNA in the adrenal gland and kidney, respectively. At the same time, expression of calcitonin receptor-like receptor mRNA was significantly upregulated in both kidney and adrenal gland, as was expression of receptor activity-modify protein 1 (RAMP1) and RAMP2 mRNA in the adrenals and expression of RAMP3 in kidneys. Taken together, these results suggest that AM plays a role in the regulation of water and electrolyte balance in animals chronically ingesting high levels of salt.
Hypertension 2003 Sep
PMID:Chronic salt loading upregulates expression of adrenomedullin and its receptors in adrenal glands and kidneys of the rat. 1291 64

Adrenomedullin (ADM) is a 52-amino acid peptide with structural homology to calcitonin gene-related peptide (CGRP) initially isolated from human pheochromocytoma. ADM is synthesized by many mammalian tissues including the adrenal medulla, endothelial and vascular smooth muscle cells, myocardium and central nervous system. ADM binds to plasma membrane receptors composed of calcitonin receptor-like receptor (CRLR), a member of serpentine receptor superfamily, and receptor activity modifying protein (RAMP) type 2 or 3. ADM has also some affinity for CGR(1) receptor composed of CRLR and RAMP1. ADM dilates blood vessels in both endothelium-dependent and independent manner and decreases systemic arterial pressure. Intrarenally administered ADM increases natriuresis by vascular and tubular mechanisms. In addition, ADM inhibits migration and proliferation of vascular smooth muscle cells and attenuates myocardial remodelling by inhibiting protein synthesis in cardiomyocytes and proliferation of cardiac fibroblasts. ADM is expressed in various tissues from early stage of embryogenesis and is also synthesized in placenta, uterus and fetal membranes. Plasma ADM level is increased in arterial hypertension, acute coronary syndromes, heart failure, renal diseases and septic shock, being involved in the pathophysiology of these disorders. Experimental ADM treatment is beneficial in arterial and pulmonary hypertension, heart failure, septic shock and ischemia/reperfusion injury. Proadrenomedullin N-terminal peptide (PAMP) is another product of ADM gene which is co-secreted by ADM-producing tissues, with some effects similar and some opposite to ADM.
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PMID:Adrenomedullin--what do we know 10 years since its discovery? 1504 74

In this study, reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the changes in mRNAs levels of preproadrenomedullin (ppADM) gene encoding adrenomedullin (ADM) and the essential receptor components of ADM, calcitonin receptor-like receptor (CRLR), and the receptor activity modifying protein 2 and 3 (RAMP2 and RAMP3) in the medulla oblongata, hypothalamus, midbrain, pituitary gland and adrenal gland of the stress-induced hypertensive rats. It was shown that chronic foot-shock and noise stress for 15 consecutive days induced a significant increase in systolic blood pressure (SBP) and unique changes in ppADM and its receptor components mRNAs in all areas studied. As compared with the control group, the level of ppADM mRNA, normalized against a glyceraldehydes-3-phosphate dehydrogenase (GAPDH) control, was up-regulated in the hypothalamus-pituitary-adrenal (HPA) axis, but down-regulated in the medulla oblongata and midbrain (P<0.01 and P<0.05, respectively). The relative amount of CRLR mRNA was higher in the hypothalamus than that in other areas. The level of CRLR mRNA expression was significantly increased in the medulla oblongata of the stress group (P<0.01), but decreased in the midbrain (P<0.01) as well as hypothalamus(P<0.05), as compared with that of the control group. Chronic stress for 15 consecutive days produced an increase in the level of RAMP2 mRNA expression in the medulla oblongata (P<0.01) and a decrease in the adrenal gland (P<0.01), as compared with the control. No significant stress-related changes in RAMP2 mRNA were observed in the midbrain, hypothalamus and pituitary gland. The amount of RAMP3 mRNA was relatively higher in the midbrain and hypothalamus than that in the medulla oblongata, adrenal gland and adrenal gland. Stress-induced hypertensive rats exhibited an increased RAMP3 mRNA expression in the hypothalamus and pituitary gland (P<0.01 and P<0.05, respectively) and a decrease in the adrenal gland and midbrain (P<0.05). No significant stress-related change in RAMP3 mRAN was observed in the medulla oblongata. Taken together, our results indicate that the significant changes in ppADM and its receptor components mRNAs expression in the HPA axis and autonomic centers may be related to the development of the stress-induced hypertension. Nevertheless, the pathophysiological significance of brain-derived ADM and its receptors in stress and blood pressure regulation and their roles in stress-induced hypertension still await further investigation.
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PMID:Changes of adrenomedullin and its receptor components mRNAs expression in the brain stem and hypothalamus-pituitary-adrenal axis of stress-induced hypertensive rats. 1561 22

In this work, we aimed to observe the changes in adrenomedullin (ADM) and its receptor-calcitonin receptor-like receptor (CL), receptor activity-modifying protein (RAMP) 1, RAMP2 and RAMP3-in cardiac ventricles and aortas of hypertensive rats, and the responsiveness of injured cardiovascular tissue to ADM, then to illustrate the protective mechanism of ADM on the cardiovascular system. Male SD rats were subjected to treatment with chronic N(G)-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide synthase. The ADM contents and cAMP production in myocardia and aortas were measured by RIA. The mRNA levels of ADM, CL, and RAMP1-3 were determined by RT-PCR. L-NNA induced severe hypertension and cardiomegaly. The ir-ADM content in plasma, ventricles and aortas in L-NNA-treated animals increased by 80%, 72% and 57% (all p<0.01), respectively. Furthermore, mRNA levels of ADM, CL, RAMP2 and RAMP3 were elevated by 91%, 33%, 50% and 72.5% (all p<0.01), respectively, in ventricles and by 95%, 177%, 74.7% and 85% (all p<0.01), respectively, in aortas. mRNA level of RAMP1 was elevated by 129% (p<0.01) in aortas but no significant difference in ventricles. The elevated mRNA levels of RAMP2 and RAMP3 were positively correlated with that of ADM in hypertrophic ventricles (r=0.633 and 0.828, p<0.01, respectively) and the elevated mRNA levels of CL, RAMP2 and RAMP3 were positively correlated with that of ADM in aortas (r=0.941, 0.943 and 0.736, all p<0.01, respectively). The response of ventricular myocardia and aortas to ADM administration potentiated, and the production of cAMP was increased by 41% and 68% (both p<0.01), respectively. ADM-stimulated cAMP generation in ventricular myocardia and aortas was blocked by administration of both ADM22-52, the specific antagonist of ADM receptor, and CGRP8-37, the antagonist of the CGRP1 receptor. The results showed an increased in cardiovascular ADM generation and an up-regulation of the gene expression of ADM and its receptor-CL, RAMP1-3 during hypertension, augmented responsiveness of ventricular myocardia and aortas of hypertensive rats to ADM, suggesting that these receptors may play a role in the cardiovascular adaptation in response to sub-chronic NO-inhibition.
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PMID:Hypertension induced by nitric oxide synthase inhibitor increases responsiveness of ventricular myocardium and aorta of rat tissue to adrenomedullin stimulation in vitro. 1621 82


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