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)

Pituitary adenylyl cyclase-activating polypeptide (PACAP) is a potent endogenous secretagogue for chromaffin cells. We previously reported that PACAP coupled to the PAC1 receptor to evoke dihydropyridine-sensitive early (15 to 20 minutes) catecholamine secretion and cAMP response element binding protein-mediated trans-activation of the secretory protein chromogranin A promoter in PC12 pheochromocytoma cells. In this report, we studied whether the secretory and transcriptional responses elicited by PACAP were subject to desensitization. We found that PACAP evoked distinct immediate (initial, 0 to 20 minutes) and long-lasting (20 to 180 minutes) effects on catecholamine secretion. Initial secretory and chromogranin A trans-activation responses induced by PACAP were desensitized in a dose-dependent fashion after preexposure of cells to PACAP, and the IC(50) doses of PACAP for desensitization were approximately 18- to approximately 32-fold lower than the EC(50) activating doses for secretion or transcription. Desensitization of the initial secretion response was associated with decreased Ca(2+) influx through L-type voltage-operated Ca(2+) channels. Acute exposure to PACAP also triggered long-lasting (up to 3 hours), extracellular Ca(2+)-dependent, pertussis toxin-insensitive catecholamine secretion; indeed, even after short-term (20 minutes) exposure to PACAP and removal of the secretagogue, PC12 cells continued to secrete norepinephrine up to 76.9+/-0.22% of cellular norepinephrine content after 3 hours. A phospholipase C-beta inhibitor (U-73122) blocked this extended secretory response, which was dependent on low-magnitude Ca(2+) influx resistant to several L-, N-, P/Q-, or T-type Ca(2+) channel antagonists, but sensitive to Zn(2+), Ni(2+), Cd(2+), or to the store-operated Ca(2+) channel blocker SKF96365. A less than additive effect of the sarco-endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin plus PACAP on this sustained secretion also supported a contribution of store-operated Ca(2+) entry to the sustained secretory response. We propose that PACAP-evoked secretion and transcription are subject to homologous desensitization in PC12 cells; however, PACAP also induces long-lasting secretion, even under dose and time circumstances in which acute, dihydropyridine-sensitive secretion has been desensitized. Although initial secretion is mediated by an L-type voltage-operated Ca(2+) channel, extended secretion may involve a store-operated Ca(2+) channel that is activated through a G(q/11)/phospholipase C-beta/phosphoinositide signaling pathway.
Hypertension 1999 Nov
PMID:Time-dependent effects of the neuropeptide PACAP on catecholamine secretion : stimulation and desensitization. 1056 98

1. The circumventricular organs (CVO) are structures that permit polypeptide hypothalamic hormones to leave the brain without disrupting the blood-brain barrier (BBB) and permit substances that do not cross the BBB to trigger changes in brain function. 2. In mammals, CVO include only the median eminence and adjacent neurohypophysis, organum vasculosum lamina terminalis, subfornical organ and the area postrema. 3. The CVO are characterized by their small size, high permeability and fenestrated capillaries. The subcommissural organ is not highly permeable and does not have fenestrated capillaries, but new evidence indicates that it may be involved in the hypertension produced by aldosterone acting on the brain. 4. Feedback control of corticotropin-releasing hormone (CRH) secretion is exerted by free steroids diffusing into the brain, but substances such as cytokines and angiotensin II act on CVO to produce increases in CRH secretion. Gonadal steroids also diffuse into the brain to regulate gonadotrophin-releasing hormone secretion. Thyrotropin-releasing hormone secretion is regulated by thyroid hormones transported across cerebral capillaries. However, CVO may be involved in the negative feedback control of growth hormone and prolactin secretion.
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PMID:Circumventricular organs: definition and role in the regulation of endocrine and autonomic function. 1083 Dec 47

Corin cDNA encodes an unusual mosaic type II transmembrane serine protease, which possesses, in addition to a trypsin-like serine protease domain, two frizzled domains, eight low-density lipoprotein (LDL) receptor domains, a scavenger receptor domain, as well as an intracellular cytoplasmic domain. In in vitro experiments, recombinant human corin has recently been shown to activate pro-atrial natriuretic peptide (ANP), a cardiac hormone essential for the regulation of blood pressure. Here we report the first characterization of corin protein expression in heart tissue. We generated antibodies to two different peptides derived from unique regions of the corin polypeptide, which detected immunoreactive corin protein of approximately 125-135 kDa in lysates from human heart tissues. Immunostaining of sections of human heart showed corin expression was specifically localized to the cross striations of cardiac myocytes, with a pattern of expression consistent with an integral membrane localization. Corin was not detected in sections of skeletal or smooth muscle. Corin has been suggested to be a candidate gene for the rare congenital heart disease, total anomalous pulmonary venous return (TAPVR) as the corin gene colocalizes to the TAPVR locus on human chromosome 4. However examination of corin protein expression in TAPVR heart tissue did not show evidence of abnormal corin expression. The demonstrated corin protein expression by heart myocytes supports its proposed role as the pro-ANP convertase, and thus a potentially critical mediator of major cardiovascular diseases including hypertension and congestive heart failure.
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PMID:Localization of the mosaic transmembrane serine protease corin to heart myocytes. 1108 6

We have isolated a novel human cDNA coding for human salt-tolerant protein (HSTP), that is a homologue of the rat salt-tolerant protein (STP) and may contribute to salt-induced hypertension by modulating renal cation transport. The nucleotide sequence (1988bp) of the HSTP cDNA contains an open reading frame encoding a polypeptide comprising 545 amino acids, two residues fewer than the rat STP cDNA. The predicted amino acid sequence exhibits 92% identity to that of the rat protein. HSTP contains predicted coiled-coil domains and Src Homology 3 domain, and shows a high degree of identity to CIP4 (Cdc42 target protein) and human Trip 10 (thyroid-hormone receptor interacting protein). We have mapped the HSTP gene to human chromosome 19 by fluorescence in situ hybridization.
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PMID:Molecular cloning and chromosomal localization of human salt-tolerant protein. 1129 12

Thus, the evidence summarized here supports an important role for insulin and the sympathetic nervous system in the pathogenesis of obesity-related hypertension. Is it possible that insulin-mediated sympathetic stimulation contributes a pro-hypertensive effect in non-obese as well? It seems possible in young borderline hypertensives where sympathetically mediated thermogenic mechanisms are potent enough to compensate for the increased caloric intake, thereby enabling these young hypertensives to avoid obesity. This is consistent with an observation made in the original Framingham cohort that not only did obesity predict the eventual development of hypertension, but hypertension, as well, predicted the eventual development of obesity. A reasonable interpretation of these data suggests that as subjects age and the effectiveness of thermogenic mechanisms wanes, obesity might develop as a consequence of increased caloric intake no longer effectively buffered by the increased SNS activity. It is important to note that the mechanisms described here exert a pro-hypertensive effect and cannot properly be considered to 'cause' hypertension. Hypertension is rarely the consequence of a single mechanism. It is also true, as pointed out convincingly by Julius and his colleagues, that enhanced sympathetic activity, as a primary factor, can be associated with both hypertension, insulin resistance and, possibly, obesity [39]. And, finally, it should be noted that the mechanism described here is not the only mechanism linking obesity and hypertension. A rapidly emerging body of evidence indicates that leptin, the polypeptide product of the ob/ob gene secreted from adipose tissue, exerts potent central neural effects on both appetite and sympathetic activity. Leptin levels, elevated in obese humans, have the potential to increase both sympathetic activity and blood pressure [40-43]. A more comprehensive summary of the relationships between hypertension and obesity may, therefore, involve insulin and leptin, as well as the SNS, as represented in the schema presented in Figure 7. Both leptin and insulin may, therefore, be considered as compensatory mechanisms recruited to restore energy balance, with the SNS as one of the effector arms. Viewed in this way, obesity-related hypertension is inextricably linked to the metabolic economy of the obese.
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PMID:Insulin-mediated sympathetic stimulation: role in the pathogenesis of obesity-related hypertension (or, how insulin affects blood pressure, and why). 1132 24

The effects of inhibition of carotenoid biosynthesis by 2-hydroxybiphenyl on the photosynthetic growth, pigment composition and chlorosome structure of Chlorobium phaeobacteroides strain CL1401 were examined. At a concentration of 20 micrograms 2-hydroxybiphenyl .ml-1, carotenoid synthesis was largely inhibited (85%), but the photosynthetic growth rate was almost unaffected (mu control = 0.00525 +/- 0.00007 h-1 and mu HBP-treated = 0.00505 +/- 0.0005 h-1). Cells grown in the presence of the inhibitor were 5 microns-70 microns long, while control cells were between 2-5 microns long. Moreover, 2-hydroxybiphenyl-treated cells contained fewer, unevenly distributed chlorosomes per micron of cytoplasmic membrane with an irregular arrangement (2.5 +/- 1.5 vs of 9.1 +/- 1.9). This was concomitant to the 83% decrease in the content of bacteriochlorophyll (BChl) e in 2-hydroxybiphenyl-treated cells. Electron microscopy revealed that the shape of carotenoid-depleted chlorosomes changed from ellipsoidal to spherical, although the mean volume was similar to that of control chlorosomes. SDS-PAGE analysis of the chlorosome polypeptide composition showed that the amount of CsmA protein decreased by 60% in carotenoid-depleted chlorosomes. This was paralleled by a decrease in the baseplate BChl a content. The data suggest that carotenoids are close to the chlorosomal baseplate, where they carry out both structural and photoprotective functions.
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PMID:Effect of carotenoid deficiency on cells and chlorosomes of Chlorobium phaeobacteroides. 1135 15

Under physiological conditions, the endocrine heart contributes to the maintenance of cardiovascular homeostasis through the polypeptide hormones ANF and BNP, which are members of the natriuretic peptide (NP) family. Given that NPs are of interest from the basic and clinical points of view, the genetic expression and secretion of ANF and BNP as well as the nature of the interaction of these hormones with their receptors has been the subject of extensive studies since the discovery of ANF in 1980. Following hemodynamic overload, increased secretion of NPs by the heart can be seen. This change may occur without an increase in gene expression as observed for atrial NPs following acute volume expansion, or it can occur with an increase in both ANF and BNP gene expression in atria only as seen in mineralocorticoid escape during which it is obvious that a critical decrease in hormone stores must be reached before transcriptional activation occurs. Chronic hemodynamic pressure or volume overload results in increased expression of NPs in atria and ventricles. Under these circumstances, the increased production of BNP by hypertrophic ventricles changes the normal plasma concentration ratio of ANF to BNP, a fact that has clinical diagnostic and prognostic implications. There are exceptions to this rule: chronic, severe L-NAME hypertension, which may occur without left ventricular hypertrophy, does not cause this effect and increased ventricular NP gene expression can occur in mineralocorticoid hypertension before detectable ventricular hypertrophy. Atrial and ventricular NP gene expression appears to be under different transcriptional control because pharmacological treatments such as chronic ACE inhibition or ET(A) receptor blockade can reverse the increased ventricular NP expression but has no detectable effect on atrial NP gene expression. This is not unlike the myosin heavy chain switch that is observed in certain pathologies, and can be pharmacologically reversed in a manner similar to NPs in the ventricles but it does not occur in atrial muscle. These observations made in vivo or using isolated adult atria often differ strikingly from results obtained using the mixed phenotype afforded by cardiocytes in culture, indicating that the kinds of questions addressed by each approach must be judiciously chosen. G-protein coupled receptor-mediated actions of neurohumors such as endothelin and phenylephrine are normally used to stimulate NP gene expression and release in different in vitro models. The main physiological stimulus for increased ANF release, atrial muscle stretch, also appears to rely on G-protein-coupled mechanisms. Alternative agonists and receptor types at play are suggested by the finding that circulating levels of BNP are selectively increased before and during overt cardiac allograft rejection episodes in human patients. The data suggest that enhanced BNP plasma levels could form a basis for a noninvasive test for cardiac allograft rejection. However, the molecular mechanism by which expression of NPs are regulated in the transplanted heart is not well understood. Conditioned medium from mixed lymphocyte reaction cultures, considered an in vitro model of transplantation immunity, induces specific upregulation of BNP as do individual pro-inflammatory cytokines. Findings such as these suggest that the study of NPs will continue to produce a wealth of information relevant to basic and clinical scientists.
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PMID:The physiological and pathophysiological modulation of the endocrine function of the heart. 1155 79

We investigated plasma brain natriuretic polypeptide (BNP) in Type 2 NIDDM patients with albuminuria. This study involved normal control subjects (Controls), hypertensive patients without diabetes mellitus (HT) and Type 2 NIDDM patients. Diabetic patients were divided into 4 groups by urinary albumin index (Alb-I): group I <30; group II 30-149; group III 150-300; group IV >300 mg/g creatinine. BNP levels in group III or IV were significantly higher than in Controls. The diabetic patients were re-divided into 4 groups (DM: with neither diabetic retinopathy (which was one of indicators of microangiopathy) nor hypertension, DM+HT: without diabetic retinopathy and with hypertension, DM+R: with diabetic retinopathy and without hypertension and DM+R+HT: with both diabetic retinopathy and hypertension). The Alb-I levels in DM+HT and DM+R+HT were significantly higher than the Controls, indicating the development of diabetic nephropathy in those groups. BNP levels in DM+HT, DM+R or DM+R+HT were significantly higher than in Controls. This indicates that BNP levels elevate in diabetic patients with increased albuminuria due to hypertension or microangiopathy deteriorating diabetic nephropathy. Elevated plasm BNP may play a pathophysiological role in the development of diabetic nephropathy.
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PMID:Brain natriuretic polypeptide in type 2 NIDDM patients with albuminuria. 1156 15

Most forms of hypertension are associated with a wide variety of functional changes in the hypothalamus. Alterations in the following substances are discussed: catecholamines, acetylcholine, angiotensin II, natriuretic peptides, vasopressin, nitric oxide, serotonin, GABA, ouabain, neuropeptide Y, opioids, bradykinin, thyrotropin-releasing factor, vasoactive intestinal polypeptide, tachykinins, histamine, and corticotropin-releasing factor. Functional changes in these substances occur throughout the hypothalamus but are particularly prominent rostrally; most lead to an increase in sympathetic nervous activity which is responsible for the rise in arterial pressure. A few appear to be depressor compensatory changes. The majority of the hypothalamic changes begin as the pressure rises and are particularly prominent in the young rat; subsequently they tend to fluctuate and overall to diminish with age. It is proposed that, with the possible exception of the Dahl salt-sensitive rat, the hypothalamic changes associated with hypertension are caused by renal and intrathoracic cardiopulmonary afferent stimulation. Renal afferent stimulation occurs as a result of renal ischemia and trauma as in the reduced renal mass rat. It is suggested that afferents from the chest arise, at least in part, from the observed increase in left auricular pressure which, it is submitted, is due to the associated documented impaired ability to excrete sodium. It is proposed, therefore, that the hypothalamic changes in hypertension are a link in an integrated compensatory natriuretic response to the kidney's impaired ability to excrete sodium.
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PMID:The hypothalamus and hypertension. 1158 98

Seventeen alpha-hydroxylase/17,20-lyase deficiency is a rare, autosomal recessive form of congenital adrenal hyperplasia not linked to human leukocyte antigen and characterized by the coexistence of hypertension caused by the hyperproduction of mineralocorticoid precursors and sexual abnormalities, such as male pseudohermaphroditism and sexual infantilism in female, due to impaired production of sex hormones. Both 17alpha-hydroxylase and 17,20-lyase reactions are catalyzed by a single polypeptide, cytochrome P450c17 (CYP17), which is encoded by the CYP17 gene located on chromosome 10q24-q25. Mutations in the CYP17 gene have been recognized to cause the 17alpha-hydroxylase/17,20-lyase deficiency syndrome. Here, we describe two phenotypically and hormonally affected Italian patients with 17alpha-hydroxylase/17,20-lyase deficiency. The family history revealed consanguinity of the parents. Linkage and haplotype analyses using microsatellites on chromosome 10q24-q25 demonstrated that the two affected individuals were homozygous at these loci. The mutation screening of the CYP17 gene identified a new Phe93Cys missense mutation in exon 1. The amino acid substitution is located in a highly conserved region of the protein and is not a polymorphism because it is not present in one hundred normal alleles. In vitro functional studies showed that the Phe93Cys mutated CYP17 retains only 10% of both 17alphahydroxylase and 17,20-lyase activities, according to the severe phenotype. Our results shed more light on the structure-function relationship of the CYP17 protein indicating that Phe 93 is crucial for both enzymatic activities.
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PMID:Combined 17alpha-Hydroxylase/17,20-lyase deficiency caused by Phe93Cys mutation in the CYP17 gene. 1183 39


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