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)

The widespread clinical study of converting-enzyme inhibitors has shown that they are effective antihypertensive drugs even in patients who may manifest either normal or decreased plasma renin activity. This suggests either that renin in a site other than plasma may play a contributory role in essential hypertension or that the hypotensive effect is caused by increased concentrations of kinins and prostaglandins, both demonstrated consequences of converting-enzyme inhibitor administration. Specific renin inhibitors appropriate for studies in humans would aid in the resolution of this question. Four classes of compounds have been demonstrated to be renin inhibitors of high potency: specific antibody, general peptide inhibitors of acid proteases, analogs of angiotensinogens, and peptides that are related to the amino-terminal sequence of prorenin. With the purification of renin, specific polyclonal or monoclonal antibodies have become available. The former have already been used extensively in physiologic studies in intact animals. Pepstatin is an inhibitor of many acid proteases. Its in vivo application has been retarded by its relative insolubility, but recent chemical modifications, particularly the addition of charged amino acids at the carboxy terminus, have rendered it more useful. The minimal substrate for renin is an octapeptide segment of the protein substrate: His-Pro-Phe-His-Leu-Leu-Val-Tyr. Variants of this sequence have resulted in competitive inhibitors that are useful in vivo. Recently, remarkably active inhibitors have been synthesized by reducing the peptide bond that is cleaved by renin, producing what may be a transition state inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension
PMID:Is renin a factor in the etiology of essential hypertension? 641 50

A lot of over 60 atherosclerotics with clinical manifestations of senile depressive illness was studied comparatively with a lot of subjects of the same age with essential arterial hypertension (EAH). As concerns the behaviour of the catecholamine content in CSF and blood, the total catecholamines are approxiately equal in the two lots, but with a clear difference of the catecholamine fractions. The CSF catecholamines behaviour in old atherosclerotics is characterized by the presence of increased values of noradrenaline (NA) and of adrenaline (A), with increased statistical significance, but without modifications of the adrenaline percentage (A %) from the total catecholamines, comparatively to the values found in normal subjects. The serotonin (5-HT) content of the CSF in men with atherosclerotic senile depressive illness was lower even than in subjects with coronary atherosclerosis. In atherosclerosis protides modifications precede the histologic changes. In CSF, GLU, ALA, TYR increase in old subjects. In blood, GLU, ALA, TYR, HIS, LEU, SER increase in the same subjects. ARG decreases with age. THR is higher in men than in women. In the urine of all the men as well as of all the women of more than 60 years, GLN and ALA have increased values. LYS increases with age. GLN and ARG are higher in men than in women.
 ...
PMID:Pattern of the cerebrospinal fluid (CSF) and blood biogenic amines and of the CSF, blood and urine amino acids as pathogenetic ground of the senile depressive illness. 677 91

Spontaneously hypertensive rats exhibited dopamine receptor supersensitivity as evidenced by a greater hypothermic response to apomorphine in comparison with normotensive Wistar-Kyoto rats. A single injection of cyclo(Leu-Gly) given prior to apomorphine administration did no alter apomorphine induced hypothermia in either the normotensive or the hypertensive rats. Chronic administration of cyclo(Leu-Gly) for 7 days did not affect apomorphine response in normotensive rats, but blocked the exaggerated response to apomorphine in the hypertensive rats. These studies suggest that cyclo(Leu-Gly) interacts with the dopamine receptors and that the central dopamine receptors may play a role in the pathophysiology of hypertension.
 ...
PMID:Effect of cyclo(Leu-Gly) on the supersensitivity of dopamine receptors in spontaneously hypertensive rats. 684 87

One may postulate a genetic defect in membrane permeability, in the transport of sodium, or in the sodium pump in vascular muscle which could account for increased intracellular sodium and enhanced vascular contractility. If the electrogenic sodium pump is overactive, as in SHR, its inhibition may lead to significant depolarization and greater contraction. Sympathetic innervation may be essential for the development of membrane abnormality as well as for the development of hypertrophic vascular changes, both of which augment contraction and vascular tone. A similar membrane defect at the sensory endings of arterial stretch receptors may account for impaired arterial baroreceptor reflexes seen in very early phases of hypertension or, in some genetic models, before hypertension develops. This defect may be related to the sodium pump or sodium transport in the receptor region and cause a decrease in baroreceptor discharge and in the strain-sensitivity of the baroreceptors, resulting in exaggerated sympathetic drive. Further information is needed on the baroreflex control of various efferents in hypertension. Another membrane defect at the adrenergic nerve terminals may facilitate release of endogenous NE. Excessive salt intake may unmask or exaggerate the membrane defects. In the central nervous system a defect in glutamine, NE, or GABA receptors may contribute to a high central sympathetic drive. Greater receptor affinity to various pressor neuropeptides such as angiotensin and leucine enkephalin or greater release of these peptides may also account for the excessive CNS sympathetic activation or impairment of baroreflexes at a central level. Cardiac receptors may have a variable influence on sympathetic drive in the various stages of hypertension, depending on the degree of cardiac hypertrophy or cardiac size. Finally, increased renal afferent nerve activity may provoke an increase in sympathetic activity and provide a link between natriuretic factors and the sympathetic nervous system in hypertension.
Hypertension
PMID:The sympathetic system in hypertension. State-of-the-art review. 704 Feb 39

1. The basic mechanism underlying the structural vascular changes occurring in hypertension was studied in cultured aortic smooth muscle cells (SMC) obtained by an explant method from spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) and compared with that in normotensive Wistar--Kyoto (WKY) rats. 2. The growth rate of SMC from SHR and SHRSP at the age of 2.5--11 months was greater than that of SMC from WKY rats even after repeated passages. 3. [3H]Thymidine and [14C]leucine incorporation, and ornithine decarboxylase (ODC) activity of SMC were increased in SHR and SHRSP in comparison with WKY rats. 4. The application of isoprenaline but not noradrenaline to the culture media increased ODC activity acutely in SMC from WKY rats and this increase was blocked by propranolol. 5. These results indicate that SMC from SHR and SHRSP are more prone to proliferate than those from WKY rats and that a beta-adrenergic neurohumoral mechanism accelerates SMC growth independently of blood pressure.
 ...
PMID:Mechanisms of structural vascular changes in genetic hypertension: analyses on cultured vascular smooth muscle cells from spontaneously hypertensive rats. 718 65

A shortened and modified eledoisin-hexapeptide sequence (Lys-Phe-Ile-Gly-Leu-MetNH2) was tested for their action on avoidance learning and blood pressure of rats with spontaneous hypertension (SH-rats) and intact Wistar rats. Both groups were 10, 14, and 26 weeks of age. Disorders of avoidance learning and elevation of blood pressure were likely to aggravate along with growing age of SH-rat. The used eledoisin-hexapeptide sequence is related to the essential C-terminal pentapeptide sequence of Substance P (SP). After injection of the used hexapeptide at doses of 250 microgram/kg intraperitoneally disorders in avoidance learning were completely eliminated from ten-week SH-rats or conditionally for SH-rats aged 14 and 26 weeks. Elevated blood pressure in SH-rats aged 26 weeks was reduced by the hexapeptide from 220 Torr to approximately 190 Torr. Blood pressure in SH-rats aged 14 weeks, originally about 180 Torr, was almost unaffected by the hexapeptide. Blood pressure went up from about 150 Torr to 190 in ten-week-old Sh-rats. A hypothesis was made about the mode of action of Substance P and related peptides.
 ...
PMID:Effects of a substance P-analogue on blood pressure and avoidance learning of rats with spontaneous hypertension. 728 83

The cardiovascular effects of opioid peptides have been studied. Leucine-enkephalin (Leu-ENK) produced blood pressure (BP) increases following administration into the lateral brain ventricles (i.v.t.), into the cisterna magna (i.c.i.), and following intravenous (i.v.) administration. Heart rate (HR) increases were observed following all routes of administration (threshold for BP and HR effects at 0.3 nmole, maximum at 360 nmoles). The cardiovascular effects were independent of generalized seizures, which may occur at higher doses of enkephalins (ENK). D-alanine-enkephalin (D-Ala-ENK) attenuated the vagal component of the baroreceptor reflex in cats. This was indicated by the findings that HR did not decrease following D-Ala-ENK-induced BP increases and that the compensatory decreases in HR following i.v. pressor doses of angiotensin II (ANG II) were markedly attenuated in cats treated with i.v.t. D-Ala-ENK. Naloxone inhibited the BP and HR effects following i.c.i. and i.v., but not following i.v.t., administration of Leu-ENK. The i.v.t. Leu-ENK effect were inhibited by beta-adrenergic receptor blockade. Bratteboro rats homozygous for hereditary diabetes insipidus with total absence of antidiuretic hormone (ADH) synthesis responded with BP decreases following i.v.t. Leu-ENK, while BP increases were observed in control Long-Evans rats. Blood pressure increases to i.v.t. Leu-ENK were markedly greater in spontaneously hypertensive rats of the stroke-prone strain (SHR-sp) than in normotensive control rats; SHR-sp exhibit a humoral pattern of increased ADH, ACTH, and catecholamines, presumably due to central peptidergic stimulation. The known effects of opioid peptides on these hormones and the observed cardiovascular responses suggest a possible participation of this peptide system in the maintenance of high BP in the SHR-sp.
Hypertension
PMID:Enkephalin effects on blood pressure, heart rate, and baroreceptor reflex. 739 23

Many properties of urinary kallikrein are well characterized, but the intracellular processing of prokallikrein and release by kidney cells have yet to be clarified. We report here on the synthesis of prokallikrein in Madin-Darby canine kidney (MDCK) cells transfected with rat submaxillary gland kallikrein cDNA and on its activation by MDCK cells and by an enriched liver Golgi membrane preparation. Transfected MDCK cells secreted only prokallikrein at both the apical and basolateral sides in about a 4:1 ratio, but cells transfected with kallikrein cDNA in reverse orientation or untreated cells released only traces of the enzyme. Prokallikrein, in culture medium or in homogenized MDCK cells, was fully activated by trypsin but activated only to 44% by thermolysin. Prokallikrein was synthesized and released into the medium at a high rate: the enzyme secreted by 5 x 10(6) cells in 24 hours cleaved 46 nmol/min D-Val-Leu-Arg-7-amino-4-methylcoumarin and liberated 63 ng/min bradykinin after activation. Immunocytology indicated the association of prokallikrein with the Golgi apparatus in the transfected cells. Antiserum to rat urinary kallikrein detected a single band in a Western blot of conditioned medium and also immunoprecipitated the enzyme. Aprotinin inhibited activated prokallikrein. Although MDCK cells released prokallikrein, their homogenates activated prokallikrein at both pH 5.5 and 7.5. Prokallikrein was also activated by a highly enriched liver Golgi membrane fraction and by an endoplasmic reticulum preparation, but the Golgi preparation was 38-fold more active. The activation was blocked significantly by inhibitors of serine proteases and less by cysteine protease inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1995 Dec
PMID:Expression of rat kallikrein and epithelial polarity in transfected Madin-Darby canine kidney cells. 749 Jan 45

As a result of advances in technology, genome searches have been carried out for susceptibility genes for type 1 diabetes in humans and in the NOD mouse. These have shown that, in the NOD mouse, diabetes susceptibility is under the control of at least ten separate chromosomal loci. In the human, in addition to HLA and INS, two new susceptibility genes have been localized, IDDM4 on chromosome 11q and IDDM5 on 6q, demonstrating the polygenic nature of type 1 diabetes and the role of HLA as the major locus. Candidate genes at these loci are the subject of current investigation. Genetic and immunological markers of disease may be of value in screening the general population for individuals at risk of developing type 1 diabetes. The predictive power of different screening strategies should be tested in order to work out the potential value to the general population of preventive therapies that are now undergoing clinical trials in high risk 'pre-diabetics'. Type 2 diabetes is genetically heterogeneous, and, since 1992, two distinct genetic subtypes have been identified. The first is defined by mutations in the GCK gene, which cause up to 60% of cases of MODY. The second, designated MIDD (maternally inherited diabetes and deafness), is defined by mutation in the mitochondrial gene for tRNA(Leu(UUR)). MIDD patients are less obese than is usual for typical type 2 diabetes, may present in early adult life or occasionally in childhood and may have been diagnosed as having autoimmune type 1 diabetes, type 2 diabetes or MODY. Typically, patients with MIDD require insulin earlier than do type 2 diabetics without mitochondrial mutations. Genetically complex diseases, such as diabetes, hypertension, cancer and coronary heart disease, are common in most populations. The approaches to the genetic analysis of diabetes outlined in this review are likely to be useful to the genetic analysis of many of these disorders. Progress in this area will have important implications for public health strategies in the next decade and beyond.
 ...
PMID:Molecular genetics of diabetes mellitus. 757 35

Guanylate cyclase-A, the receptor for atrial natriuretic factor, contains a protein kinase-like domain and a catalytic domain in the intracellular region. To investigate the active site (the catalytic cavity) of guanylate cyclase-A, we amplified the catalytic domain plus three amino acids from the kinase-like domain of guanylate cyclase-A (GC-c) with polymerase chain reaction (PCR) and expressed it in Escherichia coli. During the screening of the PCR-cloned gene products with guanylate cyclase assay, a mutant that lacks enzyme activity was identified. Results of cDNA sequencing revealed that Leu 817 was replaced by an Arg residue in the mutated protein. The mutated GC-c bound to GTP-agarose as well as the wild-type protein, indicating that the binding capability of mutated GC-c to GTP is not significantly affected by the Arg substitution. Gel-filtration column chromatography showed that, like the wild-type GC-c, the mutated protein also formed a high-molecular-weight complex. Since mutation of Leu 817 to Arg abolishes the catalytic activity, Leu 817 is likely located near the active site of guanylate cyclase-A. These results demonstrate that the carboxyl fragment of guanylate cyclase-A is an ideal system for studying the active site of guanylate cyclase-A.
Hypertension 1995 Apr
PMID:Mutational inactivation of the catalytic domain of guanylate cyclase-A receptor. 772 18


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