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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cadmium exposure is known to induce hypertension, but development of hypertension is not universal in exposed animals. However, the cellular uptake of cadmium could also exert renal cytotoxic effects which have been, until now, essentially only studied at the proximal tubule level. Kallikrein is an enzyme synthetized in renal cortex and excreted in the urine in the distal tubule. Therefore, to evaluate the distal renal effect of cadmium, we studied the daily urinary kallikrein excretion (UKE) in conscious unrestrained female Brown Norway rats during long-term chronic exposure to 2 dosages of cadmium given subcutaneously 3 times a week, a low dose (LD): 0.25 mg/kg and a high dose (HD): 1 mg/kg. Neither dose of cadmium was able to induce significant hypertension in the treated animals. HD administration for 24 weeks resulted in a decreased UKE associated with an increase in plasma renin activity and sodium and potassium excretions. LD administration had no significant effect on UKE. Twenty weeks after stopping cadmium administration, a persistent reduction in UKE was still observed; furthermore, the group which had been previously administered a LD of cadmium, now also exhibited a reduced UKE. During this re-examination period in both groups, the UKE reductions were associated with normal systolic blood pressure, glycosuria, natriuresis. Our data show that cadmium administration can influence UKE, plasma renin activity, plasma aldosterone concentration and electrolyte excretion without inducing any variation of blood pressure. This may reflect a nephrotoxic, non-hypertensive effect. Since this effect persisted after stopping cadmium administration, it may indicate a prolonged irreversible nephrotoxic effect at the distal nephron level. Thus, UKE may be a useful non-invasive index to evaluate distal nephrotoxicity.
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PMID:Renal kallikrein excretion as a distal nephrotoxicity marker during cadmium exposure in rats. 265 77

The mechanism of suppression of renal kallikrein activity in low renin essential hypertensive and renoparenchymal hypertensive patients was investigated in this study. From Sephadex G-200 column chromatography studies, a single kallikrein peak was observed in both kallikrein radioimmunoassay and kininogenase activity in all samples from normal subjects, low renin essential hypertensive and renoparenchymal hypertensive patients, and in purified kallikrein solution. The enzyme-specific activity around the kallikrein peak in all urine samples from each group was significantly lower than that in purified kallikrein, and a significantly lower specific activity was found in both patient groups than was found in normal subjects. Moreover, it was also recognized that the specific activity of kallikrein decreased in all cases with the increase of the molecular weight of kallikrein, and this tendency was observed more obviously in the low renin essential hypertensive and renoparenchymal hypertensive patients than in the normal subjects. These results suggest the presence of a kallikrein-specific inhibitor with a low molecular weight in human urine, although the possibility of a variant form of kallikrein cannot be excluded.
Hypertension 1989 Oct
PMID:Mechanisms of suppression of renal kallikrein activity in low renin essential hypertension and renoparenchymal hypertension. 267 59

Observations over 11 years from the University of Utah Cardiovascular Genetics Research Clinic and published data from other studies are reviewed to illustrate research approaches, developing results and prospects for future studies. Strong associations with hypertension have been found for several biochemical tests that show substantial genetic determination. Suggestions of recessive major gene effects and significant polygenic background determinations have been found for several variables, including urinary kallikrein excretion, intracellular sodium concentration, sodium-lithium countertransport and sodium-potassium cotransport. Each of these variables is related in some way to sodium or potassium metabolism, or both, and may help to improve the understanding of a possibly inherited susceptibility to hypertension that is related to dietary electrolyte intake. A second major group of factors involving familial predisposition to hypertension include lipid abnormalities (increased very-low- and low-density lipoprotein cholesterol and decreased high-density lipoprotein cholesterol); increased fasting insulin levels or insulin resistance, or both; obesity (especially central or upper body obesity); and multiple environmental factors influencing these metabolic systems, including dietary fat, carbohydrate and calorie intake; physical exercise; and certain antihypertensive medications that adversely affect lipid metabolism and glucose tolerance. Some studies even suggest a possible link between these two large groups of factors (electrolyte metabolism and lipid-insulin metabolism). Hypertriglyceridaemia and hyperinsulinaemia are both significantly correlated with increased levels of several cation-flux tests. It is recommended that studies of human hypertension apply these biochemical profiles to study sibships with two or more hypertensive siblings as a cost-effective initial approach.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Current knowledge regarding the genetics of human hypertension. 269 50

The inheritance of 12-hour overnight total urinary kallikrein excretion and its association with family history of essential hypertension were studied in 405 normotensive adults and 391 youths in 57 Utah pedigrees. Total urinary kallikrein excretion was highly familial with 51% of the total variance attributable to a dominant allele for high total urinary kallikrein excretion and 27% attributable to the combined effects of polygenes and shared family environment. An estimated 28% of the population has one or two copies of the dominant allele for high total urinary kallikrein excretion (2.3 SD units higher than the low homozygotes). About 83% of the population could be assigned to one of the two genotypic populations. Individuals with the high total urinary kallikrein excretion genotype were significantly less likely to have one or two hypertensive parents (relative odds = 0.56, p = 0.042). We conclude that a dominant allele expressed as high total urinary kallikrein excretion may be associated with decreased risk of essential hypertension. Further studies should be performed to confirm this finding and to test for interactions between this apparently protective gene and other genetic and environmental determinants of essential hypertension.
Hypertension 1989 Jan
PMID:A gene for high urinary kallikrein may protect against hypertension in Utah kindreds. 291 Aug 12

1. Spontaneously hypertensive rats (SHR) excrete less kallikrein in urine than Wistar-Kyoto rats (WKY) during the developmental phase of hypertension. The present study was designed to examine whether the urinary defect is related to abnormalities in the renal kallikrein content in this hypertensive model. 2. Active and total kallikrein were measured (amidolytic assay) in the renal cortex of newborn and 4-, 8- and 12-week-old SHR and age-matched WKY. Active and total kallikrein were also measured in urine at the same ages, except at birth. 3. Tissue active kallikrein was significantly lower in SHR at birth, representing on average 53% of the values in WKY expressed as content per total cortex weight. Tissue total kallikrein did not differ between newborn SHR and WKY. 4. SHR at 4, 8 and 12 weeks of age had lower urinary active and total kallikrein excretion. Tissue active akllikrein, but not total kallikrein, was higher than in age-matched WKY per g of cortex weight or per mg of protein, whereas both tissue active and total kallikrein were lower in SHR when expressed as content per total cortex weight. At these three ages, active kallikrein represented, on average 86%, while total kallikrein represented 77%, of the values in age-matched WKY. 5. Our results indicate a defect in prokallikrein activation rather than in kallikrein synthesis in the renal cortex of SHR at birth. The reduction in urinary kallikrein excretion during the developmental phase of hypertension in young SHR is similar to the reduction observed in the renal tissue.
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PMID:Renal kallikrein activity in rats developing spontaneous hypertension. 292 23

Dipeptide and tripeptide derivatives containing a statine residue were synthesized as inhibitors of human renin. ES-305, bis[(1-naphthyl)methyl]acetyl(BNMA)-histidyl-statine 2(S)-methylbutylamide was found to be a highly potent inhibitor of human renin with a Ki value of 1.7 X 10(-9) M. Dipeptide derivatives with the BNMA group at the N-terminal (BNMA-Val-Sta-isoleucinol [ES-313], BNMA-Leu-Sta-isoleucinol [ES-316], and BNMA-Nle-Sta-isoleucinol [ES-317]) had potencies against human renin that were similar to the potency of ES-305. All these dipeptide derivatives competitively inhibited human renin. The inhibitors were also potent against monkey renin but were less effective against renins from pig, goat, dog, rabbit, and rat. ES-305 had little effect on cathepsin D and pepsin at the concentration of 10(-5) M. The other derivatives showed detectable inhibition of cathepsin D (IC50, 10(-6) - 10(-7) M) and pepsin (10(-5) - 10(-6) M). All the compounds had little or no effect on trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at the concentration of 10(-5) M. Our results indicate that ES-305 is a highly potent and specific inhibitor of human renin. This compound is superior to other, previously described statine-containing renin inhibitors with respect to molecular size and enzyme specificity.
Hypertension 1986 Jun
PMID:Statine-containing dipeptide and tripeptide inhibitors of human renin. 308 74

An orally active renin inhibitor, ES 6864 (N-[(2R)-3-morpholinocarbonyl-2-(1-naphthylmethyl)propionyl]-(4- thiazolyl)-L-alanyl-cyclostatine-(2-morpholinoethyl)amide), was synthesized. ES 6864 was found to be a highly potent inhibitor of human renin with a Ki value of 7.3 x 10(-9) M. The compound competitively inhibited human renin. The inhibitor was also potent against monkey renin but was less effective against renins from pig, goat, dog, rabbit, and rat. ES 6864 did not inhibit cathepsin D, pepsin, trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at a concentration of 10(-5) M. ES 6864 was resistant to proteolytic actions of the enzymes in rat tissue homogenates (liver, kidney, pancreas, and small intestine). Oral administration of ES 6864 at 30 mg/kg to conscious, sodium-depleted marmosets produced a significant blood pressure reduction and almost complete inhibition of plasma renin activity, which persisted for 5 hours. Oral administration of ES 6864 also produced dose-related decreases of blood pressure in hog renin-infused rats, but the duration of action was much shorter than that in conscious marmosets. The parent compound in the blood following oral administration of ES 6864 to marmosets was confirmed directly by measuring the plasma concentration of ES 6864. These results enhance the possibility of developing renin inhibitors that can be used clinically.
Hypertension 1988 Jun
PMID:A highly potent and long-acting oral inhibitor of human renin. 313 6

The level of tissue kallikrein in serum and urine, and of an erythrocyte kallikrein-like enzyme, were compared in 10 subjects without hypertension and in 10 patients with hypertension with normal renin levels. Each group consisted of five men and five women. All subjects were observed at a general clinical research center for consecutive 5- to 6-day periods of daily dietary sodium intake of 109, 9, and 259 mEq. Tissue kallikrein levels in serum and urine and levels of the erythrocyte kallikrein-like enzyme were measured with specific radioimmunoassays or with an activity assay, respectively. Mean active and total urinary kallikrein excretion rates were higher in women than in men (both with and without hypertension) when they were given all diets (p less than 0.05 to 0.025), and these rates varied inversely with sodium intake. The serum immunoreactive tissue kallikrein level was higher in men than in women when they were given all diets (p less than 0.05 to 0.001), but there was no difference between subjects with and without hypertension. There were no consistent changes in levels with altered sodium intake. Erythrocyte kallikrein-like esterase activity was greater in women without hypertension than in men without hypertension (p less than 0.05 to 0.001) when receiving the 9 and 109 mEq sodium diets, but values were similar in all groups receiving the 259 mEq sodium diet.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Gender differences of human tissue kallikrein and an erythrocyte kallikrein-like enzyme in essential hypertension. 318 93

Genes for the small human glandular kallikrein gene family were isolated. Members of this family include renal/pancreatic kallikrein, prostate-specific antigen and a kallikrein encoded by the first gene that was isolated and completely sequenced, hGK-1. All share strong nucleotide sequence homology, although hGK-1 and the prostate-specific antigen gene are more closely related (86% identity in coding nucleotides). Renal/pancreatic kallikrein has 77% nucleotide homology to prostate-specific antigen, but only 60% amino acid homology. There is strong homology in the 5'-flanking DNA with mouse kallikrein genes, suggesting common regulatory mechanisms. In the rat one-kidney, one clip model of hypertension, renal kallikrein messenger (m)RNA increased during the initial transient rise in plasma renin, and then decreased.
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PMID:Kallikrein genes: cloning in man and expression in rat renal hypertension. 324 Dec 25

The pathophysiology of renal dysfunction in generalized sepsis remains unknown. In this study, 24 hours after surgical induction of peritonitis in 20 volume-loaded sheep, three patterns of renal function were seen. In group 1 (n = 8), glomerular filtration rate (GFR) decreased by 70%, urine volume by 85%, absolute sodium excretion by 95%, and fractional sodium excretion by 83%. Group 2 (n = 4) exhibited similar sodium retention but GFR did not fall. Group 3 (n = 8) showed no change in GFR or urine volume and only minimally reduced sodium excretion. Mean arterial pressure fell 17% in group 1 only; central venous pressure, pulmonary capillary wedge pressure, and plasma volume were maintained at or above presepsis values in all groups. Cardiac index was either increased or unchanged, and renal plasma flow was maintained in all groups; there was thus no hemodynamic evidence to suggest volume contraction. Histologic examination showed only minor changes with no consistent pattern. Renal functional changes correlated with other manifestations of severe sepsis--GFR and sodium retention correlated significantly with increased cardiac index, decreased systemic vascular resistance, pulmonary arterial hypertension, leukopenia, hypoproteinemia, and hypoglycemia. All of these changes were most marked in group 1. In groups 1 and 2, plasma renin activity (PRA) increased and urinary kallikrein excretion decreased. PRA correlated inversely with GFR, urine volume, and sodium excretion; urinary kallikrein excretion correlated positively with urine volume and sodium excretion. Urinary excretion of 6-keto-PGF1 alpha was increased in groups 1 and 2 and correlated inversely with mean arterial pressure in group 1 animals. During sepsis, urinary thromboxane B2 excretion continued at presepsis values in all groups. The results suggest that unusual reciprocal changes in activity of the renin-angiotensin and renal kallikrein-kinin systems may play a role in the renal response to sepsis. PGI2 synthesis is increased and may affect systemic hemodynamics and renal function; the role of thromboxane A2 in this context is unknown.
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PMID:Vasoactive hormones in the renal response to systemic sepsis. 327 70


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