Biomedical subjects

G Schlager

Publications and source records attributed to G Schlager.

At least 19 recordsLinked to original sources

PubMed1999

Catecholamine storage vesicle protein expression in genetic hypertension.

Chromogranin A expression is heritable in humans, and both plasma chromogranin A concentration and its releasable adrenal and sympathetic neuronal pools are augmented in established essential (hereditary) hypertension. To evaluate chromogranin A further as a simpler or "intermediate phenotype" in the complex trait of hypertension, we studied chromogranin A expression in the spontaneously hypertensive rat (SHR), a rodent model of essential hypertension. Both plasma (p < 0.0001) and adrenal medullary (p = 0.003 to p < 0.0001) chromogranin A were elevated in the SHR, even at the earliest stages (3-4 weeks of age). In the adult adrenal gland, both chromogranin A (p=0.005) and norepinephrine (p=0.011) were increased in the SHR, while dopamine beta-hydroxylase activity was diminished (p < 0.0001). Chromogranin A mRNA expression was also elevated in the SHR adrenal medulla (p = 0.017). Differences in chromogranin A processing were not noted between SHR and Wistar Kyoto control (WKY) rats. In an SHR x WKY genetic intercross, control of the adrenal chromogranin A phenotype by a single major locus was suggested by comparison of phenotypic variance of the F2 vs F1 generations, and by bimodal frequency histogram (3:1 ratio), confirmed by maximum likelihood analysis (chi2 = 74.6, p < 0.000001) in the F2 generation. However, microsatellite alleles at a surrogate locus (Ighe) 12.7 cM from chromogranin A (Chga), on rat chromosome 6, failed to co-segregate with blood pressure in an F2 generation (F = 0.06, p = 0.94). In another rodent model of hereditary hypertension, the genetically hypertensive mouse (BPH/2), adrenal chromogranin A (p=0.018) and norepinephrine (p = 0.004) were actually diminished. We conclude that over-expression of chromogranin A is a variable feature of mammalian genetic hypertension. In one rodent model (the SHR), over-expression of chromogranin A is largely controlled by a single genetic locus, but the chromogranin A locus itself is not directly linked to determination of the blood pressure elevation of the SHR.

Adrenal Medulla↗

PubMed1999

Genome scan for blood pressure loci in mice.

Hypertension is a complex trait of unknown cause in humans. Mice of the inbred strain BPH/2 serve as a rodent model of human hypertension and display elevated blood pressure compared with the hypotensive strain BPL/1. An F2 intercross of BPH/2 and BPL/1 and 2 backcrosses of BPL/1 with Mus spretus were used to perform interval linkage mapping for systolic blood pressure in a genome scan. Significant linkage was observed in the F2s on chromosome 10 (logarithm of the odds score [LOD]=4.9) and on chromosome 13 in the M spretus backcross (LOD=3.3), with additional suggestive LODs on chromosomes 2, 6, 8, and 18. In addition, several suggestive linkages were observed for phenotypes associated with human hypertension. Our study is the first reported genome-wide linkage scan for blood pressure genes in the mouse.

Alleles↗

PubMed1998

Consumption of electrolytes and quinine by mouse strains with different blood pressures.

Daily fluid intakes were measured using two-bottle tests in female mice of inbred strains with high (BPH/2), normal (BPN/3) or low (BPL/1) blood pressure. The mice were offered a choice between water and different concentrations of NaCl (37.5-600 mM), KCl (1-400 mM), CaCl2 (1-100 mM) and quinine hydrochloride (0.003-1.0 mM). Compared with the normotensive strain, the hypertensive mice had higher water and total fluid intakes, and lower intakes of NaCl, KCl (only 200 mM) and quinine; the hypotensive mice had higher intakes of KCl (only 10-50 mM) and lower intakes of CaCl2 and quinine. These data suggest that fluid and salt intake are not linearly related to blood pressure, but are independently determined in these strains. Certain concentrations of the salts were preferred relative to water, which depended on mouse genotype: the BPN/3 and BPL/1 mice strongly preferred 37.5-150 mM NaCl, the BPL/1 mice preferred 10-100 mM KCl, and the BPN/3 mice preferred 1-10 mM CaCl2.

Animals↗

PubMed1997

Characterization of hypertensive and hypotensive inbred strains of mice.

The hypertensive inbred mouse strain, BPH/2, has high blood pressure early in life, compared with its hypotensive BPL/1 and normotensive BPN/3 controls. At 21 weeks of age, the hypertensive mouse has a systolic blood pressure 60 mm Hg higher than that of the hypotensive mouse. The difference in blood pressure between hypertensive and hypotensive mice is associated with strain differences in heart rate, heart weight, relative heart weight, left ventricular mass, kidney weight, and hematocrit. These strains have been inbred by brother x sister matings for nearly 50 generations in the BPH/2 and BPL/1 strains, and for nearly 40 generations in the BPN/3 strain.

Aging↗

PubMed1996

Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes.

We have generated a transgenic model consisting of both the human renin and human angiotensinogen genes to study further the role played by the renin-angiotensin system in regulating arterial pressure. Transgenic mice containing either gene alone were normotensive, whereas mice containing both genes were chronically hypertensive. Plasma renin activity and plasma angiotensin II levels were both markedly elevated in the double transgenic mice compared with either single transgenic or nontransgenic controls. The elevation in blood pressure caused by the human transgenes was independent of the genotype at the endogenous renin locus and was equal in mice homozygous for the Ren-1c allele or in mice containing one copy each of Ren-1c, Ren-1d, or Ren-2. Chronic overproduction of angiotensin II in the double transgenic mice resulted in a resetting of the baroreflex control of heart rate to a higher pressure without significantly changing the gain or sensitivity of the reflex. Moreover, this change was not due to the effects of elevated pressure itself since angiotensin-converting enzyme inhibition had minimal effects on the baroreflex in spontaneously hypertensive BPH-2 control mice, which exhibit non-renin-dependent hypertension. This double transgenic model should provide an excellent tool for further studies on the mechanisms of hypertension initiated by the renin-angiotensin system.

Angiotensinogen↗

PubMed1994

Biometrical genetic analysis of blood pressure level in the genetically hypertensive mouse.

Hypertensive mice of the inbred strain BPH/2 were mated to mice of the inbred hypotensive BPL/1, and their hybrid offspring were crossed and intercrossed. The systolic blood pressures of the resulting ten populations were then subjected to a biometrical genetic analysis to determine the mode of inheritance of genes regulating blood pressure in these strains. It was found that the inheritance of elevated blood pressure was due, primarily, to the additive effects of three to five genes. There was no evidence that genetic dominance or epistasis were involved in the genetic control of blood pressure in these strains.

Animals↗

PubMed1991

The role of dominance and epistasis in the genetic control of blood pressure in rodent models of hypertension.

Genetic analyses of crosses between hypertensive rodent models and their normotensive controls were performed on 43 sets of data published between 1970-1989. In each case, the cross involved F1, F2, and both backcross generations for a "complete genetic cross." Biometrical analysis estimated genetic parameters and their standard errors associated with dominance and epistasis (interaction of alleles that are not at the same locus). The statistical significance of these parameters was determined by comparing the parameter to its standard error. A purely additive inheritance pattern was seldom found. Additive/dominance inheritance was apparent in only two models. The prevailing pattern of inheritance was one with partial dominance for alleles for normal blood pressures and epistatic interactions. Finding epistasis in so many models will have implications for the application of cosegregation and linkage analyses in hypertension research.

Animals↗

PubMed1991

Hairpatches, a single gene mutation characterized by progressive renal disease and alopecia in the mouse. A potential model for a newly described heritable human disorder.

A new murine mutation, hairpatches (Hpt), is on chromosome 4, 18.1 recombination units distal to brown near the interferon alpha and beta chain structural gene complex. On the inbred HPT/Le strain background, Hpt is semi-dominant, and Hpt/Hpt mice die in utero by 6 to 8 days of gestation. Such death in utero is associated with abnormalities of embryonic ectodermal derivatives. However on the (C57BL/6J x C3HeB/FeJ-a/a) segregating hybrid background, Hpt is a fully dominant mutation. HPT/Le Hpt/+ mice can be recognized by 3 to 4 days of age by patches of lightly pigmented skin. These mice show reduced numbers of hair follicles, abnormalities in hair follicle structure, and patchy absence of hair throughout life. By 2 weeks of age, abnormal hair follicle development is accompanied by thickening of the epidermis, reduction in levels of subcutaneous fat, and dermal inflammation. Progressive glomerulosclerosis, resulting in chronic kidney failure, is accompanied by increases in glomerular mesangial matrix, deposition of immune complexes, and glomerular enlargement. Scanning electron microscopic studies revealed abnormalities of podocytes including disorganization, swelling, and fusion of the foot processes. Increase in serum blood urea nitrogen levels accompanies conspicuous renal histopathologic changes. Cardiovascular changes in Hpt/+ mice are evidenced by hypertrophy of the left heart ventricle. Increased systolic blood pressure in these animals was found by 3 months of age. Anemia occurs in Hpt/+ mice by 40 weeks. The Hpt/+ mutation provides a valuable new animal model for chronic kidney disease accompanied by skin abnormalities and ventricular hypertrophy. The pathologic changes caused by this mutation are similar to those reported in affected family members with a newly described autosomal dominant human disease.

Alopecia↗

PubMed1990

Decrease of blood pressure in spontaneously hypertensive mice by heat treatment.

Although the increased sensitivity of hypertensive animals to heat stress has been reported, the effect of chronic heat exposure has not been examined. The specific goal of the present investigation was to study the impact of chronic heat treatment on the blood pressure of spontaneously hypertensive mice. Chronic 40 degrees C heat exposure for 5 min daily progressively lowered basal blood pressure in hypertensive mice within 20 days, without any change in normal mice. In fact, after 35 days of chronic heat treatment, the basal blood pressure of hypertensive mice was indistinguishable from that of the normotensives. Repeated immobilization and prewarming as normal procedures for recording blood pressure contributed to the decrease in blood pressure by 10 to 12 mm Hg, but chronic heat by itself was significantly more potent in reducing it by an additional 20 mm Hg. After the discontinuation of chronic heat application, the basal blood pressure of hypertensive mice returned with time to the level registered in sham-handled hypertensive controls. These results demonstrate that, although acute heat is more detrimental to hypertensive mice, brief, chronic exposure to mild heat stress is beneficial in that it normalizes basal blood pressure.

Animals↗

PubMed1989

Thermosensitivity, a possible new locus involved in genetic hypertension.

Spontaneously hypertensive mice have been characterized as more sensitive to environmental heat than normotensive mice. A breeding program was therefore initiated to examine the possible genetic link between thermosensitivity and hypertension. Crossbreeding of spontaneously hypertensive mice with randomly bred normotensive mice produced F1 hybrids, which were then intercrossed to create a F2 population. Thermosensitivity was measured with a noninvasive method. The rate of body temperature increase was significantly (p less than 0.001) higher in the hypertensive mice (1.74 +/- 0.04 degrees C/min) compared with normal controls (1.13 +/- 0.03 degrees C/min). The frequency distribution of the rate of body temperature increase among the progenies was consistent with the hypothesis that a single gene locus determines the observed difference in thermosensitivity between normal and hypertensive mice. The allele that determines the rate of body temperature increase in normal mice was dominant in relation to the allele contributed by hypertensive mice. In the F2 population, a bimodal distribution determined two phenotypes: less than 1.40 degrees C/min and greater than 1.40 degrees C/min. A significant difference (p less than 0.01) in blood pressure of 11 mm Hg was observed between these two phenotypes. In addition, a positive correlation (p less than 0.01) was noted between the rate of body temperature increase and blood pressure in the F2 progeny. We conclude that there is possibly a single locus controlling thermosensitivity, which exhibits additive-dominance inheritance. Alleles of this particular trait segregate in part with an increment in blood pressure. The results support the possibility that the increased thermosensitivity seen in hypertensive mice is associated with one of the genes that contributes to their high blood pressure.

Animals↗

PubMed1988

Abnormality of calmodulin activity in hypertension. Evidence of the presence of an activator.

An apparent increase of calmodulin (CaM) activity was previously observed in the heart and kidney but not in the liver of spontaneously-hypertensive rats (SHR) and mice compared with their corresponding normotensive controls. As this change was due to an elevated recovery of CaM in the organs of the hypertensive animals, the present study was designed to evaluate its activity in hypertension. A CaM activator, detected in heart and kidney supernatants from hypertensive animals, was found to be responsible for this enhanced recovery. Similar results were obtained with passaged, cultured aortic smooth muscle cells from SHR, indicating that the anomaly was not a mere consequence of elevated blood pressure but rather a genetic expression of cells of hypertensive origin. The activator was heat stable, nondialyzable, and recovered in the fraction precipitated with 30-50% ammonium sulfate. Preliminary extraction studies suggest that the activator is contained in a glycolipid fraction. The stimulation of phosphodiesterase by this activator was calcium and CaM dependent. The activator appears to affect the affinity of the phosphodiesterase for CaM rather than the maximal stimulation. The activator was also present at a low concentration in the heart and kidney of normotensive animals. These findings indicate that at least some of the calcium abnormalities implicated in the pathogenesis of hypertension could be the result of interactions between CaM, calcium, and this activator.

Animals↗

PubMed1987

L-dopa metabolism in genetically hypertensive mice: effect of pargyline.

This study on the role of the sympathetic nervous system in the development of hypertension involves the measurement of dopamine and norepinephrine accumulation in various tissues of the hypertensive and random-bred normotensive strains of mice at basal levels, and following a pargyline-L-dopa treatment. Under such a treatment, designed to suppress the homeostatic action of monoamine oxidase and to better expose the relationship between dopamine and norepinephrine, the brain and heart of the hypertensive mice accumulated more dopamine than the normotensive mice. There was a significantly lower norepinephrine accumulation in the heart of the hypertensive mice in spite of comparable dopamine-beta-hydroxylase activity in this tissue between the two strains of mice. Under the pargyline-L-dopa treatment, the brain and heart of the older mice in both hypertensive and normotensive strains accumulated significantly (p less than 0.05) more dopamine than those of their younger counterparts, while their norepinephrine accumulation remained unchanged. The results demonstrated different patterns of response of dopamine and norepinephrine in the development of hypertension.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

Genetic analysis of blood pressure in the Milan hypertensive strain of rat (Rattus norvegicus).

Estimates of heritability (h2) of blood pressure level and the number of loci controlling the trait were derived from two genetic crosses involving the Milan hypertensive strain of rat and its control with normal blood pressure. In the genetic cross involving backcrosses, the estimates were h2 = 64% and the number of loci was two or three; there was some evidence of dominance of the alleles for normal blood pressures. In the other cross with only F2's, the degree of genetic determination (heritability in the broad sense) was 45%, involving at least three loci.

Alleles↗

PubMed1985

Catecholamine concentrations in discrete brain nuclei and sympathetic tissues of genetically hypertensive mice.

Catecholamine concentrations were determined at central and peripheral level in high blood pressure (HBP), low blood pressure (LBP) and random bred (RB) mice. In HBP mice compared to LBP, the noradrenaline concentration was lower in the locus coeruleus, medullary A1-C1 and A2-C2 areas, thoracic spinal cord, posteroventral hypothalamus and nucleus hypothalamicus anterior, while dopamine concentration was decreased in the striatum. Adrenal catecholamine levels were higher in both HBP and LBP compared to RB mice.

Adrenal Medulla↗

PubMed1985

Glomerular filtration and fluid balance in genetically hypertensive mice.

The Schlager genetically hypertensive mouse has been shown to be a valuable animal model with which to study human essential hypertension. Previous studies have characterized renal morphology, juxtaglomerular index, hematocrit, prostaglandin levels, brain catecholamines, social behavior, and patterns of inheritance. The present study continues the phenotypic characterization of this animal model. Using desiccation, isotope dilution, and clearance, the total body water, extracellular fluid volume, and glomerular filtration rate (GFR) in hypertensive and normotensive animals during normal postnatal development were measured. Additionally, using an electron microscopic tracer, the relative permeabilities of the glomerular filter in these animals were assessed. The data indicate a volume expansion in the young hypertensive animals along with a reduction in GFR. As the animals mature the volume expansion in the hypertensives subsides and is eventually reversed resulting in a lower than normal fluid volume level. The significance of the reduced GFR in the hypertensives is also diminished with age although not to the same degree as that of the fluid volume. The indication of a reduced glomerular permeability may account for the above in light of Guyton's cascade hypothesis.

Age Factors↗

PubMed1985

[Central and peripheral catecholamines in the genetically hypertensive mouse].

The aim of this work was to assess if biochemical alterations are present in catecholaminergic neurons of genetically hypertensive mice (HBP strain) compared to genetically hypotensive mice (LBP strain), as well as to mice of the population (R) from which HBP and LBP strains have been selected. For that purpose, dopamine (DA), noradrenaline (NA) and adrenaline (A) concentrations were determined by high performance liquid chromatography with electrochemical detection, in peripheral structures and brain nuclei of adult male mice from these three strains. In the adrenal medulla of HBP mice, DA, NA and A concentrations are increased when compared to R, but not to LBP mice. In the superior cervical ganglia of HBP mice, the NA concentration is decreased when compared to LBP, but increased when compared to R mice. At the central level, the NA concentration is decreased in HBP mice when compared to LBP, but not significantly changed when compared to R mice, in the following regions: locus coeruleus (-39 p. 100, p less than 0.001), A1-C1 (-17 p. 100, p less than 0.001) and A2-C2 (-19 p. 100, p less than 0.001) areas of the medulla oblongata, thoracic spinal cord (-26 p. 100, p less than 0.01), posteroventral hypothalamus (-18 p. 100, p less than 0.01) and nucleus hypothalamicus anterior (-14 p. 100, p less than 0.01). In the nucleus periventricularis, NA concentration of HBP mice is not changed when compared to both LBP and R animals. Finally, in the caudate nucleus of HBP mice, the DA concentration is decreased when compared to both R and LBP mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗

PubMed1984

The effect of nicotine on blood pressure in the genetically hypertensive mouse.

Mice genetically selected for high and low blood pressure were exposed to nicotine via a single injected dose or addition to drinking water for 52 weeks. In the acute study, the response of mice with high blood pressure was a statistically significant increase in blood pressure. In the chronic study the pattern of response to nicotine ingestion was similar for mice with high blood pressure and those with low. Both lines responded with an increase in blood pressure after 6 weeks followed by a decrease to below baseline blood pressure at 12 weeks.

Animals↗

PubMed1984

Renin-angiotensin system in genetically hypertensive mice.

We investigated the renin-angiotensin system in the genetically hypertensive (HBP), normotensive (NBP) and low blood pressure (LBP) mice developed by G. Schlager, one of the authors. Renin in the plasma, kidney and submaxillary gland was determined by enzymatic assay and by direct radioimmunoassay (DRIA). Trypsinization of mouse plasma was also investigated. PRA and plasma renin content were not significantly different in the different lines, sexes and generations. Trypsinization of the plasma revealed the presence of inactive renin, as has also been found in humans, hogs, dogs and rats. The proportion of active renin against trypsinized total renin was about 54-77% and was not significant in the different lines, sexes and generations. There was also no significant difference in renal renin content in the various lines, sexes and generations. However, in the submaxillary gland, renin content and activity were high in male mice, in every line. These data suggest that the renin-angiotensin system may not contribute to the established phase of blood pressure.

Animals↗