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J P Rapp

Publications and source records attributed to J P Rapp.

At least 19 recordsLinked to original sources
PubMed1992

Cosegregation of blood pressure with angiotensin converting enzyme and atrial natriuretic peptide receptor genes using Dahl salt-sensitive rats.

We have evaluated the genes for angiotensin converting enzyme (ACE) and guanylyl cyclase A/atrial natriuretic peptide receptor (GCA) for genetic effects on blood pressure response to high salt diet. In F2 rats derived from Milan normotensive and Dahl salt-hypertension sensitive (S) rats, both ACE and GCA cosegregated with blood pressure, and rats that were homozygous for the S allele at both the ACE and GCA loci had inordinately high blood pressure. In F2 derived from Wistar Kyoto (WKY) and S rats, GCA revealed positive cosegregation with blood pressure, but ACE did not. We conclude that certain alleles at the GCA and ACE loci (or at loci closely linked to them) have a significant genetic impact on blood pressure response to high salt in specific rat strains.

Animals↗
PubMed1991

Heterogeneity of renin alleles in outbred Dahl salt-sensitive (Brookhaven) rats.

Selectively outbred Dahl salt-sensitive (DS) and salt-resistant (DR) rats were compared with the inbred Dahl salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) rats developed from the original Brookhaven stocks by J.P. Rapp. The animals were evaluated for genotype at the renin locus. The inbred strains are uniformly homozygous for their respective alleles, s in SS/Jr and r in SR/Jr. DR rats were also uniformly homozygous for the r renin allele. In DS rats, however, three renin alleles were segregating. In addition to the s and r alleles, a third allele, designated the z allele, was found. The gene frequencies in DS rats were s = 0.690, r = 0.284, and z = 0.026. Continued use of DS and DR rats in most experimental work is inappropriate because of genetic heterogeneity in the DS stock.

Alleles↗
PubMed1991

Dissecting the primary causes of genetic hypertension in rats.

Blood pressure has a genetic component influenced by several to many genetic loci in both humans and animals; that is, blood pressure is a polygenic trait. Ultimately, the primary causes of genetic hypertension can only be established with genetic techniques. The primary tools for this analysis in animals are inbred strains of rodents selectively bred for differences in blood pressure and the genetic analysis of these strains by cosegregation techniques. This analysis determines whether it is possible to separate specific alleles at a candidate genetic locus from a component of blood pressure in genetically segregating populations. If the candidate alleles cosegregate with a component of blood pressure, these alleles must be the cause of the blood pressure differences or be linked on the same chromosome to alleles at other loci that cause blood pressure differences. If, on the other hand, the candidate alleles do not cosegregate with blood pressure, they cannot be the cause of the blood pressure differences. This analysis is straightforward in the case of a single-locus Mendelian candidate trait but is less informative if a candidate trait is itself polygenic. In this case, genetic analysis yields either 1) results that are compatible with, but not definitive proof for, a genetic role of the trait in causing blood pressure differences or 2) results that eliminate the trait as a cause of genetic differences in blood pressure. A complete listing of all the traits that have undergone genetic cosegregation analysis in rodents is given.

Animals↗
PubMed1990

Effect of genetic background on cosegregation of renin alleles and blood pressure in Dahl rats.

The cosegregation of renin alleles and blood pressure was evaluated in segregating populations derived from inbred Dahl salt hypertension sensitive (S) and inbred Dahl salt hypertension resistant (R) rats. The populations were raised on high salt diet (8% NaCl). In F2 and F1 X S populations, there was a significant positive gene-dosage relationship between the S-rat renin allele and blood pressure. In contrast, no such relationship was seen in the F1 X R population. Since in the F1 X R population the genetic background is strongly influenced by genes from the R rat (75% R, 25% S), the result is interpreted to mean that genes at other (unidentified) loci modify the blood pressure effect of the S-rat renin allele.

Alleles↗
PubMed1990

Failure of alleles at the Na+, K(+)-ATPase alpha 1 locus to cosegregate with blood pressure in Dahl rats.

A previously described Pst I restriction fragment length polymorphism in Dahl rats at the Na+, K(+)-adenosine 5'-triphosphatase (ATPase) alpha 1 isoform locus was tested for cosegregation with blood pressure in segregating populations. Inbred Dahl salt-sensitive (S) and inbred Dahl salt-resistant (R) rats were crossed to produce F1 rats, and three segregating populations, F1 x R, F2 and F1 x S, were produced and raised on a high-salt diet for variable periods to attain the maximal blood pressure response in each population. In no segregating population was there a significant difference in blood pressure among genotypes at the Na+, K(+)-ATPase alpha 1 locus. Power calculations suggest that single-allele dosage effects of less than 7.5 mmHg were unlikely to be detected. It is concluded that either the S and R alleles at the Na+, K(+)-ATPase alpha 1 locus do not influence blood pressure under the conditions of these experiments (high dietary salt, Dahl rat genetic background) or, if they do, their effect is small.

Alleles↗
PubMed1989

Sodium regulation of alpha 2-adrenoreceptors in Dahl rats. Effect of feeding a low or high salt diet.

Sodium regulation of alpha 2-adrenoreceptors was investigated in inbred salt-sensitive (S) and inbred salt-resistant (R) rats fed a high or low salt diet. The systolic blood pressure was higher in S rats than in R rats, and this difference was obviously greater on a high salt diet. In rats fed a low or high salt diet, S rats had higher alpha 2-adrenoreceptor density in the kidneys compared with R rats as measured by [3H]yohimbine binding and Scatchard analysis. The affinity of the receptors in the kidney for the antagonist, yohimbine, was nearly the same in these two strains either on a low or high salt diet. In the brain, the affinities or the numbers of receptors were not significantly different whether these two strains were fed a low or high salt diet. Inclusion of NaCl up to 80 mM in the assay medium did not alter the in vitro binding of [3H]yohimbine in the kidney or brain. On the other hand, inclusion of NaCl in the assay medium reduced the ability of epinephrine in competing with [3H]yohimbine for the receptor sites in the kidney and in the brain, and this effect of NaCl was the same in a given tissue between S and R rats, whether they were fed a low or high salt diet. These results suggest that: (1) in the kidneys, the receptor density and not the receptor affinity was different between S and R strains whether they were fed a low or high salt diet; (2) in the brain, the receptor density and affinity were the same between S and R rats regardless of the diet (low or high salt), indicating that the sodium salt diet modulates the peripheral but not the central alpha 2-adrenoreceptors; and this modulatory effect was observed only in S rats; (3) Na+ was able to reduce the affinity of the agonist (epinephrine) for the receptors in both S and R rats, and this effect of Na+ on central and peripheral alpha 2-adrenoreceptors was similar in prehypertensive rats and rats with salt-induced hypertension; and (4) the resistance of R rats to salt-induced hypertension was not due to the absence of Na+ binding component involved in the regulation of alpha 2-adrenoreceptor-adenylate cyclase complex.

Adenylyl Cyclase Inhibitors↗
PubMed1989

A genetic polymorphism in the renin gene of Dahl rats cosegregates with blood pressure.

Blood pressure is influenced by multiple genetic loci whose identities are largely unknown. A restriction fragment length polymorphism (RFLP) in the renin gene was found between Dahl salt-hypertension-sensitive (S) and Dahl salt-hypertension-resistant (R) rats. In an F2 population derived from crossing S and R rats, the renin RFLP cosegregated with blood pressure. One dose of the S-rat renin allele was associated with an increment in blood pressure of approximately 10 mmHg, and two doses of this allele increased blood pressure approximately 20 mmHg. From this it can be definitively concluded that in the rat the renin gene is, or is closely linked to, one of the genes regulating blood pressure.

Alleles↗
PubMed1989

Hyposecretion of atrial natriuretic factor by prehypertensive Dahl salt-sensitive rat.

Studies were carried out to determine if the release of atrial natriuretic factor (ANF) is altered in the inbred Dahl salt-sensitive (SS/Jr) rat. Isolated heart-lung preparations of prehypertensive young SS/Jr rats (6-8 weeks of age) and age-matched inbred Dahl salt-resistant (SR/Jr) rats were used. At this relatively young age the blood pressure difference between strains (SS/Jr, 108 +/- 3 mm Hg; SR/Jr, 103 +/- 2 mm Hg) was minor. ANF release was stimulated with preload-induced or afterload-induced atrial stretch. Increased preload produced increases in right and left atrial pressures that were equivalent between young SS/Jr and SR/Jr rats; increased afterload produced increases only in left atrial pressures, which again were equivalent for young rats of the two strains. At any preload-induced change in atrial pressure SS/Jr rat hearts released less ANF than those of SR/Jr rats. Similarly, at any afterload-induced increase in left atrial pressure, SS/Jr rat hearts released less ANF than those of SR/Jr rats. In contrast to the above results in young rats, the strain differences were dramatically reversed when older rats (5-6 months of age) were used; at this age SS/Jr rats were markedly hypertensive (SS/Jr, 211 +/- 8 mm Hg; SR/Jr 130 +/- 4 mm Hg). Hearts from adult hypertensive SS/Jr rats released more ANF than hearts from adult normotensive SR/Jr rats at any left atrial pressure as afterload was increased. This reversal of SS/Jr rats from hyposecreters to hypersecreters of ANF is probably a consequence of hypertension-induced changes such as cardiac hypertrophy and recruitment of the ventricles to produce ANF. It is concluded that the hyposecretion of ANF by prehypertensive SS/Jr rats may represent a genetic trait relevant to the pathogenesis of genetic hypertension and that this is obscured by adaptive changes in the heart as hypertension progresses.

Animals↗
PubMed1989

Regulation of adrenal renin messenger ribonucleic acid by dietary sodium chloride.

Zona glomerulosa (ZG) and zona fasciculata (ZF/M) poly(A)+ RNA were isolated from the adrenals of bilaterally nephrectomized female Sprague-Dawley rats and hybridized to a full-length 32P-labeled 1423-base pair (bp) renin cDNA as well as a 698-bp renin cDNA KpnI segment (corresponding to amino acids 92-325) by the dot blot procedure using Bio-Rad Zeta Probe membranes. Extensive hybridization was observed with ZG mRNA, and only slight binding was seen with ZF/M mRNA. These results extend earlier reports from this laboratory indicating that the enzymic activity for renin is predominantly localized in ZG cells. Hence, high message levels account for the high enzymic activity. Adrenal ZG poly(A)+ RNA was also isolated from rats maintained on normal and sodium-deplete diets for 15 days and was hybridized to the radiolabeled 698-bp renin probe. Essentially twice the amount of probe was bound to the message from salt-deplete ZG tissue compared to message from normal ZG per microgram mRNA. Hybridization was proportional to the amount of poly(A)+ RNA employed over the range of 0-1 microgram, suggesting the applicability of this procedure for approximate quantitation purposes. The membranes were freed from the 32P-labeled renin cDNA and subsequently rehybridized with a 32P-radiolabeled 1200-bp beta-actin cDNA probe. It was observed that ZF/M poly(A)+ RNA contained more beta-actin message than ZG poly(A)+ RNA, indicating a greater transcription rate for beta-actin in ZF/M tissue in contrast to transcription of the renin gene.

Adrenal Glands↗
PubMed1989

Structural differences in the renin gene of Dahl salt-sensitive and salt-resistant rats.

Genomic libraries in lambda EMBL4 phage were constructed from both inbred Dahl salt-hypertension-sensitive (S) and inbred Dahl salt-hypertension-resistant (R) rats. Overlapping clones containing the renin genes were isolated from these libraries by screening with a renin cDNA probe. Clones were characterized by a combination of restriction mapping and Southern blot analysis. The results showed that the S-rat renin gene is remarkably different from the R-rat renin gene. The major differences are 1) a 1.2-kilobase (kb) insertion in the first intron of the S-gene which accounts for most of the restriction fragment length polymorphisms found in the renin genes between S and R strains, such as those generated with Bg/II [2.7 kb (S)/1.5 kb (R)], EcoRI [6.4 kb (S)/5.2 kb (R)], and HindIII [9.6 kb (S)/8.4 kb (R)]; 2) an additional HindIII site located at the 3' end of the R-gene which accounts for another HindIII restriction fragment length polymorphisms [25 kb (S)/22 kb, 3.4 kb (R)]; 3) two SmaI sites at the 5' flanking region of the first exon of the S-gene, whereas there is only one SmaI site in the corresponding region of the R-gene; and 4) three AvaI sites in the first intron of the S-gene in contrast to two AvaI sites in the same region of the R-gene These differences in the renin genes of Dahl rats might affect renin gene expression, which could account for the known strain differences in plasma and tissue renin activities. These structural studies provide a basis for genetic investigation into the relationship of the renin gene to blood pressure in Dahl rats.

Animals↗
PubMed1989

Quantitation of renal renin and renin mRNA in Dahl rats in response to provocative stimuli.

It is known that inbred Dahl salt-sensitive (S) rats carry a different renin allele than inbred Dahl salt-resistant (R) rats. The levels of, and responses of, renal renin and renal renin mRNA to sodium deficient diet and to sodium deficient diet plus Captopril treatment were compared in S and R rats. S rats had lower renal renin and lower renal renin mRNA than R rats on control (1% NaCl) diet. Sodium deficient diet caused a modest increase, and sodium deficient diet plus Captopril caused a very large increase in both renal renin and renal renin mRNA in both strains. In general, both S and R strains appeared to regulate renin similarly in response to provocative stimuli.

Animals↗
PubMed1989

Restriction fragment length polymorphisms for the renin gene in Dahl rats.

Genomic DNAs from inbred Dahl salt-hypertension sensitive (S) and inbred Dahl salt-hypertension resistant (R) rats were examined for restriction fragment length polymorphisms (RFLPs) using a rat renin cDNA probe. Eight of the 28 restriction enzymes used yielded polymorphic fragments between S and R strains. This suggests a major structural difference in or near the renin gene of Dahl rats. Some, but not all, of the polymorphisms are compatible with an insertion/deletion mutation of about 1.1 kb in size. The ratio of renin gene copy numbers for S to R was found to be 1, showing that the RFLPs are not likely to be due to gene duplication.

Animals↗
PubMed1989

Morphometric evaluation of the renal arterial system of Dahl salt-sensitive and salt-resistant rats on a high salt diet. II. Interlobular arteries and intralobular arterioles.

The progression of small vessel renal vascular disease was studied in inbred Dahl salt-sensitive (SS/Jr) and salt-resistant rats with acute hypertension induced by a high salt diet. Corrected cross-sectional areas of wall (WAC) and lumen were measured by planimetry and histologic staining for fibrin, hyalin deposition, and elastic lamellae was performed. In SS/Jr rats on the high salt diet, the hallmarks of malignant hypertension (fibrinoid necrosis, hyperplastic and necrotizing arteritis) appeared by week 2 and were intensified after 4 weeks on the high salt diet. Renal vascular lesions from SS/Jr rats were characterized by: hyperplasia and/or hypertrophy of medial smooth muscle cells; intimal proliferation; fibrin, basophilic mucoid, and hyalin deposition within the the subendothelial space and media; variable adventitial fibrosis; and accumulation of mononuclear inflammatory cells in the adventitia and media. Interlobular arteries from both rat strains exhibited significantly increased cross-sectional areas over time for all measured parameters. Intralobular arterioles from both rat strains exhibited significantly increased cross-sectional areas over time for all measured parameters except lumen from SS/Jr rats. For SS/Jr rats, increased WAC from both arterial divisions correlated positively with systolic blood pressure, but not body weight. In salt-resistant rats, increased WAC from both arterial divisions correlated positively with body weight, but not systolic blood pressure. We concluded that the rapid increase in WAC from SS/Jr rats could not be attributed solely to the normal growth of the rat. With the development of acute hypertension in the SS/Jr rat, these results demonstrate the potential usefulness of this model to investigate the pathogenesis of similar renal vascular alterations which are observed in man.

Analysis of Variance↗
PubMed1988

Recruitment of the left ventricle for production of atrial natriuretic factor in Dahl salt-hypertension sensitive rats.

Dahl salt-sensitive (S) rats on normal salt intake develop a chronic form of hypertension with aging whereas Dahl salt-resistant (R) rats do not. In old hypertensive S rats the left ventricle is recruited for the production of ANF as evidenced by a seven- to ten-fold increase in atrial natriuretic factor (ANF) mRNA and increased ANF in ventricular tissue. Plasma ANF is also markedly increased in hypertensive S rats but there is no direct proof that ventricular production of ANF contributes to high plasma ANF. Atrial ANF is higher in S than R rats but this strain difference is not associated with strain differences in ANF mRNA in atria and atrial ANF mRNA does not increase dramatically in hypertensive S rats as does ventricular mRNA. Recruitment of the ventricle to produce ANF is clearly a secondary consequence of hypertension, but its functional significance is not established.

Animals↗
PubMed1988

Biochemically stimulated release of atrial natriuretic factor from heart-lung preparation of Dahl rats.

We investigated the effect of sodium chloride and adrenergic agents on the release of atrial natriuretic factor (ANF) using working heart-lung preparations from Dahl salt-hypertension sensitive (S) and Dahl salt-hypertension resistant (R) rats. High concentrations of NaCl moderately increased ANF release, but this was attributed to small increases in left atrial pressure rather than to a direct effect of NaCl on ANF release; S and R rats responded similarly. Neither isoproterenol (beta 1 + beta 2 agonist) nor clonidine (alpha 2 agonist) had any effect on ANF release in the heart-lung preparation. In contrast, phenylephrine (alpha 1 agonist) stimulated ANF release. This could not be accounted for by change in atrial pressure and appeared to be a direct effect. S and R rats both released ANF in response to phenylephrine, but there was a modest tendency for hypertensive S rats to release more ANF than normotensive R rats, which is consistent with previous data on mechanically induced (atrial stretch) ANF release in these strains.

Animals↗
PubMed1987

Binding characteristics of atrial natriuretic factor and the production of cyclic GMP in kidneys of Dahl salt-sensitive and salt-resistant rats.

The binding of atrial natriuretic factor (ANF) was studied in kidney membranes of inbred salt-sensitive (S) and inbred salt-resistant (R) rats on high or low salt diet. Important differences between strains were seen in the rate of dissociation of ANF from its renal receptor(s) and this was dependent on salt (NaCl) intake. On low salt diet ANF dissociation rates were similar between strains. R rats responded to high salt diet with a decrease in the rate of ANF dissociation from its renal receptor, but ANF dissociation in S rats was not altered by dietary salt. Receptor density was similar between strains. Basal cGMP production was slightly higher for renal membranes of S rats, but ANF stimulation of cGMP production was similar between strains and was not influenced by salt intake in either strain. Since strain-related salt-induced changes in ANF-receptor binding kinetics were not reflected in any strain-related salt-induced changes in ANF stimulated cGMP production, it is tentatively concluded that the ANF receptor likely to be different between S and R strains is the ANF receptor not linked to cGMP production.

Animals↗
PubMed1987

Release of atrial natriuretic factor from heart-lung preparations of inbred Dahl rats.

Isolated heart-lung preparations from hypertensive inbred Dahl salt-hypertension sensitive (S) and normotensive inbred Dahl salt-hypertension resistant (R) rats were perfused using 15% washed rat red blood cells in Krebs-Ringer bicarbonate buffer. Atrial pressures were increased by increasing venous return (preload) or by increasing the arterial resistance (afterload). Increases in preload at a constant afterload produced increases in the right and left atrial pressures equivalent between S and R strains. Atrial natriuretic factor (ANF) release was linearly related to right atrial pressure (RAP) or left atrial pressure (LAP) in either strain, but S released more ANF at each level of preload, and the slope of the line relating ANF release to RAP was significantly greater in S than R. When the heart-lung preparations were subjected to changes in afterload at a constant preload, LAP was significantly increased in R but not in S rats, and concomitantly ANF increased in R but not in S. In the afterload experiments, as in the preload studies, S released more ANF than R for comparable LAP. It is concluded that 1) at any atrial pressure, hearts of hypertensive S rats release more ANF than hearts of normotensive R rats, 2) this strain difference is probably a consequence of hypertension, and 3) the observed relationships between ANF release and atrial pressures support the contention that atrial distention stimulates the release of ANF.

Animals↗