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K Lindpaintner

Publications and source records attributed to K Lindpaintner.

At least 109 records · Page 6Linked to original sources
PubMed1992

Genetic linkage analysis in hypertension: principles and practice.

BACKGROUND: Primary hypertension is a hereditary disorder characterized by a complex etiological interplay of multiple genetic and environmental factors, until now defying attempts at identifying pathogenetically important genes. The marriage of classical genetics and molecular techniques is now offering a powerful set of tools to uncover such disease-relevant genes. SUMMARY: Based upon the availability of methods to directly examine chromosomal and genomic DNA structures, molecular genetics has at its disposal today an array of markers far more numerous and specific than the phenotype parameters used in classical genetics. In addition, use of DNA polymorphisms takes the process of genetic analysis immediately to that level of investigation--the genome--from which relevant data will ultimately come forth. The deployment of these tools in the pursuit of elucidating the pathogenesis of hereditary hypertension, and their use for two commonly applied strategies, candidate gene analysis and reverse genetics, are discussed. SIGNIFICANCE: Whilst still in its early stages, the application of molecular genetic methods to the study of hereditary hypertension now holds the realistic promise of identifying disease-relevant genes. This will provide the basis for advanced diagnostic, preventive and therapeutic approaches.

Animals↗
PubMed1992

Left ventricular remodeling after myocardial infarction: does the cardiac renin-angiotensin system play a role?

Possible cardioprotective effects are one of the most intriguing aspects of the expanding spectrum of clinical indications for the use of converting-enzyme inhibitors. Among them, the prevention of postinfarction ventricular remodeling--a deleterious process leading to eccentric cardiac hypertrophy and, eventually, to congestive heart failure--has attracted particular interest and attention. This communication examines the possible role of the endogenous cardiac renin-angiotensin system in the pathophysiology of ventricular remodeling. Although much of the evidence is indirect, there are several lines of investigation that strongly support the causative participation of the cardiac renin-angiotensin system in ventricular remodeling.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats.

The spontaneously hypertensive rat and the stroke-prone spontaneously hypertensive rat are useful models for human hypertension. In these strains hypertension is a polygenic trait, in which both autosomal and sex-linked genes can influence blood pressure. Linkage studies in crosses between the stroke-prone spontaneously hypertensive rat and the normotensive control strain Wistar-Kyoto have led to the localization of two genes, BP/SP-1 and BP/SP-2, that contribute significantly to blood pressure variation in the F2 population. BP/SP-1 and BP/SP-2 were assigned to rat chromosomes 10 and X, respectively. Comparison of the human and rat genetic maps indicates that BP/SP-1 could reside on human chromosome 17q in a region that also contains the angiotensin I-converting enzyme gene (ACE). This encodes a key enzyme of the renin-angiotensin system, and is therefore a candidate gene in primary hypertension. A rat microsatellite marker of ACE was mapped to rat chromosome 10 within the region containing BP/SP-1.

Animals↗
PubMed1991

Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat.

The stroke-prone spontaneously hypertensive rat (SHRSP) is a well-characterized model for primary hypertension in humans. High blood pressure in SHRSP shows polygenic inheritance, but none of the loci responsible have previously been identified. To locate genes controlling this quantitative trait, we mapped a large collection of DNA polymorphisms in a cross between SHRSP and the normotensive WKY strain. Here we report strong genetic evidence that a gene, Bp1, having a major effect on blood pressure maps to rat chromosome 10 with a LOD score of 5.10 and is closely linked to the rat gene encoding angiotensin-converting enzyme (ACE), an enzyme that plays a major role in blood pressure homeostasis and is an important target of anti-hypertensive drugs. We also find significant, albeit weaker, linkage to a locus, Bp2, on chromosome 18. We discuss the implications of genetic dissection of quantitative disease-related phenotypes in mammals.

Animals↗
PubMed1991

Tissue renin-angiotensin systems and their modulation: the heart as a paradigm for new aspects of converting enzyme inhibition.

Local tissue-resident renin-angiotensin systems are increasingly recognized as important elements of neurohumoral mediation which may act in concert with, but also independently of, the circulating system. The presence of such a system within the heart is of particular interest; current evidence supporting its existence, functional integration, and physiopathological importance as well as the role which its pharmacological modulation may play are reviewed. The elements of the catalytic cascade, renin, angiotensinogen, and angiotensin-converting enzyme, have all been demonstrated in cardiac tissues; both at the protein level and (with the exception of converting enzyme) with regard to local expression of the respective genes. Modulation of gene expression in response to various perturbations has been demonstrated and may occur independently of the plasma or other tissue renin-angiotensin systems. In isolated hearts the generation of biologically active peptides, angiotensins I and II, has been documented, establishing the capability of this system to act as an independently regulated, functionally integrated catalytic pathway for the production of angiotensin II. Activation of either angiotensinogen to angiotensin I or of angiotensin I to angiotensin II is dose dependently inhibited by the administration of renin inhibitors and converting enzyme inhibitors, respectively. Through specific receptors, present in the heart as in other tissues, angiotensin mediates profound effects on cardiomyocyte function and, as we are beginning to learn, on structure and growth. We now have strong evidence that converting enzyme inhibition at a tissue level may profoundly influence and modulate these actions of the cardiac renin-angiotensin system, particularly in the setting of myocardial ischaemia. This may, in the future, open up new vistas for the application of converting enzyme inhibitors and their indications in a widening spectrum of cardiovascular disorders.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

The cardiac renin-angiotensin system: a synopsis of current experimental and clinical data.

Local tissue-resident renin-angiotensin systems are increasingly being recognized as important neurohumoral mediators which may act in concert with, but also independently of the circulating system. Here we review the evidence supporting the existence, functional integration, and physiopathological role of a cardiac renin-angiotensin system which has recently been defined. The elements of the catalytic cascade of the system, renin, angiotensinogen, and angiotensin-converting enzyme have all been demonstrated in cardiac tissues, both on the protein-level and with regard to local expression of the respective genes. Modulation of gene expression in response to various perturbations has been demonstrated, and may occur independently of the plasma or other tissue renin-angiotensin systems. In isolated hearts, generation of the biologically active peptides, angiotensin I and II, has been documented, establishing the capability of this system to act as an independently regulated, functionally integrated catalytic pathway for the production of angiotensin II. Through specific receptors, present in the heart as in other tissues, angiotensin mediates profound effects on cardiomyocyte function and, as we are beginning to learn, on structure and growth. Furthermore, indirect evidence based on specific, beneficial effects of angiotensin converting enzyme inhibiting drugs which are distinct from those of other vasodilators, points to the potential role which this local system may play for physiological function of the heart as well as in a number of pathological derangements of the cardiovascular system.

Angiotensin II↗
PubMed1990

Structural alterations of the renin gene in stroke-prone spontaneously hypertensive rats: examination of genotype-phenotype correlations.

Primary hypertension is considered a polygenic, inherited disorder; to date, the nature of the genes involved remains unknown. In this study we present evidence for a structural difference in the gene coding for renin between the stroke-prone, spontaneously hypertensive rat (SHRSP) and its normotensive control, the Wistar-Kyoto rat (WKY). Restriction fragment analysis using hybridization against probes complementary to defined regions of the renin gene identified a deletion, approximately 700 base pair in size, within the first intron in SHRSP compared with WKY. This restriction fragment length polymorphism (RFLP) affects a part of the gene that is characterized by the presence of a multimeric tandem repeat element, where the occurrence of insertional/deletional events might be expected and have recently been shown in other rat strains. In order to test for a possible phenotypical representation of this RFLP, we studied a population (n = 115) of F2 hybrid rats derived from cross-breeding SHRSP with WKY. Using direct blood pressure measurements in conscious animals, we ruled out a cosegregation of systolic or diastolic blood pressure with renin genotype. Several other phenotypical parameters examined (heart rate, absolute and relative magnitude of changes in blood pressure induced by stress or dietary sodium loading, plasma renin activity, ventricular hypertrophy and tissue water content) also showed no cosegregation with genotype. Our findings are in contrast to a recently published study examining an RFLP of the renin gene distinguishing salt-sensitive and salt-resistant Dahl rats. Thus, cosegregation of genotype and phenotype are not consistent, although in both cases, structural differences in the same region of the renin gene separate the hypertensive strain from its normotensive controls. These data may suggest differential roles of the renin-angiotensin system in these two models of genetically predetermined hypertension.

Animals↗
PubMed1990

Cardiac angiotensinogen and its local activation in the isolated perfused beating heart.

Increasing evidence suggests that the renin-angiotensin system modulates cardiovascular homeostasis both via its circulating, plasma-borne components and through locally present, tissue-resident systems with site-specific activity. The existence of such a system in the heart has been proposed, based on biochemical studies as well as on the demonstration of renin and angiotensinogen messenger RNA in cardiac tissue. We conducted the present study to determine whether biologically active angiotensin peptides may be cleaved within the heart from locally present angiotensinogen. Isolated, perfused rat hearts were exposed to infusions of purified hog renin; the coronary sinus effluent was collected and subsequently assayed for angiotensin I (Ang I) and angiotensin II (Ang II) by high-pressure liquid chromatography and specific radioimmunoassay. Both Ang I and II were undetectable under control conditions but appeared promptly after the addition of renin. Dose-dependent peak values for Ang I release ranged from 2.42 +/- 0.65 fmol/min to 1.38 +/- 0.18 pmol/min during renin infusions at concentrations between 10 microunits/ml and 5 milliunits/ml. Ang II levels measured in the perfusate reflected a mean fractional intracardiac conversion of Ang I to Ang II of 7.18 +/- 1.09%. Generation of Ang I and Ang II was inhibited in the presence of specific inhibitors of renin and converting enzyme, respectively. To investigate the source of angiotensinogen, we measured spontaneous angiotensinogen release from isolated perfused hearts. In the absence of renin in the perfusate, angiotensinogen was initially released in high, but rapidly declining, concentrations and subsequently at a low, but stable, rate. Prior perfusion with angiotensinogen-rich plasma resulted in enhanced early angiotensinogen release but did not alter the second, delayed phase, suggesting that, in addition to plasma-derived substrate, locally produced angiotensinogen may also participate in the intracardiac formation of angiotensin. Supporting this interpretation, hearts from animals pretreated with dexamethasone showed increased angiotensinogen messenger RNA concentrations as well as increased rates of angiotensinogen release not only during the early but also during the late phase. Our study newly demonstrates that Ang I and II may be formed within the isolated heart from locally present substrate, which appears to be derived in part from the circulating pool and in part from endogenous synthesis. These findings add support to the concept of a functionally active and locally integrated cardiac renin-angiotensin system and emphasize its potential physiological and pathological relevance.

Angiotensin I↗
PubMed1989

Cardiac renin-angiotensin system.

Based on molecular, biological, biochemical, and pharmacological data, evidence is presented for a cardiac renin-angiotensin system. Using radiolabeled cRNA probes prepared from specific cDNA fragments, we were able to document renin and angiotensinogen gene expression in atria and ventricles of the rat heart by Northern blot and liquid hybridization analysis. Relative signal strength for both mRNAs was highest in the atria and next highest in the right and left ventricle. We also demonstrated the presence of both angiotensin I and angiotensin II in all anatomical regions of the monkey and rat heart using specific, high pressure liquid chromatography (HPLC) controlled radioimmunoassays (RIAs) for angiotensin peptides. The presence of converting-enzyme activity was also ascertained by direct in vitro determinations. Infusion of angiotensin I into the isolated perfused rat heart resulted in the prompt appearance of angiotensin II; the single pass fractional conversion was 6.42 +/- 0.33%. Dose-dependent inhibition of this effect by simultaneous infusion of converting-enzyme inhibitor supports the existence of a specific intracardiac pathway for the activation of angiotensin II. When the isolated, perfused rat hearts were exposed to infusions of purified renin, angiotensin I, undetectable before renin, was dose-dependently released into the coronary circulation at peak rates ranging from 2.4 +/- 0.7 fmol/min to 1.4 +/- 0.2 pmol/min, of which 7.2 +/- 1.1% was intracardially converted to angiotensin II. All renin effects were blocked in the presence of a specific pentapeptide renin inhibitor. Together, the results of these studies add support to the concept of a functionally active cardiac tissue renin-angiotensin system.

Animals↗
PubMed1989

DNA fingerprinting of spontaneously hypertensive and Wistar-Kyoto rats: implications for hypertension research.

Probes to hypervariable minisatellite regions of DNA identify multiple loci scattered over the autosomal chromosomes and produce a complex Southern blot pattern of fragments termed a DNA 'fingerprint'. As concern has been raised that different stocks of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) may not be biologically identical, we have compared the DNA of SHR and WKY from several sources using two such probes which identify different sets of minisatellite sequences. While the DNA fingerprints of SHR from the various sources were identical, variability was observed in those of WKY, indicating genetic heterogeneity between different WKY stocks. In animals from one of the commercial suppliers even inter-rat variability in DNA fingerprints was seen, suggesting genetic heterogeneity within that single colony. These observations indicate that experimental results obtained using WKY from different sources may not be directly comparable and could provide an explanation for some of the conflicting data that exist on the comparative characteristics of SHR and WKY. In separate studies, direct comparisons both of the DNA fingerprints of SHR and WKY and of SHR and stroke-prone spontaneously hypertensive rats (SHRSP) showed multiple differences between the strains. The polymorphisms seen could provide useful linkage markers in locating the chromosomal sites of the genetic loci responsible for raised blood pressure in the SHR and the propensity to strokes in the SHRSP.

Animals↗
PubMed1989

Aspects of molecular biology and biochemistry of the cardiac renin-angiotensin system.

1. Recent evidence for the existence of extrarenal tissue renin-angiotensin systems has raised the question of whether such a system also exists in the heart. 2. Evidence is presented for a cardiac renin-angiotensin system based on molecular biological and biochemical data. In addition, the question of whether the components of this system interact as a locally integrated, biologically functioning unit is addressed. 3. Using radio-labelled cRNA probes prepared from specific cDNA fragments, renin and angiotensin gene expression in atria and ventricles of the rat heart have been documented by Northern blot and liquid hybridization analysis. Relative signal strength for both mRNAs was highest in the atria, followed by the right and left ventricle. 4. Using specific, h.p.l.c.-controlled RIAs for angiotensin peptides, the presence of both angiotensin I and angiotensin II in all anatomical regions of the monkey and rat heart have been demonstrated; similarly, presence of converting enzyme activity was also ascertained by direct in vitro determinations. 5. Additional experiments evaluating the spontaneous release of angiotensin from rat isolated, perfused hearts revealed a bimodal pattern of high, but rapidly declining rates during the first hour (perhaps representing washout of a pool sequestrated from plasma), followed by a prolonged period of steady, low level release, consistent with the secretion of locally synthesized protein. 6. In separate experiments aimed at examining the possible local integration of the components of the cardiac renin-angiotensin system, angiotensin II concentrations were measured in the coronary sinus effluent of rat isolated, perfused hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The tissue renin-angiotensin system: a target for angiotensin-converting enzyme inhibitors.

The actions of ACE inhibitors at the tissue level (brain, heart, blood vessels) and their interference with the automatic nervous system through central and peripheral actions may, under certain conditions, be more important than inhibition of the hormonal circulating plasma angiotensin (ANG) II. Recent clinical and experimental studies and new insights into the molecular biology of the renin-angiotensin system support this view, in particular gene expression of renin and angiotensin in tissues of the cardiovascular system. These findings have implications not only for understanding the pharmacokinetics and pharmacodynamics of ACE inhibitors, but also for their therapeutic use.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

Endogenous tissue renin-angiotensin systems. From molecular biology to therapy.

Expression of the genes for renin and angiotensinogen has been documented in the heart and brain of several species, including rodents and primates. In the same tissues, local generation of angiotensin II has also been demonstrated. Neuropeptidergic brain angiotensin and local cardiac angiotensin participate in cardiovascular regulation. Inhibition of cardiac angiotensin II protects against deleterious arrythmogenic and metabolic effects of transient regional myocardial ischemia, and blockade of brain angiotensin II effectively lowers blood pressure in spontaneously hypertensive rats. It is surmised therefore that the therapeutic effects of converting enzyme inhibitors are, in part, brought about by inhibition of local tissue angiotensin II generation in addition to their interference with the hormonal plasma renin-angiotensin system. This would help to explain their therapeutic efficacy in pathophysiologic conditions in which hypertension is associated with low plasma renin activity.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

Tissue renin-angiotensin systems aspects of molecular biology and pharmacology.

Advances in molecular biology over the last few years have made it possible to extend studies concerned with the role of renin in blood pressure regulation and fluid balance to the genetic level. Epidemiological data from cross-sectional population studies as well as experimental findings in spontaneously hypertensive rats suggest a greater disposition towards hypertension in males than in females. Testosterone (T) is known to raise blood pressure in female and castrated male SH-rats, while concomitantly increasing tissue renin activities. The availability of recombinant DNA technology and of a 32P labeled mouse submandibular gland renin cRNA as a hybridization probe enabled us to quantitatively assess whether this increase is paralleled by enhanced renin gene expression. In groups of female NMRI mice injected with DHT, we were able to show, that cardiac renin activity was significantly increased after 2 hours (1.6 fold) and 21 days (1.9 fold) of dihydrotestosterone (DHT) treatment compared to controls. DHT had no effect on renin mRNA concentration in the uterus, whereas in the ovary it resulted in a 50% decrease. We conclude that enhanced renin-activity and mRNA levels in peripheral organs and in the central nervous system are due to direct or indirect effects (cis, transacting) of T on renin gene expression. Thus, T may participate in the development of hypertension by stimulating the activity of tissue renin-angiotensin systems.

Animals↗