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D Ganten

Publications and source records attributed to D Ganten.

At least 289 records · Page 16Linked to original sources
PubMed1990

Atrial natriuretic peptides in brain nuclei of rats with inherited diabetes insipidus (Brattleboro rats).

The concentration of atrial natriuretic peptides (ANF) was measured radioimmunologically in 18 selected microdissected brain areas of rats with inherited diabetes insipidus (Brattleboro rats) and their control rats (Long-Evans rats). In 7 brain areas known to be involved in the regulation of fluid homeostasis or blood pressure (subfornical organ, organum vasculosum lamina terminalis, periventricular preoptic nucleus, perifornical nucleus, nucleus of the solitary tract, tegmentum pontis, arcuate nucleus) ANF concentration was significantly changed. After restoration of antidiuresis with the V2 receptor agonist 1-desamino-8-D-arginine vasopressin (DDAVP) ANF levels of Brattleboro rats adapted at least partly to those of the control rats in all brain areas except the subfornical organ. Furthermore, ANF was then significantly changed in the supraoptic and paraventricular nuclei of DDAVP-treated diabetes insipidus rats. These data show that the central ANF system is sensitive for changes in electrolyte and fluid homeostasis.

Animals↗
PubMed1990

Regulation of myosin heavy chain expression in the hearts of hypertensive rats by testosterone.

Stroke-prone spontaneously hypertensive rats were used for our investigation of the influence of prepubertal gonadectomy and testosterone substitution on blood pressure, cardiac hypertrophy, and the expression of ventricular myosin heavy chain (MHC) isoenzymes at different developmental stages. Blood pressure and the degree of cardiac hypertrophy were decreased by castration and increased by testosterone substitution. We found the same relative distributions of MHC isoforms on the protein level (investigated by pyrophosphate electrophoresis) and on the messenger RNA level (investigated by the polymerase chain reaction). Castration favored the expression of the beta-MHC form, and testosterone substitution enhanced the expression of the alpha-MHC form. These effects were more pronounced in 8-week-old than in 14-16-week-old animals. We conclude that testosterone regulates cardiac MHC expression on a pretranslational level. This regulation is independent of hemodynamic load or cardiac hypertrophy.

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↗
PubMed1990

Transgenic animals: new approaches to hypertension research.

We have shown that it is possible to generate transgenic rats efficiently, allowing direct experimentation in this species, without first testing constructs in the mouse. Having developed the technology for producing transgenic rats, we now hope to generate new and precise models of hypertension and to test candidate genes that may be responsible for the phenotype in existing animal models. The potential to choose between the rat and the mouse for these studies will allow much greater flexibility in experimental design. Many molecular questions are more appropriately addressed in the mouse but questions concerning physiology and development of the cardiovascular system are more appropriately addressed in the rat. With a large number of genes relevant to cardiovascular research now available, transgenic technology will become increasingly important in the future, and even more so if homologous recombination becomes feasible in the rat. The transgenic rat therefore heralds an exciting new dimension in hypertension research.

Animals↗
PubMed1989

The supraoptic nucleus: afferents from areas involved in control of body fluid homeostasis.

Physiological evidence indicates that the supraoptic nucleus may be an important integrating region for information relating to body fluid homeostasis. It is known that the supraoptic nucleus receives neural influences from brain receptive zones for plasma osmolality and angiotensin II, as well as from relay centers for blood pressure and blood volume. It is also known that these influences interact to modulate vasopressin release from the supraoptic nucleus. Therefore, a detailed investigation of the neurochemical afferents to the supraoptic nucleus from regions of the lamina terminalis and the brainstem was undertaken. Injection of a fluorescent retrograde tracer, doxorubicin, into the supraoptic nucleus was combined with histochemistry of angiotensin II and catecholamines. Following supraoptic nucleus injection, retrograde label was found in forebrain neurons of the subfornical organ, median preoptic nucleus, and organum vasculosum of the lamina terminals. Some labeled cells in the subfornical organ and organum vasculosum of the lamina terminalis were also found to contain angiotensin II immunoreactivity. In the brainstem, retrograde label was found in neurons of the A1, A2 and A6 cell groups. Many of these cells were also found to contain catecholamine fluorescence or tyrosine hydroxylase immunoreactivity. Corroboration of the A2 projection was obtained by lesions of this nucleus, which reduced catecholamine fluorescence in the supraoptic nucleus. These findings provide an anatomical basis for the functional observations that the supraoptic nucleus plays a key integrative role in the maintenance of body fluid homeostasis.

Angiotensin II↗
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

Angiotensin formation in the isolated rat hindlimb.

Local vascular generation of angiotensin was investigated in isolated perfused rat hindquarters. Extraction and combined high-performance liquid chromatography (HPLC)/radioimmunoassay analysis of hindlimb perfusate showed a spontaneous release of angiotensin I (Ang I; 5.0 +/- 3.4 fmol/h) and angiotensin II (Ang II; 31.8 +/- 7.9 fmol/h). Angiotensin converting enzyme (ACE) inhibition with captopril abolished Ang II release while Ang I levels increased more than 10-fold. Perfusion with purified hog renin caused a dose-dependent angiotensin release and vasoconstriction. The renin inhibitor H-142 abolished all effects of renin whereas ACE inhibition prevented Ang II formation and vasoconstriction but increased Ang I levels. Metabolism and pressor effects of synthetic tetradecapeptide renin substrate (TDP), Ang I and Ang II were studied using a recirculating rat hindlimb perfusion system. TDP-dependent formation of Ang I and II, and an increase in perfusion pressure was shown; ACE inhibition reduced but did not abolish Ang II formation and vasoconstriction. Ang I was converted to Ang II by about 50% during one pass through a hindlimb. This conversion was abolished by ACE inhibition. These data add support to the presence of a functional vascular renin-angiotensin system.

Angiotensin I↗
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

Converting enzyme inhibitors and their effects on the renin-angiotensin system of the blood vessel wall.

A local vascular tissue renin-angiotensin system (RAS) may contribute to blood pressure control and the maintenance of high blood pressure in some forms of hypertension, independently of the plasma RAS. Vascular converting enzyme (CE), present mainly in the endothelial layer of arteries and veins, can be altered in hypertension. Locally generated vascular angiotensin II (ANG II) may exert a number of actions on vascular tone and function, including directly and sympathetically mediated vasoconstriction, changes in vascular compliance in larger vessels, influence on vascular reactions to inflammation and injury, and alterations in vascular texture. Orally administered CE inhibitors have been shown to block not only the plasma RAS but also CE in the vasculature, leading to decreased vascular ANG II concentrations and possibly to an accumulation of locally generated vasodilator peptides and prostaglandins in the vascular wall. In spontaneously hypertensive rats, the slow recovery of CE activity in the vasculature on drug withdrawal was more closely associated with the slow return of blood pressure to hypertensive levels than the fast recovery of the plasma RAS. These and other experimental data discussed in this article favor the hypothesis that local CE inhibition in the vascular wall of resistance vessels, large arteries and veins contributes to the beneficial therapeutic effects of CE inhibitors in cardiovascular disorders such as hypertension and congestive heart failure.

Angiotensin-Converting Enzyme Inhibitors↗
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

Hypertension transmitted by kidneys from stroke-prone spontaneously hypertensive rats.

We determined whether transplantations of kidneys from stroke-prone spontaneously hypertensive rats (SPSHR) and from normotensive Wistar-Kyoto rats (WKY) alter blood pressure in renal graft recipients. Kidneys taken from seven male SPSHR and seven male WKY rats (blood pressure 186 +/- 4.8 and 111 +/- 3.7 mmHg, respectively) at the age of 20 wk were transplanted, using microsurgical techniques, to bilaterally nephrectomized age-matched male F1 hybrids (blood pressure 136 +/- 2.6 and 138 +/- 6.3 mmHg, respectively) bred from SPSHR and WKY parents. After renal transplantation, blood pressure in recipients of SPSHR kidneys rose to 146 +/- 11.8 (week 2), 163 +/- 16.4 (week 3), 192 +/- 17.1 (week 4), 222 +/- 17.7 (week 5), 221 +/- 12.6 (week 6), 218 +/- 20.3 (week 7), and 239 +/- 9.2 mmHg (week 8). There was no significant change in blood pressure in recipients of WKY kidneys. All rats recovered rapidly from surgery. After renal transplantation, there was a significant increase in daily water intake, a decrease in plasma renin activity, and a slight rise in plasma urea concentration. Our data show that transplantation of kidneys from adult SPSHR causes hypertension in normotensive recipients, indicating a major function for the kidney in SPSHR hypertension.

Animals↗
PubMed1989

Angiotensin-induced hypertension in the rat. Sympathetic nerve activity and prostaglandins.

To elucidate mechanisms of angiotensin II (Ang II)-related hypertension, we infused angiotensin (76 ng/min s.c.) into rats with minipumps for 10-14 days. Control rats received sham pumps. We measured blood pressure by tail-cuff, and the excretion of aldosterone and prostaglandins (PG) (PGE2, prostacyclin derivative 6kPGF1 alpha, and thromboxane [Tx] derivative TxB2). Angiotensin II increased blood pressure by 20 mm Hg by day 2 and by 90 mm Hg by day 10. Aldosterone excretion increased from 10 to 70 ng/day in Ang II rats by day 7. Urine PGE2 did not increase in angiotensin rats; however, both 6kPGF1 alpha and TxB2 excretion increased with angiotensin. Control rats had no changes in any of these parameters. A sympathetic component was tested in a separate group of angiotensin rats that received phenoxybenzamine (300 micrograms/kg/day) during angiotensin infusion; their increase in blood pressure of 40 mm Hg at 10 days was less than in those rats with angiotensin alone but more than in control rats. Phenoxybenzamine did not influence the angiotensin-induced increases in excretion of 6kPGF1 alpha or TxB2. Additional groups of conscious angiotensin and control rats were equipped with splanchnic nerve electrodes on day 14 for recording of sympathetic nerve activity. Angiotensin rats had greater basal sympathetic nerve activity than the control rats. Incremental methoxamine injections demonstrated altered baroreceptor reflex function in rats receiving angiotensin. We conclude that increased blood pressure with chronic angiotensin infusion is accompanied by increased production of aldosterone and increased sympathetic tone. The latter may be modulated by PG.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Converting enzyme inhibition specifically prevents the development and induces regression of cardiac hypertrophy in rats.

Antihypertensive agents have been shown to differ markedly in their effects on the development and regression of cardiac hypertrophy. In view of possible trophic properties of angiotensin II (ANG II), we compared the effects of equipotent antihypertensive doses of the converting enzyme (CE) inhibitor ramipril (1 mg/kg), the calcium antagonist nifedipine (30 mg/kg), and the arterial vasodilator dihydralazine (30 mg/kg) on cardiac mass in rats subjected to banding of the abdominal aorta. Treatment was started either immediately after banding ("prevention experiments") or after hypertension and hypertrophy had already developed ("regression experiments"). Groups of untreated animals with aortic constriction and sham-operated animals served as controls. In the prevention experiments heart weight, myocardial protein content and ANG II plasma levels were significantly increased in untreated animals and in those receiving nifedipine and dihydralazine. In contrast, values obtained in animals treated with ramipril were not different from those seen in normotensive, sham operated controls with the exception of plasma ANG II levels which were lower. Similar results were observed in the second series of studies which examined the effect of antihypertensive agents on the "regression" of cardiac hypertrophy. Treatment was started 6 weeks after aortic banding and continued for another 6 weeks. While all three drugs lowered blood pressure equally well, only ramipril induced a significant and complete regression of cardiac hypertrophy to values not different from sham-operated controls. In addition we studied a group of animals treated with a nonantihypertensive low dose of ramipril (10 micrograms/kg). Remarkably, these animals showed the same complete regression of cardiac hypertrophy as seen in the group receiving the antihypertensive dose of CE inhibitor. Our study indicates a selective advantage of CE inhibitors over other antihypertensive drugs in the prevention and regression of hypertensive cardiac hypertrophy. Importantly, the dissociation between effects on blood pressure and cardiac mass demonstrated in the experiments with a low dose of ramipril stresses the role of factors other than blood pressure and afterload on the development of hypertensive cardiac hypertrophy. One such peptide, thus, may be ANG with its known potential as a growth factor.

Angiotensin II↗
PubMed1989

Sexual dimorphism of blood pressure in spontaneously hypertensive rats: effects of anti-androgen treatment.

The mechanisms resulting in the greater predisposition of male subjects towards hypertension were investigated in different strains of rats with genetic hypertension [spontaneously hypertensive rats of the stroke-prone strain (SHRSP) and spontaneously hypertensive rats (SHR)] and their respective normotensive controls. Blood pressure was reduced in young (9 weeks of age) hypertensive rats by (1) surgical castration, (2) treatment with the testosterone receptor antagonist cyproterone acetate (CPA), which does not elevate testosterone, or (3) with the testosterone receptor antagonist flutamide, which leads to a feedback elevation of gonadotrophic hormones and plasma testosterone. These treatments had no effect on high blood pressure in old hypertensive rats aged 25 weeks. Both androgen receptor antagonists attenuated high blood pressure development when given for the first 10 days after birth. These data clearly relate the sexual dimorphism of hypertension to testosterone produced during male brain maturation in the early phase of hypertension development. Testosterone appears not to contribute directly to the maintenance of high blood pressure in established hypertension.

Androgen Antagonists↗
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

Angiotensinogen gene expression in extrahepatic rat tissues: application of a solution hybridization assay.

Angiotensin II has numerous biological effects in a hitherto unsuspected variety of tissues. The generation of angiotensin in tissue requires the local presence of its high molecular weight precursor angiotensinogen and is best tested by investigating angiotensinogen gene expression. A quantitative solution hybridization assay for rapid and sensitive measurement of angiotensinogen mRNA was therefore established to study the extrahepatic expression of the angiotensinogen gene. We used a 714 bases BamHI angiotensinogen cDNA fragment cloned into vector pSPT18 and developed a sensitive and rapid assay with a detection limit of 0.5 pg RNA. Quantification of angiotensinogen mRNA from male Sprague-Dawley rats resulted in the following tissue levels (n = 10 for all tissues, except pituitary where n = 5), was expressed as fg mRNA per microgram total RNA, in descending order: liver (9950), hypothalamus (6050), midbrain (4450), brainstem (3950), total brain (2325), aorta (625), kidney (338), adrenal gland (170), and heart atrium (140). The high sensitivity of the assay in addition also allowed for the first time measurement of angiotensinogen mRNA in the low gene expression tissues pituitary (70), heart ventricle (30), and testis (30). This assay will allow detailed studies on the regulation of tissue angiotensinogen and the pathophysiological role of the tissue renin angiotensin systems.

Adrenal Glands↗