[A test for assessing the responsiveness of plasma renin activity].
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Angiotensin II↗
Biomedical subjects
D Ganten
Publications and source records attributed to D Ganten.
Evidence of renin release or production in splanchnic territory.
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Animals↗
Reduction of cardiac hypertrophy in TGR(mREN2)27 by angiotensin II receptor blockade.
TGR(mREN2)27 is a transgenic rat harboring the murine Ren-2 gene and exhibit fulminant hypertension and marked heart hypertrophy. In order to study the role of angiotensin II in the increase of cardiac mass, these animals were treated with antihypertensive and non-antihypertensive doses of the angiotensin II receptor AT1 antagonist Telmisartan for 9 weeks. All doses led to significant reductions of heart hypertrophy detected by the evaluation of the diameter of cardiac muscle bundles. We conclude from this study that cardiac hypertrophy in TGR(mREN2)27 is characterized by an increased volume of cardiomyocytes and an unchanged amount of fibrous tissue and that angiotensin II plays an important role in the mechanisms leading to this phenotype.
Angiotensin Receptor Antagonists↗
Enhanced cardiac angiotensinogen gene expression and angiotensin converting enzyme activity in tachypacing-induced heart failure in rats.
The aim of the study was to analyze changes in myocardial angiotensinogen gene expression and myocardial angiotensin converting enzyme activity in slowly progressing low-output failure. In adult, male Wistar rats, acute ventricular tachypacing by 610 to 620 impulses per minute lowered end-diastolic external diameter of the left ventricle by 2.6% (p less than 0.01), but did not lower cardiac output or abolish coronary reserve, since left-ventricular subendocardial blood flow of paced rats increased under dipyridamole (2 mg/kg i.v.) by 56% (p less than 0.01). Systemic neuroendocrine activation and ventricular dilation without enlargement of ventricular mass developed subsequent to chronic tachypacing, but left-ventricular diameter during pacing never exceeded the value of sham rats on sinus rhythm. After 2 weeks, cardiac output was lowered by 14% (p less than 0.001), cardiopulmonary blood volume was elevated by 30% (p less than 0.001), and angiotensinogen mRNA and angiotensin converting enzyme activity in ventricular myocardium were doubled. We conclude that conditions for an enhanced intracardiac angiotensin II-formation developed in tachypacing-induced heart failure, but that enhanced systolic wall stress or myocardial ischemia are not required for this activation of the local cardiac renin-angiotensin system.
Angiotensinogen↗
The semi-quantitative distribution and cellular localization of angiotensinogen mRNA in the rat brain.
The present study describes the regional distribution and cellular localization of angiotensinogen-mRNA in the rat brain as investigated by means of in situ hybridization also in combination with immunocytochemistry for glial fibrillary acidic protein. The angiotensinogen gene expression seemed to be restricted to astroglia and showed marked regional differences. In some areas angiotensinogen-mRNA was present in almost all astrocytes with a strong signal (e.g. hypoglossal nucleus), whereas in other areas the angiotensinogen gene was expressed only in a certain population of glial cells. Some areas like the lateral septum were devoid of any detectable angiotensinogen-mRNA. A semi-quantitative atlas of the regional distribution of brain angiotensinogen-mRNA was obtained by using computer-assisted microdensitometry and revealed considerable rostro-caudal fluctuations of the angiotensinogen-mRNA content of certain regions (e.g. the subfornical organ). Furthermore, a semi-quantitative analysis on the cellular level of angiotensinogen gene expression was performed showing a correlation of the angiotensinogen gene expression to the glia content of the regions examined. It was also demonstrated that the angiotensinogen gene expression had its highest levels in several distinct areas of the brain (e.g. the preoptic region and the hypothalamus), whereas other areas showed only low to moderate levels (e.g. the thalamus). The expression of the angiotensinogen gene in the rat brain was not only restricted to areas involved in cardiovascular and neuroendocrine control, but was also present in functionally different regions. Our data thus indicate that, based on the regional distribution of angiotensinogen-mRNA, angiotensin peptides may have other functions besides participation in cardiovascular and neuroendocrine control.
Angiotensinogen↗
Atrial natriuretic factor--a circulating hormone stimulated by volume loading.
The cardiocytes of mammalian cardiac atria contain granules very similar to those in endocrine cells. The number of these atrial granules is related directly to salt loading and blood volume. Furthermore, crude extracts of rat atria and granule preparations have powerful natriuretic and diuretic effects. These effects are mediated by peptides identified previously as atrial natriuretic factor (ANF). The peptides are derived from a common precursor, whose structure has been elucidated recently. Although there is indirect evidence from morphological studies that at least some of these peptides may be released into the blood and function as hormones, their presence in the blood has not yet been demonstrated. Here we describe a sensitive and specific radioimmunoassay for ANF and its stimulation on volume loading.
Animals↗
Adrenal renin expression and its role in ren-2 transgenic rats TGR(mREN2)27.
Transgenic rats, termed TGR(mREN2)27, have been generated carrying the mouse ren-2 renin gene. As intended the gene was expressed highly within the adrenal gland offering the opportunity to study the intraadrenal renin-angiotensin system in vivo. Concomitantly with increased adrenal renin activity, the production of adrenocortical steroids are elevated and the regulation of aldosterone production is impaired in TGR(mREN2)27. Furthermore, the transgenic rats develop severe sodium dependent hypertension. Since kidney and plasma renin concentrations and plasma angiotensins are low in the transgenic model, those factors cannot account for the altered regulation of aldosterone production. Instead the experiments with TGR(mREN2)27 demonstrate the functional role of the local adrenal renin-angiotensin system.
Adrenal Glands↗
Vasopressin in deoxycorticosterone acetate hypertension of rats: a hemodynamic analysis.
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Animals↗
Is tissue converting enzyme inhibition a determinant of the antihypertensive efficacy of converting enzyme inhibitors? Studies with the two different compounds, Hoe498 and MK421, in spontaneously hypertensive rats.
The mechanism of antihypertensive action of converting enzyme (CE) inhibitors was studied by comparing two compounds of different potency. Spontaneously hypertensive rats (SHRSP) were treated orally with the CE inhibitors Hoe498 and MK421 for periods of 2 and 4 weeks. The threshold antihypertensive dose of Hoe498 was below 0.1 mg/kg/day, and of MK421 1 mg/kg/day. Blood pressure was normalized with 10 mg/kg/day Hoe498 and 30 mg/kg/day MK421. The reduction of the pressor responses to intravenous angiotensin I (ANG I), the potentiation of the bradykinin depressor responses, and the decreases of plasma angiotensin II levels or urinary aldosterone excretion were nor correlated to the antihypertensive potency of the drugs. However, following equi-dose treatment (10 mg/kg/day) with both compounds inhibition of tissue CE activity in the vascular wall of the aorta, in the lung, the kidney, and the brain cortex was more marked with Hoe498 than with MK421. Hoe498 also reduced CE activity in the heart, and adrenal gland, and in other brain areas, and attenuated the pressor responses to intracerebroventricularly injected ANG I. Our results provide the first direct evidence for tissue CE inhibition following chronic oral CE inhibitor treatment, and support the contention that inhibition of the enzyme in target organs such as vascular wall, kidney, heart, or brain may be involved in the antihypertensive action of these drugs.
Aldosterone↗
Persistent tissue converting enzyme inhibition following chronic treatment with Hoe498 and MK421 in spontaneously hypertensive rats.
Inhibition of angiotensin II generation in the plasma does not fully explain the antihypertensive effects of converting enzyme (CE) inhibitors. Thus, we investigated the role of CE inhibition in the tissue for the antihypertensive action of these drugs. After discontinuation of 4 weeks of oral treatment with either Hoe498 (3 mg/kg/day) or MK421 (30 mg/kg/day) in spontaneously hypertensive rats (SHRSP), the reduced pressor response to intravenous angiotensin I was normalized within 1 day, although systolic and diastolic blood pressure remained decreased during a 1 week post-treatment follow-up period. Two weeks of oral treatment with Hoe498 (1 mg/kg/day) and MK421 (30 mg/kg/day) in SHRSP lowered blood pressure markedly and inhibited CE in the plasma (43% and 22%), lung (85% and 33%), kidney (76% and 76%), aortic wall (75% and 48%), and (with Hoe498) in the heart (55%). After drug discontinuation, blood pressure remained decreased for an additional 2 weeks, whereas plasma CE was normal or elevated during the follow-up period. However, tissue CE activity measured 1 week after drug withdrawal was still inhibited in the aortic wall (67% and 30%) and in the kidney (48% and 41%). These results support the hypothesis that the prolonged antihypertensive action of CE inhibitors may be related to persistent CE inhibition in tissues such as vascular wall and kidney. Further, the data support the importance of CE inhibition at target sites other than plasma and lung vascular endothelium.
Angiotensin I↗
Antihypertensive action of the converting enzyme inhibitor perindopril (S9490-3) in spontaneously hypertensive rats: comparison with enalapril (MK421) and ramipril (Hoe498).
The novel prodrug-converting-enzyme (CE) inhibitor perindopril (S9490-3) diacid was found to be as potent as ramipril (Hoe498) diacid and more potent than enalapril (MK421) diacid and captopril against rat plasma CE in vitro (IC50 values were 3 X 10(-9), 2 X 10(-9), 1 X 10(-8), and 6 X 10(-8) mol/L, respectively). Four-week oral treatment with perindopril (0.1, 1, 3, and 10 mg/kg/day) in spontaneously hypertensive rats (SHRSP) lowered blood pressure (BP) dose-dependently with a threshold dose of 0.1 mg/kg/day and normalization of BP following doses between 1-3 mg/kg/day. Plasma CE was inhibited, angiogensinogen lowered, plasma renin concentration (PRC) and angiotensin I (ANGI) increased, all dose-dependently. CE was also inhibited in kidney, aortic wall, heart, lung, hypophysis, and brain cortex. Upon drug withdrawal, the BP depressant effect outlasted the effects on the plasma renin-angiotensin system (RAS) by more than a week. Perindopril, ramipril (both 1 mg/kg/day), and enalapril (30 mg/kg/day) showed equal antihypertensive actions in SHRSP, although their effects on parameters of the RAS in plasma were different. Our data reveal perindopril to be a potent antihypertensive drug. The findings are consistent with the view that the antihypertensive actions of CE inhibitors cannot be directly related to inhibition of the RAS in the plasma. Local interference with the RAS in tissue appears to be an additional factor involved.
Administration, Oral↗
The iso-renin angiotensin systems in extrarenal tissue.
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Angiotensin II↗
Differences in rat kidney morphology between males, females and testosterone-treated females.
Kidneys of normal female and male Wistar-Kyoto rats were studied by standard morphological techniques and morphometry in order to evaluate possible differences in the overall kidney morphology between both sexes. Furthermore, we investigated the role of testosterone (DHT) on kidney morphology by treating females with daily DHT injections. Kidney weight and volume in relation to body weight were not significantly different between males and females and were not affected by DHT. Differences were found in the volume distribution among the kidney zones. The cortex was larger in males than in females, whereas the medulla was conspicuously larger in females than in males. The greater volume of the cortex in males was mainly due to a more extensive development of proximal tubules. DHT treatment in females increased the volume of their proximal tubules. Glomerular volume was similar among the three groups. Within the medulla, the difference was most prominent in the inner stripe (14.9% of the total kidney volume in females vs. 8.9% in males) and was also important in the inner medulla (7.0 vs. 4.8%). The absolute epithelial volume of thick ascending limbs in this zone was larger in females than in males. This difference was more pronounced in short loops (approximately 20%) than in long loops (approximately 10%). The values of the DHT-treated females ranged in between. In spite of the greater development of medulla and thick ascending limbs in females, urine concentration was higher in males than in females and maximum urinary concentrating ability after 48 h dehydration was not different between both sexes.
Animals↗
Enkephalin effects on blood pressure, heart rate, and baroreceptor reflex.
The cardiovascular effects of opioid peptides have been studied. Leucine-enkephalin (Leu-ENK) produced blood pressure (BP) increases following administration into the lateral brain ventricles (i.v.t.), into the cisterna magna (i.c.i.), and following intravenous (i.v.) administration. Heart rate (HR) increases were observed following all routes of administration (threshold for BP and HR effects at 0.3 nmole, maximum at 360 nmoles). The cardiovascular effects were independent of generalized seizures, which may occur at higher doses of enkephalins (ENK). D-alanine-enkephalin (D-Ala-ENK) attenuated the vagal component of the baroreceptor reflex in cats. This was indicated by the findings that HR did not decrease following D-Ala-ENK-induced BP increases and that the compensatory decreases in HR following i.v. pressor doses of angiotensin II (ANG II) were markedly attenuated in cats treated with i.v.t. D-Ala-ENK. Naloxone inhibited the BP and HR effects following i.c.i. and i.v., but not following i.v.t., administration of Leu-ENK. The i.v.t. Leu-ENK effect were inhibited by beta-adrenergic receptor blockade. Bratteboro rats homozygous for hereditary diabetes insipidus with total absence of antidiuretic hormone (ADH) synthesis responded with BP decreases following i.v.t. Leu-ENK, while BP increases were observed in control Long-Evans rats. Blood pressure increases to i.v.t. Leu-ENK were markedly greater in spontaneously hypertensive rats of the stroke-prone strain (SHR-sp) than in normotensive control rats; SHR-sp exhibit a humoral pattern of increased ADH, ACTH, and catecholamines, presumably due to central peptidergic stimulation. The known effects of opioid peptides on these hormones and the observed cardiovascular responses suggest a possible participation of this peptide system in the maintenance of high BP in the SHR-sp.
Animals↗
Effects of [D-Ala2]-methionine-enkephalin on blood pressure, heart rate, and baroreceptor reflex sensitivity in conscious cats.
Effects of intracerebroventricular (i.c.v) injection of [D-Ala2]-methionine-enkephalinamide (DAME) on blood pressure (BP), heart rate, and baroreceptor reflex sensitivity were studied in conscious cats. DAME was administered at doses between 5 and 100 nmoles. Blood pressure and heart rate increased dose dependently. The sensitivity of the baroreceptor reflex was attenuated for 15 to 60 minutes after DAME administration; this was independent of the BP changes. The effects of enkephalin on BP and baroreceptor reflex were abolished by i.c.v. naloxone. DAME caused pathological changes in the electroencephalogram (EEG) characterized by sharp waves in the hippocampus recordings and a loss of theta activity in the electrocorticogram. Behavioral changes were characterized by decreased physical mobility and anxiousness. These behavioral and EEG changes lasted for a longer period of time than the cardiovascular changes; they were also counteracted by naloxone. It is concluded that DAME produces a centrally mediated vasopressor response and a baroreceptor reflex attenuation and that, with respect to the time course, the effects on the baroreceptor reflex are separated from those on BP behavior and EEG, but not on heart rate. The fact that all effects of enkephalin on the parameters tested in the present experiment were completely antagonized by naloxone suggests that they are mediated by naloxone-sensitive enkephalin brain receptors.
Animals↗
Development of a new strain of spontaneously hypertensive rats homozygous for hypothalamic diabetes insipidus.
The aim of the present study was to investigate whether the presence of arginine vasopressin (AVP) is necessary for the establishment of high blood pressure in spontaneously hypertensive rats (SHR). For this purpose we crossbred SHR of the stroke-prone substrain (SHRSP) with rats homozygous for hypothalamic diabetes insipidus of the Brattleboro strain (DI) which are unable to synthetize AVP. The successful introduction of the DI gene into the SHRSP strain (SHRDI) was demonstrated by the following observations: In 10-month-old rats, water intake was similarly elevated in SHRDI as in DI rats (137 +/- 6.5 vs 125 +/- 10.5 ml per 24 hours). AVP was undetectable in the plasma, in the hypothalamus, and in the pituitary of SHRDI and DI rats. Urine osmolality and urinary concentration of sodium and potassium were markedly reduced. SHRDI and DI did not adequately concentrate their urine during an 8-hour period of water deprivation, but both strains of rats responded well with a fall in urine output and a rise in urine osmolality to subcutaneous administration of the non-pressor analog of AVP, DDAVP. Mean arterial blood pressure was markedly increased in SHRDI as well as in SHRSP (184 +/- 9.7 vs 197 +/- 5.2 mm Hg). Thus, we have developed a new line of spontaneously hypertensive rats homozygous for hypothalamic diabetes insipidus. From this finding it is concluded that AVP is not essential for the development and maintenance of spontaneous hypertension of rats.
Animals↗
Local angiotensin II generation in the rat heart: role of renin uptake.
To elucidate the local effects of renin in the coronary circulation, we examined local angiotensin (Ang) I and II formation, as well as coronary vasoconstriction in response to renin administration, and compared the effects with exogenous infused Ang I. We perfused isolated hearts from rats overexpressing the human angiotensinogen gene in a Langendorff preparation and measured the hemodynamic effects and the released products. We also investigated cardiac Ang I conversion, including the contribution of non-angiotensin-converting enzyme-dependent Ang II-generating pathways. Finally, we studied Ang I conversion in vitro in heart homogenates. Renin and Ang I infusion both generated Ang II. Ang II release and vasoconstriction continued after renin infusion was stopped, even though renin disappeared immediately from the perfusate. In contrast, after Ang I infusion, Ang II release and coronary flow returned to basal levels. Ang I conversion (Ang II/Ang I ratio) was higher after renin infusion (0.109+/-0.027 versus 0.026+/-0.003, 15 minutes, P<.02) compared with infused Ang I. Remikiren added to the renin infusion abolished Ang I and II; captopril suppressed only Ang II, whereas an AT1 receptor blocker did not affect Ang I and II formation. All the drugs prevented renin-induced coronary flow changes. Total cardiac Ang II-forming activity was only partially inhibited by cilazaprilat (4.1+/-0.1 fmol x min(-1) x mg[-1]) and on a larger extent by chymostatin (2.6+/-0.3 fmol x min(-1) x mg[-1]) compared with control values (5.6+/-0.4 fmol x min(-1) x mg[-1]). We conclude that renin can be taken up by cardiac or coronary vascular tissue and induces long-lasting local Ang II generation and vasoconstriction. Locally formed Ang I was converted more effectively than infused Ang I. Furthermore, the comparison of in vivo and in vitro Ang I conversion suggests that in vitro assays may underestimate the functional contribution of angiotensin-converting enzyme to intracardiac Ang II formation.
Angiotensin I↗
Neurotransmitters and neuropeptides in the baroreceptor reflex arc: connections between the nucleus of the solitary tract and the ventrolateral medulla oblongata in the rat.
The primary baroreceptor area (nucleus of the solitary tract-NTS) is anatomically interconnected with the rostral ("vasomotor area") and the caudal ("vasodepressor area") ventrolateral medulla by a well-defined arc of neuronal pathways. The chemical character and the direction of these pathways have been investigated with immunohistochemical and neurochemical techniques in intact and brainstem-operated rats. The transection of the neuronal arc resulted in an accumulation of tyrosine hydroxylase immunoreactivity in a small group of cells in the NTS adjacent to the area postrema, ipsilateral to the knife cut. Decreased angiotensinogen mRNA and atrial natriuretic peptide concentrations were measured in the ventrolateral medulla after the cut, and an accumulation of angiotensin II-immunoreactivity was found in neuronal perikarya in the ipsilateral NTS. Intracranial vagotomy caused marked depletions in glutamate levels in the subcommissural portion of the NTS and in the caudal ventrolateral medulla but nowhere else in the brainstem investigated including the rostral ventrolateral medulla.
Angiotensin II↗