Catecholamines and atrial natriuretic factor in Dahl and spontaneously hypertensive rats

We have previously demonstrated two different catecholaminergic patterns in genetic and experimental hypertension: a hyperdopaminergic state in spontaneously hypertensive (Okamoto) rats (SHR) and a hypernoradrenergic state in salt-sensitive Dahl rats. Plasma immunoreactive atrial natriuretic factor (IR ANF) concentrations increase in both models as a response to hypertension. To distinguish between the genetic and acquired components of these abnormalities, we measured adrenal dopamine-beta-hydroxylase (D beta H) activity and coeliac ganglionic atrial natriuretic factor (ANF) like immunoreactivity in the two animal strains. While adrenal D beta H activity was increased in Dahl S rats, it was diminished in SHR in the prehypertensive as well as in the hypertensive stages. In the hypertensive stage, the ANF-like immunoreactivity in the coeliac ganglia was lower in the Dahl S group but higher in SHR than in their respective normotensive controls; there were no changes in these animals when they were prehypertensive. Differences in D beta H activity, which determines the fine tuning of sympathoadrenomedullary catecholamine synthesis may account for the inheritance of mechanisms resulting in salt-sensitive hypertension (as in SHR) or salt-dependent hypertension (as in Dahl salt-sensitive rats). In contrast, plasma IR ANF concentrations may reflect a defense mechanism against hypertension. However ANF-like immunoreactivity in coeliac ganglia does not follow its plasma concentrations and changes in different directions in the two hypertensive strains; it may reflect a neuromodulatory function of ANF in the ganglionic neurotransmission and different implications of this role of ANF in the two hypertensive models.     

Resistance of W/Fu rats to adrenal regeneration hypertension.

The procedure for producing adrenal regeneration hypertension did not cause an increase in the systolic blood pressure of W/Fu animals. The regenerating adrenal gland in W/Fu animals was not restored to normal; reduced numbers of mitochondrial cristae were seen and the mitochondria were smaller in size; regeneration was complete in Sprague-Dawley rats of the Holtzman strain and there was a severe form of hypertensive, cardiovascular disease.     

Altered secretion of corticosteroids and prolactin in adrenal regeneration hypertensive rats.

To assess the possible role of mineralocorticoids in the onset and maintenance of hypertension in adrenal regeneration hypertensive (ARH) rats, the change in plasma mineralocorticoids, with adrenal regeneration after enucleation in ARH rats was investigated and compared with those in unilaterally nephroadrenalectomized, 1% saline-fed (UNA) rats, sham-operated, 1% saline-fed (1% NaCl) rats and water-fed (water) rats. Plasma aldosterone was determined by RIA and the other mineralocorticoids were measured by HPLC. How plasma PRL, a marker of central dopaminergic activity, affected aldosterone secretion was determined by RIA. In ARH, plasma corticosterone (B), 18-OH-DOC and aldosterone levels 2 weeks after operation were as low as 20-30% of corresponding values, but the plasma DOC level was almost 100% of the corresponding value in the other groups. Four weeks after operation plasma B increased to a level comparable with that in the other groups and the plasma aldosterone level remained low. However, plasma DOC and 18-OH-DOC levels 4 weeks after operation were as high as 120-200% of corresponding values in the other groups. Six weeks after operation, the plasma aldosterone level returned to a value comparable with that in UNA and 1% NaCl and plasma DOC and 18-OH-DOC levels returned to corresponding values in the other groups. The plasma PRL level 4 weeks after operation was significantly lower in ARH than in the other groups. These results suggest that transient DOC and 18-OH-DOC increases observed in ARH may be important in the onset of hypertension, while other factors may be involved in its maintenance and that the transient central dopaminergic hyperactivity observed in ARH may be responsible for a delayed return from aldosterone deficiency.     

Adrenal and vascular renin-like activity in chronic 'two-kidney, one-clip' hypertensive rats

In order to study the vascular and adrenal renin angiotensin system in the chronic phase (4 months after clipping) of 'two-kidney, one-clip' hypertension in rats, systolic blood pressure, plasma renin activity, and tissue renin-like activity in both aorta and adrenal have been measured. Renin activity in adrenal gland was studied in both the zona glomerulosa (GLO) and the remainder of the gland. Results showed an increase in vascular renin activity in chronic hypertensive rats. Moreover it was found that GLO of hypertensive rats presented a significant increase in renin-like activity compared with controls (349.43 +/- 43.86 versus 167 +/- 34.25 ng AI/g/20 h, p less than 0.01) and the fasciculata-reticular-medullar (FRM) portion also showed greater renin activity (345.16 +/- 64.36 versus 57.90 +/- 4.83 ng AI/g/20 h, p less than 0.01). The higher levels of vascular and FRM renin-like activity in chronic renal hypertension are probably a consequence of plasma renin increase. This hypothesis is supported by the fact that bilateral nephrectomy in normal rats induces a significant decrease in plasma renin activity and both aortic and FRM renin-like activity. On the other hand the GLO renin-like activity could depend on both plasma renin and local synthesis since bilateral nephrectomy induces an increase in the renin-like activity in this tissue. These data support the idea that aortic and FRM renin are, at least in part, due to plasma renin uptake and GLO renin is an autonomic system.     

Increased production of angiotensin II in the adrenal gland of stroke-prone spontaneously hypertensive rats with malignant hypertension

Angiotensin(Ang) contents in the adrenal gland of stroke-prone spontaneously hypertensive rats(SHRSP) and age-matched Wistar Kyoto rats(WKY) were determined using reverse phase high performance liquid chromatography combined with a specific radioimmunoassay. In normotensive 5 wk-old SHRSP, the adrenal renin activity was about 3 times higher than that of age-matched WKY while the adrenal Ang I and Ang II concentrations did not differ from those of WKY. In the severely hypertensive 25 wk-old SHRSP, the adrenal Ang II and Ang I, and plasma aldosterone concentrations were about 5-fold, 2-fold and 4-fold, respectively, increased compared with levels in the WKY. In the 25 wk-old SHRSP 24 h after bilateral nephrectomy, the adrenal Ang II and plasma aldosterone levels were not decreased and were 10 and 3 times, respectively, higher than those of nephrectomized control WKY. Thus, the enhanced local generation of Ang II in the adrenal gland may contribute to the increased release of aldosterone in SHRSP with malignant hypertension.     

Decreased tyrosine hydroxylase activity in the adrenals of spontaneously hypertensive rats

Higher activity of the peripheral sympathetic nervous system, accompanied by higher tyrosine hydroxylase activity is frequently and consistently reported in human essential hypertension as well as in animal models of hypertension. However, results obtained in the adrenals, particularly in young animals before the development of hypertension, are scarce and controversial. In the present study tyrosine hydroxylase activity and catecholamine content in the adrenals of spontaneously hypertensive rats and of age-matched control Wistar Kyoto rats were evaluated before, during and after the development of hypertension (5, 12 and 22-week-old animals). Results show that both tyrosine hydroxylase activity and total amine content in the adrenals of spontaneously hypertensive rats were significantly reduced (35% reduction) at all studied ages. Determination of the kinetic parameters for tyrosine hydroxylase in the adrenals of 5 week-old spontaneously hypertensive rats revealed a 38% reduction in V(max) values (13.4 versus 21.3 nmol L-DOPA/mg prot/h in age-matched controls) accompanied by lower levels of expression of both tyrosine hydroxylase total protein and phosphoSer40 observed by Western-Blot. In contrast, norepinephrine content in both plasma and tail artery were significantly higher in the spontaneously hypertensive strain. In conclusion, contrary to the higher peripheral sympathetic activity, tyrosine hydroxylase activity and catecholamine content in the adrenals of spontaneously hypertensive rats are markedly reduced before, during and after the development of hypertension. End product, long-term feedback inhibition by the high norepinephrine plasma levels could be responsible for this reduction, establishing yet another regulatory mechanism of tyrosine hydroxylase operating in adrenal cromaffin cells.     

Abnormal regulation of the sympathoadrenal system in deoxycorticosterone acetate-salt hypertensive rats

With the use of circulating norepinephrine (NE) and epinephrine (E) levels, the sympathoadrenal activity as well as its local modulation by adrenoceptors were studied in normotensive (NT) and DOCA-salt hypertensive (HT) rats. In anesthetized hypertensive rats, plasma NE levels were higher, whereas in conscious animals both NE and E levels were found to be increased, suggesting an increased basal sympathoadrenal tone in these animals. The finding of a close correlation between blood pressure levels and NE levels suggests that the elevation of blood pressure may be linked to sympathetic system activity in this experimental model of hypertension. The reactivity of the sympathoadrenal system was also found to be increased in DOCA HT rats. Following a bilateral carotid occlusion of 1 min, which specifically activates the adrenal medulla, the elevation of E levels was found to be potentiated in intact or vagotomized HT rats. Moreover, in response to prolonged or acute hypotension in anesthetized and conscious animals, the elevation in plasma NE and E levels was found to be markedly potentiated in DOCA HT rats. The local modulating adrenoceptor-mediated mechanisms of the sympathoadrenal system appeared to be altered in this model of hypertension. Although it was possible to demonstrate that the E response to carotid occlusion can be greatly potentiated by administration of an alpha2-antagonist (yohimbine) and completely abolished by an alpha2-agonist (clonidine) in NT rats, the E response was found to be unaffected by the same treatments in HT rats, suggesting a reduced sensitivity in the alpha2-mediated inhibitory modulation of the adrenal medulla. Moreover, the acute treatment with a beta-blocker (sotalol) lowered circulating NE levels and blood pressure only in HT rats, suggesting the possibility of a more sensitive beta-receptor-mediated presynaptic facilitatory mechanism on sympathetic fibers of these animals. Finally, it was observed that the functional balance which exists between the activities of sympathetic fibers and the adrenal medulla in normotensive animals appears to be impaired in DOCA HT rats. In conclusion, the present studies suggest that the increased sympathoadrenal tone and reactivity may be due, in part, to a variety of dysfunctions in local adrenoceptor modulatory mechanisms of the sympathoadrenal system in DOCA hypertensive rats.     

Decreased serum 19-nor-deoxycorticosterone (21-hydroxy-19-nor-4-pregnene-3, 20-dione) level in adrenal regeneration hypertensive rats

An enzyme immunoassay of 19-nor-deoxycorticosterone in rat serum was established. The normal value of 19-nor-DOC in rat serum obtained from 9:00 am to 10:00 am was 148 +/- 30 ng/dl (mean +/- SE,n = 10). Serum levels of this steroid decreased in rats with adrenal regeneration hypertension during the course of the experiment up to 8 weeks, while systolic blood pressure rose progressively. We concluded that this mineralocorticoid is not involved at least as a circulating hormone in the pathogenesis of adrenal regeneration hypertension in rats.     

Cytochrome P450(11β): Structure-function relationship of the enzyme and its involvement in blood pressure regulation

Cytochrome P450(11β) is deeply involved in the final steps of biosynthesis of mineralocorticoids. This paper deals with following issues about this enzyme. (1) The structure and function of the enzymes of various animal species are discussed. By making alignment of amino acid sequences of the enzymes, we identified peptide domains essential for the enzyme actions such as a putative steroid binding domain and a heme binding region. Estimates of molecular similarity among the P450(11β) family enzymes suggested that the enzymes having both 11β-hydroxylation activity and aldosterone (ALDO) synthetic activity of certain animals such as frog, cattle and pig are more similar to the ALDO synthases of the other animals, such as rat, mouse and human, than the 11β-hydroxylases of these animals. (2) The molecular nature of the P450(11β) family enzymes of genetically hypertensive rats as well as adrenal regeneration hypertension (ARH) rats is examined. (i) Mutation was found in the P450(11β) gene of Dahl's salt-resistant normotensive rat. Steroidogenic activity expressed by the mutated gene accounted well for abnormal plasma levels of steroid hormones in this rat. (ii) 11β-, 18- and 19-Hydroxylation activities of adrenal mitochondria prepared from spontaneously hypertensive rat (SHR), Wistar-Kyoto rat (WKY), and stroke-prone (SP)-SHR were not significantly different from each other. Levels of mRNA of ALDO synthase in adrenal glands of 50-week-old SHR was significantly lower than those of 10-week-old SHR, WKY and SHR-SP. (iii) No significant difference in 19-hydroxylation activity was found between adrenal mitochondria prepared from ARH rat and those from control rat. The level of message of ALDO synthase was lower in adrenal glands of ARH rat.     

Fasudil attenuates sympathetic nervous activity in the adrenal medulla of spontaneously hypertensive rats

We investigated the effects of fasudil, a Rho kinase inhibitor, on hypertension in spontaneously hypertensive rats and on the catecholamine synthetic pathway. Ten-week-old male SHR and Wistar-Kyoto rats were administered fasudil (10 mg/kg/day s.c.) for 4 days. Systolic blood pressure was measured using the tail-cuff method. Catecholamine levels were measured with high-performance liquid chromatography-ECD methods. Tyrosine hydroxylase protein levels were measured in Western blot analysis. The tyrosine hydroxylase mRNA level was measured using real-time PCR methods. Fasudil significantly decreased systolic blood pressure in spontaneously hypertensive rats, but not in Wistar-Kyoto rats. Fasudil also significantly decreased catecholamine, tyrosine hydroxylase protein, and tyrosine hydroxylase mRNA levels in the adrenal medulla of spontaneously hypertensive rats. These results suggest that the depressor effects of fasudil on hypertension in spontaneously hypertensive rats may be related to inhibition of the catecholamine synthetic pathway.     

Lowering of blood pressure in chronic aortic coarctate hypertensive rats with anti-digoxin antiserum

A marked lowering of arterial blood pressure was observed in chronic aortic coarctate (CAC) hypertensive rats after intravenous administration of anti-digoxin antiserum. The hypotensive effect lasted for about 30 min after dosing. In contrast to the pronounced changes observed following treatment with anti-digoxin antiserum in CAC rats, only a transient pressor effect was observed in both water-and saline-drinking CAC rats following injection of normal goat serum. In addition, a transient depressor effect was observed in normotensive rats after injection of anti-digoxin antiserum. The results of this study provide additional evidence indicating that an endogenous digoxin-like substance may play an important role in the maintenance of chronic low-renin hypertension induced by aortic coarctation.     

Effect of losartan on insulin plasma concentrations and LPL activity in adipose tissue of hypertensive rats.

The aim of this study is to determine the effect of losartan on insulin and angiotensin II (Ang II) concentrations in plasma as well as on lipoprotein lipase activity (LPL) and angiotensin II content in the adipose tissue of hypertensive rats. Fifty male rats were divided in five groups. Group A served as controls. Group B underwent renal artery stenosis. Group C were administered losartan (10 mg/kg/day) per os, while rats in group D were submitted to renal artery stenosis and were treated with losartan as above. Group E was used as sham-operated control. The animals were sacrificed at day 21. Blood samples were collected, and perirenal adipose tissue was isolated. Furthermore, adrenal's were removed and their relative weight (adrenal weight/body weight) was used as an index of sympathetic stimulation. According to our results, renovascular hypertension resulted in lower insulin concentrations and higher Ang II content in plasma. In hypertensive rats, LPL activity was decreased, while the adrenals' relative weight was elevated. On the other hand, losartan administration resulted in normalization of insulin concentrations in plasma and adrenals' relative weight, with consequent up regulation of LPL activity in adipose tissue. In conclusion, renovascular hypertension interferes in lipid metabolism by reducing LPL activity in adipose tissue, while losartan administration reverses this effect by enhancing insulin release and reducing sympathetic nervous system (SNS) stimulation.     

Correlation between cardiac hypertrophy and plasma levels of atrial natriuretic factor in non-spontaneous models of hypertension in the rat

We have compared atrial and plasma concentration of atrial natriuretic factor (ANF) in 4 models of non spontaneous experimental hypertension with different pathogenic mechanisms in the rat: two-kidney, one-clip (2-K, 1-C), one-kidney, one-clip (1-K, 1-C), DOCA-NaCl and adrenal regeneration hypertension (ARH) and their respective normotensive controls. All hypertensive groups developed cardiac hypertrophy. In all hypertensive groups plasma ANF was higher than in controls. Atrial ANF concentration was lower in the right and left atrium of 1-K, 1-C rats and in the left atrium of ARH. A good correlation was found between systolic BP and plasma ANF in 2-K, 1-C (r = 0.82; p less than 0.01) and 1-K, 1-C animals (r = 0.70; p less than 0.01). This correlation was less good in DOCA-NaCl (r = 0.41; p less than 0.05) and non existent in ARH (r = 0.28; NS). A negative correlation between plasma ANF and atrial ANF concentrations was found only in the 1-K, 1-C group (r = 0.41; p less than 0.05). A good correlation between plasma ANF levels and cardiac weight was found in all groups: 2-K, 1-C (r = 0.83; p less than 0.01), 1-K, 1-C (r = 0.73; p less than 0.01), DOCA-NaCl (r = 0.69; p less than 0.01) and ARH (r = 0.71; p less than 0.01). We suggest that the release of ANF in experimental hypertension depends of the pathogenesis and could be related either to the level of BP (hence the magnitude of the left ventricular end-diastolic pressure) or to the existence of an expanded blood volume. The correlation between plasma ANF levels and cardiac hypertrophy suggests that ANF could be partially released by the ventricles.     

The influence of age on the activity of the renin-angiotensin system in rats with adrenal-regeneration hypertension

In female rats aged 21 and 80 days, uninephroadrenalectomy with enucleation of the remaining adrenal was performed and 0.17 mol X l-1 saline offered as the only drinking fluid. The changes of plasma concentration of renin (PRC), and its substrate (RSC) and renal renin activity (RRA), considered as an indicator of the secretory activity of the regenerating adrenal were studied 5, 10, 20, 40 and 60 days after the adrenal enucleation to look for possible age differences related to the higher susceptibility of immature rats to the hypertensive influence of the regenerating adrenal. It has been found that: 1. In adrenal-enucleated rats the saline-induced decrease of RRA was delayed for a shorter time period in immature rats than in adult ones (5 vs. 10 days), during which blood pressure, saline consumption and RSC were lowered. The decrease of PRC was retarded in the older group only. 2. In rats with regenerating adrenals the PRC and RRA decrease was greater in animals subjected to enucleation of the remaining adrenal gland when immature, than in those operated when adult. At the end of the experiment this age difference disappeared. 3. The age difference in PRC and RRA suppression appeared during the period, when neither blood pressure nor saline consumption were higher in immature rats than in adult ones. 4. In rats with regenerating adrenals the renal mass was greater than in saline drinking controls. In the younger group, which in contrast to the adult one developed hypertension, this increase was greater and directly related to the blood pressure level from the 20th post-enucleation day onwards. It is being suggested that the changes of PRC, RRA and RSC observed up to the 10th post-enucleation day indicates relative adrenal insufficiency, the shorter duration of which in immature rats reflects their higher sensitivity to mineralocorticoids produced by the regenerating adrenal. This also manifests itself by greater PRC and RRA suppression in this age group. The haemodynamic results of the greater RRA suppression in the not yet fully developed kidneys of immature rats may facilitate the development of a "vicious circle" mechanism between blood pressure and hypertensive renal damage and thus contribute to the higher sensitivity to adrenal-regeneration hypertension.     

Plasma concentrations of endothelin-1 in spontaneously hypertensive rats and DOCA-salt hypertensive rats

To investigate the possible involvement of endothelin-1 (ET-1), an endothelium-derived potent vasoconstrictor peptide, in the pathophysiology of hypertension, plasma ET-1 levels in 15-week-old spontaneously hypertensive rats (SHR) and DOCA-salt hypertensive rats were measured with a sandwich-type enzyme immunoassay. The vasocontractile effect of ET-1 in aortic helical preparations was significantly more sensitive in DOCA-salt hypertensive rats than in control sham-operated rats, but plasma levels of ET-1 did not differ between them. Plasma ET-1 levels in genetically hypertensive rats (SHR and stroke-prone SHR) were significantly lower than those in age-matched normotensive Wistar-Kyoto (WKY) rats. The plasma concentrations of big ET-1, a precursor of ET-1, in both SHR and SHR-SP were significantly lower than those of WKY, suggesting that the production of ET-1 is decreased in rats of genetic hypertension. Although the vascular reactivity to ET-1 increased in both DOCA-salt hypertensive and genetically hypertensive rats, present findings of the plasma ET-1 levels suggest that the role of ET-1 in the vascular control system may be different in DOCA-salt hypertensive rats and genetically hypertensive rats.     

Serum 11-deoxycorticosterone levels in adrenal-regeneration hypertension under conditions of quiescence and stress.

A time course study to measure adrenal cortical function was undertaken for the period prior to the development of hypertension until the onset of hypertension in the adrenal-regeneration hypertension (ARH) model. Quiescent rat kills were used so that all adrenal cortical parameters investigated would reflect basal or resting levels for controls. Thus a more accurate determination of the differences between control and experimental animals could be made. A radioimmunoassay procedure for deoxycorticosterone was developed to measure this steroid in individual rat serum samples. Elevated serum deoxycorticosterone levels were observed in rats with regenerating adrenals when they were killed under quiescent conditions. This agreed with our recently reported in vitro finding of restoration of cholesterol side chain cleavage activity while 11beta-hydroxylase activity remained imparied 25 days after adrenal enucleation. When rats were killed after ether stress, deoxycorticosterone levels were elevated in both control rats and in rats with regenerating adrenals but the difference was not significant. In contrast, after ether stress serum corticosterone levels were lower in rats with regenerating adrenals than in controls. These studies, in conjunction with our previous in vitro findings, point to the importance of deoxycorticosterone in the pathogenesis of adrenal regeneration hypertension and help to explain the anomalous corticosteroid secretion rate data found in this experimental hypertension model.     

Selective 19-hydroxylase inhibition by an aromatase inhibitor, 4-hydroxyandrostenedione

19-Nor-deoxycorticosterone is a newly recognized mineralocorticoid which has been associated with some forms of genetic, experimental, and human hypertension. To further examine this relationship, specific inhibitors of 19-nor-deoxycorticosterone biosynthesis must be developed. Since 19-hydroxylation is the pivotal step in both 19-nor-deoxycorticosterone biosynthesis and aromatization of androgens to estrogens, we evaluated an aromatase inhibitor, 4-hydroxyandrost-4-ene-3,17-dione on the inhibition of 19-hydroxylation in both rat and human adrenal mitochondria in vitro and 19-nor-deoxycorticosterone production and blood pressure in spontaneously hypertensive rats in vivo. Adrenal mitochondria from 48 male Sprague-Dawley rats and 1 patient with an aldosterone-producing adenoma were incubated in the presence of deoxycorticosterone substrate both with and without 4-hydroxyandrost-4-ene-3,17-dione. 4-Hydroxyandrost-4-ene-3,17-dione produced significant inhibition of 19-hydroxy-deoxycorticosterone production in both rat and human adrenal mitochondria, with a smaller and not significant inhibition of corticosterone and 18-hydroxy-corticosterone. 4-Hydroxyandrost-4-ene-3,17-dione given subcutaneously to spontaneously hypertensive rats lowered 19-nor-deoxycorticosterone by 69% and completely abolished hypertension compared to Wistar-Kyoto controls. These data demonstrate that 4-hydroxyandrost-4-ene-3,17-dione is a specific inhibitor of 19-hydroxylase, that it lowers 19-nor-deoxycorticosterone production and prevents hypertension in the spontaneously hypertensive rat. These studies reinforce the possible pathogenic significance of 19-nor-deoxycorticosterone in hypertension in spontaneously hypertensive rats.     

Effect of exercise training on liver antioxidant status of deoxycorticosterone acetate salt induced hypertensive rats

Several animal models have been developed to study the pathogenesis of hypertension. Deoxycorticosterone acetate (DOCA) salt induced hypertensive rats are adrenal models used to mimic human Conn's syndrome. Because previous studies showed a beneficial effect of chronic exercise (swimming) on the development of arterial hypertension in spontaneously hypertensive rats (which appears similar to human essential hypertension), we decided to evaluate the effects of swimming on DOCA-salt induced hypertension and liver antioxidant status. Therefore, the aim of this experiment was to study whether the swim training would improve hypertension and liver antioxidant status in DOCA-salt rats. DOCA-salt rats and control Sprague-Dawley rats were trained to swim 1 h/day, 5 days/week for 6 weeks and were sacrificed 48 h after the last exercise period. Systolic blood pressure was recorded before the sacrifice, and liver antioxidant status was evaluated in hepatic homogenates after the sacrifice. Swim exercise did not decrease systolic blood pressure in control and DOCA-salt rats but induced changes in liver activities of antioxidant enzymes, showing that exercise provoked liver oxidative stress in control and DOCA-salt rats. In comparison with our previous studies using spontaneously hypertensive rats, we conclude that the beneficial effects of chronic exercise on systolic blood pressure in rats are dependent on strain and the type of experimental hypertension.     

Adrenal, kidney, and heart angiotensins in female murine ren-2 transfected hypertensive rats

We analyzed by high-performance liquid chromatography and radioimmunoassay angiotensin I (Ang I), Ang II, Ang-(1–7), and metabolites in the adrenal, kidney and heart of normotensive female Sprague–Dawley (SD) and transgenic hypertensive [TGR(mRen-2)27] rats carrying the murine Ren-2^d renin gene. The monogenetic model of hypertensive rats had significant increases in adrenal Ang II; whereas in the kidney Ang II was unchanged, but Ang I and Ang-(1–7) were significantly lower. Cardiac Ang I, Ang II, and Ang-(2–10) were significantly reduced in transgenic rats, while Ang-(2–7) was increased. In SD and transgenic rats kidney and adrenal angiotensins increased primarily during estrus or proestrus. In female transgenic rats the increased adrenal Ang II and the sustained renal Ang II may contribute to the established phase of hypertension.