Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease.

Stroke is a complex disorder with a poorly understood multifactorial and polygenic aetiology. We used the stroke-prone spontaneously hypertensive rat (SHRSP) as a model organism, mated it with the stroke-resistant spontaneously hypertensive rat (SHR) and performed a genome-wide screen in the resultant F2 cohort where latency until stroke, but not hypertension (a major confounder) segregated. We identified three major quantitative trait loci, STR1-3, with lod scores of 7.4, 4.7 and 3.0, respectively, that account for 28% of the overall phenotypic variance. STR2 colocalizes with the genes encoding atrial and brain natriuretic factor, peptides with important vasoactive properties. Our results demonstrate the existence of primary, blood pressure-independent genetic factors predisposing to a complex form of stroke.

Angiotensin synthesis in the brain and increased turnover in hypertensive rats.

The missing link in the evidence for an active endogenous renin angiotensin system in the brain has been the demonstration of local angiotensin synthesis in the central nervous system in vivo. In this report the extraction and characterization of angiotensin I and angiotensin II from the brain of rats is described. The accumulation of angiotensin I was enhanced in hypertensive rats when the conversion to angiotensin II was blocked in vivo by the converting enzyme inhibitor captopril.

Angiotensin-forming enzyme in brain tissue.

A renin-like enzyme is present in brain tissue and is independent of kidney and plasma renin. In the presence of homologous substrate it forms angiotensin. Administration of aldosterone significantly decreases this angiotensinforming enzyme activity, while administration of progesterone markedly enhances it.

Increased adrenal renin in transgenic hypertensive rats, TGR(mREN2)27, and its regulation by cAMP, angiotensin II, and calcium.

The newly established rat strain TGR(mREN2)27 is a monogenetic model in hypertension research. Microinjecting the mouse Ren-2d renin gene caused it to become a stable part of the genome. The rats are characterized by fulminant hypertension, low plasma active renin, suppressed kidney renin, high plasma inactive renin, and high extrarenal transgene expression, most prominently in the adrenal cortex. Additionally, they exhibit significantly enhanced excretion of corticosteroids. Here we demonstrate that part of the plasma renin and most of the adrenal renin are transgene determined and that the adrenal renin is strongly activated. TGR(mREN2)27 adrenal cells may serve as a new tool to investigate the regulation and processing of Ren-2d-derived renin and its significance in hypertension and steroid metabolism. Adrenal renin in TGR(mREN2)27 is stimulated by 8-bromo-cAMP (8-Br-cAMP), angiotensin II (ANGII), and calcium. 8-Br-cAMP significantly stimulates active renin and prorenin release, as well as Ren-2d mRNA. Interestingly, within 60 min 8-Br-cAMP, ANGII, and calcimycin stimulate active renin, but not prorenin release. This indicates different intracellular pathways. An activated adrenal renin-angiotensin system in TGR (mREN2)27 as well as the lack of negative feedback on renin secretion by ANGII may be of pathophysiological significance in this hypertensive model.

Augmented agonist-induced Ca(2+)-sensitization of coronary artery contraction in genetically hypertensive rats. Evidence for altered signal transduction in the coronary smooth muscle cells.

The Ca2+ responsiveness of vascular smooth muscle myofilaments is not unique: it is increased during neuro-humoral activation and decreased during beta-adrenergic stimulation. In this study we tested whether an augmented Ca2+ responsiveness of smooth muscle myofilaments may contribute to the increased coronary tone observed in hypertension using beta-escin-permeabilized coronary arteries from 3-mo-old stroke-prone spontaneously hypertensive rats (SHRSP) and their age matched normotensive reference strain (WKY rats). In intact coronary arteries, the response to 5-hydroxytryptamine (5-HT) but not to KCl was larger in SHRSP than in WKY rats. In beta-escin permeabilized coronary arteries in which the receptor effector coupling is still intact, 5-HT enhanced force at constant submaximal (Ca2+) (pCa 6.38) to a greater extent in SHRSP. The Ca2+ sensitizing effect of 5-HT was mimicked by GTP gamma S (0.01-10 microM); again this effect was larger in SHRSP. In the absence of 5-HT or GTP gamma S the Ca2+ force relation was similar in both groups. Forskolin induced relaxation at constant submaximal (Ca2+). This desensitizing effect was smaller in SHRSP than in WKY rats. In conclusion, this study shows that intracellular signalling pathways involved in modulating the Ca2+ responsiveness of coronary smooth muscle myofilaments are altered in the genetically hypertensive animals favoring a hypercontractile state in the coronary circulation.

Association and cosegregation of stroke with impaired endothelium-dependent vasorelaxation in stroke prone, spontaneously hypertensive rats.

While hypertension is a major risk factor for stroke, it is not its sole determinant. Despite similar blood pressures, spontaneously hypertensive rats (SHR) do not share the predisposition to cerebrovascular disease typical of stroke-prone spontaneously hypertensive rats (SHRSP). We investigated vascular function in male SHR and SHRSP as well as in SHRSP/SHR-F2 hybrid animals. Animals were maintained on the appropriate dietary regimen necessary for the manifestation of stroke. Among the hybrid animals, a group of stroke-prone and a group of stroke-resistant rats were selected. Blood pressure was similar in all groups. Endothelium-independent vascular reactivity tested on isolated rings of thoracic aorta and basilar artery after death showed similar contractile and dilatory responses to serotonin and nitroglycerin, respectively, in all groups. In contrast, endothelium-dependent relaxation, in response to acetylcholine or substance P, was markedly reduced in SHRSP compared with SHR. Similarly, reduced vasodilatory responses were present in aortae of F2 rats that had suffered a stroke when compared with SHR or F2 rats resistant to stroke. The observed association and cosegregation of stroke with significant and specific impairment of endothelium-dependent vasorelaxation among SHRSP and stroke-prone F2 hybrids, respectively, suggest a potential causal role of altered endothelium-dependent vascular relaxation in the pathogenesis of stroke.

Effect of estrogen on neprilysin expression in uterus and kidney of Sprague-Dawley normotensive and heterozygous (mRen2)27-transgenic hypertensive rats.

The present study was designed to determine whether estrogen modulates the angiotensin processing enzymes in membrane homogenates obtained from uterus and kidney cortex and medulla of Sprague-Dawley (SD) and heterozygous (mRen2)27-transgenic hypertensive (Tg(+)) female rats treated with or without 17beta-estradiol (E2). We evaluated estrogen's influence on neprilysin (NEP), an endopeptidase that forms angiotensin-(1-7) [Ang-(1-7)] and on aminopeptidase (AMP), which degrades Ang-(1-7). Renal tissue from normotensive and hypertensive male rats was also evaluated. E2 up-regulated NEP mRNA in the uterus of both SD and Tg(+) and this was associated with increased NEP activity in the uterus of SD (0.31+/-0.03 nmol/min/mg versus 0.18+/-0.04 nmol/min/mg of protein, p<0.05) and Tg(+) (0.26+/-0.04 nmol/min/mg versus 0.13+/-0.02 nmol/min/mg of protein, p<0.05) female). E2 had no significant effect on NEP activity in cortex and medulla of hypertensive and normotensive female. In female animals, cortical NEP activity is two-fold higher than medullary; in males there is a four-fold higher cortical NEP activity as compared to medulla. In male animals, medullary NEP was significantly lower than females with or without E2 treatment; no gender specific effect was found in cortex. E2 treatment also caused a two-fold increase in AMP activity in the uterus and 1.6-fold decrease in kidney cortex of SD and Tg(+) female (p<0.05). Our studies indicate that NEP may be a primary candidate for increased Ang-(1-7) processing in the uterus with estrogen treatment; kidney NEP, on the other hand, showed no modulation by estrogen, suggesting that down regulation of other processing enzymes, like AMP and ACE, may come into play in the kidney with estrogen replacement. In addition, these studies showed that there is tissue-specific regulation of NEP with estrogen treatment that is strain independent.

Rat gene mapping using PCR-analyzed microsatellites.

One hundred and seventy-four rat loci which contain short tandem repeat sequences were extracted from the GenBank or EMBL data bases and used to define primers for amplification by the polymerase chain reaction (PCR) of the microsatellite regions, creating PCR-formatted sequence-tagged microsatellite sites (STMSs). One hundred and thirty-four STMSs for 118 loci, including 6 randomly cloned STMSs, were characterized: (i) PCR-analyzed loci were assigned to specific chromosomes using a panel of rat x mouse somatic cell hybrid clones. (ii) Length variation of the STMSs among 8 inbred rat strains could be visualized at 85 of 107 loci examined (79.4%). (iii) A genetic map, integrating biochemical, coat color, mutant and restriction fragment length polymorphism loci, was constructed based on the segregation of 125 polymorphic markers in seven rat backcrosses and in two F2 crosses. Twenty four linkage groups were identified, all of which were assigned to a defined chromosome. As a reflection of the bias for coding sequences in the public data bases, the STMSs described herein are often associated with genes. Hence, the genetic map we report coincides with a gene map. The corresponding map locations of the homologous mouse and human genes are also listed for comparative mapping purposes.

Regulation of renin: new evidence from cultured cells and genetically modified mice.

Renin, as the rate-limiting enzyme in the synthesis of the potent vasoactive peptide angiotensin II, has been studied for more than 100 years. Transgenic and knockout mice for renin and other proteins involved in renin regulation and function have recently revealed new evidence that can improve our understanding of its biological relevance. Furthermore, transgenic mice have been the source of the novel cell line As4.1. This cell line has been effective in the analysis of renin secretion and regulation because of its similarity with renin-producing juxtaglomerular (JG) cells. Renin secretion and synthesis by the JG cells of the kidney is upregulated by cAMP and downregulated by intracellular calcium. The effect of cGMP, once elevated by nitric oxide, depends on the present level of cAMP in the cells, which can be stimulatory in the presence of and inhibitory in the absence of the other cyclic nucleotides. All known effectors of renin regulation affect one of these molecules. Adenosine and ATP, released by macula densa cells in response to high salt load in the distal tubule and stretch of the JG cell by renal perfusion pressure, increase calcium. Furthermore, noradrenaline, derived from sympathetic nerve endings, and prostaglandins, generated by macula densa cells under low-salt conditions, increase cAMP. In addition to its stimulatory effect on secretion, cAMP also effectively augments renin mRNA levels by acting at the transcriptional and posttranscriptional levels. Several DNA elements in the distal and proximal promoter regions as well as in intron I have been implicated in cAMP regulation and in tissue specificity of renin gene expression. A second intracellular renin isoform, coded by the same gene but applying a different promoter located in intron I, has recently been detected. Transgenic technology will help to clarify the function of this isoform as well as some of the other unresolved aspects of renin regulation and function and may become the motor of the second century in renin research.

Induction of cardiac angiotensin I-converting enzyme with dietary NaCl-loading in genetically hypertensive and normotensive rats.

We have recently shown that the angiotensin I converting enzyme (ACE) gene is linked to NaCl-loaded blood pressure in the stroke-prone spontaneously hypertensive rat (SHRSP), and that high-NaCl loading selectively stimulates ACE in the aorta of SHRSP but not in normotensive Wistar-Kyoto (WKY) rats. We therefore investigated the relationship between cardiac ACE and the development of hypertension and left ventricular hypertrophy in response to normal- and high-NaCl diet in these rats. ACE mRNA and ACE activity were measured in left ventricular tissue after completion of hemodynamic characterization of the animals. While SHRSP rats increased blood pressure (P < 0.0001) and heart rate (P < 0.005) in response to high NaCl, blood pressure remained unchanged in WKY. Similarly, relative left ventricular weight increased only in SHRSP after high NaCl (P < 0.002). A significant two- to threefold increase of cardiac ACE mRNA and fourfold stimulation of ACE enzyme activity in response to high NaCl was found in both WKY and SHRSP rats (P < 0.005). The induction of ACE gene expression was significantly more pronounced in SHRSP compared to WKY (P < 0.02), whereas no significant strain differences in left ventricular ACE activity were found after either normal- or high-NaCl diet. Thus, arterial blood pressure and left ventricular weight remained unchanged in the WKY rats despite the activation of left ventricular ACE activity after high-NaCl exposure. These results demonstrate that left ventricular ACE activity is equally upregulated in response to high-NaCl in the normotensive and hypertensive strain, independently from the development of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Tissue renin-angiotensin systems: new insights from experimental animal models in hypertension research.

Renin was first isolated in the kidney by Tigerstedt and Bergman over 100 years ago. Almost 50 additional years were necessary to isolate the renin substrate angiotensinogen and to show its cleavage to angiotensin (Ang). Further studies were then needed to demonstrate that Ang I is converted via an angiotensin-converting enzyme to Ang II. The circulating renin-angiotensin system, with blood pressure regulatory and aldosterone stimulatory roles, served well for decades. However, more recent information on Ang II and its action in terms of cell proliferation, hypertrophy, and hyperplasia as well as immune-modulatory and even intracellular functions, have focused attention on local Ang II generation and effects. These investigations necessarily began in the kidney, but quickly moved to other organs including the brain, heart, adrenal gland, and vessel wall and formed the basis for the concept of independent tissue renin-angiotensin systems. Both renin and Ang II have even been implicated in intracellular activities. This review presents some selected aspects of the historical development of this concept and summarizes discoveries relying primarily on animal models which demonstrate that Ang II is generated locally and acts in tissues as a local peptidergic system. Comprehensiveness in such an endeavor is not possible. We focus largely on work from our own group, not because the work is necessarily worthy of such scrutiny but rather because of our own familiarity with the contents.

Overexpression of the human angiotensin II type 1 receptor in the rat heart augments load induced cardiac hypertrophy.

Angiotensin II is known to stimulate cardiac hypertrophy and contractility. Most angiotensin II effects are mediated via membrane bound AT1 receptors. However, the role of myocardial AT1 receptors in cardiac hypertrophy and contractility is still rarely defined. To address the hypothesis that increased myocardial AT1 receptor density causes cardiac hypertrophy apart from high blood pressure we developed a transgenic rat model which expresses the human AT1 receptor under the control of the alpha-myosin heavy-chain promoter specifically in the myocardium. Expression was identified and quantified by northern blot analysis and radioligand binding assays, demonstrating overexpression of angiotensin II receptors in the transgenic rats up to 46 times the amount seen in nontransgenic rats. Coupling of the human AT1 receptor to rat G proteins and signal transduction cascade was verified by sensitivity to GTP-gamma-S and increased sensitivity of intracellular Ca2+ [Ca2+]i to angiotensin II in fluo-3 loaded transgenic cardiomyocytes. Transgenic rats exhibited normal cardiac growth and function under baseline conditions. Pronounced hypertrophic growth and contractile responses to angiotensin II, however, were noted in transgenic rats challenged by volume and pressure overload. In summary, we generated a new transgenic rat model that exhibits an upregulated myocardial AT1 receptor density and demonstrates augmented cardiac hypertrophy and contractile response to angiotensin II after volume and pressure overload, but not under baseline conditions.

Effects of sodium restriction and cyclooxygenase-2 inhibition on the course of hypertension, proteinuria and cardiac hypertrophy in Ren-2 transgenic rats.

The present study was performed to evaluate the effects of sodium intake and of chronic cyclooxygenase-2 (COX-2) inhibition on systolic blood pressure (SBP) in heterozygous male transgenic rats harboring the mouse Ren-2 renin gene (TGR) and in transgene-negative normotensive Hannover Sprague-Dawley (HanSD). Twenty-eight days old TGR and HanSD were randomly assigned to groups fed either normal salt (NS) or low sodium (LS) diets. COX-2 blockade was achieved with NS-398 (1 mg x kg(-1).day(-1) in drinking water). During an experimental period of 26 days, SBP was repeatedly measured by tail plethysmography in conscious animals. We found that the LS diet prevented the development of hypertension in TGR and did not change SBP in HanSD. Low sodium intake also prevented proteinuria and cardiac hypertrophy in TGR. On the other hand, irrespective of sodium intake chronic COX-2 inhibition did not alter the course of SBP in either TGR or HanSD. The present data indicate that TGR exhibit an important salt-sensitive component in the developmental phase of hypertension. They also suggest that systemic COX-2-derived prostaglandins do not act as vasodilatory counterregulatory agents in TGR in which an exaggerated vascular responsiveness to angiotensin II is assumed as the pathophysiological mechanism in the development of hypertension.

The tissue renin-angiotensin systems in cardiovascular disease.

The renin-angiotensin system, in its classic definition, is known as an endocrine system that exerts its actions through the effector peptide, angiotensin II, in various organs to act as a vasoconstrictor and a regulator of salt and volume homeostasis. The availability of more sensitive methods to study the biochemistry and pharmacology as well as the molecular biology of the RAS has expanded our knowledge of the system and provided new perspectives of autocrine and paracrine functions of the RAS in cardiovascular regulation. One of the more exciting of these recently described actions is the possible involvement of the RAS in the adaptive processes related to cardiovascular hypertrophy and angiogenesis.

Lessons from rat models of hypertension: from Goldblatt to genetic engineering.

Over the past 50 years various animal models of hypertension have been developed, predominantly in the rat. In this review we discuss the use of the rat as a model of hypertension, and evaluate what these models have taught us. Interestingly, the spontaneously hypertensive rat (SHR) is by far the most widely used rat model, although it reflects only a rare subtype of human hypertension, i.e. primary hypertension that is inherited in a Mendelian fashion. Many other aspects of the etiology of hypertension are found in other rat models, but these models are less frequently employed. The widespread use of the SHR suggests that this rat model is often chosen without considering alternative (and possibly better suited) models. To illustrate the importance of the choice for a particular model, we compared the natural history and response to antihypertensive drugs in different rat models of hypertension (SHR, Dahl, deoxycorticosterone acetate (DOCA)-salt, two-kidney one-clip, transgenic TGR(mRen2)27. This revealed that the outcome of hypertension can be similar in some respects, as all models exhibit cardiac hypertrophy, and all demonstrate impaired endothelium-dependent relaxations. However, the more severe forms of end-organ damage such as heart failure, stroke and kidney failure, occur only in some models and then only in a subset of the hypertensive rats. The effects of antihypertensives varies even more in the different models: antihypertensive treatment only attenuates end-organ damage if it decreases blood pressure. Moreover, if a given antihypertensive is effective, it sometimes even attenuates end-organ damage in nonhypotensive doses. On the other hand, some agents do decrease blood pressure but do not prevent end-organ damage (e.g. hydralazine in SHR). Furthermore, not all classes of antihypertensives are equally effective in all rat models of hypertension: endothelin-receptor antagonists are not effective in SHR, but have beneficial effects in the DOCA-salt model. The comparison of models, and the comparison of treatment effects suggests that end-organ damage critically depends upon not only on the stress imposed by high blood pressure and its underlying biochemical disturbance, but also upon the ability of the organism to recruit adequate 'coping' mechanisms. These coping mechanisms deserve greater attention, as failure to recruit such mechanisms may indicate an increased risk. The current development of transgenic techniques will provide new opportunities, to develop specific models to address this balance between stress and coping.

Angiotensin peptides acting at rostral ventrolateral medulla contribute to hypertension of TGR(mREN2)27 rats.

We have previously demonstrated that microinjections of the selective angiotensin-(1-7) [ANG-(1-7)] antagonist, A-779, into the rostral ventrolateral medulla (RVLM) produces a significant fall in mean arterial pressure (MAP) and heart rate (HR) in both anesthetized and conscious rats. In contrast, microinjection of angiotensin II (ANG II) AT(1) receptor antagonists did not change MAP in anesthetized rats and produced dose-dependent increases in MAP when microinjected into the RVLM of conscious rats. In the present study, we evaluated whether endogenous ANG-(1-7) and ANG II acting at the RVLM contribute to the hypertension of transgenic rats harboring the mouse renin Ren-2 gene, TGR(mREN2)27. Unilateral microinjection of A-779 (0.1 nmol) produced a significant fall in MAP (-25 +/- 5 mmHg) and HR (-57 +/- 20 beats/min) of awake TGR rats. The hypotensive effect was greater than that observed in Sprague-Dawley (SD) rats (-9 +/- 2 mmHg). Microinjection of the AT(1) antagonist CV-11974 (0.2 nmol) produced a fall in MAP in TGR rats (-14 +/- 4 mmHg), contrasting with the pressor effect observed in SD rats (33 +/- 9 mmHg). These results indicate that endogenous ANG-(1-7) exerts a significant pressor action in the RVLM, contributing to the hypertension of TGR(mREN2)27 transgenic rats. The role of ANG II at the RVLM seems to be dependent on its endogenous level in this area.

Pressor action of centrally perfused angiotensin II in rats with hereditary hypothalamic diabetes insipidus.

A method was devised for the perfusion of the cerebral ventricles in conscious rats. Using this method a basal secretion rate of 15 +/- 3 pg of immunoreactive angiotensin II per min was calculated. This material was suggested to be of extrarenal origin. In comparison to findings in normal Long-Evans rats, pressor responses to intraventricular perfusions of angiotensin II were reduced in rats heterozygous for hypothalamic diabetes insipidus and virtually absent in rats homozygous for the hypothalamic deficiency whether they were treated with vasopressin or not. The pressor response to intraventricular angiotensin II is suggested to be related to the release of vasopressin.

Effects of nephrectomy and adrenalectomy on the renin-angiotensin system of transgenic rats TGR(mRen2)27.

The transgenic rat TGR(mRen2) develops severe hypertension with high renin activity in the adrenal and low renin activity in the kidney. To clarify the role of the adrenal gland as a source of circulating renin in TGR rats, we investigated the effects of nephrectomy (NEPEX) and adrenalectomy (ADX) on the adrenal and plasma renin-angiotensin system. TGR rats had a high basal plasma renin concentration (PRC; 18.2 +/- 1.0 ng angiotensin-I (AngI)/ml.h) compared with Harlan Sprague-Dawley (SD) rats (7.4 +/- 0.5 ng AngI/ml.h; P < 0.01) and SD rats of the Hannover strain from which the TGR rat was derived (5.3 +/- 0.6 ng AngI/ml.h, P < 0.01); TGR rats also had high adrenal renin (83.3 +/- 8.9) compared with Harlan SD rats (5.5 +/- 0.7; P < 0.01) and Hanover SD rats (6.1 +/- 0.6 ng AngI/ml.h). NEPEX markedly increased PRC (82.4 +/- 18.8 ng AngI/ml.h, P < 0.01) and adrenal renin levels (386.3 +/- 43.9 ng AngI/adrenal.h; P < 0.01) in TGR rats. ADX significantly lowered control levels of PRC and plasma AngII in the TGR rats (19.0 +/- 1.2 to 7.7 +/- 1.2 ng AngI/ml.h and 33.5 +/- 5.6 to 12.8 +/- 2.1 pg/ml, respectively) and suppressed the increases in PRC (119.4 +/- 20.2 to 61.8 +/- 4.0 ng AngI/ml.h) and plasma AngII (95.8 +/- 9.8 to 55.1 +/- 4.3 pg/ml; P < 0.01) caused by NEPEX in TGR rats. However, the levels of PRC and plasma AngII remained high after NEPEX/ADX in TGR rats. Our results suggest that the adrenal gland is one of the main sources of circulating renin in the TGR rat, but other extrarenal sources of plasma renin also exist in these animals.

Zonal distribution and regulation of adrenal renin in a transgenic model of hypertension in the rat.

The hypertensive transgenic rat [TGR (mRen-2)27] is a genetic model of hypertension in which transfection of the Ren-2 mouse renin gene into rats results in severe hypertension. These transgenic rats express a high level of renin in the adrenal gland, and the hypertension is ameliorated by treatment with angiotensin-converting enzyme inhibitors. In this study we investigated the distribution of adrenal renin in the TGR rat and examined the regulation of adrenal renin in a monolayer culture of adrenal cells. High concentrations of active renin and prorenin were found in the adrenal capsular (glomerulosa) and decapsular (fasciculata-medullary) portions of the TGR adrenal. This is in contrast with the Sprague-Dawley (S-D) rat, in which adrenal renin is found mostly in the active form and located primarily in the glomerulosa cells. The zonal distribution of aldosterone was also different in the TGR, with substantial amounts of aldosterone in the zona fasciculata as well as in the glomerulosa, while in the S-D rat, aldosterone is limited to the zona glomerulosa. In the primary monolayer culture of glomerulosa cells, TGR cells had significantly higher levels of active renin and prorenin and showed an increased response to ACTH and high potassium in the medium. Renin activity in the medium was predominantly in the form of prorenin and significantly higher than that in the S-D rat. Cultured fasciculata cells from TGR also produce renin that is stimulated by ACTH, but not by a high potassium concentration. Renin activity in the adrenal homogenate, medium, and plasma from TGR rats was completely inhibited by the renin inhibitor (CP 71362; 1 microM), but only slightly inhibited (12.3 +/- 3%) by a monoclonal antibody that inhibits renin activity from S-D rat tissues by 79.2 +/- 2.5%, suggesting that renin in the plasma and adrenal glands from TGR appears to derive primarily from mouse renin. In conclusion, the TGR (mRen-2)27 rats have higher than normal levels of adrenal renin, and the cultured cells show an exaggerated renin response to ACTH and potassium. The distribution of the renin enzyme in the adrenal zones of the TGR is similar to the distribution of mouse adrenal renin.