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The role of the renin-angiotensin-aldosterone system in the development of cardiac fibrosis was investigated in a murine model of mineralocorticoid excess. Morphological and biochemical analyses revealed that aldosterone rather than the renin-angiotensin system contributes to cardiac fibrosis. Aldosterone induced increases in blood pressure and collagen levels by binding mineralocorticoid receptors.

The effects of sodium depletion on the production of renal bradykinin (BK) were analyzed in conscious uniephrectomized dogs by utilizing the ACRIP renin inhibitor and losartan. The elevated levels of bradykinin in the renal interstitial fluid (RIF) during sodium depletion were reduced by the ACRIP non-specific renin inhibitor but it was not altered by losartan. Furthermore, the activity of the renin-angiotensin system during sodium depletion regulated the levels of RIF BK, cyclic guanosine monophosphate and prostaglandin E2.

The renin-angiotensin system plays an important role in the regulation of blood circulation and sodium fluid balance. In a study of male rats, hearts from infarcted animals showed an increase in renin mRNA in the infarcted left ventricle two to seven days after myocardial infarction (MI). There were no differences in angiotensin mRNA levels in infarcted and sham animals. In situ hybridization showed high renin mRNA levels around the infarcted area, and a twofold increase in atrial natriuretic factor mRNA. These results indicate that renin plays an important role in infarct healing and not in the development of MI.

The effect of captopril, an angiotensin-converting enzyme (ACE) inhibitor, on remodeling of the components of the myocardium was investigated in a rat model of cardiac hypertrophy. Minimal coronary resistance (MCR) and mean arterial pressures (MAP) was measured in sham rats and captopril-treated rats. Treated rats showed decreased femoral MAP compared to sham controls, but carotid MAP was significantly higher in untreated and treated rats than sham rats. Total heart weight and left ventricular weight-to-body weight ratios, and MCR were higher in untreated and treated rats than sham rats. Captopril treatment had no effect on medial thickness.

The response of the renal renin-angiotensin system to angiotensin (ANG) I and ANG II was investigated in moderately hyperglycemic diabetic rats. Intravenous studies revealed increases in mean arterial pressure (MAP) in both diabetic rats and controls, but only diabetic rats showed a decrease in glomerular filtration rate. Both groups showed a decline in renal plasma flow, but the decrease was greater in diabetic rats. In contrast, intra-arterial studies revealed showed no differences in MAP before and after ANG treatment. Renal hemodynamics were identical to those seen in the intravenous studies. These results indicate that response to ANG is mediated by the renal rather than the systemic pathways in diabetic rats.

Immunocytochemical techniques revealed an intracellular a renin-angiotensin system (RAS) in rat adrenal glomerulosa cells. Preabsorption study identified renin at two distinct sites within the cells: at membrane-bound vesicle-like structures, and within the mitochondria of the zona glomerulosa. Bilateral nephrectomy and hemodialysis separated the components of the RAS system and increased intradrenal renin concentration, indicating that renin is localized in the adrenal cells. Also detected in these cells were the angiotensin-converting enzyme and angiotensin.

Regulation of the human renin (hREN) gene was investigated in a model using a human pulmonary carcinoma cell line (Calu-6) expressing this gene. Transfection analysis ofhREN constructs identified multiple weak regulatory elements in the 5'-flanking region and a classic silencer element in the first intron of the coding region. Hybridizations and nuclear runoff transcription showed that forskolin induces a 100-fold increase in hREN mRNA levels but not in hREN promoter activity. These results suggest that hREN expression in Calu-6 cells is mediated by transcriptional and posttranscriptional mechanisms.

The role of the renin-angiotensin system in renal hemodynamics with relation to posture was investigated in the dog. Plasma renin activity increased twofold when dogs were standing. Standing had no effects on mean arterial pressure, heart rate and plasma norepinephrine concentration. Glomerular filtration rate and renal plasma flow declined when dogs were standing, whereas filtration fraction increased. These results suggest that standing causes an activation of the renin-angiotensin system.

Cell proliferation in the adrenal gland of rats was investigated as uptake of 5-bromo-2'-deoxyuridine (BrdUrd) in the nuclei. Rats were randomized into three treatment groups: angiotension II (ANG II) infusion, dietary sodium intake and angiotensin-converting enzyme (ACE) inhibition. ANG II and sodium restriction increased BrdUrd uptake, caused hypertrophy of the zona glomerulosa and the proliferation of zona reticularis epithelial cells. ACE inhibitor captopril increased BrdUrd uptake in the medulla, caused atrophy of glomerulosa but had no effect on zonae intermediae and fasciculata. ANG II also inhibited uptake in the medulla. Data suggests that ANG II, ACE inhibitors and dietary sodium influence cell proliferation.

The rise in blood pressure caused by the air-jet stress is induced by the sympathetic nervous system rather than the renin-angiotensin system. However, both the systems are synergetically involved in the heart rate and blood pressure variability changes related to stress. Prazosin inhibits blood pressure rises and blood pressure variability changes. Losartan decreases blood pressure response to air-jet stress in spontaneous hypertensive rats but is ineffective in Wistar-Kyoto rats. It abolishes blood pressure and heart rate variability changes in both strains.

The effects of uninephrectomy (UNX) on the pathophysiological regulation of the renal system in relation to the role of angiotensin II were investigated in the rat. The results suggested differential regulation of the circulating, juxtaglomerular, glomerular, and proximal tubule renin systems following UNX. The differences are related to the effect of increased ANG II secretion in the kidneys after UNX.

Angiotensin II (ANG II) receptors mediate the effects of ANG on renal structures such as the glomeruli and preglomerular vessels through changes in the renin-angiotensin system (RAS). These changes may be induced by sodium intake and ANG II infusion. The preglomerular vessels are regulated by the effects of ANG II through specific nonpeptide antagonist AT1 receptors, which respond to changes in endogenous RAS. On the other hand, glomerular ANG II receptors are regulated by sodium restriction.

Conscious rats were treated with inhibitors of nitric oxide synthase and cyclooxygenase to determine the role of nitric oxide (NO) and prostaglandins (PG) in the signaling mechanism by which the macula densa regulates renin synthesis and secretion in juxtaglomerular cells. The results show that NO and PG are involved in the regulation of renin gene expression, but only NO is required for macula densa-induced renin secretion.

White adipose tissue is a rich source of angiotensinogen protein and mRNA. Studies in clonal cells suggest that angiotensinogen, and its cleavage product, angiotensin II, are involved in preadipocyte differentiation into mature fat cells. No studies have determined whether angiotensinogen is also involved in adipose tissue development in vivo. In this report, we studied male Wistar rats at two stages of development to determine if angiotensinogen protein and mRNA are increased in retroperitoneal fat depots of rapidly growing young, lean, 8-week-old rats compared to 26-week-old rats that are fatter, but are undergoing less rapid adipose tissue growth. We also assessed renin mRNA and angiotensin I-generating activity, since it is less clear whether renin is locally produced in adipose tissue. We found that angiotensin I-generating activity was measurable in adipose tissue and adipocytes, but renin mRNA was undetectable by Northern blot analysis. Angiotensinogen mRNA was abundant in adipocytes, but was absent in stromal-vascular cells of adipose tissue. Angiotensinogen content per 10 million fat cells was threefold higher in 8-week-old rats compared to 26-week-old rats (p

Glomerular micropuncture and whole kidney clearance analyses of the influence of selective A1 receptor blockade on glomerular hemodynamics in rats reveal that the genous renin-angiotensin system plays a vital role in the glomerular functions and mediates adenosine effects on them. The receptor antagonist increases sodium and urine discharge and the Kf values. Losartan pretreatment inhibits antagonist-induced urine and sodium discharge increases.

Reverse transcriptase polymerse chain reaction (PCR) and Southern blot analyses of the effects of aortocaval shunt-induced volume overload on cardiac renin gene reveal that volume overload induces reproducible stretch-mediated hypertrophy of the cardiac muscle and an increase in cardiac renin gene expression. The effects of volume overload suggest the presence of a myocardial renin-angiotensin complex, which is sensitive to locally generated renin. Shunt surgery increases renin functions in the left ventricle and plasma by two- and four-folds.

Study of renin secretion in sheep indicates that renal nerves are essential for renin response to renal perfusion pressure reductions. Lowered arterial blood pressure may cause the increased plasma renin activities observed during pregnancy. Bitateral renal vein catheters and a unilateral renal denervated preparation are used.

Studies on bilaterally nephrectomized rats were conducted to test the hypothesis that increases in plasma angiotensinogen is regulated after nephrectomy by endogenous renin and angiotensin (ANG) II. It was observed that an increase in plasma angiotensinogen after nephrectomy is regulated by ANGII through an undefined adrenal factor. It was suggested that this process is activated by renin expressed during surgery.

A genetically growth hormone (GH)-deficient strain of Lewis rats were used to examine the assumption that the renin-angiotensin-aldosterone system (RAAS) mediates the influence of GH on electrolyte and fluid homeostasis. Saline-injected dwarf and normal Lewis rats were compared with dwarf rats, injected with recombinant bGH for 7 days and 28 days respectively. Interactions with RAAS cascade at the source and the area of action of angiotensin II are parts of the influence of GH on electrolytes and the fluid.

The mediation of angiotensin (ANG) II depressor action by the activation of angiotensin receptor subtype 2 (AT2) was examined. Arterial pressure and maximum changes in pressure from control were the parameters measured in thiobutabarbital anesthetized rats subjected to bolus injections of angiotensin III. The mediation of depressor response to ANG by AT2 receptors was demonstrated.

Changes in the systemic and renal adaptation to dietary sodium restriction of the renin-angiosten system due to age were investigated. Mean arterial pressure and plasma renin activity were monitored in 10-, 20- and 30-month old female rats prior to and during sodium restricted diets. The relationship of dietary sodium restriction to arterial pressure and sodium conservation was established.

Changes in the renin-angiotensin (ANG) and kallikrein-kinin systems in the rat due to prolonged unilateral ureteral obstruction (UUO) were investigated. Experiments involved the monitoring of systolic blood pressure in the conscious state throughout the duration of the study and the measurerement of circulating and renal ANG peptides by specific radioimmunoassays. The role of ANG in UUO-induced hypertension was established.

The effect of the angiotensin-converting enzyme inhibition and glomerular hemodynamics in aortocaval and atrioventricular (AV) fistula rats with high-cardiac-output failure using micropunctures in the abdominal aorta and inferior vena cava were investigated. The creation of AV fistula and simulation of mild and moderately severe cardiac failure through micropunctures were used to create an animal model for studies of heart failure and cardiac hypertrophy.

The effect of endogenous angiotensin II on the increase in hematocrit induced by atrial natriuretic peptide (ANP) was examined on nephrectomized rats. Endogenous angiotensin II modulated the effect of ANP on vascular permeability. This was attributed to the supression of angiotensin II generation and antagonism of its receptors which abolishes the effect of ANP on hematocrit. The result suggests a possible role for tissue renin-angiotensin interaction in controlling endogenous ANP on transcapillary shift and formation of edema.

Interactions of renal nerves with atrial natriuretic factor (ANF) and mineralocorticoids in sodium balance regulation were studied using dogs with arteriovenous (AV) fistula and high-output heart failure (HOHF) syndrome. Observations indicate that mineralcorticoids control sodium retention in HOHF, leading to the conclusion that inhibition of efferent renal sympathetic nerve activity restores natriuretic effect of acute increase in circulating ANF.

Binding properties of angiotensin (ANG) II receptors in proximal tubules (PT) were studied and rabbit PT ANG II receptors cloned using nonpeptide antagonists cortical basolateral and brush-border membranes. Sodium transport was inhibited by maximal concentrations of ANG II and inhibited by low ANG II levels indicating regulatory functions on apical sodium-hydrogen ion exchange. Results confirm the presence of ANG II receptors in the proximal tubule suggesting a single gene encoder for AT1 ANG II receptor in rabbits.

The renin-angiotensin system of kidney-related hormones and enzymes is known to be intimately involved in the control of blood pressure, and drugs that influence this system are undergoing careful scrutiny as antihypertensive (blood pressure-lowering) agents. Many of the drugs that are widely prescribed today act by inhibiting the conversion of an inactive form of the vasoconstrictor angiotensin to an active form (angiotensin converting-enzyme, or ACE inhibition). Recently, drugs that block the biological effects of renin (an earlier step in the metabolic pathway) have also been evaluated. Although both classes of drugs are known to have potent antihypertensive effects, little is known about the comparative efficacy of renin inhibitors and ACE inhibitors. To compare the antihypertensive effects of the renin inhibitor enalkiren with those of the ACE inhibitor enalaprilat, a study was carried out involving 17 patients with high blood pressure (14 white and 3 black; average age 57 years). This group of patients was expected to be particularly responsive to drugs interacting with the renin-angiotensin system, having just completed a course of diuretic treatment that stimulates this hormonal pathway. Patients were studied on three separate in-hospital test days; they were given inactive placebo, enalkiren, or enalaprilat. In all cases, the renin inhibitor (enalkiren) was at least as effective as the ACE inhibitor (enalaprilat) in reducing blood pressure; when patients were grouped into ''high-renin'' and ''low-renin'' populations, based on prestudy blood levels of this enzyme, the ''high-renin'' patients were found to be more responsive to enalkiren than to enalaprilat. (Consumer Summary produced by Reliance Medical Information, Inc.)

The kidney regulates blood pressure by several mechanisms, including the renin-angiotensin-aldosterone system, which affects vasoconstriction (constriction of blood vessels), sodium excretion, and other factors. To learn more about the role of the kidney in the development of high blood pressure (hypertension), a study was performed with young people (aged 7 to 32) who were at high or low risk of developing hypertension based on their family histories. Research has shown that a person's risk of developing hypertension is related to the blood pressure of his parents: those with hypertensive parents are at greater risk than those with parents who are normotensive (have normal blood pressure). Several aspects of kidney (renal) function were measured in the subjects, who did not yet have hypertension. The goal was to study early, subtle factors that might be involved in the genesis of the disorder. A variety of tests were carried out on 41 subjects with two normotensive parents; 52 subjects with one normotensive and one hypertensive parent; and 61 subjects with two hypertensive parents. Results showed that the subjects in the latter group had higher systolic and diastolic blood pressures (the top and bottom number of a blood pressure reading) than those in the other two groups. Test results are presented for a variety of measurements, including renal blood flow, glomerular filtration rate (the rate at which the kidney filters fluid from the blood), blood levels of renin, aldosterone, and angiotensin, and other factors. In summary, subjects with hypertensive parents had lower renal blood flow, lower renin activity in the blood, and lower blood levels of renin and aldosterone than those with normotensive parents. Test values of the subjects with one normotensive and one hypertensive parent usually fell in between the other two groups. Although the mechanisms responsible for these differences have not been identified, the results show that changes in kidney hemodynamics in the direction of hypertension occur early in life in people at risk for the disorder. (Consumer Summary produced by Reliance Medical Information, Inc.)

High blood pressure is a well established risk factor for heart disease and stroke. However, patients with hypertension are a heterogeneous group, and within this group there is wide variation for both the risk of disease and the response to therapy. Research conducted over 15 years ago indicated that the renin-sodium profile might be an important prognostic determinant of the risk of heart attack in patients with hypertension. In 1981, a study to prospectively confirm the prognostic importance of the renin-sodium profile was begun involving 1,717 patients with mild or moderate hypertension. Renin is a key hormone involved in the regulation of blood pressure, but the absolute renin level in the blood plasma is less informative than the relationship between the plasma level of renin and the rate of excretion of sodium by the kidneys; this is the renin-sodium profile. When the renin-sodium profiles were determined for the study patients, 12 percent were higher than average, 56 percent were classified within the normal ranges, and 32 percent were low. In a period of 8.3 years, 27 heart attacks were observed in the patient population. When the statistics were adjusted for variations due to race and sex, the rate of hear attacks was found to be 14.7 per 1,000 person-years in the high profile group, 5.6 in the normal profile group, and 2.8 among the patients with a low renin-sodium profile. A similar relation was not observed for stroke. When the prognostic value of the renin-sodium profile was compared with other known prognostic indicators such as body-mass index (a measure of obesity), history of cardiovascular disease, high blood sugar or blood pressure, it was found that the renin-sodium index was, in fact, independent of these other factors. It remains to be determined how the renin-sodium profiles measured during treatment might be applied to clinical practice. (Consumer Summary produced by Reliance Medical Information, Inc.)

Neuropeptide Y (NPY) depolarizes the arterioles and enhances Ca2+ influx through voltage-dependent channels resulting in direct vasoconstriction of blood vessels. NPY also stimulates vasoactive compounds and electrical nerve endings thereby initiating secondary indirect vasoconstriction of the arterial blood vessels. Additionally, NPY inhibits the release of renin which is secreted in response to various stimuli. The physiological effects of the peptide is indicative of its applicability as a new cardiovascular agent.

The active kidney enzyme renin is produced from an inactive form, prorenin, that transforms the liver protein angiotensinogen to angiotensin I, which is then converted by angiotensin-converting enzyme to angiotensin II. This factor, angiotensin II, constricts blood vessels and activates the production and release of the adrenal hormone aldosterone, which regulates sodium, potassium, and chloride metabolism. Prorenin is also secreted into the blood, and has been shown to be elevated in patients who have insulin-dependent diabetes mellitus (IDDM, sugar diabetes requiring insulin injections). Microvessel disease normally begins in patients with IDDM approximately five years after the onset of their disease. Changes in the vessels of the eye frequently lead to retinal disease or retinopathy, which can lead to blindness. Similar changes in the kidney make diabetic patients liable for severe kidney disease which can become end-stage, i.e. resulting in nonfunctional kidneys. Blood levels of the hormone precursor (as indicated by angiotensin activity) were measured in a group of 135 children and adolescent IDDM patients, and 54 similarly aged nondiabetic control subjects. Increased levels of blood prorenin activity were detected in children with diabetic complications. In this experiment the blood levels of 14 adolescent IDDM patients, who did not have measurable levels of urinary albumin, had blood levels of prorenin approximately twice those seen in normal children. Adolescent IDDM patients who demonstrated diabetic complications (urinary albumin or retinopathy) had significantly higher prorenin than those patients who did not exhibit such diabetic changes. When plasmal prorenin levels were elevated, kidney or retinal pathology developed more rapidly. The study shows that high blood levels of prorenin indicate a high risk of impending diabetic complications. (Consumer Summary produced by Reliance Medical Information, Inc.)

Polycystic kidney disease is characterized by the development of many cysts, sac-like structures that contain fluid or solid material, in the kidney. Hypertension (high blood pressure) is found in 50 to 75 percent of patients with this disorder and has been putatively linked to inadequate blood flow (ischemia) to the kidney caused by compression of the renal vessels by cysts. This study investigates the possibility that hypertension in polycystic kidney disease is produced by pathologic alterations of the renin-angiotensin-aldosterone system. The active kidney enzyme renin is produced from an inactive form, prorenin, that transforms the liver protein angiotensinogen to angiotensin I, which is then converted by angiotensin-converting enzyme to angiotensin II. This factor, angiotensin II, constricts blood vessels and activates the production and release of the adrenal hormone aldosterone, which regulates sodium, potassium, and chloride metabolism. Through a prospective study of polycystic kidney disease, patients' blood and urine levels of these hormones and other factors have been measured and related to blood pressure readings. Various drugs that block specific metabolic steps in this hormonal system were used to identify elements of the system that affected hypertension. The renin-angiotensin-aldosterone system is found to be significantly stimulated in hypertensive polycystic kidney disease patients. Increased renin release may be related to kidney ischemia. (Consumer Summary produced by Reliance Medical Information, Inc.)