Replete Animals Research Articles

NK cells and monocytes modulate primary HTLV-1 infection.

We investigated the impact of monocytes, NK cells, and CD8+ T-cells in primary HTLV-1 infection by depleting cell subsets and exposing macaques to either HTLV-1 wild type (HTLV-1WT) or to the HTLV-1p12KO mutant unable to infect replete animals due to a single point mutation in orf-I that inhibits its expression. The orf-I encoded p8/p12 proteins counteract cytotoxic NK and CD8+ T-cells and favor viral DNA persistence in monocytes. Double NK and CD8+ T-cells or CD8 depletion alone accelerated seroconversion in all animals exposed to HTLV-1WT. In contrast, HTLV-1p12KO infectivity was fully restored only when NK cells were also depleted, demonstrating a critical role of NK cells in primary infection. Monocyte/macrophage depletion resulted in accelerated seroconversion in all animals exposed to HTLV-1WT, but antibody titers to the virus were low and not sustained. Seroconversion did not occur in most animals exposed to HTLV-1p12KO. In vitro experiments in human primary monocytes or THP-1 cells comparing HTLV-1WT and HTLV-1p12KO demonstrated that orf-I expression is associated with inhibition of inflammasome activation in primary cells, with increased CD47 “don’t-eat-me” signal surface expression in virus infected cells and decreased monocyte engulfment of infected cells. Collectively, our data demonstrate a critical role for innate NK cells in primary infection and suggest a dual role of monocytes in primary infection. On one hand, orf-I expression increases the chances of viral transmission by sparing infected cells from efferocytosis, and on the other may protect the engulfed infected cells by modulating inflammasome activation. These data also suggest that, once infection is established, the stoichiometry of orf-I expression may contribute to the chronic inflammation observed in HTLV-1 infection by modulating monocyte efferocytosis.

Controversies regarding choice of vasopressor therapy for management of septic shock in animals.

To review and appraise common vasopressor drugs used to treat septic shock-induced hypotension in volume replete animals. Human and animal publications were searched using PubMed without time limits and the following keywords were used: "vasopressor," "septic shock," "norepinephrine," "dopamine," "epinephrine," and "vasopressin." The choice of vasopressor drug is unlikely to have a marked impact on outcome, but the incidence of adverse events (eg, tachycardia) varies greatly between the various treatment options. In agreement with the 2012 Cochrane Database consensus, norepinephrine is the first-choice vasopressor to maintain a mean arterial pressure ≥65 mm Hg. If an additional agent is required, epinephrine should be administered. Low-dose vasopressin can be added to norepinephrine to either increase the arterial blood pressure to the target goal value or decrease the norepinephrine dose, but should not be used as the initial vasopressor. Dopamine is not recommended except in highly selected circumstances. There is insufficient evidence to make definitive conclusions regarding the treatment of naturally occurring septic shock, but clinical studies are underway to provide further data. The treatment of hypotension in people or animals with septic shock is challenging and vasopressor therapy is associated with a variety of adverse effects. Further research is warranted in dogs and cats to establish evidence-based guidelines.

A Choline-Deficient Diet Exacerbates Fatty Liver but Attenuates Insulin Resistance and Glucose Intolerance in Mice Fed a High-Fat Diet

Liver fat accumulation is proposed to link obesity and insulin resistance. To dissect the role of liver fat in the insulin resistance of diet-induced obesity, we altered liver fat using a choline-deficient diet. C57Bl/6 mice were fed a low-fat (10% of calories) or high-fat (45% of calories) diet for 8 weeks; during the final 4 weeks, diets were either choline deficient or choline supplemented. In choline replete animals, high-fat feeding induced weight gain, elevated liver triglycerides (171%), hyperinsulinemia, and glucose intolerance. Choline deficiency did not affect body or adipose depot weights but amplified liver fat accumulation with high-fat diet (281%, P < 0.01). However, choline deficiency lowered fasting plasma insulin (from 983 +/- 175 to 433 +/- 36 pmol/l, P < 0.01) and improved glucose tolerance on a high-fat diet. In mice on 30% fat diet, choline deficiency increased liver mRNA levels of the rate-limiting enzyme in phosphatidylcholine synthesis and of enzymes involved in free fatty acid esterification, without affecting those of de novo lipogenesis or fatty acid oxidation. We conclude that liver fat accumulation per se does not cause insulin resistance during high-fat feeding and that choline deficiency may shunt potentially toxic free fatty acids toward innocuous storage triglyceride in the liver.

Adult‐onset deficiency in growth hormone and insulin‐like growth factor‐I decreases survival of dentate granule neurons: Insights into the regulation of adult hippocampal neurogenesis

Insulin-like growth factor-I (IGF-I), long thought to provide critical trophic support during development, also has emerged as a candidate for regulating ongoing neuronal production in adulthood. Whether and how IGF-I influences each phase of neurogenesis, however, remains unclear. In the current study, we used a selective model of growth hormone (GH) and plasma IGF-I deficiency to evaluate the role of GH and IGF-I in regulating cell proliferation, survival, and neuronal differentiation in the adult dentate gyrus. GH/IGF-I-deficient dwarf rats of the Lewis strain were made GH/IGF-I replete throughout development via twice daily injections of GH, and then GH/IGF-I deficiency was initiated in adulthood by removing animals from GH treatment. Bromodeoxyuridine (BrdU) labeling revealed no effect of GH/IGF-I deficiency on cell proliferation, but adult-onset depletion of GH and plasma IGF-I significantly reduced the survival of newly generated cells in the dentate gyrus. Colabeling for BrdU and markers of immature and mature neurons revealed a selective effect of GH/IGF-I deficiency on the survival of more mature new neurons. The number of BrdU-labeled cells expressing the immature neuronal marker TUC-4 did not differ between GH/IGF-I-deficient and -replete animals, but the number expressing only the marker of maturity NeuN was lower in depleted animals. Taken together, results from the present study suggest that, under conditions of short-term GH/IGF-I deficiency during adulthood, dentate granule cells continue to be produced, to commit to a neuronal fate, and to begin the process of neuronal maturation, whereas survival of the new neurons is impaired.

A novel assay of cell rubidium uptake using graphite furnace atomic absorption: Application to rats on a magnesium-deficient diet

The [Na,K]ATPase or sodium pump (SP) is a ubiquitous membrane cation transport system. Because of its potential participation in the pathophysiology of essential hypertension and cataract formation, the SP is under active investigation to detail its function and control. In this paper, we describe a novel, nonradioactive method of measuring SP ion transport activity in intact red blood cells (RBCs) using graphite furnace atomic absorption measurement of rubidium ion (Rb) uptake. This method provided sensitivity comparable to radioactive techniques, as assessed by experiments with human red blood cells (RBC) and ouabain, a known SP inhibitor, but this analytical approach eliminates the use of radioisotopes common to other Rb uptake assay methods. As a demonstration of its broader utility, the assay was used to assess the effects of dietary magnesium intake on SP-mediated ion transport in the RBCs of diet-controlled rats. Rats on 7 weeks of a magnesium-deficient (MgD) diet showed significant reductions in serum magnesium concentration, although levels remained in the lower region of the reference interval for healthy, magnesium replete animals. Red cell Rb uptake was significantly reduced in cells from the magnesium-restricted animals, demonstrating the sensitivity of Rb uptake to reduced magnesium intake, despite serum levels that fell within the reported normal range, and the utility of this Rb uptake assay in measuring physiological changes in SP function.

Evidence for cystic fibrosis transmembrane conductance regulator-dependent sodium reabsorption in kidney, using Cftr(tm2cam) mice.

The aims of this study were to investigate (a) if renal Na(+) handling was normal in Cftr(tm2cam) delta F508 cystic fibrosis mice, (b) whether adaptation to dietary salt depletion was preserved and (c) whether Cftr(tm2cam) delta F508 mice exhibited enhanced amiloride-sensitive Na(+) absorption. In Na(+)-replete animals (maintained on a 0.32 % NaCl diet) given a 150 mM NaCl i.v. maintenance infusion, there was no difference in fractional Na(+) excretion (FE(Na)) between wild-type (0. 42 +/- 0.06 %, n = 12) and Cftr(tm2cam) delta F508 mice (0.47 +/- 0.13 %, n = 7). Amiloride infusion significantly increased FE(Na) in both wild-type (3.14 +/- 0.83 %, n = 6) and Cftr(tm2cam) delta F508 mice (3. 47 +/- 0.63 %, n = 9), though with no significant difference between genotypes. A 14 day dietary salt restriction (animals maintained on a 0.03 % NaCl diet) and maintenance infusion with a 15 mM NaCl vehicle caused a reduction in FE(Na) to 0.14 +/- 0.05 %, n = 8 in wild-type mice and 0.14 +/- 0.04 %, n = 8 in Cftr(tm2cam) delta F508 mice. No significant difference in the ability to adapt to low salt conditions was apparent comparing the two genotypes. Treatment of salt-restricted mice with amiloride resulted in a blunted natriuresis in both wild-type mice (FE(Na) = 1.10 +/- 0.16 %, n = 7) and Cftr(tm2cam) delta F508 mice (FE(Na) = 1.97 +/- 0.29 %, n = 9). The natriuresis induced by amiloride was significantly greater in Cftr(tm2cam) delta F508 mice than in wild-type controls. In conclusion, Cftr(tm2cam) delta F508 mice exhibit normal renal salt excretion when either salt replete or salt restricted. Enhanced amiloride-sensitive FE(Na) is consistent with increased Na(+) absorption via the amiloride-sensitive sodium channel ENaC, in cystic fibrosis kidney, but this was only observed during salt restriction.

The effect of vitamin D on osteoblasts and osteoclasts

Vitamin D, when administered for severe vitamin D deficiency or in large doses, stimulates osteoclastic bone resorption, presumably through a molecular interaction between recently identified receptor activator of NF-κB ligand/osteoprotegerin ligand on marrow stromal cells and receptor activator of NF-κB on osteoclast precursors. In contrast, small pharmacologic doses of active vitamin D that do not cause hypercalcemia, when administered in vitamin D–sufficient animals with high bone turnover, can suppress bone resorption while maintaining or even stimulating bone formation. In patients with severe vitamin D deficiency, the anabolic effect of vitamin D is mediated primarily through increased serum calcium, whereas active vitamin D can stimulate bone formation in vitamin D–replete animals, independently of serum calcium or parathyroid hormone level. Therefore, the effects of vitamin D on bone depend on its dosage and on the conditions under which it is administered.

Nutritional Folate Status Influences the Efficacy and Toxicity of Chemotherapy in Rats

The effect of folate status on the efficacy and toxicity of chemotherapy was investigated in weanling Fischer 344 rats maintained on diets of varying folate content or supplemented with daily injections of folic acid, 50 mg/kg, for 6 to 7 weeks. MADB106 rat mammary tumor growth rate was the same in folate replete and supplemented rats, but retarded in the low folate groups. The tumor growth inhibitions in low folate, replete and high folate rats treated with cyclophosphamide were: 53%, 98%, and 97% (P = .048); with 5-fluorouracil (5-FU): 46%, 49%, and 66%; and with doxorubicin: 25%, 55%, and 61%. Significant differences in survival were observed for cyclophosphamide (P = .0084) and 5-FU (P = .025) related to dietary folate content. Thus, folate deficiency impedes tumor growth rate, but supplementation does not accelerate it in folate replete animals. Correction of folate deficiency approximately doubles the efficacy of cyclophosphamide in rats with much less host toxicity. Folate repletion improves survival in 5-FU–treated animals. These studies indicate that nutritional folate status has an important influence on the efficacy and toxicity of some commonly used cancer chemotherapeutic drugs.

Nutritional Folate Status Influences the Efficacy and Toxicity of Chemotherapy in Rats

The effect of folate status on the efficacy and toxicity of chemotherapy was investigated in weanling Fischer 344 rats maintained on diets of varying folate content or supplemented with daily injections of folic acid, 50 mg/kg, for 6 to 7 weeks. MADB106 rat mammary tumor growth rate was the same in folate replete and supplemented rats, but retarded in the low folate groups. The tumor growth inhibitions in low folate, replete and high folate rats treated with cyclophosphamide were: 53%, 98%, and 97% (P = .048); with 5-fluorouracil (5-FU): 46%, 49%, and 66%; and with doxorubicin: 25%, 55%, and 61%. Significant differences in survival were observed for cyclophosphamide (P = .0084) and 5-FU (P = .025) related to dietary folate content. Thus, folate deficiency impedes tumor growth rate, but supplementation does not accelerate it in folate replete animals. Correction of folate deficiency approximately doubles the efficacy of cyclophosphamide in rats with much less host toxicity. Folate repletion improves survival in 5-FU–treated animals. These studies indicate that nutritional folate status has an important influence on the efficacy and toxicity of some commonly used cancer chemotherapeutic drugs.

Effect of iron deficiency anemia on lead distribution after intravenous dosing in rats.

To determine the effect of iron deficiency anemia on blood and tissue lead distribution. 24 weanling rats were divided into 2 groups. One group received an iron replete diet (200 ppm); the other received a low iron diet (20 ppm). After 24 days, each group was further subdivided into two doses of lead (5 mg/kg and 10 mg/kg) which was administered intravenously. Rats were continued on their respective diets for 7 days post-lead injection to allow tissue distribution, then sacrificed and blood and tissue lead concentration measured. Prior to lead administration, baseline blood lead concentrations were not significantly different between groups. At sacrifice, whole blood lead levels were significantly higher in iron deficient animals than in iron replete at both 5 and 10 mg/kg administered lead. Iron deficient animals had comparable lead concentrations to iron replete animals in brain, kidney and liver. Femur lead concentrations were higher at 10 mg/kg administered lead. Iron deficiency alters lead distribution such as that increased lead is found in blood for a given exposure.

The role of zinc and vitamin A in persistent diarrhea among infants and young children.

The role of zinc and vitamin A in persistent diarrhea among infants and young children.

Impact of schedule on leucovorin potentiation of fluorouracil antitumor activity in dietary folic acid deplete mice

A dietary folic acid depleted mouse model was established and used to evaluate the relationship between elevation of reduced folates after leucovorin (LV) administration and potentiation of fluorouracil (FU) response of an implanted tumor. C3H mouse mammary adenocarcinomas from mice maintained on a folic acid deplete diet had modestly decreased methylenetetrahydrofolate and tetrahydrofolate levels, and were somewhat less responsive to FU alone compared with replete animals. LV administration resulted in a substantial increase in tumor folate by 1 hr that returned to near basal levels by 12 hr. Reduced folates were elevated to a lesser extent in animals on a standard diet. Tumor growth was suppressed approximately 80% when FU was administered to depleted animals 1 hr after LV administration, compared with approximately 50% suppression in control mice. LV administered 12 hr before FU resulted in tumor growth stimulation that was consistent with the pronounced growth stimulation when LV was administered without FU. These results show that dietary folic acid depletion can lead to a more responsive FU/LV model and that administration of LV at an improper time before FU not only can fail to potentiate but also can result in tumor growth stimulation.

Converting enzyme inhibition in rabbits: Effects on sodium and water intake/excretion and blood pressure

Earlier studies in rabbits revealed that in this species, in contrast to most other species studied, water intake was not influenced by injection or infusion of angiotensin II (ANG II). In order to establish whether ANG II has any role in the regulation of water intake of rabbits, a comprehensive study of the effect of converting enzyme inhibition was undertaken. Enalaprilat was given systemically in various doses to sodium- and water-replete, sodium-deplete, and water-deprived rabbits, and the intake and excretion of water and sodium was measured. In replete rabbits systemic injection of enalaprilat, 8 mg/kg and 8 μg/kg, but not 0.8 mg/kg, was followed by increased daily water intake. In sodium-deplete rabbits injection of enalaprilat, 80 mg/kg, was followed by water drinking within 1 h, and daily sodium intake was reduced. Systemic administration of ANG II increased, but did not restore to control level the sodium appetite of sodium-deplete rabbits attenuated by 80 mg/kg enalaprilat. Rabbits deprived of water for 24 h, however, drank the same amount of water after injection of vehicle or enalaprilat, 80 and 8 mg/kg. The efficacy of converting enzyme inhibition was also tested by measuring the blood pressure response to ANG I. Blood pressure responses revealed that in replete animals converting enzyme activity was depressed below control levels for 30 h after injection of 80 mg/kg enalaprilat. In sodium-deplete rabbits blood pressure fell following injection of 80 mg/kg enalaprilat and did not return to control level until 48 h after the injection. These results indicate that in rabbits, similar to other species studied, ANG II plays a role in the regulation of water intake, though probably through mechanisms that are not as well developed or used in other species. Further results suggest that rabbits react to the combination of converting enzyme inhibition and Na-depletion similar to hypertensive patients in regards to renal complications.

A concise review: Iron absorption—The mucin‐mobilferrin‐integrin pathway. A competitive pathway for metal absorption

Newly identified iron binding proteins isolated from rat duodenal homogenates permit better understanding of iron absorption. Mucins bind iron at acid pH to keep iron soluble and available for absorption at the more alkaline pH of the duodenum; this explains iron deficiency following prolonged achlorhydria. Integrin (90/150 kD) was identified on the absorptive surface of enterocytes in association with radioiron and is believed to facilitate transit of iron through the microvillous membrane. Mobilferrin, a 56 kD iron binding protein, was isolated from enterocyte cytosol. It coprecipitates with integrin and appears in close association with integrins in the apical cytoplasm. We postulate it accepts dietary iron from integrin and acts as the shuttle protein for iron in the cytoplasm. Since iron in enterocytes remains in equilibrium with body stores, we postulate mucosal iron uptake is regulated by the number of iron binding sites either occupied or unoccupied by iron on mobilferrin. Iron repletion of enterocytes from body stores is accomplished via transferrin receptors on the posterolateral membranes of enterocytes. Increased transfer of iron from blood into absorptive enterocytes occurs in iron replete animals to inhibit mucosal uptake of dietary iron. Little transfer of iron from plasma to enterocytes occurs in iron deficiency. Enhanced mucosal transfer of iron into the body occurs with increased body need for iron. The exact mechanism for mucosal transfer of iron into the plasma has not been defined but may also be mediated by an integrin.

A contrarian view of the wisdom of the body as it relates to dietary self-selection.

The history of studies of dietary self-selection in cafeteria-feeding situations is reviewed briefly. The evidence is not consistent with the view that replete animals can reliably compose a nutritionally adequate diet from an array of food in a cafeteria situation. Similarly, the evidence is not consistent with the view that when deficient in a nutrient (excepting the case of sodium and, perhaps, of phosporus), animals can reliably select a nutritionally adequate diet when it is present among several deficient diets. General acceptance of the view that omnivores can easily self-select nutritionally adequate diet is attributed both to overreliance on theory and to lack of critical attention to data. The adequacy of functional arguments suggesting that omnivores must be able to self-select nutritionally adequate diets is questioned.

Taste responses in the nucleus tractus solitarius of sodium-deprived rats.

1. Maintenance of sodium balance is crucial to mammals and is expressed in the innate salt appetite. With depletion, sodium preference is exaggerated, hypertonic solutions accepted and salt balance restored. This compensatory behaviour is thought to result from a centrally induced change in taste responsiveness. This proposal was tested by recording taste activity from ninety-four single neurones in the nucleus tractus solitarius of sodium-replete (N = 44) and of deprived (N = 50) rats. Twelve Wistar rats were given a nominally sodium-free diet for 10-13 days, and the resulting sodium depletion confirmed by flame photometry of their urine. Nine rats provided control data. Taste stimuli included five concentrations of NaCl (0.003-0.3 M) plus eight other salts, acids, sugars and alkaloids. 2. Taste responsiveness was generally reduced in sodium-depleted rats. Spontaneous activity was 33% lower while responses to sodium salts lagged by a mean of 30%, to acids by 25% and to bitter salts and quinine by 17%. Mean activity to sugars was 60% higher in the deprived group. 3. Activity in sugar- and salt-profile neurones was most affected. In deprived animals responses to sodium salts were lower by 80% among salt-profile cells while among sugar-profile neurones activity to these stimuli was nearly 10 times greater than in controls. These changes in activity resulted in a dramatic shift in the participation of sodium- and sugar-profile cells in the afferent signal for NaCl. In replete animals 60% of sodium-induced activity was transmitted through salt-profile cells while only 1% occurred in sugar-profile neurones. In deprived subjects this situation was nearly reversed as 7% of the total NaCl response was conveyed through salt-profile cells while the contribution of neurones with sugar-profiles rose to 46%. 4. Multidimensional stimulus spaces based on average activity in each of four identifiable neurone subgroups demonstrated a shift in the affiliation of sodium salts away from bitter and acid stimuli and towards sugars. 5. These results confirm earlier findings from the chorda tympani that sodium deprivation suppresses activity evoked by sodium salts. However the application of more recent analytical procedures permits quite a different interpretation of this finding. The overall decrease is merely the net effect of a shift in the major responsibility for encoding sodium from salt-profile neurones to those whose primary sensitivity is to sugars.(ABSTRACT TRUNCATED AT 400 WORDS)

The role of angiotensin II in the antidiuresis and antinatriuresis induced by stimulation of the sympathetic nerves to the rat kidney.

1 Stimulation of the renal sympathetic nerves in pentobarbitone anaesthetized rats at low frequencies, which did not statistically change renal blood flow and glomerular filtration rate, significantly reduced urine flow by 35%, absolute sodium excretion by 44% and fractional sodium excretion by 40%. 2 In rats fed a low sodium diet for 2 to 3 weeks, similar renal nerve stimulation caused no consistent changes in renal haemodynamics but decreased urine flow by 38%, absolute sodium excretion by 44% and fractional sodium excretion by 38%, which were identical responses to those obtained in sodium replete animals. In contrast, stimulation of the renal nerves in sodium depleted rats given a constant infusion of captopril at 500 micrograms/kg/h had no statistically significant effect on either water or sodium excretion. 3 Renal nerve stimulation in rats given saline to drink and DOCA for 2 to 3 weeks did not significantly change either renal haemodynamics or the output of water or sodium. However, in other animals maintained on a high salt intake but given a constant infusion of angiotensin II (20 ng/kg/min), renal nerve stimulation caused minimal changes in renal haemodynamics but significantly reduced urine flow by 41%, absolute sodium excretion by 54% and fractional sodium excretion by 49%. 4 These results show that the neurally-mediated tubular responses require the presence of a minimal circulating level of angiotensin II since, when its production is blocked, either acutely or chronically, the renal nerve-induced antinatriuresis and antidiuresis is inhibited but can be restored by the infusion of angiotensin II. These findings provide direct evidence that angiotensin II has an important potentiating action at the renal nerve junctions, most probably at the epithelial cells of the renal tubule.

The contribution of PGI2 to the effects of captopril in conscious dogs in differing states of sodium balance

There is some evidence that increased prostaglandin synthesis may mediate some of the effects of the angiotensin converting enzyme inhibitor captopril. The potential role of prostaglandin (PG)I2 in this process was assessed by measurement of changes in urinary 6-keto-PGF1 alpha excretion after captopril in eight sodium replete and depleted conscious dogs. In sodium replete animals captopril induced a small decrease in blood pressure, transient increases in effective renal plasma flow and urinary 6-keto-PGF1 alpha excretion, and progressive increases in plasma renin activity (PRA) and urinary sodium excretion. By contrast, during sodium depletion captopril induced a large decrease in blood pressure, a transient increase in effective renal plasma flow and urinary 6-keto-PGF1 alpha excretion, an early large but transient increase in PRA and small progressive increase in sodium excretion. The time course of changes after captopril suggested that increased PGI2 synthesis may contribute to the transient decrease in renal vascular resistance. The increase in PRA during sodium depletion was not associated with any change in urinary 6-keto-PGF1 alpha excretion.

Augmented plasma renin levels in dehydrated sheep with periventricular lesions

Ablation of tissue in the midline anterior wall of the third ventricle (AV3V) of sheep did not consistently alter baseline plasma renin concentration (PRC) in water replete animals, but caused a greatly augmented increase in PRC in response to water deprivation. PRC might increase in these sheep in order to maintain blood pressure, however it is possible that a central inhibitory influence on renal renin release, operative during dehydration, is disrupted by AV3V-lesions.

Comparison of the Actions of the Angiotensin-Converting Enzyme Inhibitors Enalapril and S-9490-3 in Sodium-Deplete and Sodium-Replete Spontaneously Hypertensive Rats

The hypotensive action of the angiotensin-converting enzyme (ACE) inhibitors enalapril and S-9490-3 was examined in conscious, chronically cannulated Na+-replete and Na+-deplete spontaneously hypertensive rats (SHR) of the Okamoto strain. Blood pressure, plasma ACE activity, plasma renin activity (PRA), and pressor responses to intravenous bolus injections of angiotensin I (AI) were measured over a 24-h period following a single oral dose of ACE inhibitor (0.3, 1.0, and 3.0 mg/kg) or vehicle. S-9490-3 caused a significantly greater hypotensive response and inhibition of plasma ACE and AI pressor responses than enalapril for each dose in both diet groups. Single oral doses of both drugs (3 mg/kg) caused slow, progressive falls in blood pressure which were maximal at 12 h. In contrast, inhibition of plasma ACE was maximal 1 h following the oral dose and returned to control levels over the 24-h period. The inhibition of the pressor response to intravenous AI paralleled, and was significantly correlated with, the inhibition of plasma ACE. There was no correlation between the maximal fall in blood pressure with PRA or with inhibition of plasma ACE activity in either diet group. The hypotensive response to both drugs at the 3-mg/kg dose was greater in Na+-deplete SHR than in Na+-replete animals. Both drugs caused large rises in PRA. The ACE inhibitor S-9490-3 is a significantly more potent hypotensive agent than enalapril in the SHR and a significantly more potent ACE inhibitor in vivo. The hypotensive response to both drugs was dissociated in onset and duration from the inhibition of plasma ACE and AI pressor responses.