Left ventricular finite element model bounded by a systemic circulation model.

A series of models were developed in which a circulatory system model was coupled to an existing series of finite element (FE) models of the left ventricle (LV). The circulatory models were used to provide realistic boundary conditions for the LV models. This was developed for the JSim analysis package and was composed of a systemic arterial, capillary, and venous system in a closed loop with a varying elastance LV and left atria to provide the driving pressures and flows matching those of the FE model. Three coupled models were developed, a normal LV under normotensive aortic loading (116/80 mm Hg), a mild hypertension (137/89 mm Hg) model, and a moderate hypertension model (165/100 mm Hg). The initial step in the modeling analysis was that the circulation was optimized to the end-diastolic pressure and volume values of the LV model. The cardiac FE models were then optimized to the systolic pressure/volume characteristics of the steady-state JSim circulatory model solution. Comparison of the stress predictions for the three models indicated that the mild hypertensive case produced a 21% increase in the average fiber stress levels, and the moderate hypertension case had a 36% increase in average stress. The circulatory work increased by 18% and 43% over that of the control for the mild and moderate hypertensive cases, respectively.

Vascular mechanics of the coronary artery.

UNLABELLED: This paper describes our research into the vascular mechanics of the coronary artery and plaque. The three sections describe the determination of arterial mechanical properties using intravascular ultrasound (IVUS), a constitutive relation for the arterial wall, and finite element method (FEM) models of the arterial wall and atheroma. METHODS: Inflation testing of porcine left anterior descending coronary arteries was conducted. The changes in the vessel geometry were monitored using IVUS, and intracoronary pressure was recorded using a pressure transducer. The creep and quasistatic stress/strain responses were determined. A Standard Linear Solid (SLS) was modified to reproduce the non-linear elastic behavior of the arterial wall. This Standard Non-linear Solid (SNS) was implemented into an axisymetric thick-walled cylinder numerical model. Finite element analysis models were created for five age groups and four levels of stenosis using the Pathobiological Determinants of Atherosclerosis Youth (PDAY) database. RESULTS: The arteries exhibited non-linear elastic behavior. The total tissue creep strain was epsilon creep = 0.082 +/- 0.018 mm/mm. The numerical model could reproduce both the non-linearity of the porcine data and time dependent behavior of the arterial wall found in the literature with a correlation coefficient of 0.985. Increasing age had a strong positive correlation with the shoulder stress level, (r = 0.95). The 30% stenosis had the highest shoulder stress due to the combination of a fully formed lipid pool and a thin cap. CONCLUSIONS: Studying the solid mechanics of the arterial wall and the atheroma provide important insights into the mechanisms involved in plaque rupture.

Chronic regulation of arterial blood pressure in ANP transgenic and knockout mice: role of cardiovascular sympathetic tone.

OBJECTIVE: Atrial natriuretic peptide (ANP) lowers arterial blood pressure (ABP) chronically, in association with vasodilation of the resistance vasculature. The mechanism mediating the chronic relaxant effect of ANP is likely indirectly mediated by interactions with tonic vasoeffector mechanisms, inasmuch as the resistance vasculature is relatively insensitive to direct cGMP-mediated relaxation by ANP. On the basis of evidence that ANP has widespread sympatholytic activity, the current study investigated whether the chronic hypotensive effect of ANP is mediated by attenuation of tonic cardiovascular sympathetic tone. METHODS: Total plasma catecholamine concentration and changes in basal ABP and heart rate (HR) following autonomic ganglionic blockade were measured as indices of underlying sympathetic nerve activity in hypotensive ANP-overexpressing transgenic mice (TTR-ANP), hypertensive ANP knockout mice (-/-) and the genetically-matched wild type (NT and +/+, respectively) control mice. Pressor and chronotropic responses to norepinephrine infusion were measured in ganglion-blocked mice of all genotypes, and norepinephrine receptor binding was assessed in representative tissues of -/- and +/+ mice, in order to determine whether peripheral adrenergic receptor responsiveness is altered by ANP-genotype. RESULTS: Basal ABP was significantly lower in TTR-ANP and higher in -/- compared to their wild-type controls. Basal HR did not differ significantly between mutant and control mice. Autonomic ganglionic blockade reduced ABP and HR in all genotypes, however, the relative decrease in ABP was significantly smaller in TTR-ANP and greater in -/- mice than in their respective controls. Total plasma catecholamine was significantly higher in -/- than in +/+ mice but did not differ significantly between TTR-ANP and NT mice. Norepinephrine infusion during ganglionic blockade elicited quantitatively similar pressor and chronotropic responses in mutant and control mice. Tissue norepinephrine binding did not differ significantly between -/- and +/+ mice. CONCLUSIONS: The present study shows that differences in endogenous ANP activity in mice, resulting in chronic alterations in ABP are accompanied by directional changes in underlying cardiovascular sympathetic tone, and suggests that the chronic vasodilator effect of ANP is, at least partially, dependent on attenuation of vascular sympathetic tone, possibly at a prejunctional site(s).

Salt-sensitive hypertension in ANP knockout mice is prevented by AT1 receptor antagonist losartan.

Mice harboring a functional deletion of the pro-atrial natriuretic peptide (ANP) gene (-/-) develop salt-sensitive hypertension relative to their wild-type (+/+) counterparts after prolonged (>1 wk) maintenance on high-salt (HS, 8% NaCl) diet. We reported recently that the sensitization of arterial blood pressure (ABP) to dietary salt in the -/- mice is associated with failure to downregulate plasma renin activity. To further characterize the role and mechanism of ANG II in the sensitization of ABP to salt in the ANP "knockout" mice, we measured ABP, heart rate (HR), and plasma catecholamine and aldosterone concentrations in -/- and +/+ mice maintained on HS for 4 wk and treated with daily injections of AT1 receptor antagonist DuP-753 (losartan) or distilled water (control). Daily food and water intake and fluid and electrolyte excretion were also measured during the first and last weeks of the dietary regimen. Cumulative urinary excretion of fluid and electrolytes did not differ significantly between genotypes and was not altered by chronic treatment with losartan. Basal ABP and HR were significantly elevated in control -/- mice compared with control +/+ mice. Losartan did not affect ABP or HR in +/+ mice, but reduced ABP and HR in the -/- mice to the levels in the +/+ mice. Total plasma catecholamine was elevated by approximately ten-fold in control -/- mice compared with control +/+ mice. Losartan reduced plasma catecholamine concentration significantly in -/- mice and abrogated the difference in plasma catecholamine between -/- and +/+ mice on HS diet. Plasma aldosterone did not differ significantly between genotypes and was not altered by losartan. We conclude that salt sensitivity of ABP in ANP knockout mice is mediated, at least in part, by a synergistic interaction between ANG II and sympathetic nerve activity.

Chronic hypertension in ANP knockout mice: contribution of peripheral resistance.

Atrial Natriuretic Peptide (ANP) exerts a chronic hypotensive effect which is mediated by a reduction in total peripheral resistance (TPR). Mice with a homozygous disruption of the pro-ANP gene (-/-) fail to synthesize ANP and develop chronic hypertension in comparison to their normotensive wild-type (+/+) siblings. In order to determine whether alterations in basal hemodynamics underlie the hypertension associated with lack of endogenous ANP activity, we used anesthetized mice to measure arterial blood pressure (ABP) and heart rate (HR), as well as cardiac output (CO) by thermodilution technique. -/- (n = 7) and +/+ (n = 10) mice of comparable weight and age were used. Stroke volume (SV) and TPR were derived from CO, HR, and ABP by a standard formula. ABP (mm Hg) was significantly higher in -/- (132+/-4) (P < 0.0001) than in +/+ mice (95+/-2). CO (ml min(-1)), HR(beats min(-1))and SV (microl beat(-1)) did not differ significantly between -/- and +/+ mice (CO -/- = 7.3+/-0.5, +/+ = 8.3+/-0.6; HR -/- = 407+/-22, +/+ = 462+/-21; SV -/- = 17.6+/-1.1, +/+ = 17.6+/-1.7). However, TPR (mm Hg ml(-1) min(-1)) was significantly elevated in -/- mice (18.4+/-0.7) compared to +/+ mice (12.3+/-1) (P = 0.0003). Autonomic ganglion blockade with a mixture of hexamethonium and pentolinium was followed by comparable percent reductions in CO (-/- = 28+/-4, +/+ = 29+/-3), HR (-/- = 9+/-4, +/+ = 16+/-4) and SV(-/- = 21+/-4, +/+ = 15+/-6) in both genotypes. However, the concomitant decrease in ABP (%) in -/- (41+/-2) was significantly greater than in +/+ (23+/-4) mice (P = 0.0009) and was accompanied by a significant reduction in TPR. We conclude that the hypertension associated with lack of endogenous ANP is due to elevated TPR, which is determined by an increase in cardiovascular autonomic tone.

Chronic regulation of arterial blood pressure by ANP: role of endogenous vasoactive endothelial factors.

Atrial natriuretic peptide (ANP) exerts a chronic hypotensive effect due to a decrease in total peripheral resistance (TPR). This study examines if chronic ANP-dependent vasodilation is attributable to differences in the cardiovascular regulatory activity of vascular endothelium (VE), based on evidence that ANP affects synthesis/release and target cardiovascular effects of endothelin-1 (ET-1), C-type natriuretic peptide (CNP), and nitric oxide (NO). To determine if the synthetic activity of resistance vasculature VE is chronically altered by plasma ANP activity, we measured ET-1, CNP, and endothelial constitutive NO synthase (ecNOS) concentration and total NOS enzyme activity in homogenates of kidney, heart, lung, hindquarter skeletal muscle, and brain from hypotensive transgenic mice with elevated plasma ANP, hypertensive knockout mice (-/-) characterized by the absence of ANP, and the corresponding normotensive wild-type (NT, +/+) mice. Tissue distribution and abundance patterns of ET-1, CNP, ecNOS, and NOS enzyme activity were comparable between the different genotypes and did not differ significantly between mutant and control mice. Antagonism of ETA/B receptors in -/- and +/+ mice in vivo with SB-209670 reduced arterial blood pressure (ABP) significantly and comparably in both genotypes (-27 +/- 4 and -25 +/- 2% change for -/- and +/+ mice, respectively) independent of any significant changes in heart rate (HR) (-6 +/- 8 and -4 +/- 4% change for -/- and +/+ mice, respectively). Immunoneutralization of CNP-specific guanylate cyclase-linked receptors (GC-B) with monoclonal antibodies (3G12) increased ABP slightly, but not significantly, by similar relative amounts in both -/- (10 +/- 6% change) and +/+ mice (8 +/- 3% change), without changing HR significantly (4 +/- 1% change for both +/+ and -/- mice). Inhibition of NOS activity (by NG-nitro-L-arginine methyl ester) significantly increased ABP, but the changes were comparable between -/- (53 +/- 5% change) and +/+ mice (50 +/- 6% change) and occurred in the absence of significant changes in HR (-1 +/- 5 and 7 +/- 5% change for -/- and +/+ mice, respectively). We conclude that the differences in ABP associated with chronic variations in endogenous ANP activity are not due to alterations in synthesis or responsiveness of the cardiovascular system to the effects of ET-1, CNP, or NO.

Age-related development of atherosclerotic plaque stress: a population-based finite-element analysis.

BACKGROUND: In order to identify those age-related factors in the development of coronary atherosclerosis that would affect the stability of the plaque system, we have developed idealized, finite-element, cross-sectional models of the arterial wall and associated lesions, derived from population-based data. METHODS: The physical development and morphology of coronary plaques was documented in the Pathobiological Determinants of Atherosclerosis in Youth histological study. Using this database, finite-element analysis models were created for five age groups (15-19, 20-24, 25-29 and 30-34 years) and for the 25 largest lesions. Cosmos (Structural Research, Inc., Los Angeles, California, USA) was used to create and analyze the models. RESULTS: The area of greatest stress shifted from the intima opposite the lesion in the 15-19 years age group to the edge of the cap and adjacent healthy tissue in the later age groups. Increasing age had a strong positive correlation with the shoulder stress level (r = 0.95) and the per cent stenosis correlated well with shoulder stress (r = 0.99, P < 0.002). Increasing the cap stiffness from a soft cap to a fibrous cap in the 30-34 year age group model resulted in a localized increase in shoulder surface stress by 10%. A calcified cap increased this shoulder surface stress by 30%. CONCLUSIONS: This finite-element analysis of the population-based data shows that the increase in stress appears to be closely related to the impaired load-bearing capability of the lipid pool that develops with age. The shoulder area of the lesion has been shown to be the location of most of the plaque fractures.

Salt-sensitive hypertension in ANP knockout mice: potential role of abnormal plasma renin activity.

Atrial natriuretic peptide (ANP), a peptide hormone produced by the heart, exerts a chronic hypotensive effect. Knockout mice with a homozygous disruption of the pro-ANP gene (-/-) are incapable of producing ANP and are hypertensive relative to their wild-type (+/+) siblings. Previous studies showed that arterial blood pressure (ABP) was further increased in conscious -/- mice kept for 2 wk on 2% salt, but not in anesthetized -/- mice after 1 wk on 8% salt. To determine whether inconsistencies in observed effects of salt on ABP of -/- mice are due to duration of increased salt intake and/or the state of consciousness of the animals, we measured ABP from an exteriorized carotid catheter during and after recovery from anesthesia with ketamine-xylazine in adult +/+ and -/- mice kept on low (LS; 0.008% NaCl)- or high (HS; 8% NaCl)-salt diets for 3-4 wk. Conscious ABP +/- SE (mmHg) of +/+ mice did not differ significantly on either diet (HS, 113 +/- 3; LS, 110 +/- 5). However, on HS diet -/- mice had significantly higher ABP (135 +/- 3; P < 0.001) than both -/- (115 +/- 2) and +/+ (110 +/- 5) mice on LS diet. Anesthesia decreased ABP in all groups, but the the genotype- and diet-related differences were preserved. Plasma renin activity (PRA, ng ANG I.ml-1.h-1) in blood collected at termination of experiment was appropriately different on the 2 diets in +/+ mice (HS, 4.9 +/- 1.9; LS, 21 +/- 2.8). However, PRA failed to decrease in -/- mice on HS diet (HS, 18 +/- 2.9; LS, 19 +/- 3.7). Independent of genotype, concentration of endothelin-1 (ET-1, pg/mg protein) and endothelial constitutive NOS (ecNOS, density/100 micrograms protein) was significantly elevated in kidneys of mice fed on HS diet (ET-1 -/-, 31 +/- 4.7 and +/+, 32 +/- 4.1; ecNOS -/-, 160 +/- 19 and +/+, 156 +/- 19) compared with mice fed on LS diet (ET-1 -/-, 19 +/- 1.9 and +/+, 21 +/- 1.8; ecNOS -/-, 109 +/- 13 and +/+, 112 +/- 18). We conclude that, regardless of the state of alertness, -/- mice develop salt-sensitive hypertension after prolonged feeding on HS, in part due to their inability to reduce PRA, whereas the specific renal upregulation of ecNOS and ET-1 in response to HS intake may be an ANP-independent adaptive adjustment aimed at improving kidney function and counteracting the pressor effect of salt.

Effect of sympathetic and angiotensin-aldosterone systems on renal salt conservation in the rat.

During dietary salt deprivation, the sympathetic nervous system and the angiotensin-aldosterone system are stimulated. Both systems are thought to be essential for maximal salt conservation by the kidney. To study their relative contributions, we produced negative salt balance in rats by intraperitoneal injection of furosemide, followed by a low-salt diet (<0.008% NaCl). In a 1-wk metabolic study, the animals were unable to replace the drug-induced salt deficit. Six groups of rats were studied. A control group established baseline function, a second group of 6-hydroxydopamine (OHDA) rats were treated with OHDA to destroy sympathetic efferent nerve terminals, and a third group (losartan) were treated with the angiotensin-receptor antagonist losartan. The influence of catecholamines and aldosterone released from the adrenal gland was studied in a further three groups. Rats were sham-adrenalectomized (sham), subjected to bilateral adrenal enucleation (Enuc) to eliminate catecholamine secretion, or were bilaterally adrenalectomized (Adx), eliminating both catecholamine and corticosteroid release. Dexamethasone was used as glucocorticoid replacement in this group. Steady-state urinary salt excretion was not different between control and OHDA rats. The losartan group showed significantly increased sodium but not chloride excretion. Surprisingly, there were no differences in salt excretion among sham, Enuc, and Adx groups. We conclude that, during a state of chronic salt depletion, renal mechanism(s) independent of neuronally released or systemically circulating catecholamines or of adrenally released aldosterone can ensure maximal salt conservation by the kidney. Although our data show that losartan increased sodium excretion under these conditions, we suggest that the losartan effect can be explained by a reduction of bicarbonate reabsorption, obligating simultaneous excretion of the cation.

Renal resistance to ANF in salt-depleted rats is independent of sympathetic or ANG-aldosterone systems.

Chronic salt depletion was used as a model to study the mechanism of renal resistance to the natriuretic effect of atrial natriuretic factor (ANF). Rats were pretreated with furosemide and placed on a low-salt diet (<0.008% NaCl) for 1 wk before a clearance experiment. Compared with animals on a normal salt diet (0.4% NaCl), the natriuretic reponse to ANF administration was reduced by one order of magnitude and was quantitatively trivial. To assess the influence of the sympathoadrenergic system, different groups of rats were either subjected to acute unilateral renal denervation, to chronic adrenal enucleation to reduce circulating catecholamines, or to pretreatment with 6-hydroxydopamine (OHDA) to destroy sympathetic postganglionic nerve endings. None of these treatments was able to fully or even partially restore ANF natriuresis. To determine whether an effect of angiotensin on the kidney prevented the response, the specific receptor antagonist losartan (DuP-753) was administered during the week prior to the experiment. This treatment also did not influence ANF resistance. Similarly, bilateral adrenalectomy 2 wk before the experiment did not affect the renal ANF resistance in salt-depleted rats. The depressed excretory response could not be explained on the basis of reduced renal perfusion pressure or glomerular filtration rate. We conclude that undetermined compensatory mechanism(s) ensures renal salt conservation in this model in the face of even supraphysiological levels of ANF.

Mechanical response of an artery using a standard nonlinear solid.

INTRODUCTION: The stress and deformation in an artery are determined from an axisymmetric analysis of thick-walled cylinder with a time-dependent internal pressure. The purpose is to understand how different constitutive, loading, and geometric conditions affect the stress and deformation state within the artery. MATERIALS AND METHODS: The equilibrium, compatibility, and constitutive equations are applied at N discretized points in the arterial wall, in an efficient scheme using Mathcad software on a desktop computer. The constitutive equations are a modification to a standard linear solid, so that one of the linear elements is nonlinear, and so that the 3-D response is anisotropic and dissipates energy only under deviatoric (shearing) stress states. Solution at each successive time increment requires inversion of a 6N by 6N matrix. RESULTS: The model reproduces experimental stress relaxation data with a correlation coefficient of 0.985 and can reproduce quasi-static stress strain data with equal accuracy. Features such as conditioning of the tissue are understood in terms of the time-dependent properties of the tissue. CONCLUSION: The program can produce transient and steady-state responses that closely mimic tissue response. The analysis allows for quick and stable determination of the stress and strain states for a variety of loading conditions.

Blood pressure and fluid-electrolyte balance in mice with reduced or absent ANP.

Atrial natriuretic peptide (ANP)-gene knockout mice of three genotypes (+/+, +/-, and -/-) were maintained on a low-salt diet (0.008% NaCl). They were then fed either the same low-salt diet or a high-salt diet (8% NaCl) for 1 wk. No differences were found among genotypes in daily food and water intakes or in urinary volume and electrolyte excretions. Arterial blood pressures measured in anesthetized animals at the end of the dietary regimen were significantly and similarly increased in -/- compared with +/+ mice on each diet. Renal excretion of fluid and electrolytes was measured in anesthetized mice before and after acute blood volume expansion. No genotype differences were observed before volume expansion. After volume expansion the wild-type (+/+) mice had much greater saluretic responses than either the heterozygous (+/-) or the homozygous mutant (-/-) animals on the low-salt diet but not on the high-salt diet. We conclude that ANP lowers blood pressure in the absence of detected changes in renal function; ANP is not essential for normal salt balance, even on high-salt intake; and ANP is essential for the natriuretic response to acute blood volume expansion on a low-salt but not high-salt intake.

Blood pressure and fluid-electrolyte balance in ANF-transgenic mice on high- and low-salt diets.

Transgenic mice overexpressing an atrial natriuretic factor (ANF) fusion gene (TTR-ANF) and their nontransgenic siblings were placed on a high- (8%) or low (< 0.008%)-salt diet for 14 days to determine whether the lifelong elevation of ANF in the transgenic animals compromised their ability to maintain fluid-electrolyte balance. Steady-state dietary intake and urinary output of sodium and chloride were not statistically different between TTR-ANF and control groups on either diet. By contrast, water intake and urine volume were markedly elevated in the TTR-ANF group on either diet. Arterial blood pressure, measured in anesthetized mice at the end of the dietary regimen, was significantly and similarly reduced in the TTR-ANF compared with control groups on either diet, although high salt intake was associated with increased pressure in both groups. Renal excretion of fluid and electrolytes was studied in the anesthetized mice before and after acute blood volume expansion. Although the absolute increase in fluid and electrolyte excretion was much greater on the high- than on the low-salt diet in both groups, TTR-ANF mice had an exaggerated response relative to controls on either diet. On the basis of these results, we conclude the following. 1) When they are stimulated, renal salt-conserving mechanisms are sufficiently powerful to overcome the expected natriuretic effects of chronic elevation of plasma ANF; however, the natriuretic potential of ANF can be expressed in the short term when the counterregulatory mechanisms are inactivated. 2) ANF exerts a chronic hypotensive effect that is independent of changes in renal salt excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of bradykinin B2 receptor antagonist and indomethacin on natriuretic and hypotensive responses to atrial natriuretic factor.

The effects of inhibition of bradykinin and prostaglandin on the renal and blood pressure responses to atrial natriuretic factor (ANF) were studied in anesthetized rats. Intraarterial infusion of the receptor antagonist D-Arg[Hyp3,Thi5,8,D-Phe7]bradykinin (BKA) at 14 micrograms/min, a rate sufficient to block the hypotensive response to 250 micrograms of bradykinin, did not affect the natriuresis due to injection of ANF (UNaV: control, before ANF, 393 +/- 101, after ANF, 2322 +/- 400 nmol/min; BKA, before ANF, 261 +/- 72, after ANF, 2259 +/- 390 nmol/min). In contrast, infusion of indomethacin (Indo) reduced the level of sodium excretion both before and especially after ANF administration (UNaV: Indo, before ANF, 75 +/- 15, after ANF, 320 nmol/min). The effect of combining BKA with Indo was not different from the effect of Indo alone (UNaV: BKA + Indo, before ANF, 119 +/- 26, after ANF, 469 +/- 167 nmol/min). The bradykinin antagonist, with or without Indo, was associated with significant hypotension relative to control. Indo, both in the absence and presence of the antagonist, was associated with a progressive decrease in blood pressure compared with control. However, in each the hypotensive responses to ANF were not different from those in the control group. We conclude that under the present experimental conditions bradykinin does not modify ANF-induced natriuresis. However, inhibition of prostaglandin synthesis by Indo is associated with renal salt retention, reducing natriuresis both before and after ANF administration.

Proximal tubular function in transgenic mice overexpressing atrial natriuretic factor.

A transgenic mouse model in which atrial natriuretic factor (ANF) expression is targeted to the liver was used to study intrarenal adjustments to the chronically elevated hormone level. Such animals, designated TTR-ANF, are characterized by reduced arterial blood pressure but similar sodium excretion compared with nontransgenic siblings. Proximal tubular micropuncture gave the following results: single-nephron filtration rate = 12.7 +/- 1.1 vs. 15.6 +/- 1.9 nL/min (TTR-ANF versus nontransgenic, ns); end-proximal tubular fluid/plasma concentration ratio of inulin = 1.93 +/- 0.09 vs. 1.97 +/- 0.15 (ns); fractional reabsorption of sodium = 45.5 +/- 2.8 vs. 46.0 +/- 3.8% (ns); fractional reabsorption of chloride = 33.6 +/- 3.3 vs. 32.4 +/- 4.1% (ns). These data indicate that life-long elevation of plasma ANF concentration was not associated with significant alteration in single-nephron filtration rate and proximal tubular function. We conclude that compensatory antinatriuretic mechanisms, localized downstream from the proximal tubule, can prevent ANF natriuresis.

Blood pressure regulation in ANF-transgenic mice: role of angiotensin and vasopressin.

Transgenic mice overexpressing a transthyretin promoter-ANF structural fusion gene have a life-long reduction in arterial blood pressure compared to nontransgenic littermates. The present study was designed to test the hypothesis that the high plasma level of ANF in the transgenic mice inhibits the renin-angiotensin and/or vasopressin systems, thereby causing the hypotension. Mice were anaesthetized with Inactin and arterial pressure and heart rate were monitored before and during Saralasin infusion and vasopressin V1 receptor blockade. Effectiveness of the blockade was determined by injection of angiotensin and vasopressin before and during Saralasin and V1 receptor antagonist administration. Saralasin was associated with hypotension in both transgenic and nontransgenic mice. The decrease in blood pressure was proportionally greater in the transgenic animals. Vasopressin receptor blockade had little effect on blood pressure in either group. Heart rates were not different between the groups during any maneuver. We conclude that the chronic hypotensive effect of ANF overproduction does not involve the inhibition of either renin-angiotensin or vasopressin systems. The data, however, suggest that the renin-angiotensin system may be stimulated in the ANF-transgenic mice.

Effect of potassium infusion on renal function in ANF-transgenic mice.

Transgenic mice expressing an ANF fusion gene in the liver were used to study renal function before and during an intravenous KCl load. These animals are characterized by a 10- to 20-fold elevation in plasma ANF concentration, and by a reduction in arterial blood pressure by 20-30 mm Hg, compared to nontransgenic littermates. Before the KCl infusion, renal excretions of fluid, sodium, potassium, and chloride were not different from corresponding values in the nontransgenic sibling mice. Glomerular filtration rates were slightly lower in the transgenic animals. During the KCl infusion, diuresis, saluresis, and kaliuresis were found in both groups. However, salt and water excretion, but not potassium excretion, were significantly greater in the transgenic group. In a separate series, plasma aldosterone concentrations were significantly higher in the transgenic, compared to the nontransgenic mice. These data are interpreted as indicating that antinatriuretic mechanisms, including aldosterone-dependent sodium reabsorption in the cortical collecting tubule, can counteract the effect of ANF to inhibit sodium reabsorption in the medullary duct system, thus allowing maintenance of salt balance. Furthermore, a reduced tubular flow rate at the aldosterone-sensitive site would ensure normal potassium excretion despite the elevated mineralocorticoid level. During KCl infusion, the known increase in tubular delivery of salt and water to the duct would allow full expression of the downstream ANF effect, accounting for the relatively greater diuresis and saluresis in the transgenic mice. We conclude that both renal and adrenal actions of ANF can be rendered ineffective by countervailing mechanisms, suggesting an explanation for the apparent lack of biological activity of endogenously elevated plasma NAF in some disease states.

Renal response to blood volume expansion in Brattleboro rats after acute treatment with vasopressin.

The renal response to iso-oncotic blood volume expansion with bovine serum albumin was studied in anaesthetized homozygous Brattleboro (DI) rats after acute (1 day) pretreatment with 1 U arginine-vasopressin (AVP) compared to heterozygous controls. In AVP-treated DI (DI + AVP) rats, basal urine flow as well as urinary sodium, chloride, and potassium excretion, were not different from controls. Diuresis and kaliuresis induced by volume expansion were blunted in DI + AVP rats. However, natriuresis and chloruresis were exaggerated in DI + AVP rats. They increased faster, reached a higher maximum, but declined earlier, compared to controls. The blunted diuresis resulted in a positive volume balance by the end of the experiment in DI + AVP rats, whereas the controls showed restoration of normal balance. Significant retention of sodium and chloride was observed in controls, but not in DI + AVP rats, over the time of the experiment. DI + AVP rats lost significantly less potassium than controls during the experiment. As judged from the lithium clearance method, the exaggerated saluresis in DI + AVP rats was mainly due to a reduced proximal sodium reabsorption. Plasma immunoreactivity of atrial natriuretic peptide (ANP) rose during blood volume expansion and fell in the recovery period. It was not different between AVP-treated DI rats and controls at any time of the experiment. Inulin clearance was slightly, but not significantly, lower in DI + AVP rats and increased after blood volume expansion in DI + AVP rats only.(ABSTRACT TRUNCATED AT 250 WORDS)

Kidney function in ANF-transgenic mice: effect of blood volume expansion.

Transgenic mice, created from inbred C3HeB/FeJ embryos, were used to overexpress selectively in the liver a fusion gene comprising mouse transthyretin (TTR) regulatory and atrial natriuretic factor (ANF) structural sequences. Animals were anesthetized, and kidney function was studied before and after blood volume expansion. Baseline urine volumes and electrolyte excretions were not significantly different from those of non-transgenic littermates, despite a markedly lower arterial blood pressure in the experimental group. A slightly lower glomerular filtration rate (GFR) in transgenics was not different statistically. Plasma ANF levels measured by radioimmunoassay were approximately 10-fold higher in the transgenic animals, compared with their nontransgenic siblings. After acute blood volume expansion, the diuretic, natriuretic, kaliuretic, and chloruretic responses were markedly enhanced in the transgenic group. Arterial pressure was increased as a result of hypervolemia, although it remained relatively depressed relative to the controls. GFR again was not different. We conclude that transgenic mice overexpressing ANF can maintain normal excretion of salt and water, possibly via ANF-induced reduction of renal perfusion pressure. After acute blood volume expansion, an increase in pressure may allow full renal expression of the chronically elevated ANF levels.

Nephron site responsible for the reduced kaliuretic response to mineralocorticoids during hypokalemia in rats.

Rats with hypokalemia induced by eating a low-K diet have a diminished kaliuretic response to mineralocorticoids. The purpose of this study was to determine if this was the due to a lower rate of net secretion of K in the cortical collecting duct (CCD) and/or an enhanced rate of reabsorption of K in the medullary collecting duct (MCD). Secondary active secretion of K in the CCD raises the [K] in the lumen as compared to the plasma [TF/P)K). If the (TF/P)K is greater than 1, there was secondary active secretion of K in this nephron segment. The (TF/P)K in the CCD was measured by microcatheterization of the collecting duct. Three groups of rats were studied: rats on a low-K diet with and without the acute administration of DOCA, and rats on a normal-K diet treated with DOCA on a chronic basis. Rats on the low-K diet had a (TF/P)K of 0.8 +/- 0.11; this value did not rise to values significantly greater than 1 after the acute administration of DOCA (1.4 +/- 0.35). In contrast, chronic administration of DOCA to rats fed a normal-K diet did result in a (TF/P)K which was significantly greater than unity (3.1 +/- 0.39). The degree of hypokalemia was not significantly different in these rats. The absolute and fractional reabsorption of K in the MCD was not different in the rats on the low-K diet with or without DOCA. We conclude that the nephron segment which is responsible for the reduced kaliuretic response to mineralocorticoids is the CCD.