Accelerated growth without prepubertal obesity in nutritionally programmed microswine offspring.

Poor fetal growth and associated prepubertal growth acceleration are linked to increased risk of cardiometabolic dysfunction in later life, but whether obesity is integral to 'catch-up' growth and its ensuing risks are unknown. In microswine offspring exposed to perinatal maternal protein restriction (MPR), we measured body and organ sizes (during MPR); linear growth and weight gain (birth to 5 months of age); feed intake and utilization efficiency (5-14 weeks); and body composition at 6 and 11 weeks of age (by dual-energy X-ray absorptiometry, DEXA). During MPR, low protein offspring (LPO) showed asymmetric growth restriction with reduced body weight (Wt):length (Lth) at birth and elevated heart Wt:liver Wt ratio by 2 weeks of age. In LPO, after slow early postnatal growth (0-5 weeks), subsequent linear growth on ad libitum normal feed was absolutely accelerated (cm/week; P < 0.001) over 6-11 weeks but normal thereafter, whereas absolute weight gain (kg/week) was similar to controls but accelerated relative to lower LPO nadir weights. Concurrently, rates of fat and lean tissue accrual in LPO over 6-11 weeks were similar to normal protein offspring in absolute terms (g/5 weeks) but increased relative to lower mass at 6 weeks, yielding normal lean:Lth but reduced fat:Lth ratios at 11 weeks. LPO had higher relative feed intake (g/kg/meal) in both sexes and higher feed efficiency in females over 5-11 weeks of age. Findings suggest that postnatal linear growth acceleration preserved thinness in juvenile LPO. Given separately reported abnormalities of vascular (Bagby et al., 2011) and adipocyte function in juvenile LPO, (DuPriest et al., 2011) findings demonstrate that perinatal MPR programs catch-up growth and cardiovascular abnormalities independently of obesity.

Altered adipocyte structure and function in nutritionally programmed microswine offspring.

Adipose tissue (AT) dysfunction links obesity of any cause with cardiometabolic disease, but whether early-life nutritional deficiency can program adipocyte dysfunction independently of obesity is untested. In 3-5-month-old juvenile microswine offspring exposed to isocaloric perinatal maternal protein restriction (MPR) and exhibiting accelerated prepubertal fat accrual without obesity, we assessed markers of acquired obesity: adiponectin and tumor necrosis factor (TNF)-α messenger ribonucleic acid (mRNA) levels and adipocyte size in intra-abdominal (ABD-AT) and subcutaneous (SC-AT) adipose tissues. Plasma cortisol, leptin and insulin levels were measured in fetal, neonatal and juvenile offspring. In juvenile low-protein offspring (LPO), adipocyte size in ABD-AT was reduced 22% (P = 0.011 v. controls), whereas adipocyte size in SC-AT was increased in female LPO (P = 0.05) and normal in male LPO; yet, adiponectin mRNA in LPO was low in both sexes and in both depots (P < 0.001). Plasma leptin (P = 0.004) and cortisol (P < 0.05) were reduced only in neonatal LPO during MPR. In juveniles, correlations between % body fat and adiponectin mRNA, TNF-α mRNA or plasma leptin were significant in normal-protein offspring (NPO) but absent in LPO. Plasma glucose in juvenile LPO was increased in males but decreased in females (interaction, P = 0.023); plasma insulin levels and insulin sensitivity were unaffected. Findings support nutritional programming of adipocyte size and gene expression and subtly altered glucose homeostasis. Reduced adiponectin mRNA and adipokine dysregulation in juvenile LPO following accelerated growth occurred independently of obesity, adipocyte hypertrophy or inflammatory markers; thus, perinatal MPR and/or growth acceleration can alter adipocyte structure and disturb adipokine homeostasis in metabolically adverse patterns predictive of enhanced disease risk.

Diabetic nephropathy and proximal tubule ROS: challenging our glomerulocentricity.

Diabetic nephropathy is currently viewed as a predominantly glomerular process with glomerular injury driving secondary tubular loss. Brezniceanu and colleagues apply transgenic methods to support a prominent role for reactive oxygen species as mediators and for the proximal tubule as a major site of early disease activity in diabetes. Results support evidence for early tubular apoptosis and atrophy in human diabetic nephropathy.

A crossover study of gabapentin in treatment of restless legs syndrome among hemodialysis patients.

Restless legs syndrome (RLS) is a common entity affecting hemodialysis patients. Although the cause of RLS remains unclear, a number of therapies have been used successfully to treat the disorder. Gabapentin is an anticonvulsant shown to alleviate symptoms of RLS in two small studies of nonhemodialysis patients. Because it is excreted renally, gabapentin has a long half-life among hemodialysis patients and may be advantageous if proven effective. We conducted a randomized, double-blind, placebo-crossover study of gabapentin in the treatment of RLS among a population of hemodialysis patients. Sixteen patients identified with RLS were randomized to either gabapentin or placebo. After 6 weeks of treatment with 200 to 300 mg of gabapentin after each hemodialysis session, patients' RLS was reassessed. After a 1-week washout period, patients were switched from gabapentin to placebo or placebo to gabapentin. After another 6 weeks, patients' RLS was assessed again. Patient data were analyzed using both parametric and nonparametric means. Thirteen of the 16 original patients completed the study. Two patients dropped out because of lethargy (believed to be secondary to gabapentin), and 1 patient died secondary to myocardial infarction. Eleven patients responded to gabapentin, but not placebo (P < 0.01). One patient responded to both, and 1 patient responded to placebo, but not gabapentin. Gabapentin is an effective treatment for RLS in hemodialysis patients.

Accuracy of an automated blood pressure device in stable inpatients: optimum vs routine use.

BACKGROUND: Despite widespread use of the automated blood pressure (BP) device (IVAC model 4200, IVAC Corporation, San Diego, Calif), there is little formal validation in the literature on its accuracy. OBJECTIVE: To assess the accuracy of the IVAC 4200 device, both under standardized conditions and as routinely used by ward staff, compared with the true indirect BP measured by mercury manometer (MM). METHODS: One hundred forty-five stable inpatients were randomly selected for BP measurements by 3 randomly ordered protocols: (1) MM performed by certified investigators, (2) IVAC 4200 BP performed by trained investigators (research automated [RA]), and (3) IVAC 4200 BP performed by ward personnel (ward automated [WA]). RESULTS: For RA compared with MM ("true" indirect BP), 59% of systolic and 54% of diastolic readings were within 5 mm Hg and 83% of systolic and 86% of diastolic were within 10 mm Hg for a British Hypertension Society grade C for both. For WA compared with MM, 40% of systolic and 50% of diastolic readings were within 5 mm Hg and 70% of systolic and 80% of diastolic readings were within 10 mm Hg for British Hypertension Society grades D and C, respectively. The presence of arrhythmias and/or low K5 values (fifth phase of Korotkoff sounds <30 mm Hg) significantly increased the inaccuracy for diastolic values. Inappropriate cuff selection significantly increased inaccuracy of systolic BP (WA vs MM). CONCLUSIONS: The IVAC 4200 yields substandard estimates of systolic and diastolic BP even under standardized, thus optimum conditions. The presence of arrhythmias or low K5 values and the selection of inappropriate cuff size by the ward staff also contributed to inaccuracy.

Proliferative synergy of ANG II and EGF in porcine aortic vascular smooth muscle cells.

To test growth effects of angiotensin II (ANG II) in porcine vascular smooth muscle cells (VSMC) and potential ANG II synergy with epidermal growth factor (EGF), we exposed subconfluent, near-quiescent porcine aortic VSMC to ANG II, EGF, or ANG II + EGF (each 10(-9) M) in Dulbecco's modified Eagle's-Ham's F-12 medium with insulin + 0.4% fetal calf serum (FCS) selected for minimal ANG II-degrading capacity. Cell number and DNA and protein synthesis (by [3H]-thymidine and [35S]methionine incorporation, respectively) were determined serially over 1-6 days. ANG II alone induced an early 20% increase and then a plateau in cell number over the 0.4% FCS control (P < 0.01; n = 8), thus without sustained increase in proliferation rate. Yet ANG II alone did not increase fractional DNA or protein synthesis (each as cpm/10(3) cells) and, by flow cytometry, reduced S phase fraction without increase in cell size. EGF alone induced brisk DNA synthesis yet minimal cell division over days 0-4, thus late-cycle arrest. ANG II + EGF, despite no increase in fractional DNA or protein synthesis rates over EGF alone, induced significant indomethacin-resistant dose-dependent (P < 0.001) increase in cell proliferation rate over EGF alone with a median effective dose of 5 x 10(-10) M ANG II, thus proliferative synergy. We propose that 1) ANG II induces a subpopulation of cells arrested in or beyond S phase to proceed through mitosis but does not influence G1 traversal or S phase entry and 2) ANG II + EGF achieve proliferative synergy by complementary actions at sequential cell cycle loci, with EGF supporting progression from G0/G1 to S phase and ANG II inducing completion of mitosis by cells already in or beyond S phase ("late-cycle completion").

Influence of growth oxygen level on eicosanoid release from lung endothelial cells during hypoxia.

Eicosanoid products of arachidonic acid are suspected modulators of hypoxic vasoconstriction in the pulmonary vasculature. Vascular endothelial cells (EC) release several eicosanoids, but there is disagreement regarding the effect of hypoxia on EC eicosanoid release. We postulated that the oxygen level of growth in culture might influence the release of eicosanoids during acute hypoxia. We studied EC cultured from the main pulmonary arteries of pigs and grown at either 5% or near 20% oxygen, representing the normal limits of oxygen exposure to endothelium in normal lungs. Although cultures grown in 5% oxygen grew slightly faster by 4 days, the confluent cell number, protein content, and baseline eicosanoid release were no different compared with paired cultures grown in 20% oxygen. However, with an acute decrease in oxygen level, cultures grown in 5% oxygen released less prostaglandin E2, F2 alpha, and 6-ketoprostaglandin F1 alpha compared with amounts released at the growth oxygen level. In contrast, cultures grown in 20% oxygen released increased amounts of these eicosanoids compared with release at the growth oxygen level. Release of thromboxane B2 was not significantly different during hypoxia between cultures grown at 5% vs. 20% oxygen. In other experiments, cyclooxygenase activity, stimulated arachidonic acid release by calcium ionophore A23187, and uptake of arachidonic acid were no different in cultures grown at 5% vs. 20% oxygen. However, arachidonic acid release during hypoxia was reduced in 5% cultures and increased in 20% cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

Nontraditional combination pharmacotherapy of hypertension.

Traditional drug combinations that have additive hypotensive effect include double therapy with a diuretic and any other antihypertensive agent and triple therapy with a diuretic, direct vasodilator, and either a beta blocker or reserpine. Due to the availability of new classes of antihypertensive agents, other combinations of drugs are now increasingly used. The effectiveness of combination therapy for hypertension has been investigated; the results of these studies are reviewed.

EGF is incomplete mitogen in porcine aortic smooth muscle cells: DNA synthesis without cell division.

To characterize growth effects of epidermal growth factor (EGF) in subconfluent quiescent porcine aortic vascular smooth muscle cells (VSMC), we measured DNA and protein synthesis by [3H]thymidine (Thd) and [35S]methionine (Met) incorporation, respectively, and cell proliferation rates over 0-6 days in Dulbecco's modified Eagle's-Ham's F-12 media containing 0.4% fetal calf serum (FCS) and insulin. EGF induced dose-dependent [3H]Thd uptake (P less than 0.001); after 10(-9) M EGF, DNA synthesis rate peaked at 24 h, averaging 77% of the response to 10% FCS, and then declined steeply with nadir at 48-60 h. Unexpectedly, EGF failed to induce cell proliferation in the first 4 days, leaving this initial burst of DNA synthesis (12-60 h) uncoupled from cell division. A second lesser but sustained phase of increased DNA synthesis, apparent by day 3-4, was associated with a small increase in cell number on day 6 (P less than 0.05). The early unsustained burst of DNA synthesis reflects EGF's potent mitogenic efficacy for DNA synthesis (G1- to S-phase traversal), probably acting on a subset of cells partially synchronized initially at an EGF-responsive G0/G1 locus; the minimal cell division despite brisk DNA synthesis documents EGF's limited efficacy for (or inhibition of) late cell-cycle events required for completion of mitosis. Late cell-cycle processes are thus rate limiting. EGF also increased protein synthetic rate over control (P less than 0.03) but to a lesser degree (P less than 0.01) than 10% FCS. Indomethacin (10(-6) M) did not alter DNA or proliferative responses to 10(-9) M EGF but transiently augmented EGF-induced protein synthesis (P less than 0.025) at 24 h only.(ABSTRACT TRUNCATED AT 250 WORDS)

Cognitive function in hypertensives treated with atenolol or propranolol.

STUDY OBJECTIVE: To test reports that beta blockers, particularly lipophilic forms, impair cognitive function and cause psychiatric disturbances. DESIGN: Randomized, double-blind, controlled crossover trial with eight-week treatment periods. PATIENTS: Sequential sample of 42 male veterans, with untreated diastolic blood pressures (DBP) between 90 and 110 mmHg, aged 35-64 years. INTERVENTIONS: Propranolol-LA, 80-mg tablets, or atenolol, 50-mg tablets, were given daily, incremented by one tablet at weekly intervals until DBP less than or equal to 90 mmHg. Hydrochlorothiazide was added, if necessary. MAIN RESULTS: Repeated-measures ANOVA was performed on all cognitive tests. Cognitive test performance was not affected by beta blocker therapy in seven of nine tests and was enhanced on Trail Making Test. Performance was impaired only on Digit Cancellation. Neither Speilberger's State Trait Anxiety Inventory nor the Beck Depression Inventory was affected by either beta blocker. CONCLUSIONS: Atenolol or propranolol therapy does not impair cognitive function or contribute significantly to psychiatric side effects.

An in vitro system for study of effects of angiotensin I on cultured endothelial cells.

Since certain non-vascular angiotensin II (AII) receptors may be activated by angiotensin I (AI), and since sustained increase in AI levels accompanies chronic treatment with converting enzyme inhibitors (CEI) which block conversion of AI to AII, the question of whether AI has significant biological effects is of clinical relevance. We therefore sought to develop an in vitro culture system in which effects of angiotensin I, independently of its conversion to AII, could be studied in cloned aortic vascular endothelial cells (VEC). This was complicated by peptide degradation during the period of observation, both by angiotensin converting enzyme (ACE) on the surface of VEC and by angiotensinases in either the serum component of culture media or associated with the cell monolayer. Accordingly, we examined the half life of AI under relevant cell culture conditions, with and without confluent fetal bovine aortic endothelial cells (FBAEC). Factors assessed included (1) fetal calf serum: commercial source, concentration in culture media, effects of converting enzyme inhibitor (CEI: MK422) and/or heat inactivation (superimposed on the commercially performed process); and (2) effect of FBAEC in monolayer culture, with and without CEI. Results showed that (1) in the absence of cells, loss of AI in culture media, when present, was solely due to the presence of fetal calf serum (FCS) and showed a dose dependent response; (2) FCS from differing sources may vary dramatically in capacity for AI breakdown; and (3) serum related AI disappearance included a heat resistant ACE like component (inhibitable by CEI) and a heat sensitive/CEI resistant component dominant at concentrations of FCS exceeding 5%.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic CEI alters effect of low Na+ diet in normal and coarcted pups. I. BP, renin, and GFR.

To assess the renin-angiotensin (RA) dependence of evolving neonatally induced coarctation hypertension (NICH) in inbred pups, we randomized sex-matched littermates to a high dose of converting-enzyme inhibitor (CEI:MK-421) or placebo from the time of neonatal aortic banding (coarcted) vs. no banding (control). In phase 1 studies, pups were examined serially on normal diet (Bagby and Fuchs, Hypertension In press.): chronic CEI lowered systolic blood pressure (BP) equally in coarcted and controls and failed to prevent systolic BP excess in coarcted dogs. In phase 2 studies, the same pups were exposed to a low sodium (LS) diet at 4 mo of age, a time when the untreated NICH model exhibits increased forelimb systolic BP. Measurements of systolic BP, RA components, renal function, and extracellular volume (ECV) were made before and serially during 12 days on the LS diet. Responses of coarcted and control pups to the LS diet were similar, with or without CEI, providing no evidence for exaggerated angiotensin II (ANG II) dependence in evolving NICH. Independently of coarctation status, chronic CEI significantly modified RA and renal functional responses to the LS diet: a greater renin rise but abnormal renin substrate fall, thus no rise in ANG I or ANG I generation rate; a greater rise in creatinine and a trend toward a greater fall in glomerular filtration rate (GFR). Despite these findings compatible with sustained ANG II deficit, chronic CEI unexpectedly failed to impair maintenance of systolic BP during a superimposed LS diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic CEI alters effect of low Na+ diet in normal and coarcted pups. II. Na+ and H2O balance.

To assess angiotensin (ANG II) dependence of evolving neonatally induced coarctation hypertension (NICH) in inbred pups, we randomized sex-matched littermates to high-dose converting enzyme inhibitor (CEI: MK-421, 3 mg/kg) or placebo from the time of neonatal aortic banding (coarcted) vs. no banding (control). During phase 1 studies over 4 mo postbanding during ad libitum Na+ intake (Bagby and Fuchs, Hypertension Dallas in press). CEI failed to prevent evolution of proximal blood pressure (BP) excess or to impair renal function. Phase 2 studies examine, in the same pups, responses to low Na+ (LS) diet superimposed on chronic CEI at 4 mo, timed to allow development of BP increase in untreated NICH. The present report details metabolic handling and balances of Na+, K+, and fluid for 3 days before (normal Na+ intake) and daily for 11 days after initiation of LS diet, a companion paper describes BP, renin-angiotensin (RA), and renal functional responses. In no case did metabolic responses of coarcted pups to LS diet differ from those of controls, whether on CEI or placebo, whereas responses to LS diet and to CEI reveal positive findings of independent interest. LS diet induced expected renal and fecal Na+ conservation, no net effect on K+ balance, and, despite unexpected free-water diuresis, mild hyponatremia. Chronic CEI impaired maximal renal (but not fecal) Na+ conservation during LS diet, caused exaggerated free-water diuresis but no change in fluid balance, and thus, with the larger Na+ deficit, accounted for greater hyponatremia. CEI caused no net effect on K+ balance. Results indicate normal renal handling of fluid, Na+, and K+ in evolving NICH and provide no evidence for selective intrarenal RA activation or exaggerated ANG II dependence. Findings also suggest that, during LS diet, ANG II is 1) essential for maximum renal Na+ conservation and normal free-water handling, and 2) not essential for fecal Na+ and water conservation or for maintenance of normal water and K+ balances. Results are also compatible with a CEI-induced thirst stimulation and/or osmotic insensitivity and with functional vasopressin deficiency during LS diet.

Chronic MK421 fails to modify evolution of hypertension in neonatally coarcted pups.

In inbred dogs with neonatally induced coarctation hypertension, prior serial studies during the first year after aortic banding showed extracellular volume excess with normal plasma renin activity (PRA). The present studies test the hypothesis that slowly evolving aortic constriction in this model will yield intrarenal angiotensin II excess, peripherally undetectable, with continuous slightly positive sodium balance, and thus that chronic blockade of angiotensin II formation will prevent generation of hypertension. Accordingly, we used MK421 (enalapril, 3 mg/kg twice daily), a long-acting angiotensin converting enzyme inhibitor, or placebo, administered orally, from the time of banding through 4 months after banding in sex-matched littermates randomly assigned to one of four groups: coarcted/MK421; control/MK421; coarcted/placebo; control/placebo. Results indicate that MK421 caused identical lowering of absolute forelimb systolic blood pressure in coarcted and control pups but failed to modify evolution of a significant (p less than 0.005) systolic blood pressure difference in coarcted versus control dogs. Thus, neither temporal course nor final magnitude of relative hypertension was altered by MK421. Efficacy of MK421 was documented by 83% inhibition of the pressor response to angiotensin I at nadir of drug effect and by sustained increases in angiotensin I and renin concentration throughout the period of study. Coarcted and control pups responded similarly to MK421 for all measured variables. Glomerular filtration rate and extracellular volume (measured by [14C]inulin disappearance) did not differ among groups. Thus, chronic administration of MK421 failed to prevent hypertension and did not impair maintenance of normal renal function in the evolving phase of neonatally induced coarctation hypertension. We conclude that, although angiotensin II may participate in the untreated model, it does not appear essential to generation of hypertension. We propose that the renal pressure-natriuresis mechanism regulates distal pressure, that stenosis-related resistance independently determines the proximal-distal difference, and that chronic converting enzyme inhibition lowers the set point of the former without influencing stenosis evolution, thus secondarily lowering proximal pressure by an equal degree.

Canine neonatally induced coarctation hypertension in the second year. Variably hyperresponsive plasma renin activity.

In canine neonatally-induced coarctation hypertension, we reported abnormally elevated plasma renin activity (PRA) during sodium restriction in 2-year-old dogs, but found normal PRA responses to sodium restriction +/- furosemide in coarcted dogs studied serially over the first year postaortic banding (PAB). To resolve this apparent discrepancy in PRA response, longitudinal studies were extended to 2 years PAB. In two separately-studied groups, each with three coarcted and three littermate controls, measurements of indirect forelimb blood pressure (BP) at 15 to 18 months, direct brachial arterial BP at 24 months, and serial measurement of PRA and extracellular volume (ECV, as 24Na space) were made over a 15- to 24-month age range during three sodium-volume levels: ad libitum sodium intake (NS), low-sodium diet alone (LS), and low-sodium plus Lasix (LS/Lasix). While PRA in coarcted dogs of both groups was comparable to controls at NS and LS, PRA in Group 1 coarcted dogs significantly exceeded that of littermates during LS/Lasix in both 18- and 24-month studies. In contrast, PRA in Group 2 coarcted dogs was not hyperresponsive to LS/Lasix as compared to simultaneously-studied littermates. The hyperresponsive PRA in Group 1 coarcted dogs could not be attributed to larger absolute or relative ECV deficits. Overall, ECV in coarcted dogs of each group was higher on the average but was not statistically different from controls. Results indicate that the hyperresponsive PRA in this canine model is: 1) a variable feature, developing secondarily in the late established phase; 2) reproducible for a given animal; and 3) not attributed to exaggerated ECV deficits during the LS/Lasix protocol.

Extracellular volume expansion and delayed resolution of hypertension after canine aortic coarctectomy.

The hemodynamic changes occurring after surgical correction of thoracic aortic coarctation were studied in two neonatally coarcted dogs at six months of age and compared to sham surgery in two littermate controls. Excision of the tight iatrogenic aortic band with direct aortic reanastomosis abolished pressure gradients. Post-coarctectomy systemic pressure rose, after an early transient fall, to pre-operative proximal levels and was sustained for two to four weeks before decreasing to control normotensive values. Femoral systolic pressure (and renal perfusion pressure) rose by 47-57 mmHg in coarcted dogs (p less than .001). Extracellular volume (ECV) increased in both coarcted animals, peaking 28-32 cc/kg (7.1-7.6% increase) above precoarctectomy levels. Peak ECV expansion coincided with the peak post-coarctectomy blood pressure. Fluid administration, blood losses and plasma renin activity (PRA) were comparable in all animals. Post-coarctectomy tachycardia was also noted in coarcted dogs (p less than .001), whereas neither ECV nor heart rate changes occurred in control animals. We postulate that post-coarctectomy baroreceptor stimulation results in sympathetically-mediated renal sodium retention, not only preventing a pressure diuresis, but resulting in overt volume expansion. Failure of PRA suppression despite increased distal pressure and volume excess may also reflect sympathetic activation. Data are compatible with the view that sympathetic activation and consequent volume expansion transiently sustain hypertension in the post-coarctectomy setting until baroreceptor re-adjustments permit normalization of blood pressure.

Acute responses to arterial pressure and plasma renin activity to converting enzyme inhibition (SQ 20,881) in serially studied dogs with neonatally-induced coarctation hypertension.

In six inbred dogs with neonatally-induced coarctation hypertension, and in seven littermate controls, acute responses of proximal arterial pressure and plasma renin activity (PRA) to converting enzyme inhibitor (CEI; SQ 20,881, 0.5 mg/kg i.v.) were serially examined. Studies were performed at 2, 6, and 12 months post-aortic banding under sodium-replete and -deplete conditions. Both in normotensive controls and in coarcted dogs, depressor responses (pre- minus post-CEI values) were positively correlated, not only with initial (pre-CEI) PRA, but also independently with initial blood pressure. Although absolute depressor responses in coarcted dogs exceeded those of the control group, there were no significant group differences when, by analysis of covariance, depressor responses were adjusted for the physiologic influence of initial pressure. Similarly, depressor responses expressed as a percent of initial pressure were comparable in coarcted and control groups. Initial PRA and PRA response to CEI in coarcted dogs were also comparable to control dogs; the PRA response correlated with initial PRA in both groups. CEI did not significantly diminish the magnitude of blood-pressure difference between coarcted and control dogs. Thus, in neonatally-induced coarctation hypertension, under both sodium replete- and -deplete conditions: 1) acute depressor and PRA responses to CEI are modulated by the same factors that influence responses of normotensive controls; 2) larger absolute depressor responses to CEI appear to be a physiologic function of higher initial pressure; and 3) blood pressure excess over littermate controls is largely sustained by CEI-resistant factors, potentially including the known volume excess in coarcted dogs.

In vitro determinants of plasma renin activity in serially-studied inbred dogs with neonatally induced coarctation hypertension: renin reactivity, renin substrate, and renin concentration.

Increased renin activity of plasma, suggesting an excess of circulating accelerators and/or deficit of inhibitors of the renin reaction, has been reported in a number of hypertensive states; however, its contribution to genesis and/or maintenance of hypertension is unknown. To longitudinally assess the evolution of plasma renin reactivity in relation to blood pressure in neonatally-induced coarctation hypertension, we have made serial observations in 6 coarcted dogs and in 7 littermate controls over 1-12 months post-aortic-banding during varied steady-state sodium intake. Measurements of renin activity (defined as the increment of angiotensin I-generation rate following addition of exogenous renin to plasma), renin substrate concentration (RS), and plasma renin activity (PRA), together with calculation of plasma renin concentration (PRC) (as PRC = PRA divided by renin reactivity) provided estimates of the three major determinants of PRA. RS values were adjusted for variability due to assay-control and to age via covariate analysis. Results indicate no difference in adjusted RS between coarcted and control dogs, thus obviating the influence of RS differences on renin reactivity results. Renin reactivity and PRC in coarcted dogs were also comparable to control values. Furthermore, responses of RS, renin reactivity and PRC to dietary sodium manipulation were similar in coarcted and control animals. We conclude that circulating modifiers of the renin reaction play no role in the genesis or in the first-year maintenance of neonatally-induced coarctation hypertension.