PubMed Health⌕ Search

Biomedical subjects

W L Rogers

Publications and source records attributed to W L Rogers.

At least 19 recordsLinked to original sources
PubMed1998

Preconditioning in rat hearts is independent of mitochondrial F1F0 ATPase inhibition.

Mitochondrial F1F0 adenosinetriphosphatase (ATPase) is responsible for the majority of ATP synthesis during normoxic conditions, but under ischemic conditions it accounts for significant ATP hydrolysis. A previous study showed that preconditioning in isolated rat hearts is mediated by inhibition of this ATPase during ischemia. We tested this hypothesis in our isolated rat heart model of preconditioning. Preconditioning was accomplished by three 5-min periods of global ischemia separated by 5 min of reperfusion. This was followed by 20 min of global ischemia and 30 min of reperfusion. Preconditioning significantly enhanced reperfusion contractile function and reduced lactate dehydrogenase release but paradoxically reduced the time to onset of contracture during global ischemia. Myocardial ATP was depleted at a faster rate during the prolonged ischemia in preconditioned than in sham-treated hearts, which is consistent with the reduced time to contracture. ATP during reperfusion was repleted more rapidly in preconditioned hearts, which is consistent with their enhanced contractile function. Preconditioning significantly reduced lactate accumulation during the prolonged ischemia. We were not able to demonstrate that mitochondrial F1F0 ATPase (measured in submitochondrial particles) was inhibited by preconditioning before or during the prolonged ischemia. The mitochondrial ATPase inhibitor oligomycin significantly conserved ATP during ischemia and increased the time to the onset of contracture, which is consistent with inhibition of the mitochondrial ATPase. Our results show that preconditioning in rat hearts can be independent of mitochondrial ATPase inhibition as well as ATP conservation.

Adenosine Triphosphate↗
PubMed1998

Cumulation of the tendency to segregate auditory streams: resetting by changes in location and loudness.

In four experiments, the accumulation, over time, of a tendency to hear separate high and low streams in a sequence of high (H) and low (L) tones, presented in a galloping rhythm (HLH-HLH-...), was studied. Each trial was composed of two parts, an induction sequence, then a test sequence, with no break between them. The test sequence was always heard at the far left. When the induction sequence and the test sequence were identical, the presence of the induction sequence increased the tendency for the test sequence to split into two streams. However, when the sequences differed in location (cued by differences in interaural timing or intensity over headphones and by loudspeaker placement in a free field) or when they differed in loudness, the accumulation of the segregative tendency was reset, and the test sequence sounded more integrated. When the induction sequence changed in location or loudness in gradual steps toward the value of the test sequence, resetting was much less. It appears that the accumulation of information about streams in different frequency regions is sensitive to sudden changes in parameters, even when they affect the frequency regions equally. This prevents the system from accumulating data across unrelated events.

Acoustic Stimulation↗
PubMed1996

Renal and depressor activities of inhibitors of neutral endopeptidase and angiotensin converting enzyme in monkeys infused with angiotensin II.

In a previous study, the depressor activity of combined selective inhibitors of neutral endopeptidase EC 3.4.24.11 (NEP) and angiotensin-converting enzyme (ACE) depended on the level of ACE inhibition, whereas the renal responses were determined by NEP inhibition. Our study confirmed that a mixed NEP/ACE inhibitor BMS-182657 ([S-(R*,R*)]-2,3,4,5-tetrahydro-3-[(2-mercapto-1-oxo-3- phenylpropyl)amino]-2-oxo-1H-benzazepine-1-acetic acid) reduced mean arterial pressure (MAP) when renin release was reduced by a sodium load, suggesting that the depressor response did not require suppression of endogenous angiotensin II generation. Furthermore, a pressor dose of 30 ng/min of angiotensin II was required to block the depressor response to BMS-182657 in the presence or absence of exogenous human atrial natriuretic peptide (hANP 99-126). Thirty ng/min of angiotensin II also significantly enhanced the natriuresis induced by hANP 99-126 after BMS-182657 administration. In contrast, a nonpressor dose of angiotensin II (3 ng/min) reduced basal sodium excretion and the natriuretic responses to exogenous hANP 99-126 in the presence or absence of BMS-182657. The potentiation of the urinary ANP and cyclic guanosine monophosphate (cGMP) responses to hANP 99-126 by BMS-182657 was similar for all doses of angiotensin II; therefore angiotensin did not alter the effects of BMS-182657 on ANP metabolism or cGMP accumulation in the kidney. In summary, the renal responses to mixed metalloprotease inhibitors were apparently mediated by ANP potentiation and were modulated by angiotensin II. The depressor activity depended on ACE inhibition but was not mediated solely by reductions in endogenous angiotensin II levels.

Angiotensin II↗
PubMed1996

In vivo pharmacology of dual neutral endopeptidase/angiotensin-converting enzyme inhibitors.

The natriuretic and depressor responses to novel dual inhibitors of neutral endopeptidase (NEP) EC 3.4.24.11 and angiotensin-converting enzyme (ACE) were used to assess their activity in conscious cynomolgus monkeys. A survey of mercaptopropanoyl inhibitors revealed that compounds containing alanylproline or certain surrogates reduced blood pressure and increased sodium excretion, indicating a desirable profile of in vivo activity. Additional compound evaluation required specific in vivo assays for NEP and ACE inhibition. Accordingly, the potency of novel inhibitors against NEP and ACE were determined in conscious monkeys by the potentiation of the natriuretic activity of exogenous human atrial natriuretic peptide and inhibition of the pressor response to angiotensin I, respectively. This strategy led to the discovery that optimal in vivo activity was achieved when the mercaptopropanoyl group was replaced with mercaptoacetyl and the C-terminal alanylproline was replaced with conformationally constrained dipeptidomimetics. This work culminated in the identification of BMS-182657 as a prototypic dual NEP/ACE inhibitor with a highly desirable profile of in vivo pharmacology.

Angiotensin I↗
PubMed1996

Patients' requests and satisfaction with services in an outpatient psychiatric setting.

OBJECTIVE: Patients in four major diagnostic categories were compared to determine if their satisfaction with outpatient services varied. Both overall satisfaction and the degree to which clients and therapists agreed on the importance of 16 aspects of treatment were examined. METHODS: The Patient Request Form (PRF) and the Client Satisfaction Questionnaire were used to interview 464 outpatients. The professional who was the primary contact for each patient filled out a therapist version of the PRF. Diagnoses were grouped into four major categories: anxiety disorders, affective disorders, schizophrenia, and other psychotic disorders. RESULTS: The diagnostic groups differed in overall satisfaction with treatment, treatment characteristics, patients' reasons for coming to the clinic, therapists' descriptions of treatment, and patient-therapist agreement on the importance of different aspects of treatment. Agreement between patients and providers was associated with higher levels of patients' satisfaction. Patients with schizophrenia or with other psychotic disorders had the lowest level of agreement with their therapists and also were the least satisfied. In all patient categories, therapists underestimated the importance to patients of having a reliable source of help. CONCLUSIONS: The greater dissatisfaction expressed by patients with schizophrenia and other psychotic disorders may be related to their therapists' undervaluing the nonbiological aspects of treatment such as social support. Combining medication with psychosocial approaches that have been adapted for patients with psychotic disorders is likely to improve the patients' satisfaction and compliance and increase the overall effectiveness of treatment.

Adult↗
PubMed1996

Determinants of in vivo activity of neutral endopeptidase 3.4.24.11 and angiotensin converting enzyme inhibitors.

Simultaneous inhibition of neutral endopeptidase EC 3.4.24.11 (NEP) and angiotensin converting enzyme (ACE) by equimolar doses (100 mumol/kg i.v.) of SQ 28603 (N-[2-(mercaptomethyl)-1-oxo-3- phenylpropyl]-beta-alanine) and captopril increased sodium excretion by 888 +/- 377 microEq/3 hr and significantly lowered blood pressure by -6 +/- 2 mm Hg in conscious cynomolgus monkeys. This rate of sodium excretion was not significantly different from that elicited by 100 mumol/kg i.v. of SQ 28603 alone (1453 +/- 315 microEq/3 hr). In addition, the natriuretic response to captopril plus SQ 28603 was potentiated by infusion of 10 pmol/kg/min of human atrial natriuretic peptide (hANP 99-126) despite a reduction in renal perfusion pressure from 100 +/- 2 to 86 +/- 2 mm Hg. Lower doses (0.3 to 3 mumol/kg i.v.) of SQ 28603 that had no effect on blood pressure or renal function potentiated the natriuretic, urinary cyclic guanosine monophosphate and atrial natriuretic peptide responses without affecting the depressor activity of 0.3 nmol/kg i.v. of hANP 99-126. The potentiation of the natriuretic activity of 0.3 nmol/kg of hANP 99-126 by 1 or 3 mumol/kg of SQ 28603 was not significantly affected by the addition of equimolar doses of captopril. These results confirmed that the renal responses to the combined inhibitors resulted from NEP inhibition. In contrast, the depressor activity of the combined inhibitors was dependent on the level of ACE inhibition and was not significantly affected by either infusion of hANP 99-126 or prior sodium loading. Therefore, the vascular responses to combined NEP and ACE inhibitors did not necessarily depend upon increases in circulating atrial natriuretic peptide or reductions in angiotensin II levels. The unique profile of renal and vascular responses to combined NEP and ACE inhibition suggested that dual NEP/ACE inhibitors may be useful for the treatment of cardiovascular disorders.

Alanine↗
PubMed1995

alpha-Hydroxy phosphinyl-based inhibitors of human renin.

The design and application of alpha-hydroxy phosphonates, a new class of transition state analogs, toward the discovery of novel and potent inhibitors of the aspartyl protease renin is described. Tripeptidic alpha-hydroxy diethyl phosphonate 3, the first example in this series, was found to be a good inhibitor of human renin (IC50 = 29 nM), and preliminary studies led to the choice of alpha-hydroxy dimethyl phosphonate 15 (IC50 = 16 nM) as a base-line compound for further structure-activity relationship study. Corresponding phosphinate (28-30) and phosphine oxide (23 and 24) analogs of 15 were prepared to assess the steric and electronic requirements around the phosphorus center. Evaluation of these analogs suggested that the presence of at least one alkoxy group on phosphorus was a critical requirement for good activity. Inhibitors with leucine at P2 possessed better in vitro activity than the corresponding P2 histidine analogs (15, IC50 = 16 nM vs 37, IC50 = 220 nM; 33, IC50 = 8.5 nM vs 40, IC50 = 41 nM). Compound 34 (IC50 = 31 nM), the P3 aminocaproic analog of 15, showed complete and long-lasting inhibition of plasma renin activity while eliciting a 10-15 mmHg drop in mean arterial pressure when administered intravenously at 1 mumol/kg in conscious, sodium-depleted, cynomolgus monkeys. In summary, the alpha-hydroxy phosphonates represent a promising and structurally novel class of transition state analog inhibitors of human renin.

Angiotensinogen↗
PubMed1995

Potentiation of natriuretic peptides by neutral endopeptidase inhibitors.

1. Inhibitors of neutral endopeptidase (NEP) EC 3.4.24.11 were developed to regulate endogenous levels of the natriuretic and vasodilatory hormone atrial natriuretic peptide (ANP). The selective NEP inhibitor SQ 28603 enhanced the increases in plasma ANP and urinary excretion of ANP, cyclic GMP and sodium stimulated by infusion of human ANP in conscious monkeys. SQ 28603 also potentiated the renal and depressor responses to rat brain natriuretic peptide (BNP) in conscious spontaneously hypertensive rats (SHR) and human BNP in conscious monkeys. Therefore, selective NEP inhibitors protected both natriuretic peptides from degradation in vivo and enhanced their biological activities. 2. Selective NEP inhibitors lowered blood pressure in conscious DOCA/salt hypertensive rats and SHR with antihypertensive activity similar to that of exogenous ANP. Furthermore, simultaneous treatment with an angiotensin converting enzyme (ACE) inhibitor enhanced the depressor activity of the NEP inhibitor in SHR. 3. SQ 28603 stimulated urinary excretion of cyclic GMP and sodium in a dose-related manner in conscious dogs with tachycardia-induced heart failure. Addition of the ACE inhibitor captopril significantly reduced blood pressure and systemic vascular resistance while sustaining sodium excretion and increasing cardiac output, glomerular filtration rate and renal blood flow. Therefore, combined NEP and ACE inhibition produced a unique haemodynamic and renal profile in dogs with pacing-induced heart failure. 4. The novel dual metalloprotease inhibitor BMS-182657 potentiated the renal responses to exogenous ANP and suppressed the pressor response to angiotensin I in conscious monkeys, indicating in vivo inhibition of both NEP and ACE.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1995

Atrial natriuretic peptide in chronically hypertensive dogs.

We determined the renal and depressor activities of 10, 50, and 100 pmol/kg per minute i.v. of human atrial natriuretic peptide-(99-126) in conscious one-kidney, one clip dogs with chronic hypertension and modest renal dysfunction, as indicated by mild proteinuria. Atrial natriuretic peptide increased fractional sodium excretion by 0.009 +/- 0.002, 0.042 +/- 0.005, and 0.049 +/- 0.007, respectively; urinary excretion of atrial natriuretic peptide by -0.4 +/- 0.8, 3.3 +/- 1.4, and 15.8 +/- 7.4 fmol/min; and cGMP excretion by 0.65 +/- 0.06, 1.65 +/- 0.08, and 4.88 +/- 0.85 nmol/min in one-kidney shams. The changes in fractional sodium excretion were significantly attenuated in the hypertensive dogs (0.005 +/- 0.002, 0.018 +/- 0.003, and 0.022 +/- 0.004, respectively) despite exaggerated increases in atrial natriuretic peptide excretion (3.3 +/- 1.6, 22.0 +/- 5.0, and 46.6 +/- 10.8 fmol/min) and cGMP excretion (0.96 +/- 0.47, 4.51 +/- 1.27, and 7.06 +/- 1.38 nmol/min). The slope of the line relating urinary atrial natriuretic peptide to cGMP was significantly suppressed in the hypertensive dogs, suggesting a downregulation of the guanylate cyclase-linked receptors. The slope of the relationship between cGMP excretion and the natriuretic response was also depressed in the hypertensive dogs, indicating possible impairment of cGMP signal transduction. The differences between sham and hypertensive dogs were diminished when urinary levels of atrial natriuretic peptide were maximized by prior treatment with SQ 28603, an inhibitor of neutral endopeptidase EC 3.4.24.11. Atrial natriuretic peptide caused comparable decreases in mean arterial pressure and increases in glomerular filtration rate in sham and hypertensive dogs, suggesting similar vascular reactivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1995

Simultaneous transmission-emission thallium-201 cardiac SPECT: effect of attenuation correction on myocardial tracer distribution.

UNLABELLED: This study evaluates the effect of attenuation correction on regional myocardial tracer distributions defined by 201TI cardiac perfusion SPECT images obtained from healthy volunteers and patients with coronary heart disease. METHODS: A three-detector SPECT system equipped with an 241Am line source and a fanbeam collimator was used for simultaneous transmission/emission (201TI) tomography on 40 patients and 10 normal volunteers. Uncorrected emission images were reconstructed using filtered backprojection (FBP), whereas the attenuation corrected images were iteratively reconstructed with a regularized, least-squares algorithm utilizing the attenuation map computed from the transmission data. Both sets of images were reoriented into short-axis and vertical long-axis slices. Circumferential profile analysis was applied to both datasets of short-axis slices. RESULTS: The normal volunteers demonstrated improved homogeneity in tracer distribution. For a basal short-axis slice, the lateral-to-posterior activity ratio improved from 1.17 +/- 0.12 for FBP to 1.01 +/- 0.07. Basal attenuation appeared properly compensated as the peak basal-to-apical slice activity gradient along the posterior-inferior wall changed from 1.15 +/- 0.12 for FBP to 1.01 +/- 0.09. The apex of the attenuation corrected images showed a significant decrease in activity relative to the base which appeared consistent with anatomic wall thinning. For the inferior and basal septal regions, the defect severity was slightly less in the attenuation corrected images, but the defects were more sharply defined compared to the FBP image defects. CONCLUSION: These results indicate that attenuation correction is clinically feasible and accurately corrects for photon attenuation. Clinical validation, however, is necessary to define the diagnostic benefits.

Coronary Disease↗
PubMed1994

Sodium loads enhance the natriuretic responses to atrial natriuretic peptide and neutral endopeptidase inhibitors in conscious cynomolgus monkeys.

1. The effects of sodium supplements on the renal responses to human atrial natriuretic peptide (hANP 99-126) and to the selective inhibitors of neutral endopeptidase 3.4.24.11 (NEP) SQ 28,603 and candoxatrilat were determined in conscious monkeys. 2. When the monkeys' diet was changed from 0.55% sodium to 1.1% sodium, the natriuretic response to 100 mumol/kg intravenous of SQ 28,603 increased from 665 +/- 64 to 1015 +/- 224 mu Eq/3 h. An acute oral load of 25 mEq sodium significantly increased the natriuresis stimulated by 300 mumol/kg, p.o., of SQ 28,603 from 700 +/- 332 mu Eq/3 h in normal monkey to 2437 +/- 841 mu Eq/3 h. Therefore, the non-human primate model was appropriate for investigating the effects of sodium loads on the urinary ANP and cGMP responses to exogenous ANP in the presence and absence of NEP inhibitors. 3. Graded intravenous infusions of saline increased basal urine volume and excretion of sodium and ANP. Salt supplements enhanced the diuretic, natriuretic and ANP responses to 0.3 nmol/kg intravenous of hANP 99-126 in monkeys treated with vehicle or 10 mumol/kg intravenous of candoxatrilat. The sodium and ANP excretions stimulated by hANP 99-126 were positively correlated with each other and with the calculated intravenous sodium load in the presence or absence of candoxatrilat. 4. SQ 28,603 and candoxatrilat (0.3 to 10 mumol/kg intravenous) each produced significant, dose-related potentiation of the natriuretic, cGMP and ANP responses to 0.3 nmol/kg intravenous of hANP 99-126 in monkeys receiving 5 mL/kg+0.2 mL/min saline. In addition, the highest dose of SQ 28,603 produced significant depressor activity. 5. In conclusion, the increased natriuretic activity of hANP 99-126 in sodium loaded monkeys was mediated, in part, by increased ANP delivery to the guanylate cyclase linked ANP receptors in the distal renal tubules.

Administration, Oral↗
PubMed1994

Hemodynamic, renal, and hormonal effects of rapid ventricular pacing in conscious dogs.

The interactions of the systemic adaptations during and after rapid ventricular pacing, a model of heart failure, were assessed in conscious, unstressed dogs. One week of ventricular tachycardia (260 beats/min) significantly reduced mean +/- SEM cardiac output (2.3 +/- 0.1 to 1.2 +/- 0.1 liter/min), mean arterial pressure (119 +/- 3 to 93 +/- 3 mm Hg), renal blood flow (168 +/- 19 to 96 +/- 9 ml/min), sodium excretion (36 +/- 5 to 10 +/- 4 mEq/d), increased left and right atrial pressures (8 +/- 1 to 21 +/- 1 and 4 +/- 0 to 11 +/- 1 mm Hg, respectively), plasma atrial natriuretic peptide concentration (24 +/- 4 to 141 +/- 38 fmol/ml), plasma cyclic GMP concentration (9 +/- 1 to 16 +/- 4 pmol/ml), and urinary cyclic GMP excretion (0.77 +/- 0.05 to 2.18 +/- 0.34 nmol/min). These changes persisted throughout 3 weeks of pacing. Gradual increases in systemic and renal vascular resistances (to 122 +/- 17 and 1.30 +/- 0.22 mm Hg/liter/min, respectively) and reductions in glomerular filtration rate (65 +/- 6 to 44 +/- 4 ml/min) reached significance during the third week. Resumption of sinus rhythm stimulated a brisk natriuresis and a return of cardiac output, systemic vascular resistance, and hormone concentrations to control values within 7 days. However, increases of left and right atrial pressures (14 +/- 2 and 8 +/- 1 mm Hg, respectively) were still present after 2 months of recovery. In conclusion, persistent increases in cardiac filling pressures were induced by rapid ventricular pacing in conscious, unstressed dogs, whereas the systemic hemodynamic, renal, and hormonal responses were largely reversible during recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Compartmental analysis of technetium-99m-teboroxime kinetics employing fast dynamic SPECT at rest and stress.

UNLABELLED: We have examined the feasibility of compartmental analysis of 99mTc-teboroxime kinetics in measuring physiological changes in response to adenosine-induced coronary vasodilation. To evaluate the effect of tracer recirculation on 99mTc-teboroxime kinetics in the myocardium, we also compared compartmental analysis with washout analysis (monoexponential fitting), which does not account for this effect. METHODS: Eight healthy male volunteers were imaged using fast dynamic SPECT protocols (5 sec per tomographic image) at rest and during adenosine infusion. A two-compartment model was used and compartmental parameters K1 and k2 (characterizing the diffusion of 99mTc-teboroxime from the blood to the myocardium and from the myocardium to the blood, respectively) were fitted from myocardial time-activity curves and left ventricular input functions. RESULTS: Both K1 and washout estimates for the whole left ventricular myocardium changed significantly in response to coronary vasodilation. Mean stress-to-rest (S/R) ratios were almost two times higher for K1 (S/R = 2.7 +/- 1.1) than for washout estimates (S/R = 1.5 +/- 0.3). Estimation of K1 for all local regions, except the septal wall, is feasible because variations in K1 estimates for all local regions, except the septum during stress, are comparable with those for the global region. CONCLUSIONS: We conclude that quantitative compartmental analysis of 99mTc-teboroxime kinetics provides a sensitive indicator for changes in response to adenosine-induced coronary vasodilation.

Adenosine↗
PubMed1994

Comparison of americium-241 and technetium-99m as transmission sources for attenuation correction of thallium-201 SPECT imaging of the heart.

UNLABELLED: This study compares the ability of 241Am and 99mTc to estimate 201Tl attenuation maps while minimizing the loss in the precision of the emission data. METHODS: A triple-head SPECT system with either an 241Am or 99mTc line source opposite a fan-beam collimator was used to estimate attenuation maps of the thorax of an anthropomorphic phantom. Linear attenuation values at 75 keV for 201Tl were obtained by linear extrapolation of the measured values from 241Am and 99mTc. RESULTS: Lung and soft-tissue estimates from both isotopes showed excellent agreement to within 3% of the measured values for 201Tl. Linear extrapolation did not yield satisfactory estimates for bone from either 241Am (+11.7%) or 99mTc (-15.3%). Patient data were used to estimate the dependence of crosstalk on patient size. Contamination from 201Tl in the transmission window was 5-6 times greater for 241Am compared to 99mTc, while the contamination in the 201Tl data in the transmission-emission detector head (head 1) was 4-5 times greater for 99mTc compared to 241Am. No contamination was detected in the 201Tl emission data of heads 2 and 3 from 241Am, whereas the 99mTc produced a small crosstalk component giving a signal-to-crosstalk ratio near 20:1. Measurements with a fillable chest phantom estimated the mean error introduced into the data from the removal of the crosstalk. CONCLUSION: Based on the measured data, 241Am is a suitable transmission source for simultaneous transmission-emission tomography for 201Tl cardiac studies.

Americium↗
PubMed1994

Potentiation of the renal responses to bradykinin by inhibition of neutral endopeptidase 3.4.24.11 and angiotensin-converting enzyme in anesthetized dogs.

The renal vascular and excretory responses to intrarenal bradykinin were obtained in anesthetized dogs receiving the angiotensin-converting enzyme inhibitor, captopril, and the neutral endopeptidase inhibitor SQ 28,603 (N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-beta-alanine) given individually and together. Intrarenal bradykinin injections of 0.1, 1 and 10 ng/kg, respectively, increased the area over the curve of the renal blood flow response (RBF) by 6 +/- 2, 15 +/- 2 and 101 +/- 8 ml, respectively, sodium excretion by 0.6 +/- 0.4, 2.9 +/- 0.5 and 21.8 +/- 1.3 microEq/min, respectively and urinary cyclic GMP excretion by 23 +/- 12, 56 +/- 22 and 210 +/- 35 pmol/min, respectively. After 10 mumol/kg i.v. of captopril, area over the RBF curve increased by 5 +/- 4, 30 +/- 6 (P < .05) and 142 +/- 14 ml (P < .05), respectively. Captopril also significantly prolonged the sodium response to 10 ng/kg of bradykinin although the peak natriuretic activity (32 +/- 5 microEq/min) was not significantly different from the natriuresis obtained under control conditions (22 +/- 1 microEq/min). In contrast, 30 mumol/kg i.v. of SQ 28,603 increased only the peak natriuretic responses to 1.1 +/- 3.9 (P < .05), 12.1 +/- 8.4 and 40.4 +/- 12.4 (P < .05) microEq/min without prolonging the sodium response or affecting the vascular activity of bradykinin.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1993

Inhibition of neutral endopeptidase 3.4.24.11 in conscious dogs with pacing induced heart failure.

OBJECTIVE: The effects of a selective neutral endopeptidase inhibitor, SQ 28,603 (N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-beta-alanine), were determined in an experimental model of heart failure. METHODS: The symptoms of heart failure were induced by rapid ventricular pacing for one or three weeks in dogs with surgically implanted catheters for measurement of atrial pressures and mean arterial pressure and with ultrasonic flow probes for determination of cardiac output and renal blood flow. RESULTS: Inhibition of neutral endopeptidase by 10, 30, or 100 mumol.kg-1 SQ 28,603 given intravenously increased sodium excretion, cyclic GMP excretion, and plasma concentrations of atrial natriuretic peptide in a dose related manner in conscious dogs paced for one week. SQ 28,603 (100 mumol.kg-1) stimulated similar natriuretic and cyclic GMP responses in dogs paced for three weeks although baseline glomerular filtration rate was reduced. Because the natriuresis was maintained despite the smaller filtered sodium load, the increase in fractional sodium excretion was significantly greater after three weeks of pacing (from 0.5(0.2) to 3.7(0.7)%) than after one week of tachycardia (from 0.1(0.0) to 2.0(0.3)%). By contrast, SQ 28,603 (100 mumol.kg-1) did not affect renal, haemodynamic, or hormonal variables in normal conscious dogs where baseline atrial natriuretic peptide (18(3) fmol.ml-1) was lower than in the paced animals (104(10) fmol.ml-1). CONCLUSIONS: Inhibition of neutral endopeptidase in dogs with pacing induced heart failure protected endogenous atrial natriuretic peptide from degradation and stimulated sustained natriuresis, presumably via a tubular mechanism.

Alanine↗
PubMed1993

An experimental evaluation of three theories of auditory stream segregation.

Three theories of auditory stream segregation were evaluated. In two-part trials, subjects heard an induction sequence, whose effects upon an immediately subsequent test sequence were measured. The rhythm and total duration of Induction Sequence tones were varied in two experiments. The similarity between induction and test sequences aided segregation, but rhythmic predictability and longer tone durations did not. Frequency alternation during the induction sequence was not necessary to induce segregation in the test sequence. Furthermore, peripheral processes inadequately account for the segregation effects found. The data suggest that, once a distinct percept emerges from an auditory scene, properties derived from the percept (particularly changes) are fed back to control the ongoing analysis of that auditory scene. A neural adaptation to stimuli with constant properties may form part of this analysis.

Adult↗