Acute Saline Infusion Research Articles

Quantifying preload alterations using a sensitive chest-mounted accelerometer

Abstract Seismocardiography (SCG) is a technology where the chest wall vibrations from the beating heart are measured using a highly sensitive accelerometer. SCG offers continuous measurement of cardiac function and potential applications include remote monitoring, diagnostic assessments, prognostic health checks and biventricular pacemaker optimization. Aim In the current study we examined how changes in preload influence SCG time intervals, by acute saline infusion. Methods We included twenty-six subjects, sixteen subjects with cardiac disease such as hypertrophic cardiomyopathy, dilated cardiomyopathy, aortic valve disease or ischemic heart disease (age 45.8±17.7 years and 93% male) and ten subjects without known cardiac conditions (age 42.1±14.4 years and 70% male). SCG was recorded from the xiphoid process using a custom-made sensor before and after acute infusion saline (median 2.0 L). The SCG signals were sampled with 5000 samples per second in 60 seconds, the individual heartbeats were identified using a dedicated segmentation algorithm and an average SCG beat was computed and used for the data analysis. Using a recently proposed nomenclature the following SCG fiducial points was identified: Es which coinciding with mitral valve closure, Gs which to some degree coincides with aortic opening, Bd coinciding with aortic valve closure and Fd coinciding with mitral valve opening [1]. The Es-Gs time interval was used as a measure of isovolumetric contraction time (IVCT), the Gs-Bd time interval was used as an estimate of ejection time (ET) and the Bd-Fd time interval as an estimate of isovolumetric relaxation time (IVRT). Paired t-test was used to test for significant response after infusion, while a two sample t-test was used to test for a significant difference in the observed response in subjects with or with our cardiac disease. Results For two subjects SCG after infusion was not obtained thus, twenty-four subjects were included in the final data analysis. In the whole group, acute saline infusion shortened the IVRT (Bd-Fd) from 91.0±15.3 ms to 82.7±15.3 ms (p=0.004) and prolonged the ET (Gs-Bd) from 329.4±35 ms to 343.4±33 ms (p<0.001). There was no significant change in IVCT (Es-Gs) which was 39.5±15.1 ms at baseline and 38.1±14.9 ms post-infusion (p=0.88). There was no significant difference in response between subjects with or without cardiac disease. Conclusion Increase in preload shortened the SCG time intervals related to the isovolumetric relaxation period and prolonged the period related to ejection time. SCG time intervals capture changes in preload, which demonstrates that the SCG is a potential modality for quantification of cardiac dynamics. Funding Acknowledgement Type of funding sources: None.

Quantifying preload alterations using a sensitive chest-mounted accelerometer

Abstract Seismocardiography (SCG) is a technology where the chest wall vibrations from the beating heart are measured using a highly sensitive accelerometer. SCG offers continuous measurement of cardiac function and potential applications include remote monitoring, diagnostic assessments, prognostic health checks and biventricular pacemaker optimization. Aim In the current study we examined how changes in preload influence SCG time intervals, by acute saline infusion. Methods We included twenty-six subjects, sixteen subjects with cardiac disease such as hypertrophic cardiomyopathy, dilated cardiomyopathy, aortic valve disease or ischemic heart disease (age 45.8±17.7 years and 93% male) and ten subjects without known cardiac conditions (age 42.1±14.4 years and 70% male). SCG was recorded from the xiphoid process using a custom-made sensor before and after acute infusion saline (median 2.0 L). The SCG signals were sampled with 5000 samples per second in 60 seconds, the individual heartbeats were identified using a dedicated segmentation algorithm and an average SCG beat was computed and used for the data analysis. Using a recently proposed nomenclature the following SCG fiducial points was identified: Es which coinciding with mitral valve closure, Gs which to some degree coincides with aortic opening, Bd coinciding with aortic valve closure and Fd coinciding with mitral valve opening [1]. The Es-Gs time interval was used as a measure of isovolumetric contraction time (IVCT), the Gs-Bd time interval was used as an estimate of ejection time (ET) and the Bd-Fd time interval as an estimate of isovolumetric relaxation time (IVRT). Paired t-test was used to test for significant response after infusion, while a two sample t-test was used to test for a significant difference in the observed response in subjects with or with our cardiac disease. Results For two subjects SCG after infusion was not obtained thus, twenty-four subjects were included in the final data analysis. In the whole group, acute saline infusion shortened the IVRT (Bd-Fd) from 91.0±15.3 ms to 82.7±15.3 ms (p=0.004) and prolonged the ET (Gs-Bd) from 329.4±35 ms to 343.4±33 ms (p<0.001). There was no significant change in IVCT (Es-Gs) which was 39.5±15.1 ms at baseline and 38.1±14.9 ms post-infusion (p=0.88). There was no significant difference in response between subjects with or without cardiac disease. Conclusion Increase in preload shortened the SCG time intervals related to the isovolumetric relaxation period and prolonged the period related to ejection time. SCG time intervals capture changes in preload, which demonstrates that the SCG is a potential modality for quantification of cardiac dynamics. Funding Acknowledgement Type of funding sources: None.

PROXIMAL TUBULE-SPECIFIC DELETION OF AT1A RECEPTORS ATTENUATES ANGIOTENSIN II-INDUCED HYPERTENSION BY INCREASING GLOMERULAR FILTRATION AND THE PRESSURE-NATRIURESIS RESPONSE

Objective: The present study tested the hypothesis that Ang II and AT1a receptors in the proximal tubules are required for normal blood pressure homeostasis and full development of Ang II-induced hypertension. Design and method: Six groups (n = 7–12 per group) of adult male wild-type (WT) and PT-Agtr1a-/- mice were infused with or without Ang II for 2 weeks (1.5 mg/kg/day, i.p.). Glomerular filtration rate (GFR) was measued using fluorescein-labeled sinistrin, and natriuretic responses were determined under basal conditions and after Ang II infusion. Results: Basal systolic blood pressure were ∼13 ± 3 mmHg lower in PT-Agtr1a-/- than WT mice (P < 0.01). However, basal GFR was higher in PT-Agtr1a-/- mice (WT: 160.4 ± 7.0 μl/min vs. PT-Agtr1a-/-: 186.0 ± 10 μl/min, P < 0.01). Basal 24 h urinary Na+ excretion (UNaV) was higher in PT-Agtr1a-/- than WT mice (P < 0.01). In response to Ang II infusion, both WT and PT-Agtr1a-/- mice developed hypertension with similar pressor response to Ang II in WT (43 ± 3 mmHg, P < 0.01) and PT-Agtr1a-/- mice (39 ± 5 mmHg, P < 0.01). However, systolic blood pressure was still 16 ± 3 mmHg lower in PT-Agtr1a-/- mice (P < 0.01). Ang II decreased GFR to 132.2 ± 7.0 μl/min in WT mice (P < 0.01), and to 129.4 ± 18.6 μl/min in PT-Agtr1a-/- mice (P < 0.01), respectively. In WT mice, UNaV increased from 139.3 ± 22.3 μmol/24 h in the control group to 196.4 ± 29.6 μmol/24 h in the Ang II-infused group (P < 0.01). In PT-Agtr1a-/- mice, UNaV increased from 172.0 ± 10.2 μmol/24 h in the control group to 264.7 ± 35.4 μmol/24 h in the Ang II-infused group (P < 0.01). The pressor response to Ang II was attenuated, while the natriuretic response was augmented by losartan in WT and PT-Agtr1a-/- mice (P < 0.01). Finally, proximal tubule-specific deletion of AT1a receptors significantly augmented the pressure-natriuresis response and natriuretic responses to acute saline infusion (P < 0.01) or a 2% high salt diet for 2 weeks (P < 0.01). Conclusions: The present study supports the hypothesis that Ang II and AT1a receptors in the proximal tubules are required for normal blood pressure homeostasis and the development of Ang II-induced hypertension.

Layer-Specific Strain Is Preload Dependent: Comparison between Speckle-Tracking Echocardiography and Cardiac Magnetic Resonance Feature-Tracking

Speckle-tracking echocardiographic (STE) imaging and cardiac magnetic resonance feature-tracking (CMR-FT) are novel imaging techniques enabling layer-specific quantification of myocardial deformation. Conventional echocardiographic parameters are load dependent, but few studies have investigated the effects of loading conditions on STE and CMR-FT layer-specific strain and the interchangeability of the two modalities. The aim of this study was to evaluate the effects of acute preload augmentation by saline infusion on STE and CMR-FT longitudinal and circumferential layer-specific strain parameters and their intermodal agreement. A total of 80 subjects, including 41 control subjects (mean age, 40±12years; 49% men) and 39 patients with cardiac disease (mean age, 47±15years; 92% men) were examined using STE and CMR-FT layer-specific strain analysis before and after saline infusion (median, 2.0L) with quantification of transmural global longitudinal strain (GLS), epicardial GLS, endocardial GLS, transmural global circumferential strain (GCS), epicardial GCS, and endocardial GCS in addition to epicardial-endocardial gradients. Bland-Altman plots and Pearson correlation coefficients were used to evaluate agreement between the two modalities across all strain parameters. Acute saline infusion increased all STE and CMR-FT layer-specific strain parameters in both groups. STE and CMR-FT GLS increased by 1.4±1.5% and 1.5±2.0% (P<.001) in control subjects and by 0.9±1.8% and 0.9±1.9% (P<.001) in patients with cardiac disease. STE and CMR-FT GCS increased by 2.0±2.2% and 1.8±2.3% (P<.001) in control subjects and by 1.8±2.3% and 1.7±3.6% in patients with cardiac disease (P<.001 and P=.03). STE longitudinal strain correlated strongly with corresponding CMR-FT longitudinal strain (GLS, epicardial GLS, and endocardial GLS: r=0.81, r=0.82, and r=0.81, respectively) despite poor intermodal agreement (bias±limits of agreement, -2.84±4.06%, 0.16±3.68%, and 2.33±3.52%, respectively) whereas GCS, epicardial GCS, and endocardial GCS correlated weakly between the two modalities (r=0.28, r=0.19, and r=0.34, respectively) and displayed poor intermodal agreement (bias±limits of agreement, -1.33±6.86%, 4.43±6.49%, and -9.92±8.55%, respectively). STE and CMR-FT longitudinal and circumferential layer-specific strain parameters are preload dependent in both control subjects and patients with cardiac disease. STE and CMR-FT longitudinal layer-specific strain parameters are strongly correlated, whereas circumferential layer-specific strain parameters are weakly correlated. STE and CMR-FT longitudinal and circumferential strain should not be used interchangeably, because of poor intermodal agreement.

Urinary proteomics reveals key markers of salt sensitivity in hypertensive patients during saline infusion.

Hypertension is a complex disease and is the major cause of cardiovascular complications. In the vast majority of individuals, the aetiology of elevated blood pressure (BP) cannot be determined, thus impairing optimized therapies and prognosis for individual patients. A more precise understanding of the molecular pathogenesis of hypertension remains a pressing priority for both basic and translational research. Here we investigated the effect of salt on naive hypertensive patients in order to better understand the salt intake-blood pressure relationship. Patients underwent an acute saline infusion and were defined as salt-sensitive or salt-resistant according to mean blood pressure changes. Urinary proteome changes during the salt load test were analysed by a label-free quantitative proteomics approach. Our data show that salt-sensitive patients display equal sodium reabsorption as salt-resistant patients, as major sodium transporters show the same behaviour during the salt load. However, salt-sensitive patients regulate the renin angiotensin system (RAS) differently from salt-resistant patients, and upregulate proteins, as epidermal growth factor (EGF) and plasminogen activator, urokinase (PLAU), involved in the regulation of epithelial sodium channel ENaC activity. Salt-sensitive and salt-resistant subjects have similar response to a saline/volume infusion as detected by urinary proteome. However, we identified glutamyl aminopeptidase (ENPEP), PLAU, EGF and Xaa-Pro aminopeptidase 2 precursor XPNPEP2 as key molecules of salt-sensitivity, through modulation of ENaC-dependent sodium reabsorption along the distal tubule.

Abstract P041: Proximal Tubule-specific Deletion Of Angiotensin Ii Type 1a Receptors In The Kidney Lowers Basal Blood Pressure And Attenuates Angiotensin Ii-induced Hypertension By Increasing Glomerular Filtration And The Pressure-natriuresis Response

The present study tested the hypothesis that intratubular angiotensin II (Ang II) and AT 1a receptors in the proximal tubules of the kidney plays an important role in basal blood pressure control and in the development of Ang II-induced hypertension. Mutant mice with proximal tubule-specific deletion of AT 1a receptors in the kidney, PT- Agtr1a -/- , were generated to test the hypothesis. Eight groups (n=7-12 per group) of adult male wild-type (WT) and PT- Agtr1a -/- mice were infused with or without Ang II for 2 weeks (1.5 mg/kg, i.p.). Basal systolic, diastolic, and mean arterial pressures were ~13 ± 3 mmHg lower in PT- Agtr1a -/- than WT mice ( P &lt;0.01). Basal glomerular filtration rate (GFR), as measured using transdermal FITC-sinistrin, was significantly higher in PT- Agtr1a -/- mice (WT: 160.4 ± 7.0 μl/min vs. PT- Agtr1a -/- : 186.0 ± 6.0 μl/min, P &lt;0.05). Basal 24 h urinary Na + excretion (U Na V) was significantly higher in PT- Agtr1a -/- than WT mice ( P &lt;0.01). In response to Ang II infusion, both WT and PT- Agtr1a -/- mice developed hypertension, and the magnitude of the pressor response to Ang II was similar in WT (Δ43 ± 3 mmHg, P &lt;0.01) and PT- Agtr1a -/- mice (Δ39 ± 5 mmHg, P &lt;0.01). However, the absolute blood pressure level was still 16 ± 3 mmHg lower in PT- Agtr1a -/- mice ( P &lt;0.01). Ang II significantly decreased GFR to 132.2 ± 7.0 μl/min in WT mice ( P &lt;0.01), and to 129.4 ± 18.6 μl/min in PT- Agtr1a -/- mice ( P &lt;0.01), respectively. In WT mice, U Na V increased from 139.3 ± 22.3 μmol/24 h in the control group to 196.4 ± 29.6 μmol/24 h in the Ang II-infused group ( P &lt;0.01). In PT- Agtr1a -/- mice, U Na V increased from 172.0 ± 10.2 μmol/24 h in the control group to 264.7 ± 35.4 μmol/24 h in the Ang II-infused group ( P &lt;0.01). The pressor response to Ang II was attenuated, while the natriuretic response was augmented by losartan in WT and PT- Agtr1a -/- mice ( P &lt;0.01). Finally, proximal tubule-specific deletion of AT 1a receptors significantly augmented the pressure-natriuresis response and natriuretic responses to acute saline infusion ( P &lt;0.01) or a 2% high salt diet ( P &lt;0.01). We concluded that deletion of AT 1a receptors selectively in the proximal tubules lowers basal blood pressure and attenuates Ang II-induced hypertension by increasing GFR and promoting the natriuretic response in PT- Agtr1a -/- mice.

Dietary Nitrate Counteracts The Elevated Blood Pressure Response To Nitric Oxide Synthase Inhibition In Humans

Decreased production of nitric oxide (NO) via the endogenous NO-synthase (NOS) pathway is a hallmark of impaired endothelial function and is associated with elevated blood pressure. Potentiation of the alternative nitrate-nitrite-NO pathway via the diet has been suggested as a possible therapeutic strategy to counteract NOS dysfunction, but proof-of-concept that exogenous nitrate treatment compensates in situations of NOS inhibition in humans is lacking. PURPOSE: To determine whether dietary supplementation with nitrate-rich beetroot juice attenuates the detrimental effects of acute NOS inhibition achieved by intravenous infusion of Nω-monomethyl-L-arginine (L-NMMA) on vascular function. METHODS: Seven male volunteers (age 23 ± 3 years, body mass 77.9 ± 6.8 kg) completed four conditions in a double-blind, randomised cross-over design: 1) 5-d dietary placebo supplementation with acute saline infusion (PL-CON), 2) 5-d placebo supplementation with acute L-NMMA infusion (3 mg/kgBM over 5 min followed by 55 μg/kgBM/min; PL-LNMMA), 3) 5-d dietary nitrate supplementation (12 mmol/d) with acute saline infusion (BR-CON), and 4) 5-d nitrate supplementation with acute L-NMMA infusion (BR-LNMMA). Heart rate (HR), brachial mean arterial pressure (MAP), and femoral artery blood flow (FBF) were measured every 5 min during 20 min of infusion and compared between conditions using repeated measures ANOVA. RESULTS: L-NMMA infusion resulted in decreases from baseline in HR (PL-LNMMA -5 ± 3, BR-LNMMA -6 ± 5 bpm) and FBF (PL-LNMMA -114 ± 85, BR-LNMMA -95 ± 71 mL/min) that were greater than after saline infusion (HR: PL-CON -2 ± 5, BR-CON -1 ± 4 bpm, P<0.05; FBF: 20 ± 40 and 18 ± 36 mL/min, P<0.05), with no effects of dietary supplementation. MAP was elevated by L-NMMA (PL-LNMMA 9 ± 2, BR-LNMMA 4 ± 2 mmHg) compared to saline infusion (PL-CON -2 ± 2, BR-CON 0 ± 2 mmHg, P<0.05), and this response was attenuated by ~56% following BR ingestion (P<0.05). CONCLUSIONS: Acute NOS blockade through systemic infusion of L-NMMA resulted in reduced HR and FBF, and elevated MAP, in healthy humans, resembling cardiovascular impairments observed in conditions of chronic NOS-dysfunction. BR attenuated the elevation in MAP, highlighting the potential for exogenous nitrate to improve vascular control in situations where NOS function is impaired.

The Deletion of AT1a Receptors Selectively in The Proximal Tubules of The Kidney Lowers Blood Pressure by Inducing Glomerular Hyperfiltration and Pressure‐Natriuresis Responses in PT‐Agtr1a−/− Mice

The renin‐angiotensin system (RAS) in the proximal tubules of the kidney plays a key role in the physiological regulation of proximal tubular Na+ reabsorption and normal blood pressure homeostasis. Inappropriate activation of intratubular RAS in the proximal tubules may contribute to angiotensin II (Ang II)‐induced hypertension. In the present study, we used proximal tubule‐specific knockout of AT1a receptors (PT‐Agtr1a−/−) in the kidney to test the hypothesis that Ang II and AT1a receptors in the proximal tubules are required for normal blood pressure homeostasis and full development of Ang II‐induced hypertension by altering glomerular filtration and the pressure‐natriuresis responses. To test the hypothesis, six groups (n=7–12 per group) of adult male wild‐type (WT) and PT‐Agtr1a−/− mice were infused with or without Ang II via osmotic minipump for 2 weeks (1.5 mg/kg, i.p.). Glomerular filtration rate (GFR) was monitored by an intradermal device using fluorescein‐labeled sinistrin, and natriuretic responses were determined under basal conditions and after Ang II infusion for 2 weeks. Basal systolic blood pressure were ~13 ± 3 mmHg lower in PT‐Agtr1a−/− than WT mice (P&lt;0.01). However, basal GFR was significantly higher in PT‐Agtr1a−/− mice (WT: 160.4 ± 7.0 μl/min vs. PT‐Agtr1a−/−: 186.0 ± 10 μl/min, P&lt;0.01). Basal 24 h urinary Na+ excretion (UNaV) was significantly higher in PT‐Agtr1a−/− than WT mice (P&lt;0.01). In response to Ang II infusion, both WT and PT‐Agtr1a−/− mice developed hypertension, and the magnitude of the pressor response to Ang II was similar in WT (Δ43 ± 3 mmHg, P&lt;0.01) and PT‐Agtr1a−/− mice (Δ39 ± 5 mmHg, P&lt;0.01). However, the absolute systolic blood pressure level was still 16 ± 3 mmHg lower in PT‐Agtr1a−/− mice (P&lt;0.01). Ang II significantly decreased GFR to 132.2 ± 7.0 μl/min in WT mice (P&lt;0.01), and to 129.4 ± 18.6 μl/min in PT‐Agtr1a−/− mice (P&lt;0.01), respectively. In WT mice, UNaV increased from 139.3 ± 22.3 μmol/24 h in the control group to 196.4 ± 29.6 μmol/24 h in the Ang II‐infused group (P&lt;0.01). In PT‐Agtr1a−/− mice, UNaV increased from 172.0 ± 10.2 μmol/24 h in the control group to 264.7 ± 35.4 μmol/24 h in the Ang II‐infused group (P&lt;0.01). The pressor response to Ang II was attenuated, while the natriuretic response was augmented by losartan in WT and PT‐Agtr1a−/− mice (P&lt;0.01). Finally, proximal tubule‐specific deletion of AT1a receptors significantly augmented the pressure‐natriuresis response and natriuretic responses to acute saline infusion (P&lt;0.01) or a 2% high salt diet for 2 weeks (P&lt;0.01). In conclusion, the present study supports the hypothesis that Ang II and AT1a receptors in the proximal tubules are required for normal blood pressure homeostasis and the full development of Ang II‐induced hypertension, and suggest that deletion of AT1a receptors selectively in the proximal tubules lowers basal blood pressure by inducing glomerular hyperfiltration and promoting the natriuretic response in PT‐Agtr1a−/− mice.Support or Funding InformationThis work was supported in part by NIDDK grants, 2R01DK067299‐06A2, 2R01DK067299‐10A1, 5R01DK102429‐01, and 2R01DK102429‐03A1 to Dr. Zhuo.

Effect of upright posture on natriuresis, sympathetic nerve activity and atrial natriuretic peptide after acute saline infusion in young men with mild essential hypertension

Abnormal sodium excretion by the kidneys contributes to the pathogenesis of essential hypertension. We studied the effect of upright posture on natriuresis and hormone level after a saline infusion in 8 normotensive men (23±2years old<mean±SE>) and 14 men with mild essential hypertension (25±2years old) with normal plasma renin. All subjects were hospitalized and placed on a diet containing sodium chloride at 6g per day. Physiological saline was infused intravenously during 120min at a rate of 8.3mL·min−1, while we measured urinary sodium excretion (UNaV), endogenous creatinine clearance (CCr), renal blood flow (RBF), calculated from p-aminohippuric acid clearance and hematocrit, plasma noradrenalin concentration (PNE) and atrial natriuretic peptide concentration (PANP).

Effect of acute volume overload on the magnitude of T-wave alternans

LETTERS TO THE EDITOREffect of acute volume overload on the magnitude of T-wave alternansJohn E. MadiasJohn E. MadiasPublished Online:01 Aug 2007https://doi.org/10.1152/japplphysiol.00346.2007MoreSectionsPDF (25 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations To the Editor: I read with great interest the contribution by Narayan et al. (1) on the effect of acute volume loading on the magnitude of the T-wave alternans (TWA) in five dogs without structural heart disease. The authors showed that the acute saline infusion led to a rise of pulmonary capillary wedge pressure and an increase of the magnitude of TWA in comparison with the value of TWA found prior to the acute volume infusion. Importantly, the increased magnitude of the TWA after the volume occurred at a lower atrial paced rate than the one noted at baseline. In addition, there was a linear relationship between the volume loading and the increased magnitude of TWA. Although these findings were noted in normal anesthetized dogs undergoing fluid loading, there may be clinical implications for patients with structural heart disease and associated fluid overload. The findings are also of interest in the light of the current climate that the magnitude of TWA and the heart rate at its onset matter and suggest a higher arrhythmic risk than the one associated with TWA of lower magnitude, elicited at higher heart rates. However, one wonders whether the increase in the TWA magnitude following the fluid overload was of primary nature (indicative of a more advanced electrophysiological destabilization), or secondary, due to changes in the overall T-wave magnitude/morphology/axis consequent to the volume overload and resultant heart enlargement. No data on heart volumes were acquired, but the magnitude of the administered fluid infusions would be expected to produce some heart dilation (indeed the authors refer repeatedly to a plausibly induced “stretch,” and its repolarization and arrhythmic consequences), and such increases in end-diastolic volumes elicit the “Brodie effect” (2), characterized electrocardiographically by an augmentation of the QRS complexes; also changes in the corresponding T-waves (secondary) may be noted. Were changes noted after volume infusion in the ECG QRS and/or T-waves, both before and during atrial pacing? Was the increase in magnitude of TWA after fluid infusion totally or partially secondary to the changes in the amplitude (or other attributes) of the T-waves, and could a “crude” adjustment (notwithstanding the complexity of the spectral TWA method) of the increased TWA magnitude values by possibly increased T-wave amplitude render the magnitude of the TWA after the fluid loading less impressively elevated?REFERENCES1 Narayan SM, Drinan DD, Lackey RP, Edman CF. Acute volume overload elevates T-wave alternans magnitude. J Appl Physiol 102: 1462–1468, 2007.Link | ISI | Google Scholar2 Brody DA. A theoretical analysis of intracavitary blood mass influence on the heart-lead relationship. Circ Res 4: 731–738, 1956.Crossref | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: J. E. Madias, Division of Cardiology, Elmhurst Hospital Center, 79–01 Broadway, Elmhurst, NY 11373 (e-mail:[email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByReply to MadiasSanjiv M. Narayan, Darrel D. Drinan, Robert P. Lackey, and Carl F. Edman1 August 2007 | Journal of Applied Physiology, Vol. 103, No. 2 More from this issue > Volume 103Issue 2August 2007Pages 728-728 Copyright & PermissionsCopyright © 2007 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00346.2007PubMed17666734History Published online 1 August 2007 Published in print 1 August 2007 Metrics

Effect of saline infusion on kidney and collecting duct function in atrial natriuretic peptide (ANP) gene "knockout" mice

Atrial natriuretic peptide (ANP) is thought to play a role in renal regulation of salt balance by reducing tubular reabsorption of sodium and chloride. Therefore, in the chronic absence of this hormone, a defect of salt excretion should be evident. We used an ANP gene deletion model to test this premise. F2 homozygous mutant mice (-/-) and their wild-type littermates (+/+) were fed an 8% NaCl diet prior to an acute infusion of isotonic saline. Arterial blood pressures, renal excretions of salt and water, as well as collecting duct transport of fluid and electrolytes were measured. Pressures were significantly higher in -/- compared with +/+ mice (139 +/- 4 vs. 101 +/- 2 mmHg; 1 mmHg = 133.3 Pa). There was no difference in glomerular filtration rate (-/- = 0.84 +/- 0.06; +/+ = 0.81 +/- 0.04 mL x min(-1) x g(-1) kidney weight). In the collecting duct, sodium and chloride reabsorptions were significantly higher in the -/- group than in the +/+ group. As a result, natriuresis and chloruresis were relatively reduced (U(Na)V: -/- = 8.6 +/- 1.1; +/+ = 14.0 +/- 1.1; U(Cl)V: -/- = 10.1 +/- 1.4; +/+ = 16.0 +/- 1.1 micromol x min(-1) x g(-1) kidney weight). We conclude that the absence of endogenous ANP activity in mice on a high-salt diet subjected to acute saline infusion causes inappropriately high reabsorption of sodium and chloride in the medullary collecting duct, resulting in a relative defect in renal excretory capacity for salt.

Acute saline infusion induces extracellular acidification and activation of the Na+/H+ exchanger in man.

The effect of acute expansion of the extracellular fluid volume (ECV) with isotonic (0.9%) saline on the activity of the lymphocyte Na+/H+ antiport (NHE) was studied in a total of 18 healthy volunteers. Saline was infused at a constant rate so that 4 mmol kg-1 b.w. was administered over 2 h. NHE activity was measured by quantifying cytosolic pH (pHi) recovery following acidification of the cells with propionic acid and by pH clamping at various pHi values between 7.2 and 5.8 using nigericin. Both methods demonstrate NHE activation associated with intravenous saline infusion, the kinetic difference being a marked decrease in the Hill coefficient n from 3.28 +/- 0.21 (SEM) to 2.22 +/- 0.11 in the absence of changes in baseline pHi (7.14 +/- 0.02 vs. 7.08 +/- 0.02; P = 0.15), Vmax (42.8 +/- 2.7 vs. 48.1 +/- 2.8 mmol L-1 min-1; P = 0.08) and pK (6.32 +/- 0.04 vs. 6.35 +/- 0.02). NHE activation was associated with significant decreases in serum chloride (P = 0.016), calcium (P = 0.008), total cholesterol (P = 0.008), low-density lipoproteins (P = 0.016) and high-density lipoproteins (P = 0.008). Moreover, saline infusion induced extracellular acidification with a decrease in pH from 7.39 +/- 0.01 to 7.37 +/- 0.01 (P = 0.016), HCO3- from 23.3 +/- 0.43 mmol L-1 to 21.3 +/- 0.25 mmol L-1 (P = 0.008) and base excess from -1.03 +/- 0.38 mmol L-1 to -3.00 +/- 0.31 mmol L-1 (P = 0.008). Our results show for the first time that acute ECV expansion with isotonic saline is followed by an activation of the lymphocyte NHE. The underlying mechanism(s) remain to be investigated. However, the demonstration in our study of marked changes in acid-base balance induced by acute saline points to a possible inter-relationship of antiporter activation and extracellular acidification.

Reduced natriuretic response to increased renal interstitial hydrostatic pressure in Dahl salt-sensitive rats during volume expansion.

Renal interstitial hydrostatic pressure (RIHP) plays a key role in the link between renal hemodynamics and the rate of the tubular reabsorption of sodium and water. Our objective was to determine whether the natriuretic response to a rise in RIHP induced by acute saline infusion would be altered in prehypertensive, Dahl salt-sensitive (DS) rats. We compared the effects of an acute saline load (2.5 ml/100 g BW over 30-min) on RIHP and urinary sodium excretion in Dahl salt-resistant (DR) (n = 11) and DS rats (n = 11) maintained from birth on a low-sodium diet. Baseline mean arterial pressure, glomerular filtration rate rate, and urinary sodium excretion did not differ between DR and prehypertensive DS rats. Urine flow rate and urinary sodium excretion increased significantly in both groups following saline loading. Increases were significantly (p < 0.05) less in the prehypertensive DS rats (0.32 +/- 0.07 to 3.62 +/- 0.79 microEq/min) than in the DR rats (0.71 +/- 0.22 to 6.30 +/- 1.35 microEq/min). RIHP also increased significantly in both groups, but did not differ significantly in DR (7.3 +/- 1.1 to 9.7 +/- 1.7 mmHg) vs. DS rate (7.9 +/- 1.0 to 9.8 +/- 1.3 mmHg). At an equal mean arterial pressure, DS rats showed a reduced natriuretic capacity after an acute saline load, prior to the development of hypertension. Renal tubular sensitivity to the increased RIHP that was induced by an acute saline load was blunted in prehypertensive DS rats.

The effect of intravenous saline loading on plasma levels of brain natriuretic peptide in man

Recent evidence suggests the presence of a dual natriuretic peptide system consisting of atrial natriuretic factor (ANF) from the atrium and brain natriuretic peptide (BNP) from the ventricle. Discrete roles have been postulated for these two natriuretic peptides in the control of circulatory homeostasis. We have therefore compared the release of ANF and BNP in response to an acute saline load to explore a differential pattern of release for the two natriuretic peptides in man. The effects of an acute saline infusion on plasma ANF and BNP concentrations were studied in 10 normal male volunteers. Subjects were studied on two study days in the semirecumbent position. An acute intravenous saline infusion (250 ml/min) of 18 ml/kg isotonic sodium chloride-potassium chloride solution was administered on one of the two study days. No infusion was administered on the other day as a control. Plasma ANF concentrations increased significantly (P < 0.01) with saline loading without any detectable changes in plasma BNP concentrations up to 60 min following infusion. Heart rate and systolic and diastolic blood pressure were unchanged after saline loading. We have shown that an acute intravenous saline load causes an increase in plasma ANF concentrations with no detectable increase in plasma BNP at least up to 60 min after the acute saline load in man. These results support the view that the release of ANF and BNP may be regulated differently, especially with regard to the time required for the acute release of each peptide.

Effects of an acute saline infusion on fluid and electrolyte metabolism in humans.

Several hormonal systems participating in body fluid and electrolyte homeostasis were investigated in six healthy volunteers in a supine body position during a period of 9 days and nights. Under strictly controlled conditions, striking circadian rhythms were observed for plasma levels of vasopressin, renin, aldosterone, guanosine 3',5'-cyclic monophosphate, cortisol, and epinephrine. Nocturnal decreases and diurnal increases in urine flow rate and urinary excretion of electrolytes were observed and closely paralleled the urinary excretion of urodilatin. During 48 h after an acute isotonic saline infusion (2 liters within 25 min) and after a 48-h control experiment the urinary excretion of H2O and electrolytes, and simultaneously the alterations in endocrine systems participating in body fluid homeostasis, were determined. Urine flow and urinary electrolyte excretion rates were significantly increased during 2 days after the saline infusion. The largest increase in urinary fluid and electrolyte excretion was observed between 3 and 22 h postinfusion. These long-term changes were paralleled by altered H2O and Na balances and also by elevated body weights that returned to baseline values with an approximate half-life of 7 h. These data suggest that vasopressin, atrial natriuretic peptide, and catecholamines are unlikely to be of major importance for the renal response to this hypervolemic stimulus. The renin-aldosterone system was suppressed during 2 days postinfusion. This suppression correlated with the effects of saline load on Na excretion. However, the closest relation with Na excretion was observed for the kidney-derived member of the atrial natriuretic peptide family, urodilatin, which was considerably increased during the long-term period up to 22 h postinfusion. Thus these data show that the human body in supine position requires approximately 2 days to regulate the amount of Na and H2O provided by an acute saline infusion. The data also suggest that urodilatin and the renin-aldosterone system might participate in the long-term renal response to an acute saline infusion and also in the mediation of circadian urinary excretion rhythms.

Role of vasopressin in cardiovascular responses to acute and chronic hyperosmolality

Experiments were performed in conscious chronically instrumented rats to determine the role of arginine vasopressin (AVP) in the cardiovascular adjustments to acute and chronic increases in plasma osmolality. Animals were implanted with pulsed Doppler flow probes and arterial and venous catheters for the determination of cardiac output, mean arterial blood pressure (MABP), and heart rate and for the calculation of total peripheral resistance and baroreflex sensitivity (BRS). Before and after raising plasma osmolality by either 48-h water deprivation or acute hypertonic saline infusion, specific V1- or V2-vasopressinergic receptor antagonists or vehicle were administered to the animals, and the cardiovascular responses were noted. MABP was significantly elevated in water-deprived animals. These animals also exhibited significantly increased BRS, which was further increased by administration of the V1-receptor antagonist. Animals subjected to acute hypertonic saline infusion also demonstrated increased MABP, although the infusion, unlike water deprivation, did not affect BRS. We observed no significant effects on any other variable measured. We conclude that AVP plays a relatively minor role in the cardiovascular adjustments to acute and chronic hyperosmolality.

Significant difference in the effect of acute saline loading on plasma Na-K ATPase inhibitor and blood pressure between children and adults with essential hypertension.

Twenty-one male children and 3 male adults with essential hypertension were infused with physiological saline solution (15 ml/kg/hr) for 1 hr after they had been supine for 90 min. The blood pressure and heart rate were monitored, and blood was taken twice before and after the infusion to measure the plasma Na-K ATPase inhibitor. After saline infusion, both the plasma Na-K ATPase inhibitor and blood pressure increased significantly in the hypertensive adults, and the number of Na pump sites decreased. However, such changes were not observed in the hypertensive children. These findings suggest that circulating Na-K ATPase inhibitor may not appear following acute saline infusion in hypertensive children unlike in hypertensive adults, and that the mechanisms regulating cell membrane sodium transport and high blood pressure may differ between hypertensive children and adults.

Renal vascular response to sodium loading in sons of hypertensive parents.

Studies of normotensive offspring of hypertensive parents offer the potential to identify inherited abnormalities that contribute to essential hypertension. We compared renal and systemic hemodynamic responses to saline infusion between normotensive sons of two hypertensive parents (SOHT) and sons of two normotensive parents (SONT) selected from the general population of Rochester, Minn. Hemodynamic measurements were performed after a week of low sodium intake (10 meq/day) and were repeated after a week of high sodium intake (200 meq/day). Despite being in the normotensive range, blood pressures in SOHT were higher than those in SONT during low sodium (124 +/- 3/85 +/- 3 versus 118 +/- 2/71 +/- 2 mm Hg, p less than 0.01) and high sodium (122 +/- 3/80 +/- 3 versus 112 +/- 2/70 +/- 2 mm Hg, p less than 0.05) conditions. Higher pressures in SOHT were associated with elevated systemic and renal vascular resistance. After a high sodium diet, renal vascular resistance in SOHT rose further during acute saline infusion, whereas systemic vascular resistance did not change. After a low sodium diet, this renal vasoconstrictor response to saline infusion in SOHT was not present, and renal vascular resistance fell to levels not different from SONT. Plasma renin activity, aldosterone, and atrial natriuretic peptide did not differ between SONT and SOHT. Circulating levels of norepinephrine were higher in SOHT. These data demonstrate a renal vasoconstrictor response to saline infusion in normotensive SOHT, which depends on prior sodium intake. This alteration in renal hemodynamics may represent an inherited abnormality related to the development of hypertension.

Urodilatin, a kidney-derived natriuretic factor, is excreted with a circadian rhythm and is stimulated by saline infusion in man.

Urodilatin is a recently described, presumably kidney-derived member of the atrial natriuretic peptide family. The first data on a physiological role for urodilatin in the regulation of sodium homeostasis in humans is presented in this work. Urinary urodilatin excretion during a 9-day study in healthy volunteers paralleled the circadian rhythm in urinary sodium excretion. Furthermore, urodilatin and sodium excretion were slightly increased during the first 3 h after an acute isotonic saline infusion and about three-fold elevated during 14 h postinfusion; both parameters remained closely correlated up to 28 h postinfusion. These data suggest that urodilatin is involved in the circadian regulation of sodium excretion and is a physiological regulator of long-term sodium excretion after an acute saline infusion.

Effects of saline loading during head down tilt on ANP and cyclic GMP levels and on urinary fluid excretion

In the present study the renal and humoral effects of acute saline infusions were investigated in six healthy male volunteers before, during and after a ten day period of −6° head-down-tilt (HDT). During the whole 23-day study period the subjects received a standardized diet including 40 ml water and 125 mg NaCl per kg body weight per day. After the infusion of 0.9% saline (22 ml/kg within 20 minutes) plasma atrial natriuretic peptide (ANP) levels were only slightly increased (not significant) at the end of the infusion, while plasma cyclic GMP levels were significantly increased by about 40% (p<0.05) one hour later. No difference was observed in the plasma ANP and cyclic GMP changes between the pre-HDT, the HDT and the post-HDT infusion experiment. Urine flow, sodium excretion and urinary cyclic GMP excretion were significantly increased (p<0.05 and below) by 100 to 300% during the second and third hour after each saline infusion. However, during these short-term periods only 20% of the infused water and less than 20% of the infused sodium were excreted. Furthermore, a significantly increased volume, sodium and cyclic GMP excretion was observed for over 48 hours after each fluid load experiment.These data suggest that HDT does not induce major alterations in the regulation of an acute saline infusion and plasma ANP does not play a major role in the diuretic/natriuretic effects of volume loading.