Volume expansion during acute angiotensin II receptor (AT1) blockade and NOS inhibition in conscious dogs

2002 ◽  
Vol 282 (4) ◽  
pp. R1140-R1148 ◽  
Author(s):  
Jens Lundbæk Andersen ◽  
Niels C. F. Sandgaard ◽  
Peter Bie
Keyword(s):  
Nitric Oxide ◽  
Arterial Pressure ◽  
Sodium Excretion ◽  
Volume Expansion ◽  
Filtration Rate ◽  
Receptor Blockade ◽  
Ang Ii ◽  
Angiotensin Ii Receptor ◽  
Oxide Synthase ◽  
Paired T Test

The responses to AT1-receptor blockade (candesartan 1 mg/kg) and to concomitant volume expansion (saline 35 ml/kg for 90 min) with and without nitric oxide synthase (NOS) inhibition ( N G-nitro-l-arginine methyl ester 30 μg · kg−1 · min−1) were investigated in separate experiments in normal dogs. AT1 blockade decreased arterial pressure (106 ± 4 to 96 ± 5 mmHg) and increased glomerular filtration rate (GFR) by 17% and sodium excretion threefold. NOS inhibition increased arterial pressure (103 ± 3 to 116 ± 3 mmHg) and decreased GFR by 21% and reduced sodium excretion by some 80%. Volume expansion increased arterial pressure significantly in all series involving this procedure, most pronounced during combined AT1 blockade and NOS inhibition (21 ± 4 mmHg). Volume expansion during AT1 blockade elicited marked natriuresis (26 ± 11 to 274 ± 55 μmol/min) that was severely reduced by concomitant NOS inhibition (10 ± 3 to 45 ± 11 μmol/min), but still much larger than that seen with volume expansion during NOS inhibition alone (2 ± 1 to 23 ± 7 μmol/min). Volume expansion during AT1 blockade increased GFR (+30%), less so during combined AT1 blockade and NOS inhibition (+13%), but it did not increase GFR significantly ( P = 0.07) during NOS inhibition alone. Plasma ANG II increased greater than sevenfold with AT1 blockade and doubled with NOS inhibition (paired t-test, P < 0.05), whereas it decreased by 50–80% during volume expansion irrespective of pretreatment, i.e., during NOS inhibition, volume expansion did not generate subnormal plasma ANG II concentrations. In conclusion, 1) acute AT1 blockade leads to hyperfiltration, natriuresis, and hyperresponsiveness to volume expansion, 2) these responses are >85% inhibitable by unspecific NOS inhibition, and 3) NOS inhibition alone is followed by increases in plasma ANG II, hypofiltration, and severe antinatriuresis that may be counterbalanced but not overwhelmed by volume expansion. Thus NOS inhibition virtually abolishes the volume expansion natriuresis, at least in part, due to the lack of appropriate inhibition of the renin-angiotensin-aldosterone system.

Interactions between angiotensin and nitric oxide in the renal response to volume expansion

1995 ◽  
Vol 269 (3) ◽  
pp. R504-R510 ◽  
Author(s):  
M. T. Llinas ◽  
J. D. Gonzalez ◽  
F. J. Salazar
Keyword(s):  
Nitric Oxide ◽  
Sodium Excretion ◽  
Volume Expansion ◽  
Extracellular Volume ◽  
Sodium Reabsorption ◽  
Ang Ii ◽  
Synthesis Inhibition ◽  
Renal Response ◽  
Group 2 ◽  
Extracellular Volume Expansion

This study examined, in anesthetized dogs, the possible interactions between nitric oxide (NO) and angiotensin II (ANG II) in mediating the renal response to an extracellular volume expansion (ECVE). It was found that the intrarenal maintenance of ANG II levels (group 1) or the intrarenal NO synthesis inhibition (group 2) did not induce changes in renal hemodynamics but reduced (P < 0.05) the ECVE-induced increments in sodium excretion and fractional lithium excretion (FeLi). In the third group, ANG II synthesis was inhibited during NO synthesis blockade. It was found in this group that the NO synthesis inhibition reduced the ECVE-induced increment in sodium excretion (P < 0.05) but did not modify the ECVE-induced increment in FeLi. These results suggest that the increase of proximal sodium reabsorption induced by the No synthesis inhibition is mediated by endogenous ANG II levels. In the fourth group, it was observed that NO synthesis inhibition, during the intrarenal maintenance of ANG II levels, induced a decrease of renal blood flow (P < 0.05) and reduced the natriuretic response to ECVE to a lower level (P < 0.05) than that observed in groups 1 and 2. The results of this group suggest that endogenous NO modulates the vasoconstrictor and antinatriuretic effects of ANG II during an ECVE. In summary, the results of this study suggest that there is an important interaction between NO and ANG II in mediating the renal response to an ECVE.

Effects of acute AT1 receptor blockade by candesartan on arterial pressure and renal function in rats

1998 ◽  
Vol 274 (5) ◽  
pp. F940-F945 ◽  
Author(s):  
Ludek Cervenka ◽  
Chi-Tarng Wang ◽  
L. Gabriel Navar
Keyword(s):  
Blood Flow ◽  
Arterial Pressure ◽  
Renal Blood Flow ◽  
Sodium Excretion ◽  
Urine Flow ◽  
Receptor Blockade ◽  
Ang Ii ◽  
Doppler Flowmetry ◽  
Higher Doses ◽  
Very High

Experiments were performed on normal anesthetized rats to determine the effects of candesartan, a novel AT1 receptor antagonist, on the arterial pressure and renal hemodynamic responses to bolus doses of angiotensin II (ANG II) and on renal hemodynamics and sodium excretion. Control arterial pressure responses to bolus ANG II doses of 10, 50, 100 and 1,000 ng were 26 ± 6, 54 ± 7, 57 ± 7, and 79 ± 7 mmHg; the decreases in cortical renal blood flow (CRBF), measured with laser-Doppler flowmetry, were 47 ± 9, 64 ± 8, 71 ± 6, and 82 ± 6%. The vasoconstrictor responses to ANG II up to 1,000 ng were completely blocked by candesartan doses of 1 and 0.1 mg/kg, whereas treatment with 0.01 mg/kg candesartan attenuated the arterial pressure and CRBF responses. The higher doses of candesartan (1 and 0.1 mg/kg) elicited rapid decreases in arterial pressure, leading to associated decreases in sodium excretion. Renal blood flow (RBF), glomerular filtration rate (GFR), and urine flow also decreased following treatment with candesartan at 1 mg/kg. In contrast, when candesartan was given at 0.01 mg/kg, which did not decrease arterial pressure significantly, there were significant increases in GFR (16 ± 4), RBF (9 ± 2), urine flow (11 ± 2), sodium excretion (35 ± 7), and fractional sodium excretion (39 ± 8%). The inability to overcome blockade, even with very high ANG II doses, indicates that candesartan is a potent noncompetitive blocker of ANG II pressor and renal vasoconstrictor effects. The lower candesartan dose that did not cause significant hypotension elicited substantial increases in RBF, GFR, and sodium excretion, revealing the direct renal vasodilator and natriuretic effects of AT1 receptor blockade.

Volume expansion during NOS substrate donation with l-arginine: regulatory offsetting of renal response?

2002 ◽  
Vol 282 (4) ◽  
pp. R1149-R1155 ◽  
Author(s):  
Jens Lundbæk Andersen ◽  
Niels C. F. Sandgaard ◽  
Peter Bie
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Sodium Excretion ◽  
Volume Expansion ◽  
Free Water ◽  
Urine Osmolality ◽  
Urine Flow ◽  
Ang Ii ◽  
Free Water Clearance ◽  
Arterial Blood

The responses to infusion of nitric oxide synthase substrate (l-arginine 3 mg · kg−1 · min−1) and to slow volume expansion (saline 35 ml/kg for 90 min) alone and in combination were investigated in separate experiments. l-Arginine left blood pressure and plasma ANG II unaffected but decreased heart rate (6 ± 2 beats/min) and urine osmolality, increased glomerular filtration rate (GFR) transiently, and caused sustained increases in sodium excretion (fourfold) and urine flow (0.2 ± 0.0 to 0.7 ± 0.1 ml/min). Volume expansion increased arterial blood pressure (102 ± 3 to 114 ± 3 mmHg), elevated GFR persistently by 24%, and enhanced sodium excretion to a peak of 251 ± 31 μmol/min, together with marked increases in urine flow, osmolar and free water clearances, whereas plasma ANG II decreased (8.1 ± 1.7 to 1.6 ± 0.3 pg/ml). Combined volume expansion and l-arginine infusion tended to increase arterial blood pressure and increased GFR by 31%, whereas peak sodium excretion was enhanced to 335 ± 23 μmol/min at plasma ANG II levels of 3.0 ± 1.1 pg/ml; urine flow and osmolar clearance were increased at constant free water clearance. In conclusion, l-arginine 1) increases sodium excretion, 2) decreases basal urine osmolality, 3) exaggerates the natriuretic response to volume expansion by an average of 50% without persistent changes in GFR, and 4) abolishes the increase in free water clearance normally occurring during volume expansion. Thus l-arginine is a natriuretic substance compatible with a role of nitric oxide in sodium homeostasis, possibly by offsetting/shifting the renal response to sodium excess.

Interactions between angiotensin II and nitric oxide during exercise in normal and heart failure rats

1999 ◽  
Vol 87 (2) ◽  
pp. 574-581 ◽  
Author(s):  
J. David Symons ◽  
Charles L. Stebbins ◽  
Timothy I. Musch
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Skeletal Muscle ◽  
Arterial Pressure ◽  
Regional Blood Flow ◽  
Dynamic Exercise ◽  
Treadmill Running ◽  
Receptor Blockade ◽  
Ang Ii ◽  
Vascular Conductance

We hypothesized that nitric oxide (NO) opposes ANG II-induced increases in arterial pressure and reductions in renal, splanchnic, and skeletal muscle vascular conductance during dynamic exercise in normal and heart failure rats. Regional blood flow and vascular conductance were measured during treadmill running before (unblocked exercise) and after 1) ANG II AT1-receptor blockade (losartan, 20 mg/kg ia), 2) NO synthase (NOS) inhibition [ N G-nitro-l-arginine methyl ester (l-NAME); 10 mg/kg ia], or 3) ANG II AT1-receptor blockade + NOS inhibition (combined blockade). Renal conductance during unblocked exercise (4.79 ± 0.31 ml ⋅ 100 g−1 ⋅ min−1 ⋅ mmHg−1) was increased after ANG II AT1-receptor blockade (6.53 ± 0.51 ml ⋅ 100 g−1 ⋅ min−1 ⋅ mmHg−1) and decreased by NOS inhibition (2.12 ± 0.20 ml ⋅ 100 g−1 ⋅ min−1 ⋅ mmHg−1) and combined inhibition (3.96 ± 0.57 ml ⋅ 100 g−1 ⋅ min−1 ⋅ mmHg−1;all P < 0.05 vs. unblocked). In heart failure rats, renal conductance during unblocked exercise (5.50 ± 0.66 ml ⋅ 100 g−1 ⋅ min−1 ⋅ mmHg−1) was increased by ANG II AT1-receptor blockade (8.48 ± 0.83 ml ⋅ 100 g−1 ⋅ min−1 ⋅ mmHg−1) and decreased by NOS inhibition (2.68 ± 0.22 ml ⋅ 100 g−1 ⋅ min−1 ⋅ mmHg−1; both P < 0.05 vs. unblocked), but it was unaltered during combined inhibition (4.65 ± 0.51 ml ⋅ 100 g−1 ⋅ min−1 ⋅ mmHg−1). Because our findings during combined blockade could be predicted from the independent actions of NO and ANG II, no interaction was apparent between these two substances in control or heart failure animals. In skeletal muscle, l-NAME-induced reductions in conductance, compared with unblocked exercise ( P < 0.05), were abolished during combined inhibition in heart failure but not in control rats. These observations suggest that ANG II causes vasoconstriction in skeletal muscle that is masked by NO-evoked dilation in animals with heart failure. Because reductions in vascular conductance between unblocked exercise and combined inhibition were less than would be predicted from the independent actions of NO and ANG II, an interaction exists between these two substances in heart failure rats.l-NAME-induced increases in arterial pressure during treadmill running were attenuated ( P < 0.05) similarly in both groups by combined inhibition. These findings indicate that NO opposes ANG II-induced increases in arterial pressure and in renal and skeletal muscle resistance during dynamic exercise.

Glomerular and tubular interactions between renal adrenergic activity and nitric oxide

1995 ◽  
Vol 268 (6) ◽  
pp. F1004-F1008 ◽  
Author(s):  
F. B. Gabbai ◽  
S. C. Thomson ◽  
O. Peterson ◽  
L. Wead ◽  
K. Malvey ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Glomerular Filtration ◽  
Renal Nerves ◽  
Ang Ii ◽  
Nitric Oxide Synthase Inhibitor ◽  
Adrenergic Activity ◽  
Single Nephron ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Endothelium-dependent nitric oxide (EDNO) exerts control over the processes of glomerular filtration and tubular reabsorption. The importance of the renal nerves to the tonic influence of EDNO in the glomerular microcirculation and proximal tubule was tested by renal micropuncture in euvolemic adult male Munich-Wistar rats. The physical determinants of glomerular filtration and proximal reabsorption were assessed before and during administration of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), in control animals and in animals 5–9 days after either ipsilateral surgical renal denervation (DNX) or after either sham surgery (SHX). L-NMMA caused single-nephron glomerular filtration rate to decline in control and SHX animals but not in DNX rats. L-NMMA caused a reduction in proximal reabsorption in control and SHX rats, which was prevented by prior DNX. DNX did not alter urinary guanosine 3',5'-cyclic monophosphate excretion, and, although DNX upregulates glomerular angiotensin II (ANG II) receptors, prior DNX did not alter intrarenal ANG II content as evaluated by radioimmunoassay. Some component of renal adrenergic activity is required for the full expression of the glomerular and tubular effects of blockade of nitric oxide synthase.

scholarly journals AT II Receptor Blockade and Renal Denervation: Different Interventions with Comparable Renal Effects?

2021 ◽  
pp. 1-11
Author(s):  
Kristina Rodionova ◽  
Martin Hindermann ◽  
Karl Hilgers ◽  
Christian Ott ◽  
Roland E. Schmieder ◽  
...  
Keyword(s):  
Body Weight ◽  
Volume Expansion ◽  
Neural Control ◽  
Renal Denervation ◽  
Urine Volume ◽  
Receptor Blockade ◽  
Ang Ii ◽  
Water Excretion ◽  
Arterial Blood ◽  
Renal Sympathetic

<b><i>Background:</i></b> Angiotensin II (Ang II) and the renal sympathetic nervous system exert a strong influence on renal sodium and water excretion. We tested the hypothesis that already low doses of an Ang II inhibitor (candesartan) will result in similar effects on tubular sodium and water reabsorption in congestive heart failure (CHF) as seen after renal denervation (DNX). <b><i>Methods:</i></b> Measurement of arterial blood pressure, heart rate (HR), renal sympathetic nerve activity (RSNA), glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume, and urinary sodium. To assess neural control of volume homeostasis, 21 days after the induction of CHF via myocardial infarction rats underwent volume expansion (0.9% NaCL; 10% body weight) to decrease RSNA. CHF rat and controls with or without DNX or pretreated with the Ang II type-1 receptor antagonist candesartan (0.5 ug i.v.) were studied. <b><i>Results:</i></b> CHF rats excreted only 68 + 10.2% of the volume load (10% body weight) in 90 min. CHF rats pretreated with candesartan or after DNX excreted from 92 to 103% like controls. Decreases of RSNA induced by volume expansion were impaired in CHF rats but unaffected by candesartan pointing to an intrarenal drug effect. GFR and RPF were not significantly different in controls or CHF. <b><i>Conclusion:</i></b> The prominent function of increased RSNA – retaining salt and water – could no longer be observed after renal Ang II receptor blockade in CHF rats.

Abstract 316: Effects of Inhibiting of Inducible Nitric Oxide Synthase in the Pathophysiology of Experimental Preeclampsia

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Lorena M Amaral ◽  
Ana Carolina T Palei ◽  
Lucas C Pinheiro ◽  
Jonas T Sertorio ◽  
Danielle A Guimaraes ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Inducible Nitric Oxide Synthase ◽  
Inos Expression ◽  
Oxygen Species ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

The pathophysiology of preeclampsia (PE) is not entirely known. However, increased oxidative stress possibly leading to impaired nitric oxide activity has been implicated in the critical condition. Increased oxidative stress with increased levels of highly reactive species including superoxide may generate peroxynitrite. We examined the role of inducible nitric oxide synthase (iNOS) and oxidative stress in the reduced uterine perfusion pressure (RUPP) preeclampsia experimental model. METHODS: RUPP was induced in wistar rats. Pregnant rats in the RUPP group had their aortic artery clipped at day 14 of gestation. After a midline incision, a silver clip (0.203 mm) was placed around the aorta above the iliac bifurcation; silver clips (0.100 mm) were also placed on branches of both the right and left ovarian arteries that supply the uterus. Sham-operated (pregnant control rats) and RUPP rats were treated with oral vehicle or 1 mg/kg/day 1400W (iNOS inhibitor) for 5 days. Mean arterial pressure (MAP) and plasma levels of thiobarbituric acid-reactive species (TBARS) and total radical-trapping antioxidant potential (TRAP) were measured determined. Aortic iNOS expression (Western blotting) and reactive oxygen species (ROS; assessed by fluorescence microscopy with dihydroethidium-DHE) were measured. We found increased mean arterial pressure in RUPP compared with pregnant control rats (MAP= 128±1 vs. 100±1.8 mmHg, respectively; P<0.05) and 1400W exerted antihypertensive effects (MAP= 114±2 vs.128±1 mmHg in RUPP treated and untreated rats, respectively; P<0.05). Higher reactive oxygen species (ROS) concentrations were found in RUPP compared with pregnant control rats (7.1±0.5 vs. 5.1±0.5 arbitrary units (A.U.), respectively; P<0.05) and 1400W decreased ROS production to 5.8±0.02 A.U. in RUPP treated rats, P<0.05. In addition, 1400W attenuated iNOS expression in RUPP rats (0.29±0.02 vs. 0.55±0.8 A.U. in RUPP treated and untreated rats, respectively; P<0.01) and had no effects on plasma TBARS and TRAP levels. Our results suggest that 1400w exerts antihypertensive effects in the RUPP model and suppresses ROS formation. Supported by FAPESP,Cnpq.

scholarly journals Contribution of adenosine to compensatory dilation in hypoperfused contracting human muscles is independent of nitric oxide

2011 ◽  
Vol 110 (5) ◽  
pp. 1181-1189 ◽  
Author(s):  
Darren P. Casey ◽  
Michael J. Joyner
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Steady State ◽  
Arterial Pressure ◽  
Brachial Artery ◽  
Adenosine Receptor ◽  
Receptor Blockade ◽  
Independent Manner ◽  
Control Value ◽  
Percent Recovery

We previously demonstrated that nitric oxide (NO) contributes to compensatory vasodilation in the contracting human forearm subjected to acute hypoperfusion. We examined the potential role of an adenosine-NO interaction to this response in 17 male subjects (25 ± 2 yr). In separate protocols subjects performed rhythmic forearm exercise (20% of maximum) while hypoperfusion was evoked by balloon inflation in the brachial artery above the elbow. Each trial included exercise before inflation, exercise with inflation, and exercise after deflation (3 min each). Forearm blood flow (FBF; ultrasound) and local [brachial artery catheter pressure (BAP)] and systemic [mean arterial pressure (MAP); Finometer] arterial pressure were measured. In protocol 1 ( n = 10), exercise was repeated during nitric oxide synthase inhibition [ NG-monomethyl-l-arginine (l-NMMA)] alone and during l-NMMA-aminophylline (adenosine receptor blockade) administration. In protocol 2, exercise was repeated during aminophylline alone and during aminophylline-l-NMMA. Forearm vascular conductance (FVC; ml·min−1·100 mmHg−1) was calculated from blood flow (ml/min) and BAP (mmHg). Percent recovery in FVC during inflation was calculated as (steady-state inflation + exercise value − nadir)/[steady-state exercise (control) value − nadir]. In protocol 1, percent recovery in FVC was 108 ± 8% during the control (no drug) trial. Percent recovery in FVC was attenuated with inhibition of NO formation alone (78 ± 9%; P < 0.01 vs. control) and was attenuated further with combined inhibition of NO and adenosine (58 ± 9%; P < 0.01 vs. l-NMMA). In protocol 2, percent recovery was reduced with adenosine receptor blockade (74 ± 11% vs. 113 ± 6%, P < 0.01) compared with control drug trials. Percent recovery in FVC was attenuated further with combined inhibition of adenosine and NO (48 ± 11%; P < 0.05 vs. aminophylline). Our data indicate that adenosine contributes to compensatory vasodilation in an NO-independent manner during exercise with acute hypoperfusion.

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