Pressure natriuresis and control of arterial pressure during chronic norepinephrine infusion

The goal of this study was to quantitate changes in mean arterial pressure (MAP) and renal function during chronic increases in plasma levels of norepinephrine, and to determine the role of the renal pressure natriuresis mechanism in controlling sodium balance in norepinephrine hypertension. In six conscious dogs in which renal artery pressure (RAP) was allowed to increase during 7 days of norepinephrine infusion (0.2 micrograms/kg per min), sodium excretion (UNaV) rose from 66 +/- 3 to 112 +/- 15 mmol/day and MAP increased from 100 +/- 3 to 109 +/- 3 mmHg on the first day. On days 2-7, UNaV returned toward the control level while MAP averaged 108 +/- 2 mmHg. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) did not change significantly, averaging 85.9 +/- 4.0 and 235 +/- 17 ml/min, respectively, during 7 days of norepinephrine, compared to controls of 84.1 +/- 3.9 and 252 +/- 20 ml/min. When RAP was servo-controlled for 7 days during norepinephrine infusion, the natriuresis was abolished; UNaV averaged 76 +/- 8 during control, 77 +/- 13 during the first day of norepinephrine and 65 +/- 4 mmol/day during 7 days of norepinephrine. GFR and ERPF did not change significantly during norepinephrine infusion with RAP held constant. MAP did not reach a plateau but continued to rise from 102 +/- 3 to 137 +/- 3 mmHg after 7 days of norepinephrine and servo-control of RAP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Temporal changes in natriuretic and antinatriuretic systems after closure of a large arteriovenous fistula

OBJECTIVE: Surgical closure of a large arteriovenous (A-V) fistula in patients and animals is associated with prompt diuresis and natriuresis. However, the mechanisms underlying these changes remained largely unknown. METHODS: The present study evaluated the hormonal balance between major antinatriuretic systems (plasma renin activity, PRA, and arginine vasopressin, AVP) and natriuretic systems (atrial natriuretic peptide, ANP, and renal nitric oxide, NO) in Wistar rats with an A-V fistula (1.2 mm O.D., side to side) between the abdominal aorta and inferior vena cava. RESULTS: The placement of an A-V fistula caused progressive sodium retention (UNaV decreased from 1500 to 100 microequiv./day), a significant drop in mean arterial blood pressure (MAP) from 127+/-3 to 75+/-2 mmHg (P<0.01), and a significant increase in ANP (from 94+/-12 to 389+/-135 pg/ml, P<0.05), PRA (from 22.1+/-2.0 to 47+/-14 ng angiotensin I [Ang I]/ml/h, P<0.05), AVP (from 14.2+/-3.6 to 37.7+/-9.6 pg/ml, P<0.05), norepinephrine (from 184.2+/-40.5 to 1112.6+/-293.2 pg/ml, P<0.05) and epinephrine (from 667.5+/-175.9 to 2049.8+/-496.9 pg/ml, P<0.05). Furthermore, these changes were associated with a 3-fold increase in the renal medullary immunoreactive levels of endothelial NO synthase (eNOS), an endogenous vasodilator that plays an important role in the regulation of medullary blood flow. After 6 days, rats with A-V fistula and maximal sodium retention underwent surgical closure of the A-V fistula. The A-V fistula closure was associated with dramatic natriuresis (UNaV=2563+/-78 and 1918+/-246 microEq/day on days 3 and 6 following the closure, respectively) and restoration of MAP to normal levels (111+/-6 mmHg); PRA decreased to 29+/-5 ng Ang I/ml/h, AVP to 20.3+/-7.1 pg/ml, and medullary eNOS declined to basal levels, whereas plasma ANP concentrations remained elevated (380+/-90 pg/ml) after 3 days and returned to normal (92+/-12 pg/ml) on day 6. CONCLUSIONS: These results demonstrate that the creation of A-V fistula is associated with activation of both natriuretic and antinatriuretic systems. Closure of A-V fistula is characterized by shifting the balance in favor of the natriuretic substances. Moreover, the observed alterations in medullary eNOS following the creation and closure of A-V fistula suggest that this system, an important determinant of medullary blood flow, may contribute significantly to the regulation of sodium excretion in this model.     

Effect of inhibition of angiotensin converting enzyme on hypertension following kidney transplantation

The activation of the renin angiotensin system is thought to be an important factor contributing to hypertension following kidney transplantation (TX). We studied 21 hypertensive renal transplant recipients, without evidence of acute graft rejection or transplant artery stenosis, 6 to 60 months post-TX. The acute responses of mean arterial pressure (MAP) and renal hemodynamics (ERPF: effective renal plasma flow, 131I-Hippuran clearance) and function (GFR: glomerular filtration rate, creatinine clearance; UNaV: urinary sodium excretion rate) to converting enzyme inhibition (CEI) by captopril were assessed. CEI induced a decrease in MAP (118 +/- 2 to 110 +/- 2 mmHg), renal resistance (RR: 0.27 +/- 0.02 to 0.21 +/- 0.01) and filtration fraction (FF: 0.31 +/- 0.02 to 0.23 +/- 0.01). ERPF (307 +/- 24 to 333 +/- 18 ml/min/1.73 m2) and GFR (88 +/- 5 to 78 +/- 5 ml/min/1.73 m2) were not significantly changed. UNaV increased by 53 +/- 24 mumol/min. Changes in MAP (r = -0.66), ERPF (r = 0.74) and FF (r = -0.88) were significantly correlated with the log of control plasma renin activity (PRA). In 10 patients with an increase of ERPF (range: + 30 to + 70%) and no change in GFR, the activated renin system could originate from the recipient's own kidneys. In the remaining 11 patients, CEI was associated with no increase in ERPF (change: + 2 to - 27%) and a fall in GFR, a response suggesting a possible intrarenal vascular damage. These results indicate that RAS participates in the regulation of systemic and renal vascular tone, with a possible predominant effect on efferent glomerular arteriole.     

Renal and adrenal resistance against atrial natriuretic peptide in congestive heart failure: effect of angiotensin I-converting-enzyme inhibition

We compared the natriuretic and diuretic effect of an intravenous infusion of 1-28 human atrial natriuretic peptide (hANP) (0.1 micrograms/kg/min over 30 min) in 10 patients with congestive heart failure (CHF) and in 10 control subjects of similar age and sex. In the controls, urine volume rose from 36.8 +/- 8.55 to 115.6 +/- 34.2 ml/30 min and urinary sodium excretion from 4.55 +/- 0.8 to 11.2 +/- 2.24 mEq/30 min before and during the infusion of ANP, respectively. In patients, baseline urine volume and sodium output were similar, however, rise in urine volume and urinary sodium was greatly reduced during the infusion of hANP. In patients with CHF, baseline plasma ANP levels (604.1 +/- 135.3 vs. 39.4 +/- 5.85 pg/ml; p less than 0.005) and urinary excretion of cyclic GMP (cGMP) (41.8 +/- 5.22 vs. 15.2 +/- 4.19 nmol/30 min; p less than 0.05) were significantly elevated compared to controls. The absolute and relative rise in cGMP excretion, however, was blunted in patients with CHF. In the controls, angiotensin I-converting-enzyme (ACE) inhibition by enalapril significantly reduced the urinary output of sodium and water after ANP infusion. Plasma ANP levels and urinary cGMP remained unaltered by ACE inhibition. Furthermore, treatment with enalapril resulted in a rise in renin and a drop in aldosterone levels. The reduction of plasma renin and serum aldosterone by ANP was maintained after ACE inhibition. In the patient group, administration of enalapril (3 X 2.5 mg every 6 h) reduced ACE activity in the serum from 84.7 +/- 16.9 to 2.13 +/- 0.88 U/l. Arterial blood pressure was lowered from 114.7 +/- 6.69 to 106.1 +/- 7.25 mm Hg systolic and from 76.9 +/- 3 to 69.2 +/- 3.7 mm Hg diastolic. However, natriuresis and diuresis and creatinine clearance following infusion of ANP remained unaltered.     

Renal effects of atrial natriuretic peptide during dopamine infusion

To study whether the renal effects of atrial natriuretic peptide (ANP) are different from those of dopamine, we compared the effects of dopamine and dopamine plus ANP on renal circulation. Dopamine was infused at 1 microgram/kg/min for 120 min into 7 patients with essential hypertension (EH) and 5 normotensive subjects (NT). After 40 min of dopamine infusion, ANP infusion at 25 ng/kg/min was added to dopamine for 40 min. Before, during and after the infusion, renal function and nephrogenous cGMP were determined. Dopamine did not influence blood pressure, but increased urinary Na excretion (UNaV) by 100% in EH and NT. Addition of ANP further increased UNaV by 90%, but increases in UNaV were greater in EH than in NT. Renal blood flow was increased only by dopamine, while glomerular filtration rate (GFR) was increased by both dopamine (+8%) and dopamine plus ANP (+7%) as a whole, resulting in a significant increase in filtration fraction by the addition of ANP. Plasma and urinary cGMP and nephrogenous cGMP were elevated only during ANP infusion. These results suggest that the effects of ANP and dopamine on both GFR and UNaV were additive. However, in contrast with dopamine, ANP increased efferent resistance and nephrogenous cGMP, suggesting that the renal effects of ANP are different from those of dopamine.     

Effects of centrally administered atrial natriuretic peptide on renal functions

In order to assess the effects of centrally administered atrial natriuretic peptide (ANP) on renal water and electrolytes handling, arterial blood pressure, plasma vasopressin, renin activity, aldosterone, and ANP concentrations, synthetic alpha-human ANP (alpha-hANP) was administered intracerebroventricularly at a dose of 2.6 pmol.kg-1.min-1 for 30 min in pentobarbital-anaesthetized dogs (N = 6). In the control study (N = 6), artificial cerebrospinal fluid was infused. Intracerebroventricular administration of alpha-hANP increased significantly urine flow from 178 +/- 37 to 303 +/- 43 microliter/min (mean +/- SEM), sodium excretion from 27.3 +/- 8.9 to 54.4 +/- 10.5, mumol/min, potassium excretion from 16.1 +/- 3.7 to 24.0 +/- 5.1 mumol/min, and osmolar and negative free water clearances, accompanied by a significant rise in renal blood flow from 77.0 +/- 14.6 to 94.9 +/- 16.9 ml/min. Whereas glomerular filtration rate fell significantly, blood pressure and heart rate did not change. Plasma ANP, aldosterone, and PRA did not change significantly during the experiment, but plasma AVP were slightly but significantly decreased from 52 +/- 11 to 34 +/- 6 nmol/l. On the other hand, these parameters showed no changes in the control study, except a significant fall in glomerular filtration rate and a significant rise in PRA. Thus, it has been confirmed that ANP centrally brings about diuresis, natriuresis, and kaliuresis via some unknown mechanisms independent of the release of these hormones.     

Role of atrial natriuretic polypeptides for exaggerated natriuresis in essential hypertension

Eighteen patients with essential hypertension were separated into 2 groups, renin-unresponsive and renin-responsive, on the basis of their plasma renin response when challenged by furosemide and upright posture. The response to acute infusion of hypertonic saline solution (1.4% saline solution at a rate of 0.3 ml/min/kg over 60 minutes) was then studied. In the renin-unresponsive group, peak rate of fractional excretion of sodium and peak urine flow after saline loading were 7.6 +/- 0.7% and 476 +/- 34 ml/hour, respectively, and peak value of atrial natriuretic polypeptides (ANP) was 784 +/- 140 pg/ml. In the renin-responsive group, the values were 3.1 +/- 0.4%, 194 +/- 29 ml/hour and 115 +/- 33 pg/ml. Both fractional excretion of sodium, urine flow and ANP response were significantly higher (p less than 0.01) in the renin-unresponsive group. Moreover, a highly significant relation (r = 0.82, p less than 0.01) was observed between fractional excretion of sodium and ANP levels in all hypertensive patients. The degree of saline-induced natriuresis was not related to blood pressure, heart rate, endogenous creatinine clearance, antidiuretic hormone or preexisting level of aldosterone. Plasma renin activity changed little in either group during saline infusion, but tended to be higher at all times in the renin-responsive patients. The present findings suggest that the enhanced secretion of ANP is an important determinant for exaggerated natriuresis observed in patients with renin-unresponsive hypertension.     

Effects of repeated atrial natriuretic peptide bolus injections in cirrhotic patients with refractory ascites

The renal and hormonal effects of repeated atrial natriuretic peptide (ANP) boli (1 microgram/kg of body weight) were studied in eight cirrhotic patients with refractory ascites. Under basal conditions the patients showed a striking activation of the renin-angiotensin-aldosterone system (plasma renin activity 19.3 +/- 3.0 ng/ml.h, plasma aldosterone concentration 3.87 +/- 0.58 ng/ml) and a tenfold elevation in plasma ANP levels compared to healthy subjects (131.7, range 47.0-288.6, vs. 9.8, range 5.0-15.0, fmol/ml, p less than 0.001). The first ANP injection was followed by a remarkable increase in plasma ANP levels and by a slight increase in urinary cyclic guanosine-monophosphate excretion (from 1050.8 +/- 454.8 to 1446.6 +/- 822.2 pmol/min). A significant reduction of mean blood pressure (MBP) occurred 5 min after the first injection (from 86.7 +/- 7.2 to 79.9 +/- 5.8 mmHg, p less than 0.05), but values gradually returned to the baseline after 30 min. Heart rate (HR) increased 10 min after the first bolus injection (from 83.75 +/- 4.7 to 88.1 +/- 4.6 beats/min) and reached baseline values after 30 min. Similar behaviour of MBP and HR was observed after the second, third and fourth bolus injections. Urinary sodium excretion, urinary flow, glomerular filtration rate, plasma renin activity, and plasma aldosterone concentration did not show any significant modification during ANP administration, nor did these parameters change in the following 12-h recovery period.(ABSTRACT TRUNCATED AT 250 WORDS)     

The modulating actions of sulfonylurea on atrial natriuretic peptide release in experimental acute heart failure

OBJECTIVES: This study defined the modulating actions of sulfonylurea on acute release of atrial natriuretic peptide (ANP) in experimental acute heart failure. BACKGROUND: Sulfonylurea drugs, blockers of cardioprotective ATP-sensitive K(+) (K(ATP)) channels, may increase the risk of early cardiovascular mortality. In cardiovascular diseases such as acute heart failure, early release of ANP is essential for cardiorenal homeostasis. Although K(ATP) channels regulate secretion of hormones, such as insulin, it is unknown whether sulfonylureas interfere with ANP release in acute heart failure. METHODS: The effects of acute administration of glyburide (0.3 mg/kg), a prototype sulfonylurea, on ANP release and sodium excretion were measured in vivo in a canine model of pacing-induced acute heart failure characterized by acute atrial stretch. Immunoreactivity, in atrial tissue, for ANP and the K(ATP) channel subunit, Kir6.2, was determined using specific antibodies. RESULTS: With increased left atrial pressure in heart failure, plasma levels of ANP increased rapidly and peaked within 25+/-3 min. Glyburide delayed the time required for peak plasma ANP secretion to 48+/-5 min. This resulted in reduced natriuresis from 84+/-17 microEq/min in the absence of glyburide, to 34+/-9 microEq/min in the presence of glyburide. However, glyburide did not alter the renal natriuretic responsiveness to exogenously administered ANP in normal dogs. In atrial tissue, both ANP and the K(ATP) channel subunit, Kir6.2, displayed strong immunoreactivity and co-localization. CONCLUSIONS: Glyburide delays release of ANP in acute heart failure resulting in impaired natriuresis. This cannot be ascribed to an antinatriuretic effect on the kidney, but rather may be due to interference with K(ATP) channel-dependent ANP secretion from the atrium. Such adverse outcome of sulfonylurea drug use could reduce the compensatory capacity to preserve cardiorenal homeostasis in acute heart failure.     

Responses of the stenosed and contralateral kidneys to [Sar1, Thr8] AII in human renovascular hypertension

To better define the intrarenal hemodynamic effects of angiotensin in human renovascular hypertension, 10 patients underwent renal hemodynamic and functional measurements before and during infusion of a competitive angiotensin analog, [Sar1, Thr8] AII. Eight had technically satisfactory split function studies. Despite a fall in mean arterial pressure (132 +/- 6 to 121 +/- 6 mm Hg, p less than 0.05) and humoral changes consistent with angiotensin-mediated hypertension, the intrarenal effects of this analog were commonly those of an angiotensin agonist, producing vasoconstriction and sodium retention. This was quantitatively greatest in the contralateral kidney, whose preinfusion sodium excretion (86 +/- 30 microEq/min vs 25 +/- 9 microEq/min, p less than 0.02) and glomerular filtration rate (76 +/- 7 ml/min vs 41 +/- 7 ml/min, p less than 0.01) were higher than the stenotic kidney. In some cases, an increase in renal blood flow and rise in sodium excretion were evident during angiotensin blockade, suggesting a tonic intrarenal action of angiotensin. Although renin vein renin values differed markedly between the stenotic and contralateral kidney (ratio = 2.05 +/- 0.30), relative changes in effective renal plasma flow were correlated (r = 0.84: p less than 0.01) during infusion of this analog. These results underscore the differences in sensitivities between vascular beds to the effects of angiotensin II and the major role of the contralateral kidney in renal function and sodium homeostasis in human renovascular hypertension.     

Attenuated natriuretic response to adrenomedullin in experimental heart failure

BACKGROUND: The recently discovered vasodilating and positive inotropic peptide, adrenomedullin (ADM), has strong natriuretic actions. ADM-induced natriuresis is caused by an increase in glomerular filtration rate and a decrease in distal tubular sodium reabsorption. Although ADM is activated in human and experimental heart failure, the role of ADM in the kidney in heart failure remains undefined. METHODS AND RESULTS: The present study was performed to determine the renal hemodynamic and urinary excretory actions of exogenously administered ADM in a canine model of acute heart failure produced by rapid ventricular pacing. Experimental acute heart failure was characterized by a decrease in cardiac output and an increase in pulmonary capillary wedge pressure with an increase in plasma ADM concentration. Intrarenal infusion of ADM (1 and 25 ng/kg/min) induced an increase in urinary sodium excretion in the normal control dogs (change in urinary sodium excretion [Delta UNaV], +94.5 microEq/min during 1 ng/kg/min ADM infusion and +128.1 microEq/min during 25 ng/kg/min ADM infusion). In the acute heart failure dogs, intrarenal ADM infusion resulted in an attenuated increase in urinary sodium excretion (Delta UNaV, +44.8 microEq/min during 1 ng/kg/min ADM infusion and +51.8 microEq/min during 25 ng/kg/min ADM infusion). Both glomerular and tubular actions of ADM were attenuated in the acute heart failure group compared with responses in the normal control group. CONCLUSION: The present study shows that the renal natriuretic responses to ADM are markedly attenuated in experimental acute heart failure. This study provides insight into humoral mechanisms that may promote sodium retention in heart failure via a renal hyporesponsiveness to natriuretic actions of ADM.     

Bed-rest-induced hypernatriuresis in cirrhotic patients without ascites: does it contribute to maintain 'compensation'?

Renal function, plasma renin activity, plasma aldosterone concentration and urine excretion of free norepinephrine were evaluated in 13 cirrhotics without previous or ongoing ascites and in 13 healthy subjects, after 6 days of controlled electrolyte intake (40 mmol of Na and 70 mmol of K per day) and during 24 h of recumbency. Plasma concentrations of the atrial natriuretic peptide (ANP) were also measured in 8 patients and 8 controls. Despite a low-normal filtered load of sodium (14.6 +/- 1.2 vs. 17.1 +/- 1.2 mmol/min), cirrhotic patients showed supernormal natriuresis (141.5 +/- 14.1 vs. 78.8 +/- 8.6 mmol/day; p < 0.001). Whereas the fractional excretion of sodium in these patients was twice that of controls (0.70 +/- 0.05 vs. 0.36 +/- 0.04%; p < 0.001), potassium excretion (42.5 +/- 2.7 vs. 43.1 +/- 2.7 mmol/day) and urine volume (1270 +/- 98 vs. 1452 +/- 148 ml/day) did not differ. In cirrhotics, plasma renin activity was reduced (0.50 +/- 0.12 vs. 1.39 +/- 0.33 ng/ml/h; p < 0.02), and plasma aldosterone concentration tended to be lower (66 +/- 10 vs. 86 +/- 9 pg/ml; p = 0.09), while urine norepinephrine excretion did not significantly differ from controls (961 +/- 120 vs. 782 +/- 43 ng/h). ANP was higher in patients than in controls (92 +/- 17 vs. 48 +/- 9 pg/ml; p < 0.05). Natriuresis was directly correlated with ANP (r = 0.69, p < 0.005) and ANP/plasma aldosterone ratio (r = 0.63; p < 0.01) in patients and healthy subjects taken together.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiorenal effects of atrial natriuretic factor administration in congestive heart failure: natriuresis and diuresis without hemodynamic alterations

The effects of low bolus dose (70 +/- 6 micrograms [mean +/- SEM]) atrial natriuretic factor (ANF) administration was assessed in 16 patients with chronic congestive heart failure. Measurements were made for at least 60 minutes before and after the dose of ANF. There was a significant increase in urine flow rate (0.81 +/- 0.06 to 1.81 +/- 0.23 ml/min, p less than 0.01), sodium excretion rate (56 +/- 14 to 80 +/- 23 microEq/min, p less than 0.01), fractional excretion of sodium (1.23 +/- 0.49 to 1.63 +/- 0.60 percent, p less than 0.01) and potassium excretion rate (35 +/- 7 to 42 +/- 6 microEq/min, p less than 0.02). However, no significant alterations in renal plasma flow or glomerular filtration rate were observed. Furthermore, there was no significant correlation between the change in urine flow rate or sodium excretion rate and the change in renal plasma flow or glomerular filtration rate, respectively. In addition, there was no significant effect on cardiac index, mean aortic or left ventricular filling pressures, or systemic vascular resistance. There also was no discernible relationship between the response to ANF and the baseline concentrations of plasma ANF, aldosterone, or plasma renin activity. Thus, in patients with congestive heart failure, low dose ANF boluses may produce an increase in urine flow rate and sodium excretion rate that is independent of renal plasma flow or glomerular filtration rate. This suggests a meaningful direct renal tubular effect of exogenous ANF in this setting.     

Relationships among endotoxemia, arterial pressure, and renal function in dogs

This study evaluated the effects of increasing plasma endotoxin (Difco 055:B5) concentration by intravenous and intrarenal infusion on renal hemodynamics and renal function. Plasma endotoxin was increased to 130-150 ng/ml (infusion rate of 32 micrograms/min) in two groups of dogs and changes in plasma endotoxin concentration were correlated with arterial pressure (AP), glomerular filtration rate (GFR), renal blood flow (RBF), and urinary sodium excretion (UNaV) for 4 hr. In group 1, intrarenal endotoxin infusion decreased AP, GFR, RBF, and UNaV equally between infused and contralateral noninfused kidneys. In dogs with unilateral renal denervation (group 2), intravenous endotoxin maximally decreased AP, GFR, RBF, and UNaV in both kidneys by 90 min. Despite continued endotoxin infusion, RBF and GFR then spontaneously increased after 90 min, and by 240 min these values were significantly greater in the innervated kidneys compared with denervated kidneys (P less than 0.05). In both groups of dogs, the spontaneous increase in GFR and RBF was associated with a spontaneous increase in arterial pressure. These data suggest that renal dysfunction during moderate endotoxemia may be mediated by systemic hemodynamic changes rather than by direct intrarenal toxicity and that renal innervation may protect against endotoxin-induced reductions in RBF and GFR.     

Effects of fenoldopam,a dopamine D-1 agonist,and clevidipine,a calcium channel antagonist,in acute renal failure in anesthetized rats

The present studies were conducted to: a) comparatively evaluate the effects of clevidipine, a new dihydropyridine calcium antagonist, and fenoldopam, a dopamine (D-1) receptor agonist on basal renal function, and b) to determine the efficacy of these agents in protecting renal function in an experimental model of ischemia/reperfusion (I/R) induced acute renal failure in rats. Infusions of either clevidipine or fenoldopam (5.0 nmol/kg(-1) min(-1) i.v. for 60 min) produced significant increases in urine flow (UV), urinary sodium excretion (UNaV), and fractional excretion of sodium (FENa) in inactin anesthetized rats. Unlike clevidipine, fenoldopam also produced significant increases in renal blood flow (RBF) and urinary potassium excretion (UKV). In a separate series, unilateral renal failure was induced in anesthetized rats by occluding the left renal artery for 40 min followed by reperfusion. In this model, there was a 70-75% reduction in the GFR that was paradoxically associated with several fold increases in UV, UNaV, and FENa in the vehicle treated group. In two separate groups, infusions of neither clevidipine nor fenoldopam (5.0 nmol/kg(-1) min(-1)) for 60 min beginning 10 min before reperfusion, improved filtration fraction. However, clevidipine treatment markedly improved tubular function in that loss of sodium and water were significantly attenuated and UV and UNaV were restored towards basal levels. In contrast, in the fenoldopam group, tubular function was further deteriorated as evidenced by exacerbated losses of sodium and water. These observations suggest that whereas both clevidipine and fenoldopam were potent natriuretic agents, only the calcium antagonist was effective in preserving renal function in the present experimental model of ischemic renal failure.     

Atrial natriuretic peptide in liver cirrhosis with mild ascites

To clarify the involvement of atrial natriuretic peptide (ANP) in the pathogenesis of liver cirrhosis, we measured plasma ANP in patients with various stages of cirrhosis and in age-matched normal subjects. Urinary cyclic guanosine monophosphate (cGMP) was also measured as a marker of active biological ANP. In addition, effects of exogenous synthetic human ANP (0.5 micrograms/kg) on renal functions were examined in normal subjects and in cirrhotics without ascites or with mild ascites. Plasma ANP levels were not significantly different among these 3 groups. Urinary cGMP concentrations were significantly higher in both cirrhotics without ascites and cirrhotics with mild ascites, (340 pmol/ml, P less than 0.05 and 496 pmol/ml, P less than 0.01 respectively) than normal subjects (95 pmol/ml). In normal subjects, marked increases in urinary volume (UV), sodium excretion (UNaV), fraction excretion of sodium (FENa) and free water clearance (CH2O) were induced after ANP infusion, and significant recoveries were subsequently observed in these parameters. However, in cirrhotics, the responses to ANP infusion of UV, FENa and CH2O were far less dramatic. The response of UV, UNaV and FENa in cirrhotics with mild ascites was delayed compared to cirrhotics without ascites. These results suggest that the blunted natriuretic responsiveness to ANP is contributory to the pathogenesis of initial sodium retention in cirrhotics.     

The effect of fenoldopam on renal haemodynamics and natriuresis in chronic renal failure

The effect of oral administration of fenoldopam, a dopamine-1 receptor agonist, on blood pressure, renal haemodynamics and natriuresis was studied in 12 patients with chronic renal insufficiency. In addition, the effect of administering a low intravenous dose of fenoldopam on top of the oral dose was compared with the effect of the same intravenous dose given immediately before oral fenoldopam. Oral administration of fenoldopam (50 mg t.i.d. for 3 +/- 1 days followed by 100 mg t.i.d. for 8 +/- 1 days) induced a significant fall in blood pressure (median MAP from 107 to 101 mm Hg). Compared to baseline values, body weight, effective renal plasma flow (ERPF), glomerular filtration rate (GFR) and fractional sodium excretion remained unchanged. Infusion of fenoldopam (0.05-0.1 micrograms/kg/min) on day 1 led to a significant fall in blood pressure (median mean arterial pressure from 107.0 to 98.5 mm Hg), and a significant rise in effective renal plasma flow (median ERPF from 132 to 146 ml/min/1.73 m2). Median fractional sodium excretion increased significantly from 2.1 to 3.3%. GFR, filtration fraction and plasma aldosterone concentration did not change. No relationship was found between the fenoldopam-induced changes in ERPF and natriuresis, nor between baseline GFR or ERPF and fenoldopam-induced urinary sodium loss. Infusion of fenoldopam while patients were on oral fenoldopam had no effect on blood pressure, ERPF or GFR. However, again natriuresis was induced, which did not differ significantly from the fenoldopam-induced natriuresis on day 1. We conclude that oral fenoldopam has a moderate blood pressure lowering effect in patients with chronic renal insufficiency, but exerts no effect on ERPF or GFR. Secondly, a fenoldopam-induced natriuresis does not appear to be related to changes in ERPF or aldosterone secretion.     

Role of prostaglandins in mediating the renal effects of atrial natriuretic factor

The natriuretic response to the intrarenal administration of atrial natriuretic factor (ANF) is accompanied by an increase in the synthesis of prostaglandins and by a redistribution of renal blood flow from the superficial to the deep cortex. This study was undertaken to define whether prostaglandins mediate the ANF-induced redistribution of renal blood flow and if prostaglandins and renal blood flow redistribution contribute to the natriuretic actions of ANF. In anesthetized dogs, the intrarenal administration of indomethacin (10 micrograms/kg/min) or the intravenous administration of meclofenamate (5 mg/kg) completely prevented the sixfold and twofold increments in urinary prostaglandin E2 and 6-keto-prostaglandin F1 alpha excretion, respectively; it also abolished the redistribution of renal blood flow to the deep cortex. However, ANF induced a similar natriuresis before (from 53 +/- 17 to 281 +/- 48 microEq/min) and after (from 45 +/- 13 to 273 +/- 60 microEq/min) the administration of prostaglandin synthesis inhibitors. It is concluded that the ANF-induced redistribution of renal blood flow to the deep cortex is prostaglandin-mediated but that neither redistribution nor increased prostaglandin synthesis is an important mediator of ANF's natriuretic action.     

Physiologic changes during supraventricular tachycardia and release of atrial natriuretic peptide

Plasma levels of atrial natriuretic peptide (ANP) increase markedly during supraventricular tachycardia (SVT). Although natriuresis associated with SVT may be secondary to the augmented secretion of ANP, whether or not physiologic changes other than natriuresis can be attributed to the release of ANP has not been determined. In the present study, plasma ANP levels in 10 patients with SVT were found to be significantly (p less than 0.05) increased, from 37 +/- 11 pg/ml (mean +/- standard error of the mean) during the control period to 160 +/- 54 pg/ml at 60 minutes after the induction of SVT. Urinary sodium excretion, although insignificant, tended to increase during the 30-minute period after SVT termination. The filtration fraction determined by the ratio of creatinine to para-aminohippurate clearance significantly increased during SVT. An increase in capillary permeability seemed to have occurred as there was a rise of hematocrit, the changes of which showed a different time course from that of the urine volume. The ratio of plasma aldosterone concentration to plasma renin activity significantly decreased during SVT. As the same effects are observed after ANP infusion, these changes were attributed to ANP activity.     

Effect of intrarenal angiotensin II blockade on renal function in conscious dogs.

The effects of intrarenal infusion of 1-sar-8-ala angiotension II (P 113) and a converting enzyme inhibitor, SQ 20881, at doses that did not affect systemic blood pressure (2.0 mug/kg per min) were studied in conscious, uninephrectomized dogs. In dogs receiving approximately equal to 5 mEq/day of sodium, intrarenal infusion of P 113 increased renal blood flow (RBF) from 219.8 +/- 32.3 to 282.7 +/- 20.0 ml/min (P less than 0.004), and with intrarenal SQ 20881 infusion from 215.3 +/- 14.2 to 278.0 +/- 22.2 ml/min (p less than 0.005). In sodium-restricted dogs (approximately equal to 5 mEq/day), glomerular filtration rate (GFR) also increased with intrarenal P 113 infusion from 57.9 +/- 5.7 to 66.3 +/- 6.6 ml/min (P less than 0.05), and with SQ 20881 infusion from 43.1 +/- 2.1 to 55.7 +/- 4.5 ml/min (P less than 0.01). Dogs on approximately equal to 5 mEq/day of sodium showed significant increases in plasma renin activity (PRA) with intrarenal infusion of the peptides, unmasking a negative feedback inhibition of renin release by angiotensin II. No increases in RBF, GFR, or PRA were seen with infusion without inhibitors, or in dogs give P 113 or SQ 20881 while on approximately equal to 80 mEq/day of sodium. In addition, angiotensin II inhibition increased sodium excretion during sodium restriction. These findings suggest that intrarenal angiotensin II is intimately involved in renal responses to sodium restriction which result in conservation of sodium and water.