Adrenomedullin: A newly discovered hormone controlling fluid and electrolyte homeostasis.

Neural and humoral mechanisms controlling fluid and electrolyte homeostasis employ a diverse array of physiologic mechanisms that often, when aberrant, are the underlying cause of disease. Behavioral, hormonal, renal, and vascular responses to volume and osmotic challenges must be coordinated to achieve the goal of homeostasis. In recent years, it has become apparent that there exist a number of hormonal factors produced throughout the body that can coordinate these multiple regulatory mechanisms by complementary effects in several tissues. Thus, in addition to their vasoactive properties, recently characterized hormones such as the natriuretic peptides and the endothelins, as well as the better established renin-angiotensin system, exert central nervous, renal, cardiac, and pituitary effects that regulate normal fluid and electrolyte balance. Now a new player, adrenomedullin, has been added to the cast, and the interplay of multiple hormonal factors involved in the physiology and pathophysiology of volume and osmotic status continues to be elucidated.

Renal nerves and the pathogenesis of angiotensin-induced hypertension.

The present study examined the role of the renal nerves in the development of hypertension produced by chronic infusion of angiotensin II in the conscious rat. The animals were divided into four groups, and a unilateral nephrectomy was performed. The remaining kidney was denervated in two groups, whereas in the other two groups of animals the nerves were left intact. Four days later either angiotensin II (83 ng/min) or saline infusions were begun through subcutaneously implanted osmotic minipumps. The rats were subsequently studied for 14 days. The results indicate that renal denervation significantly attenuated the pressor response to angiotensin II for approximately 6 days. Following this period, there was no difference in blood pressure between the innervated and denervated rats infused with angiotensin II, as both groups attained a hypertensive level of 170 to 180 mm Hg, which was 60 to 70 mm Hg above the blood pressure of the control rats infused with saline. Kidney norepinephrine content was reduced 95% by the denervation procedure and by 40% following infusion of angiotensin II into rats with intact renal nerves. These data demonstrate that, while the renal nerves appear to play a modulatory role in the development of the hypertension, they are not essential for the pathogenesis to occur nor do they determine the final level of hypertension achieved following chronic infusion of angiotensin II in the rat.

Renal mechanisms for suppression of renin secretion by atrial natriuretic factor.

The effects of synthetic atrial natriuretic factor on renin secretion were examined in anesthetized dogs with either a single filtering kidney or a single denervated nonfiltering kidney. In dogs with a single filtering kidney (Series 1, n = 6), a priming dose of atrial natriuretic factor (2 micrograms/kg, i.v.) followed by sustained intravenous infusions at doses of 200 and 400 ng/kg/min for 20 minutes each produced striking decrements (p less than 0.05) in renin secretion, from 1083 +/- 322 to 205 +/- 120 and 286 +/- 168 ng of angiotensin I per minute. This fall in renin secretion was associated with significant increases (p less than 0.05) in creatinine clearance, urine flow, sodium excretion, and the filtered load of sodium. Renal blood flow increased only transiently. In dogs with a single denervated nonfiltering kidney (Series 2, n = 6), infusion of atrial natriuretic factor at these doses also produced marked inhibition (p less than 0.05) of renin secretion, from 311 +/- 98 to 72 +/- 22 and 91 +/- 37 ng of angiotensin I per minute. Renal blood flow remained significantly elevated (p less than 0.05) throughout the infusion, in contrast to renal blood flow in Series I. Similar results were obtained in a third series of dogs (n = 6) with a single denervated nonfiltering kidney, during sustained intrarenal arterial infusions of atrial natriuretic factor. These results suggest that an increase in the sodium load delivered to the macula suppression of renin secretion by atrial natriuretic factor is mediated through its interactions with the two intrarenal receptor mechanisms, the renal vascular receptor and the macula densa.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of renin-angiotensin and kallikrein gene expression in experimental hypertension.

Previous studies have shown that chronic low-dose administration of 40 ng/min angiotensin II by osmotic minipump to uninephrectomized rats mimics the temporal hypertensive response and the circulating angiotensin II levels observed in two-kidney, one clip Goldblatt rats. Furthermore, renal tissue angiotensin II contents were higher than the circulating angiotensin II levels, suggesting that circulating angiotensin II induces endogenous intrarenal angiotensin II production. The present study examined the molecular mechanisms by which intrarenal angiotensin II production is modulated in angiotensin II-induced and two-kidney Goldblatt hypertension. Two weeks after clipping, intrarenal renin mRNA levels were elevated threefold in the clipped kidney of Goldblatt rats but were markedly suppressed in the nonclipped kidneys of Goldblatt rats (28% of control values) and in the remaining kidney of uninephrectomized angiotensin II-infused rats (7% of control values). In contrast, there were sustained levels of angiotensinogen mRNA in the kidneys and livers of Goldblatt and angiotensin II-infused rats, indicating differential regulation of the genes of the renin-angiotensin system. Renal kallikrein gene expression was not altered in either of the hypertensive groups 14 days after the induction of hypertension, suggesting the absence of an enhanced counteracting kinin influence.

Atrial natriuretic peptide during the elevation in blood pressure induced by sodium restriction.

This study examined the effects of dietary sodium restriction combined with unilateral nephrectomy on systolic blood pressure (SBP), heart rate, plasma renin activity (PRA) and immunoreactive atrial natriuretic peptide (iANP) in the conscious rat. SBP and heart rate, measured by photoelectric tail-cuff, were elevated in both one- and two-kidney, sodium-restricted rats compared with one- and two-kidney rats maintained on a normal-sodium intake. In addition, the SBP of one-kidney, low-sodium rats was significantly elevated compared with two-kidney, low-sodium rats on days 10 and 14 postnephrectomy. PRA was significantly elevated two- to threefold in one- and two-kidney, low-sodium rats compared with rats fed the normal-sodium chow. Plasma iANP levels in rats fed the normal-sodium diet averaged 291 +/- 45 and 277 +/- 35 pg/ml in one- and two-kidney rats, respectively. Plasma iANP levels were significantly lower in the one- and two-kidney, low-sodium rats and averaged 165 +/- 15 and 182 +/- 22 pg/ml, respectively. These results indicate that dietary sodium restriction can elevate blood pressure in the rat and that this response can be augmented by unilateral nephrectomy. In addition, the exacerbation of the hypertension by unilateral nephrectomy in sodium-restricted rats is not attributable to differences in PRA or plasma levels of iANP between one- and two-kidney, sodium-restricted rats.

Neuronal cell bodies in paraventricular nucleus affect renal hemodynamics and excretion via the renal nerves.

Several lines of evidence support the existence of an oligosynaptic projection from the paraventricular nucleus of the hypothalamus (PVN) to the kidney in the rat. We sought to provide evidence that this neural pathway is capable of influencing renal function in rats. Bilateral microinjections of bicuculline (Bic; 1 nmol) into the PVN decreased glomerular filtration rate (59%), effective renal plasma flow (71%), urine flow (UV; 57%), and urinary sodium excretion (UNaV; 54%), accompanied by increased mean arterial pressure (17%) and heart rate (17%). These results were not obtained when Bic was injected outside the PVN or when vehicle (0.9% saline) was injected into the PVN. Bilateral renal denervation (5-7 days before the experiments) significantly reduced the renal vasoconstriction, attenuated the antidiuresis, and abolished the antinatriuresis evoked by PVN stimulation. On the other hand, both the antidiuresis and antinatriuresis evoked by PVN stimulation were undiminished after treatment with either of two vasopressin receptor antagonists ([beta-mercapto-beta,beta-cyclopentamethylenepropionyl1,O-Et-Tyr2, Val4,Arg8]vasopressin, a vasopressin V1 receptor antagonist, or [adamantaneacetyl1,O-Et-D-Tyr2,Val4,aminobutyryl6,Arg8, 9]-vasopressin, a V2 receptor antagonist). In renal-denervated rats treated with the same V2 receptor antagonist, PVN stimulation produced highly variable increases in both UV and UNaV, which overall were not statistically different than zero. We conclude that the activation of neurons in PVN evokes 1) renal vasoconstriction accompanied by antinatriuresis, both of which are attributable to the renal nerves, and 2) decreased water excretion, which is mediated by the renal nerves and vasopressin V2 receptors.

In vivo proximal tubular fluid-to-plasma chloride concentration gradient in the rabbit.

It has been reported that the concentration of chloride in the proximal tubule is greater than that in plasma in several mammalian species. Much of the theory concerning fluid and electrolyte reabsorption in the proximal tubule is based on data taken from in vitro isolated proximal tubules of the rabbit nephron. This study measured in vivo the rabbit proximal tubule fluid-to-ultrafiltrate chloride concentration ratio [(TF/UF)Cl] and its relationship to proximal tubule length as estimated by the tubule fluid-to-plasma inulin concentration ratio [(TF/P)In]. From six rabbits, 19 random proximal tubules were micropunctured and analyzed for inulin and chloride concentrations, the latter being measured by microelectrometric titration. Plasma ultrafiltrate was determined by correcting plasma chloride concentration for protein concentration. The average single nephron filtration rate was 20.2 +/- 0.8 nl/min. The (TF/UF)Cl ratio was 1.10 +/- 0.03, which was significantly different from unity. Furthermore, regression analysis yielded no significant correlation between the (TF/UF(Cl and (TF/P)In ratio. This study demonstrates that a tubule lumen-to-plasma chloride concentration gradient exists in the in vivo proximal tubule of the rabbit that is apparently established early and is not correlated with proximal tubule length.

Renal autoregulation of blood flow and filtration rate in the rabbit.

Electromagnetic flow techniques and inulin clearance were used to determine the autoregulatory capabilities of the rabbit kidney in vivo. Renal blood flow was measured in 13 animals over a renal perfusion pressure range of 40-110 mmHg. Normal renal blood flow averaged 3.2 +/- 0.3 ml.min-1.g kidney-1 and was efficiently autoregulated above a renal artery pressure of 75 mmHg. For every 10 mmHg renal pressure change above 75 mmHg renal blood flow changed only 0.96%. Renal perfusion pressure was reduced from 102 +/- 3 to 74 +/- 2 mmHg in six animals. Over this pressure range glomerular filtration rate was not significantly decreased and averaged 4.2 +/- 0.5 ml/min at high pressure compared to 4.0 +/- 0.5 ml/min at low perfusion pressure. Results show that the rabbit kidney autoregulates renal blood flow and glomerular filtration rate efficiently above 75 mmHg. This range of autoregulation compares well with the autoregulatory range of the dog. The results also show that in the autoregulatory range the rabbit and the rat appear to autoregulate with equal efficiency but that the rabbit kidney begins to autoregulate at a low perfusion pressure than the average of approximately 100 mmHg usually found in the rat.

Alterations in glomerular dynamics in congenital, unilateral hydronephrosis.

We have previously shown that rats with congenital, unilateral hydronephrosis exhibit a reduction in GFR that returns to normal when either the renin angiotensin system or thromboxane A2 (TxA2) is blocked. The current study defines the single nephron defect in congenital, unilateral hydronephrosis and evaluates the roles of angiotensin II (Ang II) and TxA2 in this renal derangement. Renal micropuncture experiments were performed on the right kidney of rats from an inbred colony with unilateral right-sided hydronephrosis (HYDRO), or non-affected litter mates (CONTROL). In addition, four separate groups of hydronephrotic animals were treated with either the TxA2 receptor antagonist SQ-29548 (SQ), one of two Ang II receptor antagonists [saralasin (SAR) or DuP-753 (DUP)]; or combined treatment with DuP-753 and SQ-29,548 (S&D). SNGFR was significantly reduced (P < 0.05) in HYDRO compared to CONTROL (17.6 +/- 2.0 vs. 35.9 +/- 3.7 nl/min, respectively). Treatment with SQ-29,548 normalized SNGFR (29.0 +/- 3.0 nl/min), while saralasin and DuP-753 resulted in only a partial recovery of function (25.6 +/- 1.6 and 27.8 +/- 1.4 nl/min, respectively). Combined SQ-29,548 and DuP-753 treatment resulted in full recovery of SNGFR to 32.9 +/- 4.4 nl/min. The glomerular ultrafiltration coefficient (Kf) was reduced (P < 0.05) approximately 45% in HYDRO compared to CONTROL (1.64 +/- .08 vs. 2.84 +/- .22 nl/min/mm Hg, respectively). Kf returned to control levels in SAR, DUP and SQ, and increased above control in S&D (5.58 +/- 1.6 nl/min/mm Hg). There were no differences (P > 0.05) in hydrostatic or oncotic pressures across the glomerular capillary between any of the groups studied. The observation that Kf increases above CONTROL with combined blockade of TxA2 and Ang II suggests that these regulatory hormones decrease Kf via independent mechanisms. These data indicate that the reduction in SNGFR in congenital, unilateral hydronephrosis is a result of a marked fall in Kf that is mediated by both Ang II and TxA2.

Reversible vasoconstriction in rats with congenital unilateral hydronephrosis.

We studied the effects of inhibition of either prostaglandins or the role of prostanoids and the renin-angiotensin system on renal function in rats with congenital unilateral hydronephrosis. Wistar rats with congenital unilateral hydronephrosis were infused with normal saline (control), captopril dissolved in normal saline or indomethacin dissolved in a solution of sodium chloride and sodium carbonate. In the control group both glomerular filtration rate (GFR) and effective renal plasma flow were reduced in the right hydronephrotic kidney (RHK) compared with the normal left kidney. Indomethacin did not improve renal function in the RHK. Captopril significantly improved GFR in the RHK. These results support the conclusion that the renin-angiotensin system is an important mediator of reduced GFR in congenital unilateral hydronephrosis in rats.

Recurrent seizures alter renal function and plasma atrial natriuretic peptide levels in rats.

Status epilepticus can lead to impaired renal function, which has been attributed to complications of myoglobinuria. We confirmed changes in renal function in the absence of myoglobinuria by measuring renal hemodynamics, fluid and electrolyte excretions, and plasma levels of renin and atrial natriuretic peptide (ANP) before and after a 30-min period of recurrent generalized seizures in anesthetized, paralyzed rats. Renal plasma flow (RPF), renal blood flow (RBF) and glomerular filtration rate (GFR) decreased by approximately 60% after seizures. In contrast, urinary sodium excretion, urine flow, and plasma ANP levels increased approximately threefold. Urinary potassium excretion and plasma renin levels were unchanged. Renal function is profoundly altered after 30 min of seizures, primarily due to intense renal vasoconstriction precipitating a dramatic reduction in GFR. The concomitant increases in sodium and urine excretion may be mediated by the marked increase in plasma ANP levels. The decreases in GFR and RBF might contribute to the renal failure observed in some patients after status epilepticus.

Renal effects of adrenomedullin in the rat.

We investigated the effects of a constant infusion of adrenomedullin (ADM) on renal hemodynamics and fluid electrolyte excretion in the rat. Following baseline measurements, eight rats received an intravenous infusion of 5 micrograms of rat ADM (167 ng/min) for 30 min at 10 microliters/min. Eight additional rats received 0.9% saline at 10 microliters/min instead of ADM. Renal function was measured during this period and for two consecutive 20-min periods following termination of the ADM or vehicle infusion. Mean arterial pressure decreased from a baseline of 113 +/- 3 to 102 +/- 1 mm Hg at 25 min of ADM infusion and returned towards control after the ADM infusion was terminated. This modest hypotensive effect was associated with an increase in heart rate from 366 +/- 10 to 384 +/- 9 bpm, which continued to remain elevated after the ADM infusion was stopped. Urinary sodium excretion increased from 348 +/- 57 to 813 +/- 172 nEq/min during ADM infusion and continued to increase to 1141 +/- 347 nEq/min after the infusion of ADM was terminated. Urinary potassium excretion increased from 1.94 +/- 0.22 to 2.75 +/- 0.24 microEq/min during ADM infusion. Urine flow tended to increase (P = 0.08) from 7.0 +/- 0.5 to 8.1 +/- 0.6 microliters/min during ADM infusion and continued to increase to 9.7 +/- 1.5 microliters/min after the infusion was stopped. Renal plasma flow increased from 3.22 +/- 0.22 to 3.82 +/- 0.20 ml/min/g kidney wt during ADM infusion and continued to increase to 4.14 +/- 0.22 ml/min/g kidney wt after the ADM infusion was stopped. Glomerular filtration rate averaged to 1.11 +/- 0.07 ml/min/g kidney wt during baseline and did not significantly change during or after ADM infusion. These results indicate that a constant infusion of adrenomedullin, at a dose that results in a minimal hypotensive effect increases renal plasma flow and urinary sodium excretion in the rat.

Renal function and Ca(2+) currents after dye-labeling identification of renal sympathetic neurons.

The present study was performed to determine whether renal efferent sympathetic neurons could be identified using a retrograde neuronal tracer without compromising renal function and whether the labeling and identification procedure alters Ca(2+) currents and neuromodulation of those neurons. Renal sympathetic and superior cervical ganglion (SCG) neurons were labeled with the fluorescent retrograde tracer fast blue. Renal function studies made 1 wk after labeling revealed that renal hemodynamics and fluid and electrolyte excretion were similar between the dye-injected (left) kidney and the control (right) kidney under control conditions and after hemorrhage. After volume expansion, urine flow in the dye-injected kidney was slightly, but significantly, less than that of the control kidney, whereas urinary sodium excretion increased by approximately ninefold in both kidneys. Patch-clamp studies of SCG neurons in 10 mM external Ca(2+) revealed that peak currents were not affected by the presence of the dye or a 1-min exposure to ultraviolet (UV) light. Neither maximal norepinephrine-induced Ca(2+) current inhibition nor the sensitivity to norepinephrine was affected by the dye or 1-min UV exposure. Facilitation protocols revealed that G protein modulation of Ca(2+) currents remained intact in dye-labeled UV-exposed neurons. This study demonstrates that a retrograde fluorescent dye technique to identify renal sympathetic neurons does not compromise renal function and the presence of the dye label or UV exposure has no effect on Ca(2+) currents and neuromodulation in these neurons. Isolation of single identified renal sympathetic neurons coupled with patch-clamp techniques represents a tool to investigate the role of individual current systems in the modulation of excitability in these neurons, which play an important role in the control of renal hemodynamics and excretory function and in the pathogenesis of hypertension.

Renal response to atrial natriuretic factor in conscious dogs with caval constriction.

Constriction of the thoracic inferior vena cava to decrease venous return and atrial filling markedly elevates plasma renin activity (PRA) and plasma aldosterone concentration (PAC) and produces chronic sodium retention and ascites in the dog. Infusion of a synthetic atrial natriuretic factor into conscious dogs with caval constriction and ascites at doses of 175 and 350 ng X kg-1 X min-1 for 30 min each produced striking increases (P less than 0.05) in creatinine clearance, diuresis, and kaliuresis but failed to increase urinary sodium excretion. Infusions of atrial natriuretic factor at these doses into conscious normal dogs, however, produced a striking increase in sodium excretion from 41 +/- 14 and 55 +/- 19 mu eq/min to 150 +/- 58 and 181 +/- 49 mu eq/min (P less than 0.05 for both values). Creatinine clearance and urine flow also increased in these normal dogs, but potassium excretion remained unchanged during the infusion periods. Atrial natriuretic factor produced parallel suppression (P less than 0.05) of the elevated levels of PRA and PAC in the caval dogs but failed to significantly decrease either PRA or PAC in the normal animals. Arterial pressure, heart rate, and PAH clearance were unchanged in both groups of dogs during infusion of atrial natriuretic factor. These results suggest that the pattern of renal electrolyte excretion elicited in response to the acute infusion of atrial natriuretic factor is dependent, at least partially, on the preexisting status of the renal tubules to facilitate sodium reabsorption and potassium excretion. The results also are consistent with the concept that atrial natriuretic factor might function to tonically inhibit the renin-angiotensin-aldosterone system.

Angiotensin or thromboxane receptor antagonism in rats with congenital hydronephrosis.

A technique for the measurement of GFR without collection of urine in rats was experimentally validated and applied to experiments designed to: (1) evaluate the degree of reduction of GFR in rats with congenital, unilateral hydronephrosis; and (2) to determine if the reduction in renal function is mediated by angiotensin II and/or thromboxane A2 mechanisms. Simultaneous measurements of GFR by a constant-infusion technique and the traditional inulin clearance technique in rats with either one or two normal kidneys were highly correlated (r = 0.934; P < 0.001; N = 17). GFR was approximately 24% lower (P < 0.001) in rats with congenital unilateral hydronephrosis than in rats with a normal kidney. The GFR in rats with hydronephrosis infused with a receptor blocker for either angiotensin II or thromboxane A2 was greater than the GFR in hydronephrotic kidneys without blockade and was not significantly different (P > 0.05) from that in rats with normal kidneys. These results indicate that a constant inulin infusion technique without urine collections can be used to accurately measure GFR in congenitally hydronephrotic kidneys, rendering values free from possible residual pelvic volume artifact. In addition, these results also indicate that a significant 24% reduction in GFR occurs in congenital unilateral hydronephrosis and is mediated by angiotensin II and thromboxane A2 mechanisms.

Influence of adenosine receptor blockade on renal function and renal autoregulation.

Experiments were conducted in anesthetized dogs to evaluate the effects of adenosine receptor blockade on renal function and on autoregulation of total RBF and outer cortical blood flow. After control measurements, the adenosine receptor antagonist, 1,3-dipropyl-8-p-sulfophenylxanthine (PSPX) was infused intrarenally for 45 min at 2 or 6 microM/min. Responses to PSPX were compared with those obtained during infusions of either aminophylline or theophylline. PSPX infusion led to substantial increases in urine flow and sodium excretion (four- to fivefold). RBF increased significantly; however, outer cortical blood flow and GFR were not significantly altered. PRA increased twofold during PSPX infusion. The vasoconstrictor responses to bolus injections of 2-chloroadenosine (100 mumol) were attenuated by 58 and 86% during the low and high doses of PSPX and to a lesser extent with aminophylline/theophylline infusions. At renal arterial pressures above the inflection point, the slope of the average pressure-flow relationship during PSPX infusion was close to zero and was not significantly different from control. Similarly, autoregulatory capability was not altered during infusions of theophylline or aminophylline. These data provide further evidence that endogenous adenosine contributes substantially to the control of renin release but only modestly to the control of RBF and GFR and to renal autoregulatory capability. The natriuretic responses during adenosine blockade, which occurred in the face of elevated renin levels, support the hypothesis that endogenous adenosine enhances tubular sodium reabsorption rate.

Control of atrial natriuretic factor release in conscious dogs.

The aim of this study was to examine the changes in the concentration of plasma immunoreactive atrial natriuretic factor (iANF) that occur in response to expansion or depletion of the extracellular fluid volume in conscious dogs. The plasma iANF concentration was also measured postprandially after the ingestion of a meal containing 125 meq of sodium. Postprandial plasma iANF increased 45% (P less than 0.05) above the base-line concentration, and this increase was accompanied by a brisk natriuresis. After a low-sodium meal, however, plasma iANF and sodium excretion failed to increase. The plasma iANF concentration increased from 57 +/- 5 to 139 +/- 36 pg/ml (P less than 0.05) immediately after volume expansion with intravenous isotonic saline infusion (2.5% body wt) administered over a 30-min period; plasma iANF remained elevated at 90 +/- 14 pg/ml (P less than 0.05) for an additional 30 min before returning toward preinfusion levels. Plasma iANF decreased 45% from 78 +/- 17 to 43 +/- 7 pg/ml (P less than 0.05) in response to the administration of ethacrynic acid (2.0 mg/kg, iv bolus) that produced an estimated 15% depletion of intravascular volume. In additional experiments the infusion of synthetic alpha-human ANF at 100 and 300 ng X kg-1 X min-1 increased (P less than 0.05) both the plasma iANF concentration and the urinary excretion of iANF. This study demonstrates that the secretion of ANF is consistently influenced by changes in the extracellular fluid volume. Furthermore, the results support the concept that ANF functions to increase postprandial sodium excretion following the ingestion of a high-sodium meal.

Effects of atrial appendectomy on circulating atrial natriuretic factor during volume expansion in the rat.

This study examined the changes in the circulating level of endogenous atrial natriuretic factor during diuresis and natriuresis produced by acute volume expansion in anesthetized rats with either bilateral atrial appendectomy (n = 9) or sham operation (n = 9). Following control measurements in the sham-operated rats, 1% body weight volume expansion with isotonic saline produced an increment in urinary sodium excretion of over 4 mueq/min (P less than 0.05) while urine volume increased by more than 20 microliter/min (P less than 0.05). These responses were associated with a significant increase in immunoreactive plasma atrial natriuretic factor from a baseline value of 82 +/- 10 pg/ml to a level of 120 +/- 14 pg/ml (P less than 0.05). In contrast, in the group of rats with bilateral atrial appendectomy an identical degree of volume expansion increased urinary sodium excretion and urine volume by only 0.61 mueq/min (P less than 0.05) and 3.07 microliter/min (P less than 0.05), respectively. In this group, immunoreactive plasma atrial natriuretic factor remained statistically unchanged from a control value of 70 +/- 12 pg/ml to a level of 82 +/- 16 pg/ml (P greater than 0.05). Comparison of the two groups indicates that the natriuresis, diuresis, and plasma atrial natriuretic factor levels during volume expansion were significantly reduced in the rats with bilateral atrial appendectomy. No differences in mean arterial pressure and heart rate were observed between the two groups. These data demonstrate that removal of both atrial appendages in the rat attenuated the release of atrial natriuretic factor during volume expansion; and this effect, in turn, was associated with a reduction in the natriuretic and diuretic responses.

Effect of synthetic atrial natriuretic factor on aldosterone secretion in the rat.

Direct in vivo measurements of aldosterone secretion were made before and after infusion of synthetic rat atrial natriuretic factor (ANF) into anesthetized rats with markedly different levels of plasma renin activity. Infusion of ANF peptide at 350 ng . kg-1 . min-1 significantly decreased aldosterone secretion by 32% and plasma renin activity by 55% in rats that had been maintained on a normal-sodium diet. Similar reductions in aldosterone secretion and plasma renin activity were observed in hyperreninemic rats after chronic sodium restriction. Infusion of ANF at 350 ng . kg-1 . min-1 into anephric rats with low circulating levels of renin did not significantly decrease the secretion of aldosterone. Increasing the ANF peptide infusion dose fivefold in these anephric rats did result in a significant reduction in aldosterone secretion, but this higher dose also produced significant decreases in blood pressure not observed with the lower dose of ANF. These results demonstrate that infusion of synthetic ANF decreases the secretion rate of aldosterone in the rat, but the ability of ANF to decrease aldosterone secretion is attenuated when circulatory levels of renin and hence angiotensin II are very low. The data suggest that although ANF can exert a direct inhibitory effect on the adrenal glomerulosa in larger doses that also produce systemic cardiovascular effects, one physiological mechanism by which ANF suppresses aldosterone secretion may be related indirectly to the inhibition of renin release.

Juxtamedullary microvascular dysfunction during the hyperfiltration stage of diabetes mellitus.

This study was designed to identify and localize defects in renal microvascular function during the hyperfiltration stage of diabetes mellitus. Male Sprague-Dawley rats were injected intravenously with 65 mg/kg streptozotocin (IDDM rats) or vehicle (sham rats). IDDM rats received insulin (3 U.kg-1.day-1) via an osmotic minipump; sham rats received diluent. During the ensuing 2-wk period, blood glucose levels averaged 89 +/- 2 mg/dl in 33 sham rats and 290 +/- 13 mg/dl in 37 IDDM rats. At the end of this period, inulin clearance was elevated in eight IDDM rats (1.43 +/- 0.17 ml.min-1.g kidney wt-1) compared with six sham rats (0.78 +/- 0.05 ml.min-1.g kidney wt-1). The remaining animals served as tissue donors for study of the renal microvasculature using the in vitro blood-perfused juxtamedullary nephron technique. Kidneys from sham and IDDM rats were perfused with homologous blood at a renal arterial pressure of 110 mmHg. Juxtamedullary single-nephron glomerular filtration rate was higher in IDDM rats (41.5 +/- 5.4 nl/min) than in sham rats (25.4 +/- 2.4 nl/min). Afferent arteriolar inside diameter was greater in IDDM rats (34 +/- 2 microns) than in sham rats (22 +/- 1 microns); however, efferent arteriolar diameter did not differ between groups. The afferent arteriolar vasoconstrictor response to norepinephrine (NE) was attenuated in IDDM rats, relative to sham rats, over a wide range of NE concentrations. In contrast, NE evoked similar degrees of efferent vasoconstriction in IDDM and sham rats.(ABSTRACT TRUNCATED AT 250 WORDS)