Peptide hormones and the regulation of sodium excretion.
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Angiotensin II↗
Biomedical subjects
M H Humphreys
Publications and source records attributed to M H Humphreys.
Amplification of the natriuretic response to acute unilateral nephrectomy by volume expansion.
We examined the consequences of acute unilateral nephrectomy (AUN) on sodium (UNaV) and potassium excretion (UKV) in anesthetized rats which received either no volume replacement or an infusion of 1, 1.5, or 2% body weight of an albumin-saline solution during surgical preparation. Both UNaV and UKV during the initial control period increased progressively with graded volume repletion. AUN caused a significant increase in UNaV in each group, and the magnitude of this increment was related to the degree of volume repletion, and hence baseline UNaV: in rats replaced with 2% body weight of albumin-saline solution, UNaV rose from 1,801 +/- (SD) 260 to 3,435 +/- 1,748 nEq/min (p less than 0.005), while in rats receiving no replacement, it rose only from 213 +/- 106 to 469 +/- 186 nEq/min (p less than 0.005). In contrast, the increment in UKV was the same in each group despite higher baseline UKV related to graded volume repletion. In no group did GFR increase significantly. We conclude that volume expansion amplifies the natriuretic response to AUN by decreasing reabsorption in the proximal or distal nephron, or both. However, the postnephrectomy kaliuresis is not influenced by the degree of volume repletion, suggesting that it is mediated by a separate mechanism independent of volume expansion-induced changes in tubular function.
Absorption↗
Prevention of reflex natriuresis after acute unilateral nephrectomy by neonatal administration of MSG.
Acute unilateral nephrectomy (AUN) results in natriuresis from the remaining kidney through reflex pathways involving the central nervous system and requiring an intact pituitary gland. The natriuresis is accompanied by an increase in the plasma concentration of a peptide or peptides derived from the N-terminal fragment (NTF) of proopiomelanocortin. We measured plasma immunoreactive NTF-like material (IR-NTF) before and after AUN in control rats and rats treated neonatally with monosodium glutamate (MSG), a procedure that produces neuroendocrine dysfunction by destroying cell bodies in the hypothalamic arcuate nucleus, median eminence, and other brain regions. In control rats, IR-NTF increased from 85.8 +/- 54.9 (SD) to 207 +/- 98.1 fmol/ml after AUN (P less than 0.02) as sodium excretion (UNaV) doubled. In MSG-treated rats, AUN produced no change in plasma IR-NTF concentration (58.8 +/- 21.3 vs. 68.3 +/- 18.5 fmol/ml (P = NS), nor did UNaV increase. Tissue content of IR-NTF was reduced in the arcuate nucleus and anterior lobe of pituitaries from MSG-treated rats compared with controls, but was no different in the neurointermediate lobe. These results indicate that the hypothalamic lesion produced by neonatal administration of MSG prevents both the increase in plasma IR-NTF concentration and the natriuresis after AUN, and therefore lend further support to the concept of a causal relationship between these two consequences of AUN.
Animals↗
Renal complications in patients with the acquired immune deficiency syndrome (AIDS).
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Acquired Immunodeficiency Syndrome↗
A gamma-melanocyte stimulating hormone-like peptide causes reflex natriuresis after acute unilateral nephrectomy.
Previous studies have shown that acute unilateral nephrectomy stimulates sodium (UNaV) and potassium (UKV) excretion by the remaining kidney through reflex pathways requiring an intact pituitary gland, and the natriuresis is accompanied by an increase in the plasma concentration of a peptide or peptides derived from the adrenocorticotropic hormone-beta-endorphin precursor molecule pro-opiomelanocortin. We tested the hypothesis that gamma-melanocyte stimulating hormone (gamma-MSH) was such a peptide involved in the postnephrectomy natriuresis. In six rats undergoing sham nephrectomy, no change in UNaV or UKV occurred and plasma immunoreactive gamma-MSH-like material was 40 +/- 18 (SD) fmol/ml 2 hours after the sham procedure. In 10 rats undergoing acute unilateral nephrectomy, UNaV and UKV from the remaining kidney increased significantly, and immunoreactive gamma-MSH was 81 +/- 36 fmol/ml (p less than 0.02). In individual studies, the increase in UNaV after nephrectomy correlated with the postnephrectomy concentration of immunoreactive gamma-MSH (r = 0.75, p less than 0.001). In 17 rats injected with serum or globulin from control rabbits, unilateral nephrectomy led to the expected increases in UNaV and UKV. In 23 rats injected with serum or globulin from rabbits immunized against gamma-MSH, no postnephrectomy natriuresis occurred and the kaliuresis was blunted. In hydropenic, mineralocorticoid-treated rats, intravenous infusion of synthetic gamma-MSH led to natriuresis and kaliuresis with no change in inulin clearance; pretreatment with rabbit anti-gamma-MSH antiserum blocked this effect of peptide infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Coordinately increased lysozymuria and lysosomal enzymuria induced by maleic acid.
During the acute renal tubular dysfunction of Fanconi syndrome and type 2 renal tubular acidosis (FS/RTA2) induced by maleic acid in the unanesthetized dog, we observed: 30 minutes after the onset of FS/RTA2, the urinary excretion of lysosomal enzymes, N-acetyl-beta-glucosaminidase (NAG), beta-glucuronidase (beta-gluc) and beta-galactosidase (beta-galac), increased simultaneously with the anticipated increase in renal clearance of lysozyme; the severities of all these hyperenzymurias increased rapidly, progressively, and in parallel, all reaching a peak some 60 to 80 minutes after their onset; thereafter, while the FS/RTA2 continued undiminished in severity, the severity of the hyperenzymurias decreased rapidly, greatly, progressively, and in parallel; and sodium phosphate loading strikingly attenuated the FS/RTA2 and the hyperenzymurias. Thus, the maleic acid-induced FS/RTA2 is attended by an acute reversible-complex derangement in the renal tubular processing of proteins that: affects not only lysozyme which is normally filtered, but also NAG and other lysosomal enzymes, which are not; and is to some extent functionally separable from that of FS/RTA2. The findings suggest that the derangements in renal processing of lysozyme and lysosomal enzymes are linked, and that a phosphate-dependent metabolic abnormality in the proximal tubule can participate in the pathogenesis of both these derangements and the FS/RTA2.
Acetylglucosaminidase↗
Plasma volume expansion is necessary for edema formation in the rate with Heymann nephritis.
Edema formation in nephrotic syndrome has been attributed to intravascular volume depletion resulting from leakage of plasma water into the interstitial space and activating secondary renal sodium retention. However, clinical studies indicate that edematous patients with nephrotic syndrome may have normal or expanded plasma volumes. We evaluated the relationship between plasma volume and edema formation in control rats and rats with chronic renal failure (CRF) produced by 7/8 nephrectomy. In each group, plasma volume and 22Na space were measured during the control period and after induction of hypoalbuminemia from passive Heymann nephritis. Rats with CRF had expanded plasma volume during the initial period (4.23 +/- 0.46 vs. 3.32 +/- 0.68 ml/100 g body wt) that became significantly more expanded (to 5.44 +/- 1.16 ml/100 g body wt) when they became nephrotic as 22Na space also increased. Plasma volume and 22Na space did not change in the sham-operated rats when nephrosis was produced. Plasma renin activity was lower in the CRF rats during the control period than in the sham-operated rats and fell significantly during the nephrotic period when edema developed. Nonnephrotic rats had a plasma colloid osmotic pressure (COP) of 17.8 +/- 4.3 mmHg compared with 8.5 +/- 2.9 mmHg when nephrotic. Despite this large difference in COP, both nephrotic and nonnephrotic rats exhibited the same relationship between plasma volume and extravascular sodium space, a measure of edema formation. Hypoproteinemia is not sufficient for edema formation in the rat with passive Heymann nephritis; concomitant plasma volume expansion resulting from CRF is a necessary additional component.
Animals↗
Phosphate loading attenuates renal tubular dysfunction induced by maleic acid in the dog.
The metabolic pathogenesis of the complex renal tubular dysfunction of type II renal tubular acidosis and Fanconi's syndrome (RTA II/FS) acutely induced by maleic acid could depend on the occurrence of a positive feedback loop in cells of the proximal renal tubule: impaired mitochondrial oxidation----increased glucose uptake----increased formation and concentration of phosphorylated glycolytic intermediates----limitation on availability of cellular inorganic phosphate----more severely impaired mitochondrial oxidative metabolism. To test this hypothesis we intravenously administered maleic acid both alone and after initiating intravenously administered neutral sodium phosphate, sodium sulfate, or sodium chloride to 10 unanesthetized trained female dogs undergoing water diuresis. We made the following observations: 1) Administration of maleic acid alone predictably induced dose-dependent increments in urine flow (V) and in renal clearance of HCO3-, Na+, K+, and alpha-aminonitrogen and a pronounced increase in the renal clearance and excretion of citrate. 2) Prior phosphate loading, which increased the plasma concentration of phosphate from 2.5 +/- 0.20 to 11.3 +/- 2 mg/dl: a) attenuated the increment in renal clearance of HCO3- by one-half even though the filtered load of bicarbonate was higher by 37%, owing to the higher values of both GFR and plasma bicarbonate concentration that obtained with phosphate loading; b) prevented the increment in renal clearance and excretion of alpha-aminonitrogen; c) significantly attenuated the increments in V and renal clearance of K+; but d) did not affect the increment in renal clearance and excretion of citrate.(ABSTRACT TRUNCATED AT 250 WORDS)
Acidosis, Renal Tubular↗
Role of the pituitary in reflex natriuresis following acute unilateral nephrectomy.
We studied the role of altered pituitary function in the reflex natriuresis that occurs after acute unilateral nephrectomy (AUN). In normal rats, AUN increased both sodium (UNaV) and potassium excretion within 90 min. In hypophysectomized rats, no increase in cation excretion after AUN occurred, results which were duplicated in rats in which pituitary function was altered by prior treatment with dexamethasone (2 mg/kg ip for 3 days). In adrenalectomized rats, AUN led to increases in cation excretion similar to those seen in normal rats, indicating that intact adrenal function was not necessary for this excretory response following AUN. These changes in cation excretion were correlated with measurements in peripheral plasma of two peptides derived from the pituitary precursor molecule pro-opiomelanocortin (POMC). Radioimmunoassayable plasma beta-endorphin failed to change after AUN in any of the conditions studied. However, a sensitive radioimmunoassay for the N-terminal fragment (NTF) of POMC indicated that plasma NTF rose significantly after AUN in normal and adrenalectomized rats but did not change in hypophysectomized, steroid-pretreated, or shamoperated rats. The increase in NTF concentration correlated with the increase in UNaV after AUN. These results demonstrate that the reflex increase in cation excretion after AUN is dependent on an intact pituitary gland and is associated with an increase in peripheral plasma concentration of NTF. NTF, or some other peptide residing in the N-terminal portion of POMC, could promote the natriuresis after AUN; the importance of the pituitary gland in this response could be the secretion of this peptide.
Animals↗
Centrally administered naloxone blocks reflex natriuresis after acute unilateral nephrectomy.
Acute unilateral nephrectomy (AUN) leads to a natriuresis and kaliuresis by the remaining kidney through reflex mechanisms involving opiate receptors. To determine whether the opiate receptors mediating these responses are located in the central nervous system, we carried out AUN in anesthetized rats undergoing continuous ventriculocisternal perfusion (VCP) with artificial cerebrospinal fluid (CSF). AUN caused large increases in both Na (UNaV) and K (UKV) excretion without changes in glomerular filtration rate or arterial blood pressure. When the opiate receptor antagonist naloxone was added to the perfusate to achieve a perfusion rate of 32 micrograms X kg-1 X h-1, AUN failed to increase either UNaV or UKV by the remaining kidney. This dose of naloxone, however, was without effect when infused intravenously. Addition of thyrotropin-releasing hormone (TRH) to the artificial CSF to achieve a VCP rate of 50 micrograms X kg-1 X h-1 also blocked the expected increase in UNaV and UKV by the remaining kidney after AUN. Infusion of TRH intravenously at the same rate did not interfere with the postnephrectomy natriuresis or kaliuresis. Higher intravenous infusion rates of TRH (1 and 2 mg X kg-1h-1) prevented the postnephrectomy natriuresis without affecting the kaliuresis. These results indicate that the effect of naloxone to block the reflex natriuresis and kaliuresis after AUN resides largely in the central nervous system. The blockade by naloxone of the postnephrectomy natriuresis is duplicated by centrally administered TRH, providing another example of the interaction of this hormone with the endogenous opioid system. Large intravenous infusions of TRH also block the postnephrectomy natriuresis but not the kaliuresis.
Animals↗
Reflex responses to reductions in functioning renal mass.
Both acute unilateral nephrectomy (AUN) and unilateral ureteral obstruction (UUO) result in an acute increase in cation excretion from the contralateral kidney. AUN results in reflex changes in systemic hemodynamics owing to an acute and transient increase in arterial pressure that activates carotid sinus baroreceptors and constitutes an afferent limb in the reflex; hemodynamic adjustments and increased cation excretion result. The reflex involves participation of the endogenous opioid system, with receptors located primarily in the central nervous system, and requires intact pituitary function because both hypophysectomy and pretreatment with large doses of dexamethasone prevent the postnephrectomy natriuresis. The natriuresis is closely correlated with an increase in the plasma concentration of the NH2-terminal fragment of the pituitary peptide precursor molecule proopiomelanocortin, which suggests that such a peptide could participate directly or indirectly in the postnephrectomy natriuresis. Surgical denervation of either the ipsilateral or the contralateral kidney markedly alters the response to AUN, which prevents the natriuresis and blunts the kaliuresis, and indicates a role for renal neural reflexes. Renorenal reflex pathways also mediate the response of the contralateral kidney to UUO, because denervation of either the ipsilateral (obstructed) or the contralateral kidney abolishes both the natriuresis and kaliuresis usually seen after UUO. This reflex also involves the endogenous opioid system, for it does not occur in rats receiving an i.v. infusion of the opiate receptor antagonist naloxone.
Adaptation, Physiological↗
Determinants of the kaliuresis after acute unilateral nephrectomy in the dog.
We examined the factors regulating potassium excretion (UKV) in anesthetized, mechanically ventilated, mineralocorticoid-injected dogs undergoing acute unilateral nephrectomy (AUN). In control dogs, AUN caused both sodium excretion (UNaV) and UKV to increase in association with an increase in bicarbonate excretion (UHCO3V) but no change in chloride excretion (UClV). In dogs made acutely acidotic by intravenous infusion of dilute HCl, AUN led to comparable increase in UNaV and UKV, but with increased UClV and only a trivial change in UHCO3V. In dogs in which prostaglandin synthesis was inhibited by indomethacin or meclofenamate, AUN led to an increase in UKV but without any increase in UNaV or UHCO3V. The fractional excretion of potassium rose significantly and comparably in all groups. Our results indicate that the post-nephrectomy kaliuresis occurs without change in respiratory acid-base status or mineralocorticoid hormone activity, and can be dissociated from increased UHCO3V and, probably, increased delivery of fluid out of the proximal tubule. They therefore suggest a specific and potent effect of AUN to stimulate UKV through an increase in plasma potassium concentration or through some as yet undetermined mechanism.
Acid-Base Equilibrium↗
Renal nerves and cation excretion after acute reduction in functioning renal mass in the rat.
We evaluated the role of the renal nerves in the increased cation excretion by the contralateral kidney after acute unilateral nephrectomy (AUN) or unilateral ureteral occlusion (UUO) in anesthetized rats. Both AUN and UUO caused large increases in sodium (UNaV) and potassium excretion (UKV) by the control kidney without change in glomerular filtration rate or mean arterial pressure. Prior denervation of either the ipsilateral (experimental) kidney or the control kidney completely prevented the increase in UNaV and UKV after UUO. Prior denervation of either kidney also prevented the increase in UNaV after AUN. However, a significant kaliuresis persisted after AUN despite unilateral denervation although reduced in magnitude when compared with the increase in UKV after AUN with both kidneys innervated. These results indicate that the renal nerves play a major role in the excretory response of the control kidney after acute reduction in functioning renal mass. This role of the renal nerves may be through the activation of a renorenal reflex. The reflex is activated by afferents from the ipsilateral kidney; the efferent limb is composed of the renal nerves to the control kidney. This reflex can entirely account for the compensatory increase in cation excretion after UUO. However, a separate mechanism, not dependent on the renal nerves, contributes to UKV after AUN.
Animals↗
Anion effects on fluid absorption from rat jejunum perfused in vivo.
Perfusion of rat jejunal segments in vivo with an isotonic, HCO3-free SO4-Ringer solution resulted in low rates of net sodium (JNanet) and water absorption. When the perfusion fluid was changed to one containing 25 mM Na2SO3, JNanet increased from 4.7 +/- 1.2 to 11.6 +/- 1.5 (SE) mumol X cm-1 X h-1 (P less than 0.001). This increased absorption was accompanied by comparable increases in chloride and water absorption, occurred without a detectable change in potential difference across the perfused segment, and was readily reversed on reinstitution of perfusion with SO4-Ringer. Perfusion with SO3-Ringer had no effect on electrolyte absorption from terminal segments of rat ileum. Addition of L-phenylalanine stimulated absorption from SO4-Ringer perfusate but not from SO3-Ringer perfusate. Addition of 25 mM NaHCO3 to SO4-Ringer perfusate caused parallel increases in JNanet and JHCO3net; when 25 mM NaHCO3 was added to SO4-Ringer perfusate that also contained 25 mM NaSCN, the same increase in JHCO3net occurred but was not associated with any increase in JNanet. These results indicate a potent effect of SO2-3 and HCO-3 to stimulate JNanet from rat jejunum but not from ileum. These anion effects on intestinal transport in vivo resemble their effects on ATPase activity of brush-border fractions from small intestine in vitro and raise the possibility that these effects on ion transport could be mediated through the changes in brush-border ATPase activity, which are brought about by exposure to these anions, although other explanations are also possible.
Animals↗
Endogenous opioids and electrolyte excretion after contralateral renal exclusion.
Acute reductions in functioning renal mass result in increases in both sodium (U Na V) and potassium (U K V) excretion by the contralateral kidney (CK). We studied the role of endogenous opioids in this response. In control experiments acute unilateral nephrectomy (AUN) increased U Na V from 1,788 +/- 1,125 (SD) to 3,939 +/- 1,819 and U K V from 1,385 +/- 561 to 2,254 +/- 832 neq/min by the CK (P less than 0.005 for both); similar results occurred in rats undergoing acute unilateral ureteral occlusion (UUO). These increases occurred without overall change in GFR or mean arterial pressure. In rats receiving a continuous infusion of the opiate-receptor antagonist naloxone (0.3 mg . kg-1 . h-1) neither AUN nor UUO produced significant alterations in U Na V or U K V by the CK; naloxone infusion by itself did not alter GFR or basal rates of cation excretion. A separate group of rats was made tolerant to morphine by subcutaneous implantation of pellets containing 75 mg morphine base. In these rats, AUN also failed to produce any increase in U Na V or U K V by the CK. The results suggest that acute reductions in functioning renal mass produced by either AUN or UUO stimulate cation excretion by the remaining kidney through reflex pathways that involve opiate receptors.
Animals↗
Hemodynamic and renal functional changes after acute unilateral nephrectomy in the dog: role of carotid sinus baroreceptors.
We examined the role of the carotid sinus baroreceptors in the hemodynamic and renal functional changes initiated by acute unilateral nephrectomy (AUN). In 15 anesthetized dogs, AUN caused increases in sodium (UNaV) and potassium excretion (UKV) without significant changes in GFR, renal blood flow, or mean arterial pressure. Cardiac output (CO) was measured in five of these animals and decreased from 2.5 +/- 0.2 to 1.9 +/- 0.3 liter/min as total peripheral resistance (TPR) increased. In 11 dogs with bilateral acute surgical carotid sinus denervation, AUN failed to cause any change in renal hemodynamics, UNaV, or UKV that could be distinguished from sham-operated time controls. CO was measured in seven of these dogs and also did not change. AUN caused an immediate, transient elevation in blood pressure that returned to control levels 15 min after nephrectomy. When bilateral carotid occlusion (BCO) was carried out prior to AUN in animals with intact carotid sinus baroreceptors, AUN again caused an immediate increase in blood pressure but no changes in CO or electrolyte excretion. In separate studies, AUN increased UNaV and UKV significantly; when BCO was then carried out after AUN, cation excretion remained elevated. In seven dogs undergoing continuous perfusion of the carotid circulation bilaterally at constant pressure, AUN again failed to increase cation excretion despite a 30 mmHg rise in arterial blood pressure. These studies demonstrate that AUN fails to initiate hemodynamic or compensatory renal functional changes in dogs with bilateral carotid sinus denervation or in animals in which intact baroreceptors are shielded from the systemic circulation by BCO or perfusion at constant pressure, indicating the importance of these baroreceptors in the early changes after AUN.
Afferent Pathways↗
Dysfunction of the proximal tubule underlies maleic acid-induced type II renal tubular acidosis.
To investigate whether dysfunction of the proximal tubule underlies maleic acid-(MA) induced type II ("proximal") renal tubular acidosis (RTA II), we intravenously administered either MA or acetazolamide to eight conscious trained dogs undergoing water diuresis and examined the relationship between fractional solute-free water clearance (Ch2o/GFR), a measure of NaCl reabsorption in the post-proximal nephron, and either fractional urine flow (V/GFR), a measure of total solute rejected by the proximal tubule, or the sum of fractional excretion of Cl- and Ch2o/GFR [(Ccl + Ch2o)/GFR], a measure of proximally rejected solute that is potentially reabsorbable by the thick ascending limb. When MA or acetazolamide induced brisk bicarbonaturia at normal plasma bicarbonate concentrations: 1) V/GFR, (Ccl + Ch20)GFR, and Ch2o/GFR increased strikingly; 2) at any increment of Ch2o/GFR ws not; 3) the increments of V/GFR correlated positively with those of fractional excretion of bicarbonate (P less than 0.001); 4) during hyperchloremic acidosis, MA-induced bicarbonaturia was greatly attenuated; the increment in V/GFR was halved and approximated that in Ch20/GFR, which was unchanged; 5) when plasma bicarbonate was abruptly increased, bicarbonaturia increased strikingly and V/GFR increased further but Ch20/GFR and aminoaciduria did not. We conclude that MA induces a reduction in the net rate at which the proximal tubule reabsorbs HCO-3, Na+, and Cl-. This dysfunction underlies RTA II and evokes greatly increased reabsorption of Cl- and Na+ in the post-proximal tubule.
Acetazolamide↗
Acute vasodilator therapy increases renal clearance of digoxin in patients with congestive heart failure.
We studied the effect of vasodilator therapy on renal digoxin clearance in patients with chronic congestive heart failure. Intravenous administration of nitroprusside or hydralazine to eight patients with severe heart failure produced the expected increase in cardiac output and a decrease in central circulatory pressure. Renal clearance of sodium para-aminohippurate and estimated renal blood flow increased without a change in glomerular filtration rate. Total renal clearance of digoxin increased by 50% during vasodilator therapy. Thus, acute administration of vasodilator increases renal digoxin clearance without changing glomerular filtration rate, suggesting an increase in tubular secretion of digoxin. Long-term vasodilator therapy may alter the maintenance dosage of digoxin required for optimal treatment of patients in congestive heart failure.
Chronic Disease↗