Mechanism of Stimulation of Vasopressin Release during Beta Adrenergic Stimulation with Isoproterenol

Recent studies have demonstrated that the antidiuresis associated with intravenous (i.v.) infusion of the beta adrenergic agonist, isoproterenol (ISO), is mediated by release of endogenous vasopressin. To examine whether beta-adrenergic stimulation causes vasopressin release by a direct cerebral action, ISO was infused into the carotid artery in a dose estimated to equal the amount of catecholamine reaching the cerebral circulation in the i.v. studies. This intracarotid infusion did not alter renal or systemic hemodynamics, urinary osmolality (Uosm) or free-water clearance (C(H2O)). Although renal perfusion pressure was maintained constant in all experiments i.v. ISO was consistently associated with a decrease in total peripheral resistance and systemic arterial pressure as cardiac output increased. To investigate whether the decrease in cerebral perfusion pressure with i.v. ISO might be responsible for vasopressin release, the carotid arteries were bilaterally constricted both above and below the carotid sinus to lower carotid perfusion pressure by a mean of 25 mmHg, a decrement comparable to that observed during i.v. ISO. Constriction of the carotid arteries above the carotid sinus did not affect Uosm or C(H2O), while constriction below the sinus was associated with an antidiuresis as Uosm increased from 155+/-25 to 385+/-58 mosmol/kg (P < 0.001) and C(H2O) decreased from 1.20 to -0.44 ml/min (P < 0.001). This antidiuresis was not significantly different from that observed during i.v. ISO. Since these results suggested that changes in autonomic neural tone from arterial baroreceptors are responsible for vasopressin release with i.v. ISO, studies were performed in animals with denervated baroreceptors. While sham-operated animals and animals with bilateral cervical vagotomy showed a reversible antidiuresis with i.v. ISO infusion, dogs with complete denervation of arterial baroreceptors did not show a significant alteration in renal water excretion (Uosm, 187 to 182 mosmol/kg and C(H2O), 0.59 to 0.74 ml/min). The results therefore indicate that ISO stimulates vasopressin release by altering baroreceptor tone rather than by a direct central or depressor effect of the catecholamine. These same baroreceptor pathways have been recently shown to be involved in the suppression of vasopressin release with norepinephrine and may well be the common pathway whereby nonosmotic stimuli control vasopressin release.     

Mechanism of Effect of Hypoxia on Renal Water Excretion

The effect of lowering the pressure of oxygen from 80 to 34 mm Hg was examined in anesthetized dogs that were undergoing a water diuresis. This degree of hypoxia was associated with an antidiuresis as urine osmolality (Uosm) increased from 107 to 316 mosmol/kg H₂O (P < 0.001) and plasma arginine vasopressin increased from 0.06 to 7.5 μU/ml, (P < 0.05). However, hypoxia was not associated with significant changes in cardiac output (CO, from 4.2 to 4.7 liters/ min), mean arterial pressure (MAP, from 143 to 149 mm Hg), glomerular filtration rate (GFR, from 46 to 42 ml/min), solute excretion rate (SV, from 302 to 297 mosmol/min), or filtration fraction (from 0.26 to 0.27, NS). Hypoxia was associated with an increase in renal vascular resistance (from 0.49 to 0.58 mm Hg/ml per min, P < 0.01). The magnitude of hypoxia-induced antidiuresis was the same in innervated kidneys and denervated kidneys. To further examine the role of vasopressin in this antidiuresis, hypoxia was induced in hypophysectomized animals. The effect of hypoxia on CO, MAP, GFR, SV, and renal blood flow in hypophysectomized animals was the same as in intact animals. In contrast to intact animals, however, hypoxia did not induce a significant antidiuresis in hypophysectomized animals (Uosm from 72 to 82 mosmol/kg H₂O). To delineate the afferent pathway for hypoxia-stimulated vasopressin release, hypoxia was induced in dogs with either chemo- or baroreceptor denervation. The effect of hypoxia on CO, MAP, GFR, SV, and renal blood flow in the denervated animals was the same as in nondenervated animals. Hypoxia resulted in an antidiuresis in chemoreceptor (Uosm from 113 to 357 mosmol/kg H₂O, P < 0.001) but not in baroreceptor (Uosm from 116 to 138 mosmol/kg H₂O, NS) denervated animals. To determine if hypoxia alters renal response to vasopressin, exogenous vasopressin was administered to normoxic and hypoxic groups of dogs. The antidiuretic effect of vasopressin was no different in these two groups. These results demonstrate that hypoxia induces an antidiuresis which is independent of alterations in CO, MAP, SV, filtration fraction, renal nerves, or renal response to vasopressin and occurs through baroreceptor-mediated vasopressin release. The nature of the baroreceptor stimulation remains to be elucidated.     

Mechanism of Effect of Alpha Adrenergic Stimulation with Norepinephrine on Renal Water Excretion

The present study was undertaken to investigate the mechanism whereby alpha adrenergic stimulation with intravenous norepinephrine results in a water diuresis. Renal perfusion pressure was kept constant in all experiments by adjustment of a suprarenal aortic clamp. In hydropenic anesthetized dogs the intravenous infusion of norepinephrine (0.5 μg/kg per min) was associated with a mean decrease in urinary osmolality from 616 to 126 mosmol/kg (P < 0.001) which increased to 532 mosmol/kg (P < 0.001) after the infusion was discontinued. During the same period of time the mean free water clearance increased from -0.437 to 1.59 (P < 0.001) and then returned to -0.314 ml/min (P < 0.001) after cessation of the infusion. This diuretic effect occurred in both innervated and denervated kidneys and was not associated with an increase in glomerular filtration rate or solute excretion. Systemic arterial pressure increased from 121 to 142 mm Hg during the norepinephrine infusion. Studies were also performed in hypophysectomized animals receiving a constant infusion of either 80 μg/kg per min or 20-40 μU/kg per min of vasopressin. In these animals, intravenous norepinephrine was not associated with changes in either urinary osmolality or free water clearance. The intrarenal administration of norepinephrine, in doses comparable with those reaching the kidneys during the intravenous studies, also resulted in no significant change in either urinary osmolality or free water clearance in hypophysectomized animals receiving 20-30 μU/kg per min of vasopressin. These results thus indicate that the water diuresis associated with intravenous norepinephrine is mediated primarily by suppression of vasopressin release rather than by changes in renal hemodynamics, renal innervation, or an effect of norepinephrine on the water permeability of the tubular epithelium.     

Mechanisms of portal hypertension-induced alterations in renal hemodynamics, renal water excretion, and renin secretion.

Clinical states with portal venous hypertension are frequently associated with impairment in renal hemodynamics and water excretion, as well as increased renin secretion. In the present investigation, portal venous pressure (PVP) was increased in anesthetized dogs undergoing a water diuresis. Renal arterial pressure was maintained constant in all studies. As PVP was increased from 6 to 20 mm Hg, decreases in cardiac output (2.5-2.0 liter/min, P less than 0.05) and mean arterial pressure (140-131 mm Hg, P less than 0.05) were observed. Increases in PVP were also associated with decreases in glomerular filtration rate (GFR, 40-31 ml/min, P less than 0.001), renal blood flow (RBF, 276-193 ml/min, P less than 0.001), and increases in renin secretion (232-939 U/min, P less than 0.025) in innervated kidneys. No significant change in either GFR or RBF and a decrease in renin secretion occurred with increases in PVP in denervated kidneys. To dissociate the changes in cardiac output and mean arterial pressure induced by increase PVP from the observed decreases in GFR and RBF, studies were performed on animals undergoing constriction of the thoracic inferior vena cava. In these studies, similar decreases in cardiac output and mean arterial pressure were not associated with significant changes in GFR or RBF. Increases in PVP also were associated with an antidiuresis as urine osmolality increased from 101 to 446 mosmol/kg H2O (P less than 0.001). This antidiuresis was significantly blunted but not abolished by acute hypophysectomy. In hypophysectomized animals, changes in free water clearance and urine flow were linearly correlated as PVP was increased. These studies indicate that increases in PVP result in decreases in GFR and RBF and increases in renin secretion mediated by increased renal adrenergic tone. Increased PVP is also associated with antidiuresis; this antidiuresis is mediated both by vasopressin release and by diminished tubular fluid delivery to the distal nephron.     

Mechanism of suppression of vasopressin and adrenocorticotropic hormone secretion by clonidine in anesthetized dogs

Studies were performed in anesthetized dogs to investigate the mechanism of the suppression of vasopressin and adrenocorticotropic hormone (ACTH) secretion by clonidine. Injection of clonidine (30 micrograms/kg i.v.) produced an initial increase in arterial pressure followed by hypotension, decreased heart rate, increased right atrial pressure and decreased plasma renin activity. Plasma vasopressin concentration decreased from 14.6 +/- 3.0 to 2.2 +/- 0.4 pg/ml (P less than .01), and this was accompanied by increases in urine volume and free water clearance from 0.15 +/- 0.02 to 1.03 +/- 0.28 and -0.50 +/- 0.05 to 0.30 +/- 0.27 ml/min, respectively (P less than .01), and a decrease in urinary osmolality from 1450 +/- 124 to 372 +/- 97 mOsmol/kg of H2O (P less than .01). Plasma corticosteroid concentration, used an an index of ACTH secretion, decreased from 8.9 +/- 1.6 to 2.2 +/- 0.3 micrograms/dl (P less than .01). Plasma osmolality did not change. Pretreatment of dogs with the alpha adrenoceptor antagonist yohimbine (2 mg/kg i.p.) blocked all cardiovascular, endocrine and renal responses to clonidine. Bilateral cervical vagotomy did not block the suppression of vasopressin or corticosteroid secretion by clonidine. Intraventricular injection of yohimbine blocked the hypotension and suppression of plasma corticosteroid concentration produced by clonidine but did not block the decrease in plasma vasopressin concentration or the associated renal effects of clonidine. Intracarotid infusion of clonidine caused small decreases in plasma vasopressin and corticosteroid concentrations even though blood pressure decreased by 22 mm Hg. Intraventricular and intravertebral clonidine had no significant effect on plasma vasopressin or corticosteroid concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanism of Effect of Thoracic Inferior Vena Cava Constriction on Renal Water Excretion

Persistent secretion of vasopressin and/ or diminished distal fluid delivery have been proposed to explain the impaired water excretion associated with low-output cardiac failure. In the present investigation cardiac output (CO) was diminished in anesthetized dogs undergoing a water diuresis by constriction of the thoracic inferior vena cava (TIVC). In intact animals (group I) acute TIVC constriction decreased CO from 3.5 to 2.2 liters/min (P < 0.005) as urinary osmolality (U(osm)) increased from 103 to 543 mosmols/ kg (P < 0.001) and free water clearance (C(H2o)) decreased from 2.1 to -0.6 ml/min (P < 0.001). This antidiuretic effect was disassociated from changes in renal arterial and venous pressures, glomerular filtration rate, solute excretion, and renal innervation. To examine the role of vasopressin in this antidiuresis, studies (group II) were performed in acutely hypophysectomized, steroid-replaced animals. In these animals TIVC constriction decreased CO to a similar degree from 3.4 to 2.1 liters/min (P < 0.001). However, the effects on U(osm) (87-104 mosmols/kg) and C(H2o) (2.1-1.6 ml/min) were significantly less than in intact dogs. In another group of hypophysectomized animals, (group III) renal arterial and venous pressures were not controlled, and the effect of TIVC constriction on U(osm) was not significant (65-79 mosmols/kg) although C(H2o) decreased from 3.3 to 1.9 ml/min (P < 0.001). In both the group II and III studies, there were linear correlations between the changes in C(H2o) and the urine flow. Studies were also performed in baroreceptor-denervated animals with intact hypothalamo-neurohypophyseal tracts, and acute TIVC constriction altered neither U(osm) nor C(H2o) when renal arterial pressure was controlled. These results therefore indicate that the effect of TIVC constriction on U(osm) is primarily vasopressin mediated while the effect on C(H2o) is mediated both by vasopressin release and diminished distal fluid delivery. A decrease in renal arterial pressure, or some consequence thereof, seems to be an important determinant of the latter effect.     

Mechanism of Suppression of Vasopressin during Alpha-Adrenergic Stimulation with Norepinephrine

Recent studies have demonstrated that the water diuresis associated with intravenous infusion of norepinephrine is mediated primarly by suppression of antidiuretic hormone (ADH) release. To investigate whether the increase in cerebral perfusion pressure with intravenous norepinephrine (0.5 mug/kg/min) is directly responsible for suppression of ADH release, the carotid circulation of dogs was pump-perfused bilaterally to selectively increase cerebral perfusion pressure. In six experiments cerebral perfusion pressure was increased from a mean of 125 to 151 mm Hg and then returned to 120 mm Hg. This maneuver was not associated with a reversible increase in renal water excretion. The possibility was also examined that norepinephrine exerts a direct central effect to suppress ADH release. In 12 experiments norepinephrine was infused into the carotid artery in a subpressor dose (0.12 mug/kg/min) estimated to equal the amount of the catecholamine reaching the cerebral circulation with intravenous norepinephrine. The urinary osmolality (Uosm) was not significantly altered with intracarotid norepinephrine (932 to 959 mosmol/kg H(2)O. The possibility was also examined that changes in autonomic neural tone from arterial baroreceptors is responsible for suppression of ADH release with intravenous norepinephrine. In sham-operated animals intravenous norepinephrine diminished Uosm from 1,034 to 205 mosmol/kg H(2)O (P<0.001) whereas in animals with denervated arterial baroreceptors intravenous norepinephrine was not associated with a significant alteration in Uosm (1,233 to 1,232 mosmol/kg) H(2)O. These different effects on urinary osmolality occurred in the absence of differences in plasma osmolality and volume status. The results therefore indicate that norepinephrine primarily suppresses ADH release by altering autonomic baroreceptor tone rather than by a direct central or pressor effect of the catecholamine. This same mechanism may be the primary pathway for other nonosmotic influences on ADH release.     

Mechanism of Effect of Prostaglandin E1 on Renal Water Excretion

The present study examined the effect of prostaglandin E(1) (PGE(1)) on renal water excretion in the anesthetized dog. Renal perfusion pressure was kept constant by adjustment of a suprarenal aortic clamp. In seven experiments the intravenous administration of PGE(1) (7 mug/min) significantly increased urinary osmolality from 76 to 381 mosmol (P < 0.001) and decreased free water clearance from 2.2 to - 0.02 ml/min (P < 0.001). These effects promptly were reversed with cessation of the infusion. This antidiuretic effect occurred both in innervated and denervated kidneys and was not associated with changes in glomerular filtration rate, renal vascular resistance, or solute excretion rate. In 10 experiments in hypophysectomized dogs no effect of intravenous PGE(1) on free water clearance and urinary osmolality was observed. The intrarenal administration of PGE(1) (1 mug/min) to six water-loaded and two hypophysectomized dogs caused no systemic vascular changes and increased rather than decreased free water clearance (2.83 to 4.08 ml/min, P < 0.001). No significant change in urinary osmolality occurred. Glomerular filtration rate was not altered by the intrarenal infusion, but reversible changes in solute excretion rate and renal vascular resistance occurred. These results thus indicate that the antidiuresis associated with intravenous PGE(1) is mediated primarily by the release of vasopressin rather than alterations in renal hemodynamics or solute excretion. The diuretic effect of intrarenal PGE(1) occurs in the absence of vasopressin and is most likely mediated primarily by increased distal delivery of tubular fluid to the diluting segment of the nephron rather than changes in water permeability of the renal tubular epithelium.     

Effects of intracerebroventricular administration of adrenoceptor-agonists on the regulation of renal water and electrolytes handling through endocrine, renal and hemodynamic function

In order to assess the roles of central adrenoceptors in the release of atrial natriuretic peptide (ANP), aldosterone (ALD), vasopressin (AVP) and renin as well as in the regulation of renal and cardiovascular functions, either norepinephrine (NE; 0.07 microgram/kg/min), guanabenz (GB; alpha 2-agonist; 0.4 microgram/kg/min), methoxamine (MET; alpha 1-agonist; 0.4 microgram/kg/min), or isoproterenol (ISO; beta-agonist; 0.07 microgram/kg/min), dissolved in the artificial cerebrospinal fluid (ACSF), was intracerebroventricularly (i.c.v.) administered at a rate of 10 microliters/min for 30 min in anesthetized dogs. In the control study, the drugs were omitted. NE decreased mean arterial pressure (MAP), urinary osmolality (Uosm) and plasma ALD and AVP concentrations, and increased urine flow (UF). GB increased UF and urinary K excretion without any changes in urinary Na excretion, but decreased plasma ALD and AVP, heart rate, and Uosm without changes in MAP. ISO decreased MAP and plasma ALD, and increased Na and K output, renal plasma flow and UF with decreased Uosm. MET and ACSF failed to affect any of these parameters. Glomerular filtration rate, plasma ANP concentration and renin activity did not change in any of the studies. The present results suggest that central alpha 2- and beta-adrenoceptors may attenuate ALD and/or AVP release without changes in ANP and renin release, and decrease blood pressure, thereby causing a diuresis and natriuresis.     

Effects of physiological increments in renal arterial plasma osmolality on renin secretion rate

The present study was performed in anesthetized dogs to examine the effects of physiological increments in renal arterial plasma osmolality on basal renin secretion rate and on the response of renin secretion rate to RNS. Three concentrations of hypertonic NaCl were infused into the renal artery (i.r.a.) at 0.38 ml/min for 3 min; i.r.a. Hypertonic NaCl at 0.45M, 0.9M, and 1.8M increased the renal arterial plasma osmolality by 6 +/- 2, 8 +/- 2, and 28 +/- 9 mOsm/kg H2O, respectively. NaCl, 0.45M, did not affect renal function, whereas both 0.9M and 1.8M NaCl increased renal blood flow and urinary sodium excretion; neither 0.45M, 0.9M, nor 1.8M NaCl affected renin secretion rate. RNS was applied at two different frequencies: LFRNS and HFRNS. LFRNS did not affect renal blood flow, whereas HFRNS reduced renal blood flow by 50%. Both LFRNS and HFRNS increased renin secretion rate significantly. An i.r.a. infusion of 0.9M NaCl increased urinary sodium excretion and reduced the renin secretion rate response to LFRNS (-52% +/- 15, p less than 0.02) and HFRNS (-25% +/- 8, p less than 0.01). These findings demonstrate that increases in renal arterial plasma osmolality within the physiological range increase renal blood flow but do not affect renal secretion rate. The renal secretion rate response to RNS is attenuated by increased renal arterial plasma osmolality, an effect consistent with increased sodium chloride delivery to the distal tubular macula densa receptor.     

Evidence for an in vivo antagonism between vasopressin and prostaglandin in the mammalian kidney.

These studies were undertaken to examine whether an antagonism between vasopressin and prostaglandin occurs in vivo in the mammalian kidney. All experiments were performed in steroid-replaced hypophysectonized dogs undergoing a water diuresis. In the first group of studied the effect of two consecutive intravenous doses (100 mU) of vasopressin was examined. The second dose of vasopressin was preceded by an injection of the carrier solution for solubilizing indomethacin or neclofenamate. No enhancement of the antidiuretic effect of the second dose of vasopressin was observed as urinary osmolality (Uosm) increased from 92 +/- 5 to 252 +/- 18 mosmol/kg H2O (P less than 0.0001) after the first dose and from 109 +/- 8 to 209 +/- 10 mosmol/kg H2O (P less than 0.001) after the second dose of vasopressin. In another group of studies the second dose of vasopressin was preceded by the administration of a potent inhibitor of prostaglandin synthesis, indomethacin (2 mg/kg). The Uosm increased from 93 +/- 9 to 244 +/- 33 mosmol/kg H2O (P less than 0.001) after the first dose of vasopressin, but after the second dose of vasopressin the Uosm increased to a significantly greater degree from 106 +/- 14 to 702 +/- 69 mosmol/kg H2O (P less than 0.001). In a third group of studies the antidiuretic effect of the same 100-mU dose of vasopressin was examined before and after the administration of meclofenamate (2 mg/kg), an inhibitor of prostaglandin synthesis which is chemically dissimilar from indomethacin. Uosm increased from 83+/-7 to 216+/-16 mosmol/kg H2O (P less than 0.001) after the first dose and from 101 +/- 8 to 734 +/- 86 mosomol/kg H2O (P less than 0.001) after the second dose of vasopressin. As in the indomethacin studies this enhancement in the antidiuretic effects of vasopressin after inhibition of prostaglanding synthesis was highly significant (P less than 0.001). These results therefore implicate a physiological role of prostaglandin in modulating the hydroosmotic effect of vasopressin in the mammalian kidney.     

The osmotic thresholds for thirst and vasopressin release are similar in healthy man

The relationship between thirst perception and plasma osmolality was studied during hypertonic and physiological saline infusion in ten healthy volunteers. Thirst perception was quantified using a linear visual analogue scale which volunteers marked at intervals during the infusion periods. Infusion of hypertonic saline caused a steady rise in plasma osmolality together with a progressive linear increase in thirst perception and also plasma arginine vasopressin. No significant changes in thirst, plasma osmolality or plasma arginine vasopressin occurred during infusion of physiological saline. Linear regression analysis of the results defined the functions. Thirst (cm) = 0.3 (plasma osmolality-281) (r = +0.92, P less than 0.001) and plasma arginine vasopressin (pmol/l) = 0.4 (plasma osmolality-285) (r = +0.96, P less than 0.001). The osmolar threshold for thirst onset thus defined (281 mosmol/kg) was much lower than in previous studies and similar to the theoretical osmolar threshold for vasopressin release (285 mosmol/kg). We conclude that thirst perception rises in a progressive fashion throughout a wide range of plasma osmolality and that the osmolar threshold for thirst onset is similar to the theoretical osmolar threshold for vasopressin release. The results are compatible with the concept of either a single osmoreceptor subserving both thirst and vasopressin release, or two osmoreceptors sharing similar functional characteristics.     

Osmoregulation of thirst and vasopressin secretion in insulin-dependent diabetes mellitus

1. Osmotically stimulated thirst and vasopressin release were studied during infusions of hypertonic sodium chloride and hypertonic D-glucose in euglycaemic clamped diabetic patients and healthy controls. 2. Infusion of hypertonic sodium chloride caused similar elevations of plasma osmolality in diabetic patients (288.0 +/- 1.0 to 304.1 +/- 1.6 mosmol/kg, mean +/- SEM, P less than 0.001) and controls (288.6 +/- 0.9 to 305.7 +/- 0.6 mosmol/kg, P less than 0.001), accompanied by progressive increases in plasma vasopressin (diabetic patients, 0.9 +/- 0.3 to 7.7 +/- 1.5 pmol/l, P less than 0.001; controls 0.5 +/- 0.1 to 6.5 +/- 1.0 pmol/l, P less than 0.001) and thirst ratings (diabetic patients 1.0 +/- 0.2 to 7.1 +/- 0.5 cm, P less than 0.001; controls 1.8 +/- 0.4 to 8.0 +/- 0.5 cm, P less than 0.001) in both groups. 3. Drinking rapidly abolished thirst and vasopressin secretion before major changes in plasma osmolality occurred in both diabetic patients and healthy controls. 4. There were close and significant correlations between plasma vasopressin and plasma osmolality (diabetic patients, r = +0.89, controls r = +0.93) and between thirst and plasma osmolality (diabetic patients r = +0.95, controls r = +0.97) in both diabetic patients and healthy controls during hypertonic saline infusion. 5. Hypertonic D-glucose infusion caused similar elevations in blood glucose in diabetic patients (4.0 +/- 0.2 to 20.1 +/- 1.2 mmol/l, P less than 0.001) and healthy controls (4.3 +/- 0.1 to 19.3 +/- 1.2 mmol/l, P less than 0.001) but did not change plasma vasopressin or thirst ratings.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transient polyuria in pregnancy in diabetes insipidus and gestational diabetes]

Two pregnant women developed overt polyuria (up to 11 l/day) and polydipsia during their second and third trimesters of pregnancy. In one patient hydronephrosis was present. Both patients suffered from mild gestational diabetes mellitus. Plasma sodium was 145 and 162 mmol/l. Polyuria and urinary hypo-osmolality responded well to desmopressin acetate. After delivery, polyuria and polydipsia disappeared in one patient and significantly improved in the other. Infusion of hypertonic saline one and two weeks respectively after delivery led to plasma hyper-osmolality (294 mosmol/kg and 305 mosmol/kg) without detectable stimulation of arginine vasopressin (AVP). Anterior pituitary function was normal. No stimulation of AVP occurred following insulin-induced hypoglycemia. AVP plasma disappearance after i.v. pulse injection of 1 microgram AVP as well as AVP plasma concentration after continuous infusion of 10 ng AVP/min was studied two weeks after delivery in one patient. The results suggested markedly elevated degradation of AVP compared to control subjects, probably due to an increased vasopressin activity. Eight months after delivery, hypertonic saline infusion in one patient led to a plasma-osmolality of 312 mosmol/kg without stimulation of AVP. In the second patient, AVP was not detectable (less than 0.2 pg/ml) six months after delivery when plasma osmolality was 290 mosmol/kg. Our studies demonstrate that a subclinical compensated diabetes insipidus was preexistent in both patients. Exacerbation occurred due to an increased AVP-clearance and presumably due to the hemodynamic and hormonal alterations during pregnancy, including a mild gestational diabetes mellitus.     

Evidence for prostaglandin-independent mechanisms in renin release mediated by alpha adrenoceptors during renal nerve stimulation in anesthetized dogs

We investigated alpha adrenoceptor-mediated renin release in relation to renal prostaglandin production in anesthetized dogs. The effects of intrarenally infused phentolamine (5 micrograms/kg/min) on renin and prostaglandin E2 release induced by renal nerve stimulation (RNS, 2.5-5 Hz) were studied in indomethacin (5 mg/kg i.v.)-treated and untreated dogs. In the control group, RNS reduced renal blood flow and increased both renin and prostaglandin E2 secretion rates. Phentolamine inhibited the blood flow response and attenuated the renin response; it did not affect the prostaglandin E2 response. In the indomethacin-treated group, the renal venous plasma prostaglandin E2 concentration was not changed, the renin secretion rate was increased during RNS. Phentolamine also attenuated the renin response in this prostaglandin-depleted state. These results suggest that alpha adrenoceptors participate in renin release induced by RNS and that some of the alpha adrenoceptor-mediated renin release is independent of renal prostaglandins. Prostaglandin release induced by RNS may be mediated by mechanisms other than alpha adrenoceptors.     

Effects of blockades of alpha and beta adrenoceptors and dopamine receptors on renal nerve stimulation-induced prostaglandin E2 and renin release in anesthetized dogs

Effects of intrarenal infusions of prazosin (0.7 microgram/kg/min), yohimbine (1 microgram/kg/min), propranolol (4 micrograms/kg/min) and sulpiride (20 micrograms/kg/min) on renal prostaglandin (PG) E2 and renin release in response to renal nerve stimulation (RNS) were examined in anesthetized dogs. RNS (2.5-5 Hz, for 10 min) decreased renal blood flow and increased both PGE2 and renin secretion rates. The blood flow response was inhibited by prazosin but not by other antagonists. Prazosin and propranolol, but not yohimbine or sulpiride, attenuated the renin response. However, none of these antagonists affected the PGE2 response. The results suggest that the RNS-induced renin release is mediated by alpha adrenoceptors, which seem to be alpha-1 type, and beta adrenoceptors, but the RNS-induced PGE2 release is not mediated by these adrenoceptors. Renal dopaminergic component may play no significant role in the RNS-induced PGE2 or renin release.     

Mechanisms of the urinary concentration defect and effect of desmopressin during endotoxemia in rats

Acute renal failure during human sepsis is often nonoliguric. To study the underlying mechanisms, renal function was assessed in endotoxic and control male Wistar rats during and after saline loading and treatment with the selective V2 receptor agonist desmopressin. Escherichia coli endotoxin (dose, 8 mg/kg) was administered from time (t)=0 to t=60 min; saline loading (rate, 5 mL/100 g per hour) was administered from t=0 to t=120 min. Thereafter, half of each group received desmopressin (dose, 10 microg) for 1 h. The inner medullary (IM) osmolality, hematocrit, plasma, and urinary concentrations of sodium, potassium, urea, and osmolality were measured; then, aquaporin 2 (AQP2) immunohistochemistry was performed. Plasma vasopressin concentrations were measured at t=180 min. Saline loading increased urine volume in all rats. In the endotoxic group, mean arterial pressure decreased when saline loading was stopped. Despite increased hematocrit and vasopressin levels (>16 pg/mL), the endotoxin group had a low IM osmolality (mean +/- SEM, 412+/-0.04 mOsm/kg H2O) in comparison with the control group (mean +/- SEM, 1,094+/-0.17 mOsm/kg H2O) and was not able to either decrease urine volume or raise urine osmolality. Desmopressin treatment in endotoxin-treated rats maintained mean arterial pressure, increased sodium reabsorption, IM osmolality, and urine osmolality, and decreased urine flow. The AQP2 intensity decreased in the endotoxin group, and the apical localization disappeared; both were not affected by desmopressin. Our results indicate that endotoxemia in rats acutely diminishes renal urinary concentration capacity and is associated with a decreased IM osmolality and diminished apical AQP2 localization. These findings may help to explain nonoliguric acute renal failure in human septic shock.     

Effect of beta adrenergic blockade on renin response to renal nerve stimulation.

The ability of d,l-propranolol to block renin secretion in response to various extrarenal stimuli, such as hemorrhage and hypoglycemia, has been interpreted to indicate the presence of an intrarenal beta receptor regulating renin release. However, two problems complicate this interpretation: (a) the stimuli have effects outside the kidney, and (b) d,l-propranolol has a local anesthetic, as well as a beta adrenergic blocking, action. In the present study, the effects of a purely intrarenal stimulus, in the form of renal nerve stimulation (RNS), on renin secretion was examined. The effects of d,l-propranolol (anesthetic and beta-blocking activity), l-propranolol (beta-blocking activity only), and d-propranolol (local anesthetic activity only) on the renin response to RNS were examined. In a control group of animals, two sequential RNS increased mean renin secretion from 401 to 1,255 U/min (P less than 0.25) and from 220 to 2,179 U/min (P less than 0.01). In a second group the first RNS increased renin secretion from 201 to 1,181 U/min (P less than 0.01), but after d,l-propranolol was given RNS did not significantly alter renin secretion (33 to 55 U/min). In a third group the initial RNS increased renin secretion from 378 to 1,802 U/min (P less than 0.025), but after l-propranolol was given RNS had no significant effect on renin secretion (84 to 51 U/min). A fourth group of dogs showed a rise in renin secretion from 205 to 880 U/min (P less than 0.001) in response to the first RNS, while the second RNS, given after an infusion of d-propranolol, caused a rise in renin secretion from 80 to 482 (P less than 0.005). The nature of the electrical stimulus was consistent in all groups and caused no detectable changes in renal or systemic hemodynamics or in urinary electrolyte excretion. The results, therefore, indicate that renin secretion can be stimulated through intrarenal beta receptors independent of changes in systemic or renal hemodynamics or in tubular sodium reabsorption. Hence the effect of beta stimulation on renin secretion would appear to result from a direct action on the renin-secreting cells of the juxtaglomerular apparatus.     

Impairment of cyclic AMP response to bovine parathyroid hormone in patients on chronic lithium therapy with diminished renal urine-concentrating ability

1. Urinary and plasma levels of adenosine 3':5'-cyclic monophosphate (cyclic AMP) after an intravenous injection of bovine parathyroid hormone (PTH) were measured in 12 patients on long-term lithium treatment and in nine control subjects. The maximum urine osmolality (Umax.) after an intravenous injection of desamino-D-arginine vasopressin (DDAVP) was also measured. 2. In all the control subjects and six of the patients, the Umax. after DDAVP exceeded 700 mosmol/kg. The cyclic AMP responses in these two groups did not differ significantly. 3. In the remaining six patients whose Umax. did not reach 700 mosmol/kg, the cyclic AMP response to PTH was significantly less than that of the controls. 4. A strong correlation was demonstrated in the patients between the urinary cyclic AMP response after PTH and the maximum osmolality after the administration of DDAVP. 5. These observations are consistent with the hypothesis that reduced adenylate cyclase activity contributes to the development of nephrogenic diabetes insipidus in patients on long-term lithium treatment.     

Role of volume in the regulation of vasopressin secretion during pregnancy in the rat.

We previously observed that osmoregulation and the osmotic threshold for antidiuretic hormone secretion were altered during pregnancy in Sprague-Dawley rats and the present study evaluated the influence of volume on arginine vasopressin (AVP) release during gestation in this species. Basal plasma osmolality (Posm) and intravascular volume were 297 +/- 3 mosmol/kg and 16.2 +/- 1.2 ml in virgin animals compared with 290 +/- 2 mosmol/kg and 20.2 +/- 2.3 ml in 14-d pregnant rats and 287 +/- 3 mosmol/kg and 25.2 +/- 2.3 ml in 21-d (near-term) pregnant rats (P less than 0.001, each pregnant group vs. virgin). Isosmotic volume depletion was produced by intraperitoneal polyethylene glycol. Volume decreased from 1 to 26% and blood pressure remained stable during decrements as high as 16%. Plasma AVP (PAVP) did not rise significantly in either group of pregnant animals or virgin controls until blood volume depletion reached 6-7%, after which levels rose in a similar exponential manner in virgin, 14-d, and 21-d pregnant animals. In terms of absolute changes, however, PAVP in gravid rats started to increase when intravascular volume was still considerably greater than basal blood volume in the nonpregnant controls. Other experiments, where Posm was increased by intraperitoneal hypertonic saline, reconfirmed that the osmotic threshold for AVP secretion was reduced congruent to 10 mosmol/kg during pregnancy and that AVP release was stimulated by increments in body tonicity as small as 1-2%. In parallel studies, blood volume contraction and increases in Posm were evoked by intraperitoneal polyethylene glycol dissolved in hypertonic saline and results compared with animals receiving intraperitoneal saline alone. Decrements in volume (congruent to 7%), which alone would increase PAVP minimally, increased the sensitivity of the secretory response to changes in osmolality two- to three-fold, an effect which was similar in virgin and gravid animals. Finally, restricting water intake of pregnant rats to that of virgins on days 16-20 of gestation led to suboptimal volume expansion, hypertonicity, and an exaggerated increase in PAVP. These results demonstrate that despite an intravascular space which at term is nearly twice that of virgin rats, pregnant animals secrete AVP in response to fractional volume depletion in a manner similar to nonpregnant controls; that is, the relationship between total blood volume and AVP secretion is altered during gestation such that the expanded blood volume is recognized as normal.