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 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 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.

Correction of metabolic acidosis by the kidney during isometric expansion of extracellular fluid volume.

In dogs with chronic hypochloremic metabolic alkalosis associated with ECFV contraction, plasma [HCO-3] ([HCO-3]p) normalizes during expansion of ECFV with a solution containing Cl- and HCO-3 in concentrations duplicating those in the plasma before expansion (isometric expansion). The kidney selectively rejects administered HCO-3 and retains Cl-. If this preferential Cl- less than HCO-3 reabsorptive selectivity were a characteristic renal response to ECFV expansion, isometric expansion during hyperchloremic acidosis would exacerbate the acid-base disturbance rather than correct it as it does in alkalosis. We examined the effect of isometric expansion in dogs with chronic hyperchloremic metabolic acidosis induced by HCl feeding or mineralocorticoid hormone deficiency. During expansion, as the expected decrease occurred in the fractional reabsorption of Na+, a lesser decrease occurred in fractional reabsorption of HCO-3, whereas a greater decrease occurred in fractional reabsorption of Cl-. The kidney selectively retained administered HCO3 and rejected Cl-. [HCO-3]p normalized. The shift to bicarbonate-selective from chloride-selective anion reabsorption during ECFV expansion in metabolic acidosis vs. metabolic alkalosis indicates that in response to ECFV expansion- the kidney selectively alters the ratio of bicarbonate to chloride concentration in the tubular reabsorbate in the direction that tends to normalize plasma acid-base composition, irrespective of the direction of deviation of the initial plasma bicarbonate concentration. The signal that initiates the shift in anion reabsorptive selectivity remains to be identified.

Catecholamines and renal water excretion.

The in vivo mechanisms whereby systemic alpha- and beta-adrenergic stimulation exert opposing effects on renal water excretion are reviewed. An extrarenal mechanism is suggested since the effect of intravenous infusion of norepinephrine or isoproterenol on water excretion cannot be mimicked by the intrarenal administration of these agents. A ROLE OF VASOPRESSIN IS IMPLICATED SINCE NEITHER MAN NOR DOG WITHOUT A PITUITARY SOURCE OF VASOPRESSIN DEMONSTRATE THE SAME EFFECT OF CATECHOLAMINES ON WATER EXCRETION AS OBSERVED IN INTACT MAN AND DOG. Evidence also is presented that systemic alpha- and beta-adrenergic stimulation affect vasopressin release primarily by altering baroreceptor tone. The potential role of the autonomic nervous system in mediating other nonosmotic stimuli for vasopressin is discussed.

Effect of angiotensin II on renal water excretion.

In the present study the effect of angiotensin II (AII) on renal water excretion was evaluated. In dogs undergoing a water diuresis, neither the intravenous (IV) (40ng/kg per min) nor intracarotid (5-10 ng/kg per min) infusion of AII significantly altered urinary osmolality (Uosm) or free-water clearance (CH2O). Intravenous infusion of a competitive inhibitor of AII (1-sarcosine,8-glycine AII) into hydropenic dogs also failed to alter Uosm and CH2O significantly. To examine whether AII might suppress, rather than stimulate, vasopressin release, AII was also infused into hydropenic animals. No effect on Uosm and CH2O was observed during the intracarotid infusion. A significant fall in Uosm and rise in CH2O occurred during the intravenous AII infusion, but reversal after cessation of the infusion was incomplete and statistically not significant. Some suppression of antidiuretic hormone (ADH) release during the intravenous infusion of AII, however, was suggested since no similar alteration in renal water excretion was observed during an intravenous AII infusion in hypophysectomized animals receiving a constant infusion of ADH. Taken together, the present results provide no evidence for a direct effect of AII to alter ADH release or to interfere with the peripheral action of ADH. Suppression of ADH release may sometimes occur with pressor doses of intravenous angiotensin, but this effect is clearly less consistent than previously observed with intravenous norepinephrine.

Impaired renal H+ secretion and NH3 production in mineralocorticoid-deficient glucocorticoid-replete dogs.

When the administration of exogenous mineralocorticoid hormones was discontinued in adrenalectomized dogs maintained on glucocorticoid, net acid excretion decreased due largely to a reduction in urinary ammonium excretion (UNH4+V), and hyperchloremic hyperkalemic metabolic acidosis occurred and persisted. The reduction in UNH4+V was not associated with an increase in urine pH (UpH) or a decrease in urine flow, but correlated with the severity of hyperkalemia and was mitigated by dietary potassium restriction. UpH decreased to values as low as 5.3. During acidosis, UpH varied directly with UNH4+V, but in relation to UNH4+V, UpH exceeded that in acid-fed mineralocorticoid-replete dogs. Extrapolated to UNH4+V=0, however, UpH was not significantly different in the two groups (5.27 vs. 5.44). When distal delivery of sodium was increased by infusion of sodium phosphate, titratable acid excretion increased in both groups but pateaued at lower rates in the mineralocorticoid-deficient dogs. These results suggest that in mineralocorticoid-deficient dogs, renal ammonia production is diminished, in part due to potassium retention and hyperkalemia; renal hydrogen ion secretory capacity is reduced even when sodium and buffer delivery to the distal nephron is not reduced; and the ability of the kidney to generate normally steep urine-to-blood hydrogen ion concentration gradients is unimpaired.