Adaptive responses to sustained volume expansion in hyponatraemic rats.

Studies were carried out to evaluate adaptive responses to water retention in an experimental model of the syndrome of inappropriate antidiuresis (SIAD). Hyponatraemia was induced by continuous s.c. infusions of the antidiuretic vasopressin analogue 1-deamino-[8-D-arginine]-vasopressin in rats ingesting a 5% (w/v) dextrose solution. After 48 h of sustained decreases in the plasma concentration of Na+ to 23-25% of normal levels, all body fluid compartments were significantly expanded: plasma volume estimated by changes in plasma protein concentration was increased by 26%, extracellular fluid volume estimated by 22Na volume of distribution was increased by 24%, and total body water estimated by 3H2O volume of distribution was increased by 16%. Despite marked increases in all body fluid compartment volumes, mean arterial blood pressure was only modestly increased to 110 +/- 2 mmHg in conscious hyponatraemic rats. Consistent with the sustained volume expansion, both basal and stimulated plasma renin activities were significantly suppressed in the hyponatraemic rats. Plasma vasopressin levels were similarly suppressed, and the hyponatraemic rats showed a striking absence of endogenous vasopressin secretion in response to marked intravascular volume depletion (15-45%) produced by s.c. administration of polyethylene glycol. Plasma concentrations of atrial natriuretic peptide were initially stimulated four- to fivefold above basal levels in response to the water-induced volume expansion, but by 48 h fell to ranges not significantly different from basal unstimulated levels, despite continued plasma and extracellular fluid volume expansion at that time. These results illustrate that multiple haemodynamic and hormonal adaptive responses occur with sustained dilutional hyponatraemia in rats, and suggests that these can be of sufficient magnitude to allow continued water retention without necessarily provoking either escape from antidiuresis or continued natriuresis. In contrast with previous studies in experimental animals in which hyponatraemia was maintained by continuous forced administration of hypotonic fluid, rats in this model reached a steady state with characteristics resembling many of those observed clinically in patients with SIAD.

Measurement of cytosolic calcium with aequorin in dispersed rat ventricular cells.

The changes in the cytosolic concentration of free calcium of adult rat cardomyocytes were monitored using aequorin incorporated by hypoosmotic shock. The majority of the myocytes retained their rod-like appearance and their tolerance to a normal concentration of extracellular calcium. The aequorin signal was increased by depolarization, by an increase in extracellular calcium, by substitution of extracellular sodium with either choline or tetramethylammonium, by 20 mM NH4Cl or by hypoxia. In these myocytes, isoproterenol or the phosphodiesterase inhibitor MIX (3-isobutyl-l-methylxanthine) enhanced the ability of the cells to buffer calcium loads while the mitochondrial inhibitor FCCP (carbonyl cyanide p-trifluoromethoxy-phenyl-hydrazone), decreased their calcium buffering capacity.

Diminished sympathetic responsiveness in nephrectomized rats-role of the renin angiotensin system.

Experiments were conducted in pithed Wistar rats to assess the effects of nephrectomy on the responsiveness of the cardiovascular system to sympathetic neurohumoral stimuli. Blood pressure and heart rate increases produced in response to stimulation of the spinal sympathetic outflow and to norepinephrine were compared in nephrectomized (NXR) and sham operated animals (SOR). Both the blood pressure (BP) and heart rate (HR) increases to nerve stimulation were markedly attenuated in the NXR, however, only the reduction in BP responses could be attributed to the absence of a functional renin angiotensin system. Infusion of angiotensin II (10 ng/kg/min) in NXR enhanced the neurally mediated increments in BP to the extent that the responses were not different from SOR. Angiotensin II administration also enhanced BP responses in SOR but to a lesser extent than in NXR. HR responses were not altered by angiotensin in NXR or SOR. Blockade of the renin angiotensin system in SOR with the converting enzyme inhibitor, captopril, reduced BP responses to the same level as NXR. In contrast, HR increments were not altered by captopril. BP but not HR increments to norepinephrine were significantly reduced in NXR. Infusion of angiotensin II restored the BP responses to a level equal to SOR; HR responses were not affected. In addition, captopril reduced the norepinephrine responses of SOR but not NXR. Thus the results of the present study indicate that endogenously formed angiotensin facilitates sympathetically mediated vasoconstrictor activity but does not influence heart rate responses. Therefore, the attenuation of neurally elicited increases in HR observed in NXR does not appear to be acutely related to reduced levels of angiotensin II.

Role of the renin-angiotensin system in the blood pressure rebound to sodium nitroprusside in the conscious rat.

Intravenous infusions of sodium nitroprusside (SNP) at doses of 20, 40 or 80 micrograms/kg min-1 for 30 min produced dose-related decrements in blood pressure in conscious rats fitted with indwelling aortic and vena caval catheters. Immediately upon termination of SNP infusions, blood pressure rebounded to levels which were significantly above pre-SNP control values. The following evidence indicates that the rebound increase in blood pressure was due to increased activity of the renin-angiotensin system: (1) plasma renin activity was increased approximately four-fold by SNP, (2) rebound did not occur in nephrectomized rats, (3) rebound was markedly attenuated in animals treated with an angiotensin converting enzyme inhibitor, SQ14225, (D-3-mercapto-2-methylpropanoyl-L-proline) and (4) beta-adrenergic receptor blockade with propranolol reduced the rebound response. In addition, the magnitude of the rebound following SNP infusions was directly related to the dose of SNP infused. These results are consistent with the hypothesis that renin accumulates during SNP infusion more rapidly than it is metabolized. Consequently, the accumulated renin elicits a hypertensive response when SNP treatment is withdrawn.