Effects on renal sodium and potassium excretion of vasopressin and oxytocin in conscious dogs.

Renal effects of arginine vasopressin and oxytocin were studied in conscious dogs, made water-diuretic by a waterload equivalent to 2% of body weight. Body water and content of sodium were maintained by separate servo-controlled infusions. Peptides were infused for 60 min at rates of 50 pg kg-1 min-1 (arginine vasopressin) or 1 ng kg-1 min-1 (oxytocin), either separately or combined. Infusions increased plasma arginine vasopressin to 1.9 +/- 0.2 (arginine vasopressin alone) and 1.8 +/- 0.3 pg kg-1 (arginine vasopressin plus oxytocin and plasma oxytocin to 72 +/- 5 (oxytocin alone) and 77 +/- 8 pg ml-1 (oxytocin plus arginine vasopressin). Arginine vasopressin or arginine vasopressin plus oxytocin increased urine osmolality similarly by a factor of 13, decreased urine flow to between 5 and 7% of control and decreased free water clearance. Oxytocin reduced urine flow and free water clearance and increased urine osmolality by a factor of 2. Oxytocin and arginine vasopressin separately increased excretion of sodium from 4 +/- 2 to 15 +/- 6 mumol min-1 and from 7 +/- 4 to 25 +/- 13 mumol min-1, respectively. Arginine vasopressin plus oxytocin led to a pronounced natriuresis (13 +/- 4 to 101 +/- 27 mumol min-1). Arginine vasopressin and arginine vasopressin plus oxytocin increased the excretion of potassium by a factor of 2.5. Oxytocin and arginine vasopressin plus oxytocin increased urinary Na+/K+ ratio by a factor of 3.7.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma immunoreactive atrial natriuretic peptide and vasopressin after ethanol intake in man

To study the mechanisms of alcohol-induced diuresis, the plasma concentration of immunoreactive atrial natriuretic peptide and arginine vasopressin, serum sodium and osmolality, plasma renin activity and aldosterone, urinary sodium and volume, free water clearance, blood pressure and heart rate were measured in seven healthy men after oral intake of ethanol (1.5 g kg^-1 in 6 h). Serum ethanol levels increased to 27 ± 4 mmol 1^-l (mean ± SD) in 30 min and remained detectable for 14 h. Serum osmolality rose from 280±10 to 340 ± 4 mosm kg^-1 in 2 hours (P < 0.01) and was 300 ± 4 at 14 h (P < 0.01). Formation of hypotonic urine began after the alcohol intake and resulted in a net loss of 0.9 ± 0.1 kg water in 2 h. Free water clearance increased from -3.4 ± 1.4 to 2.8 ± 1.5ml min^-l in 2 h (P < 0.01). Plasma immunoreactive arginine vasopressin decreased from 5.7 ± 2.1 to 3.3 ± 1.3 ng 1^-1 (P = 0.05) in 30 min and increased to 17 ± 25 and 12±10 ng 1^-1 at 6 and 12 h, respectively (P < 0.05 for both). Plasma immunoreactive atrial natriuretic peptide levels decreased from 17 ± 9 to the minimum of 11 ± 3 ng 1^-1 in 2 h (P < 0.01) and returned to the initial levels in 6 h. Serum sodium, plasma renin activity and plasma aldosterone increased maximally by 4 ± 2 , 165 ± 153 and 143 ± 101 % (P < 0.01 each) during 1–6 h. No changes in blood pressure were observed during the ingestion period, but the heart rate rose significantly from 70 min^-1 at 6 p.m. to 95 min^-1 at 12 p.m. We conclude that ethanol intake in relation to serum ethanol levels caused in the first phase a rapid increase in osmolality which was associated with a decrease in plasma immunoreactive arginine vasopressin. This caused hypotonic diuresis and increased free water clearance followed by volume contraction which evidently led to decreased plasma immunoreactive atrial natriuretic peptide. Serum osmolality was significantly elevated during the whole experiment and serum sodium 1–2 h after the ethanol intake. This was associated with the return of plasma immunoreactive atrial natriuretic peptide to initial levels after 6 h, the increase in plasma immunoreactive arginine vasopressin levels and reduced diuresis after 2 h. Our results suggest that ANP is not responsible for the diuresis seen after the alcohol intake.     

Calciuresis elicited by spontaneous rehydration in dehydrated sheep

Cardiovascular and renal responses to a step-up infusion of endothelin-1 (ET-1) (1, 5, and 15 ng kg^-1 min^-1) were investigated in conscious dogs. In addition, the disappearance of ET-l in arterial and central venous plasma after an infusion of 10 ng kg^-1 min^-1 was quantified, and the effects of vasopressin (AVP, 10 ng kg^-1 min^-1) and angiotensin II (AII, 2, 5, and 10 ng kg^-1 min^-1) on plasma ET-1 were investigated. The step-up infusion of ET-1 increased the plasma level from 3.6 ± 0.3 to 243 ± 23 pg ml^-1. Concomitantly, arterial blood pressure increased and heart rate (HR) decreased dose-dependently. Diuresis, sodium, and potassium excretion did not change significantly. However, free water clearance increased during the infusion. Clearance of creatinine and excretion of urea decreased (39 ± 4 to 29 ± 3 ml min^-1 and 87 ± 16 to 71 ± 14 μmol min^-1, respectively). Decay curves for ET-1 in venous and arterial plasma were identical, and initial t_½ was 1.1 ± 0.1 min. Vasopressin increased arterial blood pressure (107 ± 4 to 136 ± 3 mmHg) beyond the infusion period and increased plasma ET-1 (85%). An equipressor dose of AII tended to decrease plasma ET-1. It is concluded that the lung is apparently not important in the removal of ET-1, that the disappearance of ET-1 follows a complex pattern, and vasopressin – in contrast to angiotensin II – is able to increase the plasma concentration of ET-1. The latter may suggest that ET-1 is involved in the prolonged pressor action of AVP observed.     

Natriuresis in conscious dogs caused by increased carotid [Na+] during angiotensin II and aldosterone blockade

The renal response to a selective increase in the Na⁺ concentration of the blood perfusing the central nervous system was investigated in conscious dogs treated with the converting enzyme inhibitor enalaprilat and the aldosterone antagonist canrenoate. In split-infusion experiments the plasma [Na⁺] of carotid blood was increased (approx. 6 mM) by bilateral infusion of hypertonic NaCl. Concomitantly distilled water was infused into the v. cava making the sum of the infusions isotonic. In control experiments isotonic saline was infused at identical rates into all three catheters. Na⁺ excretion increased markedly in both series, 103 ± 14 to 678± 84 μmol min^-1 during split-infusion and 90 ± 14 to 496 ± 74 μmol min^-1 during the isotonic volume expansion. Peak rate of excretion, peak fractional sodium excretion, and cumulative sodium excretion were all significantly higher (P < 0.05) during split-infusion than during control experiments. Plasma vasopressin increased only during split-infusion (0.68 ± 0.11 to 2.4 ± 0.8 pg ml^-1) while the increases in plasma atrial natriuretic peptide were similar in the two series. Urinary excretion of urodilatin (ANP95-126) increased significantly more during split-infusion (46 ±11 to 152 ±28 fmol min^-1) than during the isotonic volume expansion (45 ± 14 to 84 ± 16 fmol min^-1) (P < 0.05). It is concluded that the natriuretic mechanisms activated by a selective increase in the Na⁺ concentration of carotid blood and associated with increased excretion of urodilatin cannot be eliminated by blockade of the renin-angiotensin-aldosterone system.     

Acute renal denervation causes time-dependent resetting of the tubuloglomerular feedback mechanism

Renal effects of acute renal denervation (DNX) were studied in anaesthetized rats. In a first series, whole kidney clearance measurements were made 120 and 240 min after unilateral DNX. At 240 min, urine production was 3.59±0.87 μL min^-1 in control kidneys and 7.74±1.97 μL min^-1 in denervated kidneys. The corresponding values for sodium excretion were 0.56±0.17 and 1.41±0.34 μmol min^-1, potassium excretion 0.48±0.08 and 0.97±0.37 μmol min^-1 and glomerular filtration rate (GFR) 0.83±0.08 and 1.05±0.16 mL min^-1, respectively. In a second series, tubuloglomerular feedback (TGF) characteristics were determined with the stop-flow pressure (P_sf) technique. With increasing time, the sensitivity of the TGF mechanism diminished in denervated rats, as indicated by an increased turning point (TP). TP was significantly increased 2 h after DNX from 19.1±1.13 in control to 25.9±1.10 nL min^-1. TP was further increased 4 h after DNX to 37.3±3.12 nL min^-1. However, the maximal TGF response to increased flow in the late proximal tubule was not altered. But, P_st was significantly higher in DNX rats than in the controls (47.4±1.01 vs. 43.0±1.53 mmHg) in spite of a lower blood pressure (107±2.9 vs. 119±2.2 mmHg). We conclude that intact renal nerves are essential for the setting of the TGF sensitivity and hence the regulation of GFR     

Systemic effects of angiotensin III in conscious dogs during acute double blockade of the renin-angiotensin-aldosterone-system

Aims: The study was designed to determine (i) whether the effects of angiotensin III (AngIII) are similar to those of angiotensin II (AngII) at identical plasma concentrations and (ii) whether AngIII operates solely through AT₁‐ receptors. Methods: Angiotensin II (3 pmol kg^?1 min^?1–3.1 ng kg^?1 min^?1) or AngIII (15 pmol kg^?1 min^?1–14 ng kg^?1 min^?1) was infused i.v. during acute inhibition of angiotensin converting enzyme (enalaprilate; 2 mg kg^?1) and of aldosterone (canrenoate; 6 mg kg^?1 plus 1 mg kg^?1 h^?1). Arterial plasma concentrations of angiotensins were determined by radioimmunoassay using a cross‐reacting antibody to AngII. During ongoing peptide infusion, candesartan (2 mg kg^?1) was administered to block the AT₁‐receptors. Results: Angiotensin immunoactivity in plasma increased to 60 ± 10 pg mL^?1 during infusion of AngII or infusion of AngIII. AngII significantly increased mean arterial blood pressure (+14 ± 4 mmHg) and plasma aldosterone by 79% (+149 ± 17 pg mL^?1) and reduced plasma renin activity and sodium excretion (?41 ± 16 mIU L^?1 and ?46 ± 6 μmol min^?1 respectively). AngIII mimicked these effects and the magnitude of AngIII responses was statistically indistinguishable from those of AngII. All measured effects of both peptides were blocked by candesartan. Conclusion: At the present arterial plasma concentrations, AngIII is equipotent to AngII with regard to effects on blood pressure, aldosterone secretion and renal functions, and these AngIII effects are mediated through AT₁‐ receptors. The metabolic clearance rate of AngIII is five times that of AngII.     

Effects of receptor blockade on metabolism and renal actions of vasopressin in conscious dogs

Vasopressin – but not the V₂ receptor agonist [deamino-cis1,D-Arg8]-vasopressin (dDAVP) – may mediate natriuresis in dogs. The present study investigated this phenomenon by use of nonpeptide antagonists to V_1a and V₂ receptors 1-{1-[4- (3-acetylaminopropoxy)benzoyl]-4-piperidyl}-3,4-dihydro-2 (1H)-quinolinone (OPC-21268) and 5-dimethylamino-1-{4- (2-methylbenzoylamino)-benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (OPC-31260), respectively) hypothesising that only V_1a inhibition would reduce the natriuresis. In conscious dogs vasopressin secretion was suppressed by water loading (2% body weight) and replaced by infusion of vasopressin (50 pg min^?1 kg^?1) resulting in physiological plasma concentrations (plasma levels of AVP (pAVP) = 2.0 ± 0.1 pg mL^?1). In this setting, OPC-21268 did not change the rate of sodium excretion. OPC-31260 increased water excretion 12-fold without significant changes in sodium excretion. Heart rate, mean arterial blood pressure, glomerular filtration rate, and clearance of endogenous Li⁺ were unchanged. During vasopressin infusion, both antagonists increased pAVP, OPC-21268 by 20% and OPC-31260 by 100% (2.0 ± 0.2–4.0 ± 0.3 pg mL^?1). In the absence of vasopressin infusion, OPC-31260 did not increase pAVP. Thus, the increase in pAVP appeared to be due to a decrease in metabolic clearance rate. The results indicate that the present dose of V_1a receptor inhibitor OPC-21268 does not reduce sodium excretion and that both vasopressin antagonists inhibit vasopressin metabolism.     

Natriuresis obtained by intracerebroventricular infusion of hypertonic NaCI in rats with papillary necrosis.

Raising the sodium concentration in the third cerebral ventricle increases renal sodium, potassium and water excretion. The identification and characterization of the factor(s) mediating the centrally evoked natriuresis would be greatly facilitated if the exact intrarenal effector site were known. We have assessed the importance of inner medullary structures for the effects of CNS stimulation by examining its ability to alter renal excretion in rats with papillary necrosis, induced 2 d earlier with 2-bromoethylamine hydrobromide (BEA), 250 mg kg^-1 body wt i. v. Male Lewis x DA rats were divided into a BEA-treated group (n = 6) and a control group receiving vehicle alone (n = 6). In contrast to the white papillae normally seen, the papillae of BEA-treated animals were bright red and showed a clear line of demarcation at their base. The rats were anaesthetized i. p. with Inactin (120 mg kg^-l body wt). Artificial cerebrospinal fluid (CSF) was infused (520 nL min^-1) via a cannula into the left lateral ventricle. After 45 min CSF containing 1 M NaCl was used. Stimulation of the control rats with hypertonic CSF increased urine flow rate five-fold (5.4± 0.8 to 27.1±6.1 μL min^-1), Na excretion 23-fold (0.4±0.1 to 7.6±1.8 μmol min^-1) and K excretion fourfold (0.6±0.18 to 3.8±O.5 pmol min^-1). When the concentration mechanisms were damaged with BEA, the basal excretion rates of water and Na increased. The natriuretic response to ICV stimulation was severely impaired in these rats, but the kaliuretic effect was sustained. In conclusion, the natriuretic effect of ICV stimulation with hypertonic CSF is dependent on an intact renal inner medulla, which is not the case for the less pronounced kaliuretic response. Thus, either the juxtamedullary nephrons possess marked natriuretic responsiveness, not present in the cortical ones, or the responsiveness lies mainly in the papillary collecting ducts. However, it cannot be excluded that a disturbance of salt balance contributes to the observations.     

Effect of atrial natriuretic factor on renal prostaglandin E2 release in the anaesthetized dog

Experiments were undertaken in two groups of barbiturate anaesthetized dogs to examine whether atrial natriuretic factor (ANF) exerts an effect on renal release of prostaglandin E₂ (PGE₂). In the first group, intravenous infusion of ANF (50 ng min^-1kg^-1body wt) reduced basal PGE₂ release from 4.4 ± 0.8 pmol min^-1to 1.8 ± 0.7 pmol min^-1. In the second group, intrarenal infusion of an α-adrenoceptor agonist, phenylephrine (2.5–6.75 μg min^-1), raised PGE₂ release from 2.7 ± 0.5 pmol min^-1to 7.5 ± 1.3 pmol min^-1. During continuous α₁-adrenergic stimulation, intravenous infusion of ANF (100 ng min^-1kg^-1body wt) reduced PGE₂ release to 3.5 ± 1.0 pmol min^-1. These results demonstrate that ANF reduces basal and α₁-adrenergic stimulated renal PGE₂ release.     

Haemodynamic conditions for renal PGE2 and renin release during α- and β-adrenergic stimulation in dogs

Constriction of the renal artery and infusion of an α-adrenergic agonist induce autoregulated vasodilation and increase prostaglandin E₂ (PGE₂) and renin release. The enhancement of renin release during autoregulated vasodilation might be mediated by prostaglandins. To examine this hypothesis, experiments were performed in three groups of anaesthetized dogs. In six dogs constriction of the renal artery to a perfusion pressure below the range of autoregulation raised renin release from 2 ± 1 to 27 ± 6 μg AI.min^-1 and PGE₂ release from 1 ± 1 to 10 ± 2 pmol. min^-1. After administration of indomethacin (10 mg. kg^-1 b. wt), PGE₂ release was effectively blocked and constriction of the renal artery raised renin release only from 0.1 ± 0.1 to 6 ± 1 μg AI.min^-1. During subsequent continuous infusion of a β-adrenergic agonist, isoproterenol (0.2 μg. kg^-1.min^-1), constriction of the renal artery raised renin release from 0.1 ± 0.1 to 52 ± 11 μg AI.min^-1, although there was no rise in PGE₂ release. In six dogs, intrarenal infusion of phenylephrine, an α adrenergic agonist, increased PGE₂ and renin release before, but not after, indomethacin administration. In six other dogs, phenylephrine infused during isoproterenol infusion increased renin release equally before and after indomethacin administration. Thus the enhancing effect of constricting the renal artery or infusing an α-adrenergic agonist is not dependent upon prostaglandins. We propose that autoregulated dilation enhances renin release whether the stimulatory agent is a prostaglandin or a β-adrenergic agonist.     

Arginine vasopressin excretion in response to volume expansion in the healthy human,and in patients with glomerulonephritis

The urinary excretion of arginine vasopressin (AVP) was studied during volume expansion (VE) in nine healthy normotensive individuals and 14 patients with active IgA glomerulonephritis (GN). The studies were started after 17–18 h of food and fluid deprivation (hydropenia, HP) and VE was induced by a continuous infusion of Ringer solution up to an amount corresponding to 3% of the body weight. The clearance of inulin and PAH, urine osmolality and urinary excretion of sodium and AVP were determined. The AVP excretion decreased in response to VE in the healthy individuals, both when related to GFR (from 129+ 17 pg min ‘ 100 ml ’ GFR during HP to 65 ± 9 after 3% VE, P < 0.01)andtobody surface area (BSA) (from 134 ± 22 pg min“¹ 1.73 m^-2 BSA to 75 ±11, P < 0.05). In the patients with IgA GN, who had normal blood pressure and normal GFR, the AVP excretion tended to decrease, but the change was not significant (0.05 < P < 0. 1). The patients with hypertension but essentially normal GFR, and those with hypertension and markedly decreased GFR did not change their renal excretion of AVP in response to VE. If related to the GFR, the latter patients had a markedly increased AVP excretion.     

Effect of C-peptide administration on whole body glucose utilization in STZ-induced diabetic rats

Recent studies suggest that C-peptide stimulates glucose transport in isolated skeletal muscle. In order to determine the effect of C-peptide on whole body glucose utilization, streptozotocin (60 mg kg^-1) (STZ)-induced diabetic and normal rats were studied using the euglycaemic clamp procedure and continuous infusion of somatostatin (1.0 μg kg^-1 min^-1) in pentobarbital-anaesthetized rats. Plasma insulin levels during the 6.0- and 30.0-mU kg^-1 min^-1 insulin infusions rose to 70–90 μU mL^-1 and 500–700 μU mL^-1, respectively. Blood glucose concentrations were clamped at 7.5–7.9 mmol L^-1 in the diabetic rats and at basal levels or 7.7 mmol L^-1 in the non-diabetic (normal) rats. Biosynthetic human C-peptide (0.5 nmol kg^-1 min^-1) was infused in 12 diabetic and 11 normal rats, resulting in concentrations of 26–41 nmol L^-1. The metabolic clearance rate of glucose (MCR) for the diabetic rats receiving C-peptide (12.0±1.0 mL kg^-1 min^-1) was significantly (P<0.01) higher than that in the diabetic rats given saline (6.3±0.7 mL kg^-1 min^-1) or a randomly scrambled C-peptide (7.8±1.3 mL kg^-1 min^-1) at low-dose insulin infusion but not at the high-dose insulin infusion. In normal rats C-peptide did not significantly increase the MCR for glucose. These results thus demonstrate that C-peptide has the capacity to increase glucose utilization in STZ-induced diabetic rats.     

Increased plasma concentrations of vasopressin,oxytocin, cortisol and the prostaglandin F2α metabolite during labour in the dog

Aim: This study investigated if the plasma vasopressin concentration increases during labour in the dog and whether the change in vasopressin correlates with that of oxytocin, 15‐ketodihydro‐PGF_2α and cortisol. Methods: Five beagle dogs each delivered three to seven puppies. Blood samples were taken from a catheter inserted into the cephalic vein during labour and by venepuncture during the other periods. Results: Vasopressin concentration increased from 2 ± 0 pmol L^?1 (anoestrus) to 26 ± 11 pmol L^?1 at the birth of the first puppy, remained high at the birth of the second puppy and then decreased. Oxytocin increased from 63 ± 5 pmol L^?1 (anoestrus) to 166 ± 19 pmol L^?1 at the birth of the first puppy and remained elevated throughout labour. The PGF_2α metabolite concentration increased from 0.2 ± 0.0 nmol L^?1 (anoestrus) to 66 ± 17 nmol L^?1 at the birth of the first puppy and remained elevated 1 h after the completion of parturition. The cortisol concentration increased from 49 ± 9 nmol L^?1 (anoestrus) to 242 ± 35 nmol L^?1 at the birth of the first puppy, remained high during the birth of the second puppy and then declined. Conclusions: The plasma level of vasopressin was strongly correlated with that of cortisol but less with that of the PGF_2α metabolite, and not significantly with the concentration of oxytocin. This indicates that the four hormones play different roles during labour in the dog.     

Angiotensin II infusion during β-adrenergic stimulation by isoproterenol. Effects on hepatic,splenic and cardiac blood volumes and on the magnitude and distribution of cardiac output in the dog

The cardiac and peripheral vascular adjustments to angiotensin II (0.1–0.2 μg kg^-1 min^-1 i.v.) during high β-adrenergic activity by a continuous isoproterenol infusion (0.2–0.3 μg kg^-1 min^-1 i.v.) were examined in anaesthetized, atropinized dogs. Hepatic, splenic and left ventricular (LV) volume changes were estimated by an ultrasonic-technique, and the blood flow distribution was measured by injecting radioactive microspheres and by electromagnetic flowmetry on the caval veins, the hepatic artery and the portal vein. During isoproterenol infusion, angiotensin II increased the systolic LV pressure by 45 ± 3 mmHg and the stroke volume by 17 ± 6 %. Concomitantly, the hepatic and splenic blood volumes declined by 29 ± 4 and 14 ± 6 ml, respectively, and the LV end-diastolic segment length increased by 3 ± 1 %. The flow through the inferior caval vein increased by 39 ± 9%, whereas the superior vena caval flow remained unchanged. The hepatic arterial flow more than doubled. Thus, at high inotropy by isoproterenol infusion, angiotensin II relocates blood from the liver and the spleen towards the heart. By activating the Frank-Starling mechanism, cardiac output is increased and conducted through the lower body, especially through the hepatic artery, because of the poor autoregulation of flow through this vessel.,     

Effects of bradykinin and papaverine on renal autoregulation and renin release in the anaesthetized dog

The present study on six anaesthetized dogs investigates the influences of two different vasodilators, bradykinin and papaverine, on the relationship between autoregulation of renal blood flow and glomerular filtration rate, sodium excretion and renin release. At control conditions renal blood flow and glomerular filtration rate was autoregulated to the same levels of renal arterial pressure, 55 ± 3 and 58 ± 3 mmHg, respectively. Renin release increased from 0.3±0.1 to 22±4 μg AI min^-1, and sodium excretion decreased from 99 +29 to 4.6 ± 3.3 μmol min^-1 when renal arterial pressure was reduced from 122±6 to 44±2 mmHg. Infusion of bradykinin (50 ng kg^-1 min^-1) increased renal blood flow by 50% at control blood pressure without changing glomerular filtration rate, and both renal blood flow and glomerular filtration rate autoregulated to the same pressure levels as during control. Sodium excretion increased threefold at control renal arterial pressure, but was unchanged at low renal arterial pressure. Bradykinin did not change renin release neither at control nor low renal arterial pressure. Papaverine infusion at a rate of 4 mg min^-1 increased renal blood flow 50% without changing glomerular filtration rate. The lower pressure limits of renal blood flow and glomerular filtration rate autoregulation were increased to 94±6 and 93±6 mmHg, respectively. Sodium excretion increased sixfold at control renal arterial pressure and was still as high as the initial control values at low renal arterial pressure (97±27 μmol min^-1) accompanied by only a small increase in renin release (1.4±0.3 to 6±2 μg AI min^-1). We conclude that bradykinin does not influence autoregulatory pressure limits of renal blood flow and glomerular filtration rate nor the accompanying increase in renin release during reductions in renal arterial pressure. Papaverine on the other hand maintains high sodium chloride delivery to macula densa at low renal arterial ressure, suppressing renin release and impairing autoregulation through effects on the tubulo-glomerular feedback mechanism.     

Plasma ANP during hypertonic NaCl infusion in man

To determine the relationship between hyperosmolality and immunoreactive atrial natriuretic peptide of heart atrial plasma six healthy men were given 0.06 ml kg^-1 min^-1 855 mmol 1^-1 NaCI, i.v., for 2 h. The right atrial pressure and atrial plasma atrial natriuretic peptide were measured. During the infusion, right atrial pressure was kept constant by lowering the legs of the subject in a supine position downwards if any increase in the pressure was seen. There was a significant and linear increase in atrial serum osmolality, from 288 ± 3.3 to 307 ± 3.2mOsm kg^-l (P < 0.001). No statistically significant changes in right atrial pressure were seen. Regression analysis revealed that there was a statistically significant correlation between serum osmolality and plasma ANP in three subjects (responders) (r²: 0.5 241 , 0.8 965 , 0.6695). In three other subjects (nonresponders), there was no correlation between osmolality and ANP. The mean basal osmolality of responders was 280 mOsm kg^-1 and the mean basal osmolality of nonresponders was 295 mOsm kg^-1. In contrast, all subjects responded with an increase in plasma ANP (P < 0.05) after RAP had been increased by tilting the legs of the subject upwards for 30 min. We conclude that the right atrial pressure regulates the release of atrial natriuretic peptide. Serum hyperosmolality may also contribute to the the regulation of atrial natriuretic peptide independently of the right atrial pressure in man.     

Inhibitory effect of endothelin on renin release in dog kidneys

To investigate the effect of endothelin on renin release, experiments were performed in barbiturate-anaesthetized dogs with denervated kidneys. Intrarenal infusion of endothelin (1 ng min^-1kg^-1body wt) reduced renal blood flow (RBF) from 145 ± 10 ml min^-1to 98 ± 9 ml min^-1without altering renin release (1 ± 1 μg angiotensin I (AI) min^-1). Renin release was then increased either by renal arterial constriction or ureteral occlusion. When renal arterial pressure was reduced to 50 mmHg, renin release averaged 79 ± 20 μg AI min^-1in six dogs and fell significantly to 24 ± 6 μg AI min^-1during endothelin infusion. During ureteral occlusion the inhibitory effect of endothelin on renin release either during inhibition of β-adrenergic activity with propranolol or after inhibiting prostaglandin synthesis by indomethacin during intrarenal infusion of isoproterenol was examined. After propranolol administration ureteral occlusion increased renin release from 5 ± 2 μg AI min^-1to 38 ± 12 μg AI min^-1in six dogs. Subsequent intrarenal endothelin infusion (1 ng min^-1kg^-1body wt) during maintained ureteral occlusion reduced renin release to 10 ± 3 μg AI min^-1. In six other dogs prostaglandin synthesis was inhibited by indomethacin. Subsequent infusion of isoproterenol (0.2 μg min^-1kg^-1body wt) to stimulate β-adrenoceptor activity increased renin release from 13 ± 4 μg AI min^-1to 68 ± 8 μg AI min^-1during ureteral occlusion. Intrarenal endothelin infusion (1 ng min^-1kg^-1body wt) reduced renin release to 22 ± 3 μg AI min^-1during continuous isoproterenol infusion and ureteral occlusion. Hence endothelin inhibits renin release induced by renal arterial constriction or ureteral occlusion. Similar inhibitory effects whether renin release was raised by increasing prostaglandin synthesis or by stimulating β-adrenergic activity suggest a direct effect of endothelin on the juxtaglomerular cells.     

Thermogenic response to adrenaline during restricted blood flow in the forearm

To elucidate the underlying mechanism behind the thermogenic effect of adrenaline in human skeletal muscle, nine healthy subjects were studied during intravenous infusion of adrenaline. Restriction of blood flow to one forearm was obtained by external compression of the brachial artery, to separate a direct metabolic effect of adrenaline from an effect dependent on increased blood flow. The other arm served as the control arm. In the control arm, the forearm blood flow increased 4.7-fold (from 2.0 ± 0.3 to 9.3 ± 1.5 mL 100 g^–1 min^–1, P < 0.001) during the adrenaline infusion. Adrenaline significantly increased forearm oxygen consumption (from 4.7 ± 2.1 to 7.0 ± 3.6 μmol 100 g^–1 min^–1, P < 0.025). In the arm with restricted blood flow, the forearm blood flow increased 2.9-fold (from 1.6 ± 0.3 to 4.6 ± 0.8 mL 100 g^–1 min^–1, P < 0.002) but the forearm oxygen consumption did not increase (baseline period: 5.6 ± 2.3 μmol 100 g^–1 min^–1, adrenaline period: 6.1 ± 2.1 μmol 100 g^–1 min^–1, P = 0.54). The experimental design and the difficulties in interpretation of the result are discussed. The results give evidence for the hypothesis that the vascular system plays a key role in the thermogenic effect of adrenaline in skeletal muscle in vivo.     

l-Arginine-induced hypotension in the rat: evidence that NO synthesis is not involved

l -Arginine is the biological precursor for nitric oxide (NO). NO is formed continuously in endothelial cells and maintains a certain degree of vasodilator tone under physiological conditions. Although the formation of NO is not primarily controlled by precursor availability, the extent to which extra supplementation with l -arginine may affect endothelial NO formation, and hence, vasodilator tone and systemic blood pressure, is not entirely clear. To address this issue, we infused l -arginine i.v. in anaesthetized normotensive rats pretreated with N^G-nitro-l -arginine methyl ester (l -NAME, 50 or 200 mg^-1) and in untreated controls, under continued recording of mean arterial pressure (MAP). In control animals l -arginine (25 or 100 mg kg^-1 min^-1) had no effect on systemic MAP (111 ± 3 mm Hg), while l -arginine (200 mg kg^-1 min^-1) lowered MAP (to 70 ± 6mmHg). D-Arginine (200 mg kg^-1 min^-1) also induced hypotension; during infusion of D-arginine MAP fell from 106 ± 4 to 64 ± 4 mm Hg. Pretreatment with l -NAME (50 and 200mgkg^-1) elevated MAP to 140 ± 2 and 147 ± 3 mm Hg, respectively, but failed to affect the hypotensive response to l -arginine; during infusion of l -arginine (200 mg kg^-1 min^-1) in rats pretreated with l -NAME (50 and 200 mg kg^-1) MAP fell to 86 ± 9 and 104 ± 6 mm Hg, respectively. Plasma levels of the NO metabolite, nitrate, were 18 ± 4 and 17 ± 3μmol l^-1, respectively, before and after infusion of l -arginine (200 mg kg^-1 min^-1). Trapping of NO to haemoglobin (HbNO) could not be detected, either before or after infusion of l -arginine (200 mg kg^-1 min^-1). We conclude that a high dose of l -arginine may act hypotensive in normotensive rats. This effect does, however, not seem to be based on an augmented formation of NO.     

Impaired glomerular permselectivity for albumin in chemically medullectomized WKY rats

Chemical renal medullectomy with 2-bromo-ethylamine hydrobromide (BEA) has been used to study the importance of the renal medulla in blood pressure regulation. However, conclusive evidence as to whether BEA treatment affects the glomerular barrier is lacking. In the present study, the effects of BEA upon glomerular permselectivity for albumin were studied using isolated kidneys (IPK) perfused at a low temperature (8 °C) to inhibit tubular reabsorption of proteins. Sixteen WKY rats (W_B) received an i.v. injection of BEA (150 mg kg^-1) while 10 rats served as controls (W_C). Volume balance, urinary osmolality and creatinine clearance (GFR) were measured in metabolic cages. Acute paired experiments (n=9) were performed 5–7 weeks after BEA. The rats were anaesthetized and the total in vivo albumin excretion was recorded. The kidneys were then isolated and perfused for measurements of inulin clearance (GFR) and fractional albumin clearance without tubular reabsorption of protein. The nine BEA treated rats showed polyuria and hypoosmotic urine. In vivo GFR was lower in the BEA treated groups when measured with creatinine clearance (459±22 vs. 213±41 μL min^-1 100 g^-1 body wt, P<0.001), while GFR was not significantly changed in the IPK (W_C=135±27, W_B=92±14 μL min^-1 100 g^-1 body wt, n.s.) when perfused at identical pressures. The fractional albumin clearance was increased three times in the BEA group (W_B=9.6±3.4J, P<0.05). Moreover, albumin excretion in vivo was similar in the two groups despite low GFR in the BEA group. We conclude that BEA treatment affects glomerular permselectivity for albumin.