Hemodynamic effects of moderate increase of the plasma vasopressin level in conscious dogs

Summary The influence of moderate increase of the plasma ADH level on aortic and central venous pressures, heart rate, cardiac output, stroke volume, central blood volume, systemic peripheral resistance and plasma volume was examined in conscious dogs. The animals were given 0.75 mU ADH/kg b.w. in single intravenous injection as a priming dose. This was followed by a constant infusion of the hormone at a rate of 0,12 mU/min/kg/0.2 ml 0.9% NaCl solution lasting one hour. Plasma ADH level measured at 30 min of the infusion was equal to 22 ± 4 U/ml. A significant increase of aortic (mean systolic and diastolic) and central venous pressures, systemic peripheral resistance and of plasma volume was observed in the course of the infusion. It was accompanied by a decrease of heart rate, cardiac output and central blood volume. Changes of stroke volume were not significant.As the plasma level produced by the infusion was such as that following a moderate nonhypotensive haemorrhage [30], the rôle of the hemodynamic effects of vasopressin in maintenance of the blood pressure and volume in hypovolemia is discussed.     

Responsiveness of the ANP providing system to volume load in conscious dogs

We examined in detail changes in arterial plasma ANP concentration in response to volume load in conscious dogs. In a 5-min volume load experiment, 18 ml/kg of isosmotic and isooncotic 3% Dextran 40 in saline was infused over a period of 5 min. Mean left atrial pressure (MLAP) increased transiently by 7.6±0.9 mm Hg. Plasma ANP level (P-ANP) did not significantly increase. Assayed P-ANP levels were corrected for hemodilution. Corrected P-ANP (C-ANP) significantly increased from 206±17 to 348±34 pg/ml. However, the level of C-ANP did not reach a steady state. No significant linear correlation was found between increases in MLAP and normalized C-ANP. In a 45-min volume load experiment, the elevated level of MLAP caused by the 5-min volume load was maintained for 40 min by supplemental infusion. C-ANP significantly increased from 196±18 pg/ml to 435±73 ng/ml. The level of C-ANP reached a steady state. A close linear correlation was observed between increases in MLAP and normalized C-ANP. However, the peak time of C-ANP lagged 10 min behind MLAP. These results indicate that it takes 10 min for P-ANP to reach a steady state in fully responding to a volume load, and that the long-term volume load is a prerequisite to the response of the ANP providing system.     

The role of the cardiac nerves in the regulation of sodium excretion in conscious dogs

Conscious, chronically instrumented dogs, maintained on a high sodium intake, were used to investigate whether surgical cardiac denervation impairs the natriuresis associated with left atrial pressure increase produced in three ways: during an increase in left atrial pressure by means of a reversible mitral stenosis (protocol 1); after an i.v. saline load (1.0 ml 0.9%·saline min^–1·kg^–1 over 60 min) (protocol 2); after an oral saline load (14.5 mmol Na·kg^–1 given with the food as an isotonic solution) (protocol 3).During a reversible mitral stenosis, in intact dogs, urine volume and sodium excretion increased markedly (from 34–145 l·min^–1·kg^–1 and from 3–12 mol·min^–1·kg^–1); mean arterial pressure increased by an average of 2 kPa (15 mm Hg) and heart rate by 55 b/min; plasma renin activity fell from 0.37–0.21 ng Al·ml^–1·h^–1. Cardiac denervation eliminated these effects of left atrial distension except for a small increase in heart rate (12 b/min). This indicates that the natriuresis and diuresis during left atrial distension resulted from stimulation of receptors located in the left atrium.In contrast, during protocol 2 and 3, the same amounts of sodium and water were excreted in the cardiac denervated dogs as compared to the intact dogs. A comparable decrease in plasma renin activity also was observed. — Apparently the presence of the cardiac nerves is not a prerequisite for maintenance of sodium and water homeostasis.     

Dynamic pressure-flow curves in the autoregulating kidney vasculature of conscious dogs

Summary In three healthy conscious dogs blood pressure was measured in the abdominal aorta with an implanted miniature transducer. Flow velocity in the left renal artery was recorded by an electromagnetic flowmeter. An appropriate distance between the transducer sites compensated the time-lag introduced by the flowmeter system and allowed records with a negligable foot to foot phase shift between the flow- and the pressure pulse. Pressure-flow curves (I.-P. curves) were obtained recording flow versus pressure beat by beat on an oscilloscope. Electrical stimulation of the right cervical vagus nerve produced I.-P.-curves, which decayed in less than 3 sec down to a blood pressure of 25 mm Hg (dynamic I.-P.-curve). Static I.-P.-curves were recorded by reducing blood pressure within 1 to 2 min to the same pressure level. The following results were obtained:A unique dynamic I.-P.-curve, which follows the power functionI=a·P ⁿ exists for each level of arterial mean pressure i.e. myogenic vascular tone.An increase of arterial mean pressure (i.e. myogenic vascular tone) decreases the exponentn and increases the coefficienta of the power function.The static I. P.-curve, which runs parallel to the pressure axis above 90 mm Hg is actually composed of a family of different dynamic I.-P.-curves.The kidney resistance vessels are rather distensible. The pressure-dependent increase of myogenic vascular tone, which developes at perfusion pressures above 55 mm Hg, decreases the vessel distensibility.A change of mean perfusion pressure causes the kidney resistance vessels to shift from one to another dynamic I.-P.-curve without altering mean blood flow.This study was supported by the Deutsche Forschungsgemeinschaft (S.F.B. 90; Kardiovaskuläres System, Heidelberg).A preliminary report of a portion of this work was presented at the XXV. International Congress of Physiological Sciences, München, July 1971.     

Atrial pressure and postprandial volume regulation in conscious dogs

Conscious, chronically instrumented dogs (n=24; left and right atrial catheter, electromagnetic flow probe around the left renal artery, carotid loop) were used in 97 expts. to study mechanisms mediating postprandial (pp) excretion of sodium and water up to at least 180 min after food intake. The dogs were kept under standardized conditions and maintained on ahigh (14.5 mmol Na/kg b.w./day) or alow (0.5 mmol Na/kg b.w./day) sodium intake diet (HSI, LSI) which was given once daily in the morning.In HSI dogs left atrial pressure (LAP) increased from a fasting control value of 0.2 kPa (2 cm H₂O) to 0.7 kPa (7 cm H₂O) (120–180 min pp), right atrial pressure from 0.0 kPa (0 cm H₂O) to 0.3 kPa (3 cm H₂O). 25% of the sodium intake were excreted up to 180 min pp. There was a highly significant positive correlation between pp sodium excretion (U _Na V) and pp LAP.U _Na V was not related to pp increase in renal blood flow (RBF) and glomerular filtration rate (GFR). Fractional sodium excretion increased from a fasting control value of 0.6% to more than 4% in HSI dogs and from 3.3% to more than 7% in anadrenalectomized HSI dog. DOCA did not diminishU _NA V in HSI dogs.In LSI dogs, RBF and GFR increased pp, LAP did not change pp. No substantial increase inU _Na V was observed.The close correlation between ppU _Na V and pp LAP in HSI dogs supports the hypothesis that intrathoracic vascular receptors are involved in the mediation of volume regulation by stimulation of still unknown natriuretic mechanisms which operate on the tubular level in the presence of high mineralocorticoid activity.     

Antidiuretic hormone restores the endolymphatic longitudinal K+ gradient in the Brattleboro rat cochlea

In the cochlea, endolymph is hyperosmotic to plasma and perilymph. To test the hypothesis that antidiuretic hormone is involved in the modulation of endolymph secretion, the electrochemical composition of cochlear fluids, endolymph and perilymph, was studied in three groups of anaesthetized rats: control Long Evans rats, homozygous Brattleboro rats that are genetically deprived of antidiuretic hormone, and Brattleboro rats that were treated with antidiuretic hormone (dDAVP, 0.5 g/100 g body weight/24 h during 8 days). Endolymph was sampled from the scala media at each turn of the cochlea and perilymph from the scala vestibuli. In Long Evans rats, the endocochlear potential, the endolymphatic K⁺ and Cl^– concentrations decreased from base to apex of the cochlea as previously reported in guinea pigs and Sprague Dawley rats. In Brattleboro rats, the endocochlear potential and the Cl^– concentration gradients were still present, whereas the K⁺ con centration gradient was absent. This K⁺ gradient was restored by the administration of dDAVP, which increased the K⁺ concentration at the base of the cochlea. This work indicates that the K⁺ secretion in endolymph, and thus the osmolality, may be locally modulated by the antidiuretic hormone, probably via V₂ receptors.     

The influence of coronary pressure and coronary flow on intracoronary blood volume and geometry of the left ventricle

Summary Intracoronary blood volume in relation to coronary perfusion pressure was estimated in dog hearts in situ with cannulated left coronary arteries. Electromagnetically measured inflow into coronary arteries times mean transit time, obtained by a dye dilution technique determined the intracoronary blood volume. Within the range from 70 and 170 mm Hg coronary perfusion pressure the mean value of intracoronary blood volume increases from 11.0 to 17.8 ml per 100 g wet weight; an increase of about 62%. The mycocardial wall at 70 mm Hg consists of 10.4% intracoronary blood and at 170 mm Hg of 15.1%. A significant increase in intracoronary blood volume is seen with increasing coronary perfusion pressure at constant coronary flow.With increasing coronary perfusion pressure the outer volume of the heart and the volume of the myocardial wall increases while the inner volume of the left ventricle decreases in blood perfused dog hearts in situ and in isolated cat hearts. The mean radius of the left ventricle is not changed by the coronary perfusion pressure. This change in the geometry of the left ventricle influences the pressurevolume relation of the heart and can explain the effect of coronary perfusion pressure on the performance of the heart.     

Reduction of renal nerve activity by volume expansion in conscious cats

Summary In conscious cats with intact or denervated baroreceptors volume expansion of 5–15% of blood volume was, performed with dextran and isotonic sodium chloride. Renal sympathetic activity (RSA), electroencephalogram (EEG) blood pressure (BP) and heart rate (HR) were recorded. RSA was reduced by 25–85% in 10 experiments out of 11 by volume expansion both with dextran and isotonic sodium chloride. Reduction of RSA could not be related to different states of wakefulness as indicated by the EFG, so could only be caused by volume expansion, although no quantitative correlation could be detected. No differences were observed between animals with intact and denervated baroreceptors. In most experiments BP and HR decreased during volume expansion up to –25 mm Hg and up to –23 beats/min, respectively. The degree of BP and HR reduction could not be related to the degree of RSA reduction. The results suggest that changes in RSA might be involvec in the renal response to volume expansion.Supported by the Deutsche Forschungsgemeinschaft.     

Regional blood flow in response to exercise in conscious dogs

Summary Regional blood flow was measured with the microsphere method in conscious dogs under resting conditions and during moderate exercise on the treadmill.With respect to total organ blood flow, exercise induced a marked increase in blood flow to the calf muscles and to the myocardium, and a significant decrease in the arterial blood supply to the liver. Slight changes in blood flow to the other organs under study (various skeletal muscles, skin, brain, kidneys, intestine) were not significant.Study of the blood flow distribution within the myocardium showed a slight decrease of the ratio of subendocardial to subepicardial blood flow in the left ventricular free wall in response to exercise, and within the brain there was a relative increase in the blood flow to the cerebellum.     

Quantitative displacement of blood acid base equilibrium in acutely water depleted dogs

Summary Dogs were water depleted 2% of their body weight by the intraperitoneal injection of a hyperosmotic solution of saline and glucose (550 mOsm/l). During a 3-h experiment these water-depleted (WD) animals showed a significant decrease in blood pH, base excess (BE) and plasma bicarbonate (Bic_p) and an increase in both hematocrit (Ht) and blood buffer capacity (BBC). These changes were quantitatively time-dependent. The rate change of pH, BE, and Bic_p were –0.072 units h^–1, –4.7 mEq/l h^–1, and 2.9 mEq/l h^–1, respectively. As control dogs showed no significant time-dependent changes in their blood acid-base status, the observed modifications in the experimental dogs were ascribed to water depletion. Increased endogenous acid production related to tissue hypoxia is suggested to be the mechanism that could explain the increased fixed acid accumulation observed in the water-depleted animals.     

The vagal cardiac accelerator system in the reflex control of heart rate in conscious dogs

The reactions of the vagal cardioaccelerator (VCA) system to changes in mean arterial pressure (MAP) were studied in five beta-adrenoceptor blocked conscious dogs. An increase in MAP was obtained by administration of vasopressin or methoxamine, a decrease by doxazosin or nitroprusside. In the first series of experiments the MAP changes were induced after muscarinic receptor blockade, in a second series both before and after muscarinic blockade. Prior to these experiments, the maximum VCA activity, defined as the difference between maximum heart rate after muscarinic blockade and the rate after additional nicotinic blockade, was determined. We hypothesized that this quantity, as a measure of VCA activity, depends on the prevailing vagal tone. In the first series of experiments, a rise in MAP evoked an increase in heart rate, a fall in MAP indicated decrease. In the second series, when prior to muscarinic blockade the vagal tone was reflexly raised, the subsequent VCA reflex response to the rise in MAP was attenuated. Prior to the muscarinic blockade the vagal tone was reflexly lowered, the VCA reflex response was enhanced. Direct chronotropic effects of MAP-varying drugs were ruled out by the absence of a heart-rate response in experiments on vagotomized animals. We concluded that the vagal cardioaccelerator system is involved in the reflex control of heart rate. Both the VCA reflex response to changes in systemic blood pressure and the maximum VCA activity however, are determined by the prevailing vagal tone.     

Baroreflex sympathetic activation increases threshold pressure for the pressure-dependent renin release in conscious dogs

Stimulus-response curves relating renal-venous-arterial plasma renin activity difference (P.R.A.-difference) to mean renal artery pressure (R.A.P.) were studied in seven chronically instrumented conscious foxhounds with a daily sodium intake of 6.1 mmol/kg. R.A.P. was reduced in steps and maintained constant for 5 min using an inflatable renal artery cuff and a pressure control system.The stimulus-response curve obtained during control conditions (C) or during common carotid artery occlusion (C.C.O.) could be approximated by two linear sections: a rather flat section or plateau-level of P.R.A.-difference at normal blood pressure or above, and a very steep section between a distinct threshold pressure and 65–70 mm Hg. While the parameters of the curves varied from dog to dog, the curves kept their inique shape in the individual dog for at least 1 week. C.C.O. had no effect on the plateau-level of the P.R.A.-difference (C:0.98±0.14,C.C.O.:0.99±0.14 ng Al·ml^–1·h^–1) and on the slope of the curve below threshold pressure (C:–0.379±0.041,C.C.O: –0.416±0.082 ng Al·ml^–1·h^–1·mm Hg^–1) but shifted the stimulus-response curve to the right and increased threshold pressure (C:92.7±2.8,C.C.O.:109.7±4.1 mm Hg;P<0.05).Renal blood flow, which was measured simultaneously in three of the dogs, showed good autoregulation down to 70 mm Hg under resting conditions and was not affected by C.C.O. except for a 30% reduction of renal blood flow at the lowest pressure step (70 mm Hg).-Adrenergic blockade in 4 of the dogs reduced the plateau-level of the P.R.A.-difference from 0.86±0.19 to 0.36±0.05 ng AI·ml^–1·h^–1 (P<0.05) but had no effect on the increase of threshold pressure elicited by C.C.O.It is concluded that the stimulus-response curve for the pressure-dependent renin release has a remarkable long-term stability in the individual dog. The curve is shifted to the right by a moderate carotid baroreflex increase of renal sympathetic nerve discharge which leaves total renal blood flow largely unchanged. It is suggested that the increase in threshold pressure is independent of -adrenergic effects.This study was supported by the German Research Foundation within the SFB 90, HeidelbergA priliminary part of this investigation has been presented to the meeting of the German Physiological Society, Dortmund, March 1984 [Pflügers Arch (1984) suppl 400:R11,41]     

The relationship between plasma vasopressin concentration and urinary excretion during left atrial distension in anaesthetized dogs

The relationship between the changes in plasma vasopressin (AVP) concentration and urinary concentration during left atrial distension has been examined in 12 anaesthetized dogs. Left atrial pressure was increased by 1.2 kPa for 30 min. Plasma AVP concentration (radioimmunoassay) was decreased 5 min after the start of atrial distension and was increased again 5 min after the end of distension. The average decrease was about 50% from a mean of 6.4±2.4 pg · ml^–1 (SE). Urine osmolality decreased more slowly reaching its lowest value in the first 10 min after removal of atrial distension. In contrast sodium excretion increased immediately upon atrial distension. Because of the difference in the time course of the changes in plasma AVP and urine osmolality, plasma AVP was compared with the urine osmolality in samples collected 15 min after the plasma samples. At any plasma AVP concentration there was a wide variation in urine osmolality between dogs, but in any one dog there was clear relationship between plasma AVP and urine osmolality. The results support the view that the diuretic response to left atrial distension is due, at least in part to decreases in plasma AVP concentration. They also show that a stimulus arising from increased left atrial pressure influences the relationship between plasma osmolality and plasma AVP concentration.     

Left atrial pressure and sodium balance in conscious dogs on a low sodium intake

Summary 10 conscious chronically prepared dogs were used. After recovery from thoracotomy (catheter into the left atrium, nylon purse string around the mitral annulus) they were kept chronically on a low sodium intake (<0.5 meq Na/kg bw daily). On 51 days left atrial pressure (LAP) was increased for 60 min about 10 cm H₂O once daily by tightening the purse string (distension period: DP).During DP urine volume ( ) increased about threefold, and sodium excretion (E _Na) about sixfold. The amount of renal sodium loss on the days when LAP was increased exceeded the daily intake considerably. The application of DOCA (15 mg i.m.) did not diminishE _Na during DP and 60 min thereafter. During DP heart rate increased by about 70 b/min and mean arterial blood pressure increased by about 15 mm Hg.The data suggest that stimulation of intrathoracic receptors by a reversible mitral stenosis augments renal sodium excretion even in a state of a highly stimulated tubular sodium resorption.Preliminary reports of parts of this work have been presented at the meetings of the Deutsche Physiologische Gesellschaft in Bochum (1975) and Wien (1975). The authors are indebted to Dr. Üdes and Dr. Nebendahl for the invaluable veterinary assistance and to Mrs. Jäckel and Mrs. Mohr for technical assistance. Dr. Eisele is surgeon at the Schloßparkklinik, BerlinThe AG Experimentelle Anaesthesie is member of the Research Group Autonomic Regulations, FU Berlin     

Antidiuretic responses to thermal stimulation of hypothalamus and spinal cord in the conscious goat

Summary At various ambient temperatures the effects of hypothalamus temperature and spinal cord temperature on urine formation and heat production were studied in conscious goats with chronically implanted thermodes. At neutral air temperature cooling hypothalamus or spinal cord induced a fall in urine volume and a rise in urine osmolality. This antidiuretic response was concurrent with a rise in heat production. Simultaneous occurrence of antidiuresis and increased heat production was also found after cessation of hypothalamic warming. At hot ambient temperature cooling hypothalamus affected neither urine formation nor heat production. Since hypothalamic cooling and spinal cord cooling produce identical effects on kidney function it is concluded that this response is linked to the complex cold defence activity as a whole. The predominent change of free water clearance is tentatively interpreted as caused by an increased ADH concentration in the blood during the cold defence activity.     

Circulating catecholamines and control of plasma renin activity in conscious dogs.

Uninephrectomized dogs were prepared with indwelling catheters in the aorta, inferior vena cava (IVC), and renal artery, and after recovery they were studied in the conscious state. Basal aortic epinephrine and norepinephrine concentrations were 57 +/- 11 and 101 +/- 18 pg/ml, respectively. Elevation of epinephrine concentration to over 2,000 pg/ml by IVC infusion resulted in a sustained 3.5-fold increase in plasma renin activity (PRA), with only a transient decrease in arterial blood pressure. The PRA response to epinephrine was completely blocked by l-propranolol; isoproterenol increased PRA more than did epinephrine. Increasing norepinephrine concentration to 1,600 pg/ml by IVC infusion resulted in only a 1.5-fold increase in PRA. Infusion of epinephrine or norepinephrine directly into the renal artery to achieve similar increments of renal arterial concentration did not increase PRA. Insulin injection or hemorrhage resulted in elevations of arterial epinephrine (but not norepinephrine) concentration greater than the concentrations achieved during IVC infusion in these studies. We conclude that circulating epinephrine in the physiologic range plays a role in the control of PRA by activation of an extrarenal beta-receptor.     

The renin angiotensin system of amphibians

Summary Kidney extracts from several amphibian species were incubated with homologous and non-homologous serum. In a series of experiments the angiotensin formation was studied by enzyme kinetic technics, using acidified, dialysed kidney extracts and dialysed serum. In other experiments incubations were performed in the presence of Dowex 50W-X2 (NH₄ ⁺) resin. The angiotensin was then eluted from the Dowex and its pressor activity tested on the rat. If no Dowex was used in the incubation mixtures the range of the angiotensin formation was from 0 to 210 ng angiotensin formed per ml of serum. If Dowex was added, the values ranged from 0 to 300 ng angiotensin formed per ml of serum. Often angiotensinase was still present in the incubation mixtures, reducing the amount of detectable angiotensin in the incubation mixtures. Dowex protects the formed angiotensin from amphibian angiotensinases. The data suggest, however, that a large amount of angiotensin adsorbed onto the Dowex cannot be recovered. There is at least some species or class specifity of the renin-angiotensin system of the amphibians. Kidney extract of one species incubated with non-homologous serum produced less pressor substance than the same amount of kidney extract when incubated with homologous serum. Amphibian adrenal pressor substances are—at least in part—adsorbed on Dowex and can be eluted from it in a similar fashion as angiotensin.This work was supported by the Deutsche Forschungsgemeinschaft.