Effects of losartan,prazosin and a vasopressin V1‐receptor antagonist on renal and femoral blood flow in conscious sheep

The regulation of blood flow to different organs is determined by the autonomic nervous system and systemic and/or local vasoactive substances. Although the cardiovascular effects of the renin‐angiotensin system (RAS), the sympathoadrenal system and vasopressin (AVP) have been thoroughly studied, there are relatively few investigations on these systems with concomitant measurements of systemic haemodynamics and regional blood flow in conscious unstressed individuals. We therefore studied effects of pharmacological blockade of AVP V₁‐, angiotensin II (ANG II) AT₁‐and adrenergic α‐receptors on central and regional (renal and femoral blood flow) haemodynamics in adult conscious ewes. Eight adult cross‐bred ewes were chronically intrumented with peri‐vascular ultrasonic flow probes implanted unilaterally around the renal and the femoral artery. While standing in their habitual environment, systemic and regional haemodynamics were measured before and after the following treatments as single intravenous injections. Animals in group A (n=6) were given isotonic saline (NaCl) followed by the AT₁‐receptor blocker losartan (LOS, 10 mg kg^–1) 30 min later; group B (n=6) animals were given the α‐adrenoceptor blocker prazosin (PRAZ, 0.2 mg kg^–1); and group C (n=6) the vasopressin V₁ receptor antagonist [d(CH₂)₅Tyr(Me)AVP] (AVP‐a, 10 μg kg^–1). PRAZ reduced mean arterial pressure (MAP) by 11% concomitant with an increase in heart rate (HR) (32%), whereas the other substances where without effect on those variables. Femoral blood flow (FBF) was enhanced (increased by 82%) by injection of PRAZ only. Administration of LOS increased the renal blood flow (RBF) by 11% while the other drugs were without effect on that parameter. We conclude that basal renal vascular tone in conscious unstressed sheep is dependent on angiotensinergic mechanism and that blockade of this influence causes a local increase in flow without concomitant effects on systemic haemodynamics.     

Cardiovascular and renal effects of intracerebroventricular angiotensin II in conscious sheep.

Effects on systemic and pulmonary haemodynamics, renal electrolyte excretion, and plasma concentration of vasopressin, catecholamines, electrolytes and proteins in response to intracerebroventricular infusions of [Val5]-angiotensin II (ANG II) at 1, 2 and 4 pmol kg-1 min-1 in isotonic saline for 30 min were studied in conscious sheep (n = 6). Vehicle control infusions were performed in four of the animals. All three doses of ANG II were expected to increase CFS concentration of the peptide above physiological levels. All ANG II infusions were noticed to be dipsogenic, but the animals were not allowed to drink freely until at the end of the experiments (at 120 min post-infusion). The systemic arterial blood pressure increased significantly only in response to 2 and 4 pmol kg-1 min-1, concomitant with an increase of the systemic vascular resistance, whereas the cardiac output and heart rate remained unchanged. The central venous pressure increased only after administration of the highest ANG II dose, while pulmonary artery, and capillary wedge pressures were unaffected during all experiments. The plasma protein and K concentration fell in response to ANG II administration. Also here, the effects were significant only at 2 and 4 pmol kg-1 min-1. The plasma levels of vasopressin, noradrenaline, adrenaline and dopamine did not change significantly in response to any of the infusions. The renal Na excretion increased by 100-400%, but not in a strictly dose-dependent manner. Much smaller and more variable effects were seen on the renal K excretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

An investigation into the influence of vasopressin on perfusion of the cortex and papilla of the rat kidney.

An investigation was undertaken to examine the effects of vasopressin on blood pressure and perfusion of the cortical and papillary regions of the kidney, and to determine the receptor subtype involved. Pentobarbitone-anaesthetized rats were used and laser-Doppler flowmetry applied to measure regional renal haemodynamics. Infusion of vasopressin at 10, 20 and 40 mU kg-1 min-1 caused dose-related increases in blood pressure and reductions in cortical and papillary perfusion of approximately 21, 35 and 41%, respectively at the highest dose. Administration of the V1-receptor antagonist, [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-(o-methyl)tyrosine]-Arg8-vasopressin, at 1 microgram kg-1 plus 5 micrograms kg-1 h-1 or four times this dose had no effect on the basal levels of any variable. Vasopressin administration during the low dose of antagonist increased blood pressure and reduced papillary perfusion, the magnitudes of which were only slightly less than those obtained in the absence of the drug, whereas there was a significant attenuation of the response in cortical perfusion. During infusion of the V1 antagonist at 4 micrograms kg-1 plus 20 micrograms kg-1 h-1, vasopressin had no effect on either blood pressure or renal haemodynamics. Infusion of the V2 antagonist, [d(CH2)5, D-Phe2, Ile4, Arg8, Ala9-NH2]-vasopressin at 1 microgram kg-1 plus 5 micrograms kg-1 h-1, and twice this dose had no effect on the basal value of any variable and had no effect on the ability of vasopressin to induce an increase in blood pressure or cause reductions in renal cortical and papillary perfusions. However, the administration of the V2 antagonist at 4 micrograms kg-1 plus 20 micrograms kg-1 h-1 significantly attenuated blood pressure, cortical and papillary perfusion responses to the vasopressin. These studies have shown that vasopressin, given at doses which increased blood pressure, caused dose-related decreases in perfusion of renal cortex as well as the papilla. The data further show that these systemic and renal actions were mediated primarily by V1-receptors and that the contribution of V2-receptors at these vascular beds was very small.     

Effects on intravascular pressures of vasopressin and angiotensin II in dogs

The effects of 30-min intravenous infusions of 8-arginine vasopressin (AVP) and angiotensin-(1,8)-octapeptide (ANG II) to conscious dogs were studied by measurements of systolic (SABP), mean (MABP), and diastolic arterial blood pressures, central venous pressure (CVP), heart rate (HR), and plasma concentrations of vasopressin (pAVP). Infusion of AVP at six rates (0.4-12.8 ng X min-1 X kg-1) raised mean pAVP by 5-490 pg/ml and increased CVP by 2-10 cmH2O. HR decreased and arterial pressures increased with infusion rates of 1.6-12.8 ng X min-1 X kg-1. However, the increase in SABP was only transient. ANG II increased all arterial pressures; however, it barely changed CVP and did not change HR or pAVP. It is concluded that 1) AVP can elevate MABP without changes in SABP, 2) the effects of AVP on arterial pressures are buffered within 5-15 min, 3) CVP can be increased by doses of AVP that do not affect arterial pressures, and 4) the pressor activity is independent of the presence of ANG II. The results confirm that the cardiovascular response to vasopressin is qualitatively different from that elicited by ANG II.     

Atropine-antagonized miosis induced in the goat by intravenous infusions of prostaglandin E (PGE1 and PGE2)

Effects of 30 min intravenous infusions of prostaglandin (PG) E1 (total dosage 0.07 mg kg-1), E2 and F2 alpha (total dosage 0.12 mg kg-1), respectively, were studied concomitant with measurements of renal excretion of PGF metabolites in hyperhydrated goats. None of the PGs induced any rise in rectal temperature. However, the PGEs elicited pronounced, atropine-antagonized miosis and an inhibition of the water diuresis accompanied by some increase in renal excretion of arginine vasopressin (AVP). These effects were not obtained in response to PGF2 alpha. The PGF2 alpha rapidly induced a conspicuous and long-lasting increase in the renal excretion of PGF metabolites. The corresponding effect of the PGEs was more delayed, and less than 10% of the increase obtained in response to PGF2 alpha. Nevertheless, the excretion of these metabolites in response to the PGEs was of the same magnitude as that previously observed during endotoxin fever in the goat. It is concluded that endotoxin-induced miosis and stimulation of AVP secretion previously demonstrated in the goat might well have been secondary to systemic PGE production. However, this does not seem to hold true for endotoxin-induced fever.     

Tolerance to haemorrhage during vasopressin antagonism and/or captopril treatment in conscious sheep

The effect of separate and combined blockade of vasopressin (AVP) V₁-receptors and angiotensin II formation on resistance to a slow venous haemorrhage (0.7 ml kg^-1 min^-1) was studied in six conscious adult sheep by bleeding to the point of an abrupt fall in the mean systemic arterial pressure (MSAP). Intravenous administration of the V₁-receptor antagonist [d(CH₂)₅Tyr(Me)AVP] (10 μg kg^-1) and/or the angiotensin I converting enzyme inhibitor captopril (20 mg+1 mg h^-1) did not cause any significant haemodynamic changes in the normovolaemic animal. The volume of haemorrhage necessary to induce acute hypotension (MSAP < 50 mmHg) was significantly smaller after AVP blockade alone (13.8±0.7 ml kg^-1; P < 0.01) but not after captopril treatment (14.7±1.6 ml kg^-1; n.s.) compared to control animals receiving no drug treatment (16.8±0.6 ml kg^-1). The combined treatment with the AVP antagonist and captopril caused a further decrease in tolerance to haemorrhage (9.4±1.2 ml kg^-1; P < 0.001). Blockade of AVP V₁-receptors was associated with an attenuated increase in systemic vascular resistance immediately after the end of haemorrhage, concomitant with an accentuated lowering of the central venous pressure. In contrast, captopril treatment decreased the degree of vasoconstriction mainly during the second half of the post-haemorrhage observation period of 1 hour. It is concluded that both AVP and angiotensin II contribute to the maintenance of the MSAP during haemorrhage in conscious sheep. During the spontaneous recovery after hypotensive blood loss, a vasoconstrictor effect of AVP is evident mainly during the initial 15 min, whereas at later stages angiotensin II appears to be of relatively greater importance.     

Cardiovascular and renal effects of intracerebroventricular angiotensin II in conscious sheep

Effects on systemic and pulmonary haemodynamics, renal electrolyte excretion, and plasma concentration of vasopressin, catecholamines, electrolytes and proteins in response to intracerebroventricular infusions of [Val⁵]-angiotensin II (ANG II) at 1, 2 and 4 pmol kg^-1min^-1in isotonic saline for 30 min were studied in conscious sheep (n = 6). Vehicle control infusions were performed in four of the animals. All three doses of ANG II were expected to increase CFS concentration of the peptide above physiological levels. All ANG II infusions were noticed to be dipsogenic, but the animals were not allowed to drink freely until at the end of the experiments (at 120 min post-infusion). The systemic arterial blood pressure increased significantly only in response to 2 and 4 pmol kg^-1min^-1, concomitant with an increase of the systemic vascular resistance, whereas the cardiac output and heart rate remained unchanged. The central venous pressure increased only after administration of the highest ANG II dose, while pulmonary artery, and capillary wedge pressures were unaffected during all experiments. The plasma protein and K concentration fell in response to ANG II administration. Also here, the effects were significant only at 2 and 4 pmol kg^-1min^-1. The plasma levels of vasopressin, noradrenaline, adrenaline and dopamine did not change significantly in response to any of the infusions. The renal Na excretion increased by 100–400%, but not in a strictly dose-dependent manner. Much smaller and more variable effects were seen on the renal K excretion. We conclude that: (1) supraphysiological CSF ANG II levels are needed to cause a pressor effect when the peptide is administered via the intracerebroventricular route in conscious sheep; (2) the blood pressure is increased exclusively via peripheral vasoconstriction and; (3) increased vasopressin release does not contribute to the cardiovascular changes. The results also demonstrate that ANG II may cause haemodilution via a central site of action.     

Haemodynamic and neurohumoral effects of cold pressor test in severe heart failure.

The effect of a cold pressor test (CPT) on haemodynamics in relation to general and regional sympathetic activity and arginin vasopressin (AVP), was studied in eleven patients with severe congestive heart failure (CHF). Compared to an age-matched control group (C), resting arterial plasma noradrenaline (NA) (419 +/- 77 vs. 182 +/- 15 pg ml-1), and adrenaline (A) (142 +/- 28 vs 54 +/- 10 pg ml-1) were higher (P less than 0.05) in CHF. AVP showed no significant difference (14 +/- 4 vs. 9 +/- 4 pg ml-1). During CPT systolic and diastolic blood pressure and systemic vascular resistance increased (P less than 0.01), as did NA (delta 114 +/- 39 pg ml-1, P less than 0.01), A (delta 33 +/- 10 pg ml-1, P less than 0.01) and heart rate (delta 10 beats min-1, P less than 0.01). The myocardial v-a difference of NA decreased (P less than 0.05), but was unchanged across the renal vascular bed during CPT. The a-v difference of NA in the hepatic vascular bed, and fractional extraction of A in the coronary sinus, renal and hepatic vascular beds remained unchanged during CPT. AVP did not change significantly and no change in cardiac index or left ventricular filling pressure was observed during CPT. These data suggest that despite an increased activation of the sympathetic nervous system at rest, a further increase in blood pressure and catecholamines took place during CPT. Thus, the effect of a CPT which activates the central sympathetic system seems not to be altered in patients with severe CHF.     

Influence of neurohumoral blockade on heart rate and blood pressure responses to haemorrhage in isoflurane anaesthetized rats

Four groups of Sprague-Dawley rats were anaesthetized with isoflurane (ISO) (1.7% end-tidal concentration) in 40% oxygen, and mechanically ventilated. The animals were bled 15 mL kg-1 b.w. from the femoral vein over 10 min, followed by an observation period of 30 min. Ten minutes before haemorrhage each group of animals was pre-treated with intravenous injection/infusion of either: isotonic saline (Group B; CON; n=7), vasopressin V1-receptor antagonist [d(CH2)5Tyr(Me)AVP; 10 microg kg-1] (Group C; AVP-a; n=7), the non-selective angiotensin II receptor antagonist saralasin (10 microg kg-1 min-1) (Group D; SAR; n=7) or hexamethonium (10 mg kg-1) (Group E; HEX; n=7). A separate group of conscious animals were pre-treated with isotonic NaCl and subjected to the same haemorrhage protocol (Group A; AW; n=7). Mean arterial pressure (MAP), heart rate (HR) and blood gases were observed during the experiments. Only pre-treatment with SAR and HEX reduced MAP significantly. The pre-haemorrhage HR was only affected by HEX, which caused a reduction by 17%. The HR was significantly lower at the end of haemorrhage compared with pre-haemorrhage levels in all groups except that group treated with HEX. In that group the HR changed in the opposite direction. The ability to maintain MAP during haemorrhage, and the post-haemorrhage period, was significantly impaired in the groups treated with AVP-a, SAR or HEX compared with the group receiving NaCl. It is concluded that autonomic nervous activity is of major importance for the maintenance of MAP during isoflurane anaesthesia, whereas circulating angiotensin II and vasopressin levels contribute to a much smaller degree in this regard. General anaesthesia in combination with different degrees of neurohumoral blockade impairs the haemodynamic responses to blood loss, seen in conscious individuals. The impairment involves both the early and late phases during haemorrhage, as well as the post-bleeding recovery period. All three neurohumoral systems (autonomic nervous activity, angiotensin II and vasopressin) are of importance for regulating MAP during and after haemorrhage, although the autonomic nervous outflow appears to contribute to a larger extent.     

Repeated hypotension induced by nitroprusside and haemorrhage in sheep: effects on vasopressin release and recovery of arterial blood pressure

The arginine vasopressin (AVP) release in response to repeated hypotension caused by intravenous (i.v.) infusion of sodium nitroprusside (SNP) or haemorrhage was studied in conscious euhydrated sheep. Parallel determinations of renal excretion and plasma concentration of AVP were made in experiments involving two consecutive 10-min i.v. infusions of SNP (about 35 micrograms kg-1 min-1) with a 3-h interval between and repeated the next day. The AVP response to the second SNP administration was significantly reduced, but partial recovery was observed in response to the initial infusion the next day. Maximal fall in mean arterial blood pressure (MABP) and its recovery pattern did not differ in response to any of the four SNP infusions. In contrast, impaired recovery of the MABP together with markedly reduced AVP response was seen as a consequence of a hypotensive haemorrhage repeated after 3 h, but not when the interval between haemorrhages was extended to 24 h. The haemorrhage-induced increase in plasma renin activity was not affected by variations in the interval between experiments. It is concluded that the massive AVP liberation normally seen as an effect of acute isovolaemic hypotension becomes markedly reduced upon a renewed fall in the MABP occurring within 3 h. An iteration of hypotensive haemorrhage accentuates this fatigue of the hormonal response, which may contribute to the impaired recovery of the MABP.     

A study of the action of angiotensin II on perfusion through the cortex and papilla of the rat kidney.

The effect of angiotensin II on blood pressure and perfusion of blood through the cortex and papilla regions of the kidney was determined in pentobarbitone-anaesthetized rats which were subjected to laser-Doppler flowmetry to estimate regional renal haemodynamics. Angiotensin II was infused at 10, 45 and 150 ng (kg body weight-1 min-1) which caused dose-related increases in blood pressure of 3, 12 and 24%, respectively, and decreases in cortical perfusion of 9, 15 and 24%, respectively. Papillary perfusion did not change at any dose of angiotensin II. This pattern and magnitude of responses to angiotensin II in blood pressure, cortical and papillary perfusions was essentially unaffected (a) following blockade of cyclo-oxygenase activity with indomethacin (1.3 mg kg-1 plus 2 mg kg-1 h-1), (b) during infusion of a bradykinin antagonist, at 1.3 micrograms min-1, (c) when renal perfusion pressure was regulated at control levels and (d) following Methylene Blue administration to inhibit potential endothelial-derived relaxing factor production. By contrast, infusion of phenylephrine at 5, 10 and 20 micrograms kg-1 min-1 caused dose-related increases in blood pressure and decreases in both cortical and papillary perfusions reaching some 28, 7 and 17% respectively at the highest dose of phenylephrine used. These results showed that both cortex and papilla were sensitive to vasoconstrictor agents. They are compatible with the suggestion that angiotensin II regulates cortical but not papillary perfusion in the kidney, and that these responses do not depend on prostaglandin, bradykinin, renal perfusion pressure or endothelium-derived relaxing factor.     

Effects of indomethacin on systemic and renal haemodynamics in conscious lambs

Both prostaglandins (PGs) PGE(2) and PGI(2) can act as renal vasodilators, these effects being exacerbated when the renin-angiotensin system is activated. Therefore, we hypothesized that PGs would play a more predominant role in modulating renal haemodynamics in the newborn period, when the renin-angiotensin system is activated. To this end, the role of endogenously produced PGs in modulating systemic and renal haemodynamics was investigated in two groups of conscious lambs aged approximately 1 and approximately 6 weeks. Arterial pressure, venous pressure and renal blood flow were measured for 5 min before (control) and for 20 min after intravenous injection of vehicle (experiment 1). Twenty-four hours later, this protocol was repeated with intravenous injection of the non-selective cyclo-oxygenase inhibitor indomethacin (1 mg kg(-1), experiment 2). Heart rate was calculated from the systolic peak of the arterial pressure waveform, and renal vascular resistance (RVR) was calculated from the measured variables. In response to indomethacin but not vehicle, in both age groups of lambs there was an increase in mean arterial pressure and pulse interval, as well as a marked increase in RVR. These responses to indomethacin were, however, transient, with baseline levels being resumed within minutes. Although the hypothesis that PGs play a greater role in modulating renal haemodynamics early in life is not supported, these data do provide evidence that endogenously produced PGs modulate systemic and renal haemodynamics during postnatal maturation. It is apparent, however, that other vasoactive factors must be rapidly recruited in order to buffer the circulatory responses to removal of vasodilatory PGs in the developing newborn.     

Selective thromboxane A2 receptor blockade in experimental exercise-induced myocardial ischaemia in dogs

Thromboxane A2 receptor stimulation induces blood platelet aggregation and vasoconstriction, both potential causes of impaired perfusion of ischaemic myocardium. To study the potential role of thromboxane A2 receptor blockade in exercise-induced myocardial ischaemia and post-exercise myocardial dysfunction, nine conscious chronically instrumented dogs with single-vessel coronary artery stenosis (ameroid constrictor) were studied before, during and after steady-state treadmill runs which induced regional myocardial ischaemia. Three hours after a control run, the dogs were exercised again after the infusion of a selective thromboxane A2 receptor blocker: BM 13.177 (10 mg kg-1 i.v.). In the control run, systolic wall thickening (WTh, sonomicrometer) in the post-stenotic myocardium decreased from 22.1 +/- 9.1% at rest to 8.8 +/- 5.2% (mean +/- SD). Subendocardial blood flow (microspheres) in the ischaemic area decreased from 0.75 +/- 0.25 to 0.45 +/- 0.27 (ml min-1 g). The WTh in the ischaemic region remained depressed at 20 min after the run. BM 13.177 reduced peak left ventricular (+) dP/dt (micromanometer) and WTh in both control and post-stenotic myocardium at rest, during and after the run. WTh in the ischaemic area was reduced to approximately the same levels during running with BM 13.177 (not significantly different from control exercise) and remained depressed for at least 30 min after the run. Regional myocardial blood flow was not affected by BM 13.177. Thus, selective thromboxane A2 receptor blockade with BM 13.177 had a modest negative inotropic effect and did not improve regional function or blood flow in post-stenotic ischaemic subendocardium.     

Effects of AVP and DDAVP on plasma renin activity and electrolyte excretion in conscious dogs.

Uninephrectomized adult female dogs with chronic indwelling catheters were maintained on a low sodium diet and studied without anesthesia. Following hydration with 3% dextrose, an intravenous infusion of either arginine vasopressin (AVP) or of 1-desamino-8-D-arginine vasopressin (DDAVP) was begun. The dose was calculated to achieve a near maximal physiological plasma concentration of AVP, or an equimolar concentration of DDAVP. Both AVP and DDAVP increased urinary osmolality from less than 60 to over 800 mosmol/kg H2O within 1 h. AVP infusion increased mean arterial pressure and renal electrolyte excretion and decreased heart rate and plasma renin activity (PRA), while DDAVP was without effect on these parameters. AVP infused into the renal artery at doses which did not alter systemic pressure and heart rate caused kaliuresis and reduced PRA. We conclude that the AVP-induced inhibition of renin secretion and increase in renal electrolyte excretion are not secondary to increased tubular permeability to water, but must represent a more specific action of AVP which is not shared by DDAVP.     

Interaction of somatostatin with PTH and AVP: renal effects.

Six conscious intact dogs were studied to evaluate the interactions of somatostatin (SRIF) with exogenous antidiuretic hormone arginine vasopressin (AVP). SRIF administration caused a significant increase in free water clearance compared to a vehicle-treated group: -0.91 (+/- 0.41 SD) ml/min to 0.21 (+/- 0.32 SD) ml/min in the experimental group (P less than 0.01) versus 0.21 (+/- 0.81 SD) ml/min to -0.21 (+/- 0.68 SD) ml/min in the control (P greater than 0.5). Six conscious, thyroparathyroidectomized dogs were studied to test the interaction of SRIF and parathyroid extract (PTE). There were no significant changes in the phosphaturic and hypocalciuric effects of PTE with SRIF administration. We conclude that acute systemic SRIF administration interferes with the antidiuretic action of AVP, probably at the renal-tubular level, but does not antagonize the renal actions of PTE.     

Effects of steady-state plasma vasopressin levels on the distribution of intrarenal blood flow on electrolyte excretion.

1. In order to evaluate the effects of arginine vasopressin (AVP) on the distribution of intrarenal blood flow and on electrolyte excretion, steady-state plasma AVP levels (4-8, 19-1, 44-3, and 100-6 micro u./ml.) were produced in anaesthetized dogs, which were hydrated to minimize endogenous anti-diuretic hormone (ADH) release. 2. The urinary excretion of sodium and potassium increased without change in their filtered loads during AVP infusion. 3. Measurement by the 133xenon washout method revealed diphasic blood flow shifts, as a function of the plasma AVP level, between compartment 1 (outer cortex) and compartment 2 (inner cortex and outer medulla) without change in compartment 3 (inner medulla). 4. In a separate study, the radioactive microsphere (15 micronm) method was used with a plasma AVP levels of 19-8 micronu./ml. Blood flow (expressed as % flow/g tissue) decreased in the outer cortex and increased in the inner cortex. 5. Total renal blood flow did not change during infusion of AVP. However, the values measured by 133xenon were lower than those measured by the microsphere method. 6. There was agreement between these two independent methods that blood flow shifted from outer to inner cortex, with no change in total renal flow, at similar plasma AVP levels (19-1 and 19-8 micronu./ml.). The relationship of these intrarenal circulatory changes to the increased electrolyte excretion is discussed.     

Effects, release and disposal of endothelin-1 in conscious dogs.

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-1 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 mumol min-1, respectively). Decay curves for ET-1 in venous and arterial plasma were identical, and initial t1/2 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.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interaction of changes in the third ventricular CSF tonicity, central and systemic AVP concentrations and water intake

Arginine vasopressin (AVP) is assumed to be involved as a central transmitter or modulator in the control of autonomic functions including thirst. In conscious dogs AVP concentration in cerebrospinal fluid (CSF) from the anterior part of the third ventricle (A3V) was analysed before and after local elevation of CSF osmolality by intracerebroventricular (i.c.v.) infusion of 0.35 M NaCl and after i.c.v. AVP infusion at 46 and 138 fmol ml-1 for 10 min. In addition, the effects of these i.c.v. infusions on water intake, plasma AVP concentration and blood pressure were investigated. In euhydrated dogs 0.35 M NaCl i.c.v. did not alter AVP concentration in the CSF during the subsequent 2 h. In contrast, plasma AVP concentration had increased significantly from 3.4 +/- 0.3 (control) to 6.4 +/- 0.7 and 4.7 +/- 0.3 fmol ml-1, 4 and 16 min, respectively, after the hypertonic stimulus. Drinking was stimulated with an average water intake of 14.5 +/- 3.7 ml kg-1 body wt. However, AVP infusion into the A3V did not elicit water intake despite increases of AVP concentration in the A3V by factors up to 40 above control. The same animals responded with spontaneous drinking to 0.35 M NaCl i.c.v. administered 160 min after the end of AVP infusions. Exogenously administered AVP disappeared from the A3V with a time constant of 13.8 min. The results do not support the view that AVP in the A3V CSF per se stimulates drinking.     

Vasopressin release in response to acute hypotension induced at different time intervals in the conscious sheep

The renal arginine vasopressin (AVP) excretion in response to acute systemic hypotension induced by intravenous infusion of sodium nitroprusside (SNP) (30-40 micrograms/kg min-1) at different experiment intervals (0, 2, 4, 7 and greater than or equal to 12 days) was studied in the conscious hyperhydrated sheep. During the first post-infusion hour, 2.5 times more AVP was excreted in response to hypotension induced at greater than or equal to 12 day intervals than that observed at intervals of 0-7 days. No interexperimental time dependence of the AVP response to SNP infusion was seen with intervals of 0-7 days. The attenuated AVP release obtained with reduced experiment intervals (0-7 days) was accompanied by shorter antidiuresis and a less accentuated natriuresis during the post-hypotensive period in comparison to what was observed with greater than or equal to 12 day experiment intervals. There were no interval-dependent differences in maximal fall of mean arterial pressure, or onset and recovery of the hypotension induced by SNP administration. It is suggested that acute systemic hypotension causes such a massive AVP release that more than one week is needed for complete restoration of a releasable neurohypophyseal pool of the hormone.     

Increased resistance to haemorrhage induced by intracerebroventricular infusion of hypertonic NaCl in conscious sheep.

The effect of elevated cerebrospinal fluid Na+ concentration (CSF [Na+]) on the tolerance of blood loss, and concomitant cardiovascular and humoral responses were studied in conscious sheep. A slow (0.7 ml kg-1 min-1) venous haemorrhage was continued until the mean systemic arterial pressure suddenly decreased to less than 50 mmHg, or in the absence of hypotension, until a total blood loss of 25 ml kg-1. Significantly more blood had to be removed to induce hypotension in animals receiving an intracerebroventricular (i.c.v.) infusion (0.02 ml min-1) of 0.5 M NaCl (starting 30 min before haemorrhage and continued throughout the experiment) compared to control haemorrhages without concomitant i.c.v. infusion (22.7 +/- 1.2 ml vs 16.9 +/- 0.9 ml kg-1). In one animal, subjected to 0.5 M NaCl infusion, the blood pressure was still maintained at 25 ml kg-1 of haemorrhage. In spite of a larger blood loss, animals receiving i.c.v. infusion of hypertonic NaCl had an improved recovery of the blood pressure after haemorrhage, due to a better maintained cardiac output rather than to a reinforced increase of the vascular resistance. The improved cardiovascular responses to haemorrhage during elevated CSF [Na+] are not readily explained by the effects on the plasma concentrations of vasopressin, angiotensin II or noradrenaline, although the latter was augmented. The plasma protein concentration decreased already during the 30 min of hypertonic NaCl infusion preceding haemorrhage, and the haemodilution caused by the subsequent blood removal was aggravated, which indicates that this treatment also causes transfer of fluid to the plasma compartment. We conclude that elevated CSF [Na+] increases tolerance to haemorrhage and improves cardiovascular function after blood loss in sheep. Since the haemodynamic responses in many respects were similar to those reported in response to the systemic administration of a small volume of hypertonic NaCl solution in haemorrhagic shock, part of the effect of that treatment may be mediated via cerebral effects of increased Na+ concentration.