Effects of cadralazine on systemic blood pressure, renal function and plasma renin activity in anesthetized dogs

Renal effects of ethyl 6-[ethyl(2-hydroxypropyl)amino]-3-pyridazinecarbazate (cadralazine), a newly synthesized vasodilator with a pyridazine ring, were studied in anesthetized dogs. 30 min after intravenous (i.v.) injection of cadralazine in a dose of 1 mg/kg diastolic blood pressure (DBP) decreased from the control value of 115 +/- 4 mmHg to 108 +/- 3 mmHg. The decrease continued, being accompanied by an increase in heart rate, throughout the experimental period of 5 h. Renal vascular resistance was decreased significantly, while glomerular filtration rate and urine volume remained unchanged. Urinary excretions of sodium and potassium were increased about 1.5 to 2 times as compared to pre-injection control values. Hypotension and natriuresis were followed by increased plasma renin activity in the artery or renal vein. On the other hand, i.v. injection of hydralazine (0.3 mg/kg) promptly decreased DBP and urinary sodium excretion, 15 min after administration, with blood pressure tending to revert to the control value. These results indicate that cadralazine has hypotensive and renal vasodilating actions, characterized by a slow onset and long duration, when compared with hydralazine.     

Cyclooxygenase inhibition potentiates the pulmonary vascular responses to ethanol in dogs

The effects of ethanol on pulmonary hemodynamics and the role of arachidonic acid metabolites in mediating these responses were studied in the isolated, blood-perfused canine lung lobe. Ethanol added directly to the venous reservoir at a concentration of 0.01 or 0.1% did not alter the pulmonary vascular resistance, however, 1.0% ethanol increased (p less than 0.05) the pulmonary resistance. Indometacin, a cyclooxygenase inhibitor, significantly increased baseline pulmonary vascular resistance and markedly potentiated the pulmonary vascular responses to the three concentrations of ethanol. Addition of nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, followed by indometacin, did not diminish the indometacin-induced increases in basal tone or enhancement of the responses to ethanol indicating that leukotrienes are not involved in mediating the responses to ethanol. These results suggest that in isolated, blood-perfused dog lung lobe, a high concentration of ethanol increases the pulmonary vascular resistance and that cyclooxygenase inhibition markedly potentiated the responses to ethanol by reducing the production of vasodilator prostaglandin, most probably prostacyclin.     

Comparison of the acute renal and peripheral vascular responses to frusemide and bumetanide at low and high dose.

1. The effects of equipotent doses of frusemide (10 mg and 100 mg) and bumetanide (250 micrograms and 2.5 mg) upon renal and peripheral vascular responses, urinary prostaglandin excretion, plasma renin activity, angiotensin II and noradrenaline were compared in nine healthy volunteers. 2. Frusemide (10 mg and 100 mg) and bumetanide (2.5 mg) increased renal blood flow acutely compared with placebo but bumetanide (250 micrograms) had no effect. The changes in peripheral vascular responses were not significantly different from placebo. 3. Urinary prostaglandin metabolite excretion was acutely increased by all treatments, with no inter-treatment difference. Plasma renin activity was increased acutely by both doses of frusemide and by bumetanide (2.5 mg) compared with placebo and to bumetanide (250 micrograms). There were no differences between the latter two treatments. Angiotensin II was increased significantly 30 min after frusemide 100 mg and bumetanide 2.5 mg, and by all four treatments at 50 min when compared with placebo. There were no significant differences between either of the low doses or the higher doses. Plasma noradrenaline was unchanged by all treatments. 4. Frusemide 100 mg and bumetanide 2.5 mg have the same effects on the renal vasculature and the renin-angiotensin-prostaglandin system. Under the conditions of this study, frusemide 10 mg had different effects on plasma renin activity than bumetanide 250 micrograms.     

Renal vascular and sympathetic nerve responses to hypotension induced by platelet-activating factor in anesthetized dogs

This experiment was designed to determine renal sympathetic and renal vascular responses to platelet-activating factor (PAF)-induced hypotension in anesthetized dogs with and without systemic baroreceptor denervation. The left kidney was perfused at a constant flow, and renal perfusion pressure and efferent left renal sympathetic nerve activity were measured simultaneously. Intrarenal injection of PAF (1.25−5.0×10⁻² μg/kg, N = 6) produced a dose-dependent increase in renal perfusion pressure without any change in systemic blood pressure. An intravenous injection of PAF (10 μg/kg) to intact animals (n = 7) caused an initial increase in renal nerve activity (157±14%) followed by a gradual reduction below baseline (72±7%) with concomitant systemic hypotension (from 116±7 to 46±6 mmHg). Renal perfusion pressure increased significantly from 84±2 to 161±33 mmHg concomitant with an increase in renal nerve activity at 1 min and was maintained at this elevated level throughout the experiment. Similar responses of renal nerve activity and renal perfusion pressure were found in animals with complete systemic baroreceptor denervation (n = 7). These renal suggest that renal vascular response during PAF-induced hypotension may presumably be mediated by a direct vasoconstrictor effect of PAF on the renal vasculature and that baroreceptor reflex is not involved in either renal sympathetic or renal vascular changes.     

Renal vascular responses to CORM-A1 in the mouse.

CORM-A1 is a newly described water-soluble carbon monoxide (CO) releasing molecule (CORM) that can deliver CO to various vascular beds in the absence of dramatic changes in blood carboxy-hemoglobin (COHb) levels. We tested the in vivo and in vitro renal vascular effects of CORM-A1 administration using anesthetized mice instrumented with a renal flow probe as well as in isolated, pressurized renal interlobar arteries. Administration of CORM-A1 (0.96 micromol) resulted in a significant increase in renal blood flow (RBF) of 33 +/- 6% as compared to control. Administration of acetylcholine (50 pmol) caused a similar increase in RBF (25 +/- 4%). In order to determine if the vasodilatory effect of CORM-A1 in vivo was mediated through activation of soluble guanylate cyclase (sGC), mice were pretreated with the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 nmolkg(-1)min(-1)) for 30min. Pretreatment with ODQ significantly reduced the CORM-A1 mediated increase in RBF to 9 +/- 5% of control. In isolated pressurized renal interlobar arteries, CORM-A1 caused dose dependent vasodilatation of phenylephrine constricted arteries. The CORM-A1 mediated vasodilatation was significantly attenuated by ODQ to similar levels as observed in vivo. Inhibition of calcium activated potassium channels (Kca) with iberiotoxin resulted in a complete blockade of the CORM-A1 mediated vasodilatation in pressurized renal interlobar arteries. We conclude that CO released from CORM-A1 causes an increase in RBF and a decrease in vascular resistance through activation of sGC and opening of Kca channels in the kidney of the mouse.     

Effect of renal perfusion pressure on responses of intrarenal blood flow to renal nerve stimulation in rabbits

1. We investigated how sympathetic nerve activity and renal perfusion pressure (RPP) interact in controlling renal haemodynamics in pentobarbitone-anaesthetized rabbits. 2. Renal blood flow (RBF) was reduced by electrical renal nerve stimulation (0.5-8 Hz), with RPP set using an extracorporeal circuit to 65, 100 and 135 mmHg. 3. Responses of RBF and cortical laser Doppler flux to renal nerve stimulation were blunted by increased RPP. For example, 4 Hz stimulation reduced RBF by 68 +/- 7% with baseline perfusion pressure approximately 65 mmHg, but only by 22 +/- 3% at approximately 135 mmHg. Medullary laser Doppler flux was less responsive than cortical laser Doppler flux to renal nerve stimulation and its response was not dependent on perfusion pressure. 4. When perfusion pressure was clamped at its baseline level during renal nerve stimulation, responses of RBF and cortical laser Doppler flux, but not medullary laser Doppler flux, were still blunted with increased baseline perfusion pressure. 5. A frequency rich stimulus was applied to assess the effects of perfusion pressure on dynamic neural control of RBF. Renal blood flow responded similarly at each level of perfusion pressure, as a low-pass filter with a pure time delay. 6. Our results suggest that, in the rabbit extracorporeal circuit model, increased RPP blunts the ability of steady state renal nerve stimulation to reduce cortical, but not medullary perfusion. However, in this model the level of RPP appears to have little impact on dynamic neural control of RBF.     

The influence of changes in perfusion pressure and angiotensin II on the renal excretory responses to atrial natriuretic peptides.

The renal actions of atriopeptin III were examined in anaesthetised rats at differing perfusion pressures before and following blockade of the renin-angiotensin system. At normal perfusion pressure 1000 ng kg-1 atriopeptin III caused reversible increases in glomerular filtration rate, of 20%, urine flow, absolute and fractional sodium excretions of 51-93%. Reduction of left renal perfusion pressure to 80 mm Hg decreased glomerular filtration rate by 30% and urine flow, absolute and fractional sodium excretions by 80% while atriopeptin III administration only minimally changed these variables. Concomitantly, right kidney perfusion pressure rose by 15 mm Hg which significantly increased fluid output, while the atriopeptin III induced diuresis and natriuresis were significantly larger. During infusion of captopril 900 micrograms kg-1 h-1 when pressures at the left and right kidneys had been reduced and elevated, respectively, atriopeptin III caused larger excretory responses in both kidneys which were greater than without captopril. These result suggested that the atriopeptin III mediated natriuresis and diuresis were directly proportional to perfusion pressure and attenuated by angiotensin II.     

Effect of nicardipine on the relationship of renal blood flow and of renal vascular resistance to perfusion pressure in dog kidney

The effect of nicardipine, a Ca channel blocker, on autoregulation of renal blood flow and perfusion pressure-vascular resistance relationship has been investigated in perfused kidneys of anaesthetized dogs. In control animals excellent autoregulation of renal blood flow and pressure-dependent elevation of vascular resistance were observed above 100 mmHg of perfusion pressure. However, intra-arterial infusion of nicardipine at doses of 3 and 10 micrograms min-1 showed dose-dependent impairment of the autoregulatory response and of elevation of vascular resistance. Infusion of nicardipine (2.5 micrograms min-1) into the renal artery also inhibited renal vasoconstriction induced by YC-170, a Ca channel activator. These results suggest that the inhibitory effect of nicardipine upon renal autoregulation may be due to its Ca2+ channel blocking action.     

Effects of activation of renal adenosine A2 receptor on renal function and renin release in dogs.

Direct effects of adenosine A2 receptor activation on renal function were examined in dogs. When renal perfusion pressure was maintained constant at 100 mmHg, renal administration of a selective A2 receptor agonist, CGS 21680C (sodium salt of CGS 21680, 2-[p-(2-carboxyethyl) phenethylamino]-5'-N-ethylcarboxamido adenosine) (1 microg x kg(-) x min (-1)), although it decreased blood pressure by 20 mmHg, increased renal blood flow and renin release, whereas glomerular filtration rate and urine flow were unaffected. These results suggest that stimulation of renal A2 receptor led to both afferent and efferent arteriolar dilatation, whereas renal A2 receptor plays a minor role in urine formation. CGS 21680C induced renin release and tachycardia that were blocked by propranolol, indicating these effects of A2 receptor stimulation appeared to be indirect.     

Effects of nifedipine on renin release and renal function in anesthetized dogs

The effects of nifedipine, classed as a calcium entry blocker, on urinary excretion and renin release were investigated in anesthetized dogs. Nifedipine was infused into one renal artery for three consecutive 10-min periods, at incremental rates of 0.3, 1, and 3 micrograms/min. Intrarenal infusion of nifedipine (3 micrograms/min) produced marked increases in urine flow rate (by 200%) and in urinary sodium (by 210%) and potassium (by 40%) excretion rates of the infused kidney without changes in mean systemic blood pressure, heart rate, glomerular filtration rate, and filtration fraction. Urinary osmolarity was slightly decreased by the drug, but this change was not statistically significant. There were no consistent changes in these parameters for the contralateral noninfused kidney. Renin secretion rate was increased to three times the preinfusion level during infusion of the highest nifedipine dose. The blood flow to the infused kidney was increased, and ipsilateral renal vascular resistance was simultaneously decreased upon nifedipine infusion. These results suggest that a nonhypotensive dose of nifedipine causes an increase in renin secretion and that this drug has a striking effect on the reabsorption of sodium and water by the renal tubules.     

Comparison of systemic and intrarenal converting enzyme inhibition by MK-422 on renal hemodynamics in conscious dogs

The purpose of this study was to compare the effect of intrarenal angiotensin converting enzyme (ACE) inhibition with that of systemic ACE inhibition in conscious, instrumented dogs. Intrarenal ACE inhibition was achieved by infusing the potent ACE inhibitor MK-422 into the renal artery in a dose (0.32 micrograms/kg/min) that in dogs fed a normal sodium (n = 11) and low sodium (n = 10) diet markedly attenuated the renal blood flow response to intrarenal arterial angiotensin I (0.4 and 0.8 micrograms, respectively). Intrarenal arterial infusion of MK-422 decreased the responses by 76 and 72% in the normal and low sodium groups, respectively, but only decreased renal vascular resistance slightly (-9 and -8%, respectively) in the infused kidney. Following termination of intrarenal arterial infusion of MK-422, the inhibitor was administered intravenously, 0.2 mg/kg. This dose of MK-422 maximally inhibited systemic ACE, as evidenced by the complete abolition of the renal blood flow response to intravenous angiotensin I; the responses were decreased by 95 and 96% in the normal and low sodium groups, respectively. In contrast to the negligible reduction in renal vascular resistance seen during intrarenal arterial infusion of MK-422, systemically administered inhibitor decreased renal vascular resistance by 16 and 39%, respectively, in the normal and low sodium groups. These results lend additional support to our contention that systemically rather than intrarenally formed angiotensin II is mainly responsible for regulation of renal vascular resistance.     

Effects of systemic inhibition of Rho kinase on blood pressure and renal haemodynamics in diabetic rats

BACKGROUND AND PURPOSE

The RhoA/Rho associated kinases (ROCK) pathway has been implicated in the pathophysiology of diabetic nephropathy (DN). Early stages of diabetes are associated with renal haemodynamic changes, contributing to later development of DN. However, the role of RhoA/ROCK, known regulators of vascular tone, in this process has not been studied.

EXPERIMENTAL APPROACH

Blood pressure (BP), glomerular filtration (GFR), effective renal plasma flow and filtration fraction (FF) in response to the ROCK inhibitors Y27632 (0.1 and 0.5 mg·kg⁻¹) and fasudil (0.3 and 1.5 mg·kg⁻¹) were examined in streptozotocin-diabetic rats and non-diabetic controls.

KEY RESULTS

Diabetic rats demonstrated baseline increases in GFR and FF. In contrast to similar decreases in BP in diabetic and control rats, renal vasodilator effects and a decrease in FF, following ROCK inhibition were observed only in diabetic rats. The vasodilator effects of Y27632 and a further decrease in FF, were also detected in diabetic rats pretreated with the angiotensin antagonist losartan. The effects of ROCK inhibitors in diabetic rats were modulated by prior protein kinase C (PKC)β inhibition with ruboxistaurin, which abolished their effects on FF. Consistent with the renal vasodilator effects, the ROCK inhibitors reduced phosphorylation of myosin light chain in diabetic kidneys.

CONCLUSIONS AND IMPLICATIONS

The results indicate greater dependence of renal haemodynamics on RhoA/ROCK and beneficial haemodynamic effects of ROCK inhibitors in diabetes, which were additive to the effects of losartan. In this process, the RhoA/ROCK pathway operated downstream of or interacted with, PKCβ in some segments of the renal vascular tree.     

Renal effects of adenosine and their inhibition by theophylline in dogs

Summary The action of adenosine on renal blood flow and kidney function in dogs was studied with bolus injections and infusion of adenosine into the renal artery. Simultaneous infusions of theophylline, 1–5×10^–6 mol/min into the renal artery which did not affect renal function by itself inhibited the adenosine induced vasoconstriction. From the bolus injection studies a dose response curve (DRC) was constructed. Theophylline shifted the DRC to the right in a parallel manner. pA₂-pA₁₀ was 0.98 indicating that theophylline inhibition of the adenosine effects may be interpreted as a competitive antagonism. Infusions of adenosine (0.3–1.1 mol/min) caused a reduction of urine volume, sodium excretion and glomerular filtration rate (GFR). The decrease of GFR after adenosine infusion by 31.4% could be diminished by theophylline. It is suggested that adenosine action is based mainly on a constriction of the vasa afferentia in the outer zone of the cortex.with the technical assistance of O. JacobsPart of this work was presented on the 14. Frühjahrstagung der Deutschen Pharmakologischen Gesellschaft, Mainz, 18.–21. 3. 1973.Supported by Deutsche Forschungsgemeinschaft.     

Flosequinan does not affect systemic and regional vascular responses to simulated orthostatic stress in healthy volunteers.

1. The effects of a single oral dose (100 mg) of flosequinan on systemic and regional (forearm, splanchnic and renal) vascular responses to simulated orthostatic stress (lower body negative pressure, LBNP) were investigated in nine healthy male volunteers, in a double-blind, placebo-controlled crossover study. 2. Forty-five minutes after its administration and before LBNP, flosequinan induced a significant decrease in total peripheral and in forearm vascular resistances without any concomitant change in arterial pressure, in heart rate and in the investigated biological parameters (plasma catecholamines, arginine vasopressin and renin activity). 3. After flosequinan and placebo, LBNP induced similar decreases in central venous pressure at all levels of LBNP (-10, -20 and -40 mm Hg) and in pulse pressure at LBNP -40 mm Hg. LBNP-induced increase in forearm vascular resistance was significantly more marked after flosequinan than after placebo at all levels of LBNP, and this was also true for splanchnic vascular resistance but at LBNP -40 mm Hg only. However, inasmuch as the basal values of these two parameters before LBNP were lower after flosequinan than after placebo, their final values after LBNP -40 mm Hg were similar. Finally, LBNP-induced changes in renal vascular resistance, glomerular filtration rate and filtration fraction as well as in plasma catecholamines, arginine vasopressin and renin activity were similar after flosequinan and placebo at all levels of LBNP. 4. Flosequinan affected neither reflex control of heart rate (phenylephrine test) nor non-specific vasoconstrictor responses (cold pressor test). (ABSTRACT TRUNCATED AT 250 WORDS)     

Investigation of the biochemical effects of renin inhibition in normal volunteers treated by an ACE inhibitor.

1. In order to investigate accurately the biochemical effects of renin inhibition in man, we have developed a sensitive assay to measure angiotensin I (1-10) decapeptide. 2. Angiotensins were extracted from plasma by adsorption to phenylsilylsilica, and angiotensin I (Ang I) was quantified by radioimmunoassay. The detection limit was 0.77 fmol ml-1, and the extraction recovery of [125I]-Ang I added to albumin buffer was 83% at the inflection point (10 fmol ml-1) of the standard curve. The overall recovery was 98.5 +/- 3.5%. The intra- and inter-assay reproducibility was 10.4% and 9.7% respectively. Cross-reactivity of the antiserum used was low (less than 0.3%) with all angiotensin peptides tested except Ang (2-10) nonapeptide. 3. A human pharmacological model was subsequently used to assess in vivo the biochemical effects of the renin inhibitor CGP 38560A. Six healthy volunteers received 20 mg lisinopril, a long-acting ACE-inhibitor. During the following 24 h, the renin-angiotensin system was reset with typically elevated active plasma renin and Ang I, at respectively 275 and 429% of basal values. 4. In a randomized three-way cross-over protocol, the six volunteers received a 30 min infusion of the renin inhibitor CGP 38560A (125 or 250 micrograms kg-1) or 5% glucose. The fall in plasma Ang I was 92% and 97.5% after the lowest and highest dose of the renin inhibitor, respectively. A concomitant increase in active plasma renin was observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Contribution of prostaglandins to the systemic and renal vascular response to frusemide in normal man

In eight normotensive male volunteers indomethacin decreased both the peak urine flow rate and total sodium excreted within 1 h of an intravenous dose of frusemide. Resting effective renal plasma flow and glomerular filtration rate were unchanged by indomethacin, but the increase in both parameters after frusemide was inhibited. The early increase in plasma renin activity after frusemide was inhibited by indomethacin. Indomethacin decreased urinary excretion of PGE by 80% and the increase after frusemide was abolished. The urinary excretion of a metabolite of systemic PGI2 was unaltered in the 40-60 min period following frusemide. The early haemodynamic effects of frusemide are likely to be prostaglandin mediated, but there was no evidence of any change in systemic PGI2 synthesis after frusemide.     

Effects of the calcium antagonist nicardipine on renal function and renin release in dogs

The effects of nicardipine, classed as a calcium antagonist, on renal hemodynamics, renal function, and renin release were investigated in pentobarbital-anesthetized dogs. Intrarenal infusion of this drug at a rate of 5 micrograms/min in both hydrated and hydropenic dogs resulted in a significant increase in renal blood flow, glomerular filtration rate, urine flow, and renin release, with a significant fall in systemic blood pressure. The intrarenal blood flow as measured by the microsphere method indicated a greater increase in flow rate in the juxtamedullary than in the superficial area. During nicardipine infusion, free water reabsorption rate (TcH2O) in hydropenic dogs or free water production (CH2O) in hydrated dogs increased in proportion to the urine flow. Neither TcH2O/CH2O nor CH2O/osmolar clearance were significantly changed throughout the experiments. These data suggest that nicardipine did not inhibit sodium transport at the medullary portion of the ascending limb of Henle, and that the increase in GFR might induce an enhancement of the delivery of sodium to the Henle loop. In addition, an intrarenal hemodynamic alteration may be one possible mechanism involved in the diuretic action of nicardipine. Calcium-antagonistic actions of nicardipine may account for the changes in renal parameters.     

Early physiological and biochemical responses of rice seedlings to low concentration of microcystin-LR

Microcystin-leucine and arginine (microcystin-LR) is a cyanotoxin produced by cyanobacteria like Microcystis aeruginosa, and it’s considered a threat to water quality, agriculture, and human health. Rice (Oryza sativa) is a plant of great importance in human food consumption and economy, with extensive use around the world. It is therefore important to assess the possible effects of using water contaminated with microcystin-LR to irrigate rice crops, in order to ensure a safe, high quality product to consumers. In this study, 12 and 20-day-old plants were exposed during 2 or 7 days to a M. aeruginosa extract containing environmentally relevant microcystin-LR concentrations, 0.26–78 μg/L. Fresh and dry weight of roots and leaves, chlorophyll fluorescence, glutathione S-transferase and glutathione peroxidase activities, and protein identification by mass spectrometry through two-dimensional gel electrophoresis from root and leaf tissues, were evaluated in order to gauge the plant’s physiological condition and biochemical response after toxin exposure. Results obtained from plant biomass, chlorophyll fluorescence, and enzyme activity assays showed no significant differences between control and treatment groups. However, proteomics data indicates that plants respond to M. aeruginosa extract containing environmentally relevant microcystin-LR concentrations by changing their metabolism, responding differently to different toxin concentrations. Biological processes most affected were related to protein folding and stress response, protein biosynthesis, cell signalling and gene expression regulation, and energy and carbohydrate metabolism which may denote a toxic effect induced by M. aeruginosa extract and microcystin-LR. The implications of the metabolic alterations in plant physiology and growth require further elucidation.     

Effects of the angiotensin type I receptor antagonist, losartan, on systemic and regional vascular responses to lower body negative pressure in healthy volunteers.

1. The effects of a single oral dose (50 mg) of the angiotensin II AT1-receptor antagonist, losartan, on the systemic and regional vascular responses to simulated orthostatic stress by the lower body negative pressure (LBNP) technique were investigated in nine healthy volunteers, in a double-blind, placebo-controlled crossover study. 2. Arterial blood pressure remained unchanged throughout the study. Three hours after its administration and before LBNP, losartan selectively increased renal blood flow (PAH clearance) by 8.3% (3.5 to 13.1%, 95% CI) from 1.25 +/- 0.08 l min-1 (P < 0.05) and decreased plasma aldosterone levels by 58% (29 to 87%, 95% CI) from 22 +/- 3 ng 100 ml-1 (P < 0.05). 3. LBNP at -10 and -20 mm Hg induced a progressive and significant decrease in central venous pressure and increases in forearm (plethysmography) and splanchnic (indocyanine green clearance) vascular resistances which were similar after losartan and placebo administrations. Losartan blunted the LBNP-induced increase in renal vascular resistance observed at -20 mm Hg after placebo but a similar increase in glomerular filtration rate (inulin clearance) was observed at LBNP -10 and -20 mm Hg after losartan and placebo. Calculated filtration fraction increased after placebo (LBNP -10 mm Hg) and losartan (LBNP -20 mm Hg). Finally, LBNP-induced changes in biological parameters were similar after losartan and placebo at all levels of LBNP. 4. Thus, losartan does not interfere with the adaptive forearm and splanchnic vascular responses and preserves renal haemodynamics during orthostatic stress simulated by LBNP in healthy volunteers.