Renal response to captopril in conscious dogs pretreated with indomethacin

This study was designed to determine whether the prostaglandins mediate the renal effects of captopril in the conscious sodium-replete dog. In a group of control animals (n = 9), effective renal plasma flow (ERPF) increased from 185 +/- 15 to 230 +/- 12 ml/min and plasma renin activity (PRA) increased from 0.64 +/- 0.15 to 12.9 +/- 1.1 ng ANG I . ml-1 . h-1 after captopril (10 mg/kg bolus plus 10 micrograms . kg-1 . min-1 i.v.) administration. Glomerular filtration rate (GRF) and sodium excretion (UnaV) were also increased significantly following captopril treatment, whereas urine volume (V), potassium excretion (UkV), mean arterial pressure (MAP), and heart rate (HR) remained unchanged throughout the experiment. When the same dose of captopril was given to indomethacin-pretreated dogs (5 mg/kg bolus plus 2 micrograms . kg-1 . min-1 i.v.), ERPF increased from 170 +/- 8 to 265 +/- 18 ml/min and PRA increased from 1.2 +/- 0.4 to 14.6 +/- 3.0 ng ANG I . ml-1 . h-1 after the captopril, while UnaV, UkV, and V remained unchanged. These data demonstrate that the prostaglandins do not mediate the ability of captopril to increase PRA or effective renal plasma flow in this experimental model.     

Vasopressin and renin responses to hemorrhage in conscious, cardiac-denervated dogs

We measured plasma arginine vasopressin (AVP) and plasma renin activity (PRA) during continuous hemorrhage in cardiac-denervated and sham-operated conscious dogs. Hemorrhage produced comparable decreases in aortic pressure, cardiac output, stroke volume, pulmonary arterial pressure, and left and right atrial pressures in each group of dogs. After 10 ml blood/kg body wt had been removed, AVP was increased in sham-operated dogs (P less than 0.05) but not in cardiac-denervated dogs. After 20 and 30 ml blood/kg body wt had been removed, AVP was increased in all dogs, but the response was markedly attenuated in cardiac-denervated dogs. Hemorrhage at 10 and 20 ml/kg caused comparable increases in PRA in each group of dogs. However, at 30 ml/kg hemorrhage the increase in PRA was significantly higher in cardiac-denervated dogs than in sham-operated dogs. Our results suggest that cardiac receptors play a dominant role in mediating the release of AVP during hemorrhage in conscious dogs. In contrast, we found no evidence for a dominant role of cardiac receptors in mediating renin secretion during hemorrhage.     

Regional hemodynamic responses to exogenous catecholamines and vasoactive peptides in conscious rats.

The vasoactive hormones vasopressin, angiotensin II, adrenaline, and noradrenaline may all be released after central neural stimulation, but our knowledge of their relative actions on regional vascular resistances is incomplete. A comprehensive account of these patterns will help our understanding of their contributions to centrally generated patterns of blood flow. In the present study, regional blood flows and resistances of five major arteries were measured during sequential intravenous infusions of a range of doses of each substance in conscious rats. Vasopressin strongly increased superior mesenteric, hindquarters, carotid, and renal resistance but did not affect celiac artery resistance until the highest infusion rate. Both angiotensin II and noradrenaline increased resistance, although to different extents, in all vascular beds except the hindquarters, which was unaffected. Adrenaline infused at pressor rates markedly increased superior mesenteric resistance while moderately increasing renal, carotid and celiac arterial resistances. At subpressor rates, however, adrenaline increased celiac resistance but decreased hindquarters vascular resistance without significantly affecting the other beds. It is concluded that each vasoactive substance released into the systemic circulation causes its own characteristic pattern of vascular responses. This information should be useful for understanding the humoral basis of hemodynamic responses to central stimuli.     

Renal prostaglandin E2 secretion and excretion in conscious dogs.

Renal prostaglandin E2 (PGE2) secretion and excretion rates were determined in nine conscious dogs. Renal venous (RV) and urine PGE2 concentrations were measured by radioimmunoassay. In 21 controls tests RV PGE2 ranged from 37 to 215 pg/ml, with a mean concentration of 97 +/- 11 pg/ml. Basal left kidney PGE2 secretion was 317 +/- 42 pg.g-1.mm-1. Urine PGE2 concentration averaged 8,320 +/- 1,510 pg/ml with a PGE2 excretion rate of 3,260 +/- 480 pg/min from both kidneys. Indomethacin (2 mg/kg) reduced RV and urine PGE2 concentrations by 60 and 77%, respectively. Meclofenamate (2 mg/kg) decreased RV and urine PGE2 concentrations by 36 and 48%, respectively. PG inhibition had no significant influence on blood pressure or renal blood flow (RBF). PG inhibition reduced urine flow rate and increased urine osmolality. Indomethacin had no effect on urine sodium concentration or sodium excretion; meclofenamate increased urine sodium concentration and slightly diminished sodium excretion. These data demonstrate that PGE2 is released from the kidney in a conscious animal and that both indomethacin and meclofenamate significantly reduce the renal secretion and excretion of PGE2. In a normal, conscious animal prostaglandins do not control blood pressure or RBF but are involved in the excretion of water.     

Effects of naloxone on the haemodynamic and renal functional responses to plasma volume expansion in conscious rabbits

We tested whether the opioid antagonist naloxone affects responses to plasma volume expansion (PVE) in conscious rabbits. Under basal conditions, naloxone (6 mg x kg-(1) plus 0.3 mg x kg(-1) x min(-1) i.v.) had no observable effect, except to slightly reduce heart rate. During vehicle treatment, PVE (Haemaccel; 1 ml x kg(-1) min(-1) for 30 min plus 0.2 ml x kg(-1) x min(-1) for 60 min i.v.) reduced haematocrit by 7.1+/-0.8% (from 34.8+/-1.1%), and increased central venous pressure by 3.0+/-0.9 mmHg (from -2.8+/-1.5 mmHg), cardiac output by 42+/-9 ml min(-1) x kg(-1) (from 152+/-17 ml x min(-1) x kg(-1)), systemic vascular conductance by 0.49+/-0.11 ml x min(-1) x mmHg(-1) kg(-1) (from 1.58+/-0.23 ml x min(-1) x mmHg(-1) x kg(-1)), urine flow by 0.13+/-0.04 ml x kg(-)x min(-1) (from 0.12+/-0.02 ml kg(-1) x min(-1)) and sodium excretion by 21+/-5 micromol x kg(-1) min(-1) (from 5+/-2 micromol x kg(-1) x min(-1)). During naloxone treatment, the PVE-induced changes in haematocrit and central venous pressure were similar to those during vehicle treatment, but the increases in cardiac output (24+/-7 ml kg(-1) min(-1)), systemic vascular conductance (0.25+/-0.05 ml min(-1) x kg(-1) x mmHg(-1)), urine flow (0.09+/-0.03 ml x kg(-1) min(-1)) and sodium excretion (11+/-4 micromol x kg(-1) x min(-1)) were 31-49% less. These observations indicate that endogenous opioids mediate some of the circulatory and renal excretory responses to PVE in conscious rabbits.     

Characterization of antibody responses to endogenous and exogenous antigen in the nonobese diabetic mouse

It is suggested that a T-helper cell 2 (Th2) shift and Th2 spreading of autoimmunity following immunization with beta-cell antigen causes diabetes protection. To address this, antibody titer and subclass to insulin, glutamic acid decarboxylase (GAD)65, IA-2, and IA-2beta proteins were measured by radiobinding assays in untreated or immunized female nonobese diabetic mice. Untreated nonobese diabetic mice developed autoantibodies to insulin (IAA), but not GAD or IA-2/IA-2beta, and IAA-positive mice had increased diabetes risk (P < 0.001). IAA were IgG1 and IgG2b. In immunized mice, IgG1 and lesser IgG2b insulin antibodies were promoted by subcutaneous injection of insulin plus incomplete Freund's adjuvant, insulin plus Montanide ISA 720, and glucagon plus incomplete Freund's adjuvant, but not by incomplete Freund's adjuvant plus GAD65, IA-2beta, or phenylethanolamine N-methyltransferase, or adjuvant alone. Diabetes incidence was significantly reduced in immunized groups with elevated insulin antibody (IA) responses. Spreading of antibody responses to GAD or IA-2/IA-2beta following immunization was rare, and antibody epitope spreading was only detected in IA-2beta immunized mice. Humoral autoimmunity in nonobese diabetic mice is, therefore, limited to IAA with Th2 subclass phenotype and is associated with increased diabetes risk. This contrasts the diabetes protection provided by immunization protocols that promote this response and suggests that Th2 immunity may not be the principal regulator of beta-cell destruction in autoimmune diabetes.     

Regional haemodynamic responses to intracerebroventricular administration of rat calcitonin gene-related peptide in conscious, Long-Evans and Brattleboro rats

Rat calcitonin gene-related peptide (CGRP) was administered intracerebroventricularly (0.25 nmol in 5 microliter) to conscious, Long-Evans and Brattleboro rats, chronically instrumented with pulsed Doppler probes around the left renal and superior mesenteric arteries and the distal abdominal aorta. Tachycardias occurred in both strains, but only in Long-Evans rats was there a (modest) pressor effect of CGRP. However, both strains of rat showed renal vasodilatation and mesenteric vasoconstriction. These results indicate that the central pressor effect of CGRP in Long-Evans rats may not be due to generalized sympathetic activation, and make it unlikely that circulating vasopressin contributes to the mesenteric vasoconstriction.     

The antilipolytic effect of endogenous and exogenous adenosine in canine adipose tissue in situ

The effects of adenosine, 2-Cl-adenosine, two adenosine uptake inhibitors (dipyridamole and dilazep) and the adenosine deaminase (ADA) inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) were studied on basal and stimulated lipolysis in subcutaneous adipose tissue. The basal lipolysis was unaffected by all agents. Lipolysis induced by nerve stimulation (4 Hz, 5 min) was dose-dependently antagonized (up to 100%) by close i.a. infusions of adenosine (1–40 μM in blood); if the nerve induced vasoconstriction was prevented by α-adrenoceptor-blockade. 2-Cl-adenosine was a more potent antilipolytic agent than adenosine. EHNA (3–10 μM in blood) did not inhibit stimulated lipolysis in vivo possibly because of the low ADA activity in fat cells. Dipyridamole (0.5-1.5 μM in blood) in combination with EHNA increased the venous plasma concentration of adenosine from 0.3±0.05 to 0.7±0.1 μM and enhanced the tissue concentration close to 3-fold. Lipolysis induced by nerve stimulation (4 Hz) was reduced by about 40% by dipyridamole + EHNA and that induced by close i.a. noradrenaline injection (20 nmol) by approximately 60%. It is concluded that adenosine is an antagonist of stimulated lipolysis in subcutaneous adipose tissue in situ in concentrations that are reached during prolonged sympathetic nerve stimulation.     

Renal haemodynamic effects of B2 receptor agonist bradykinin and B2 receptor antagonist HOE 140 in conscious lambs

The present study was designed to test the hypothesis that the high renal vascular resistance characteristic of the newborn results from age-dependent changes in the responsiveness of the renal vasculature to kinins. Two studies were carried out in conscious, chronically instrumented lambs aged 1 and 6 weeks. Firstly, we measured the renal blood flow response to intra-arterial injection of the B2 receptor agonist bradykinin over the range of doses 0-800 ng x kg(-1). The ED50 renal blood flow response to bradykinin was 50 ng x kg(-1) in both age groups of lambs. Secondly, we measured the effects of intravenous administration of 12.5 microg x kg(-1) of the specific B2 receptor antagonist HOE 140; this dose attenuated the renal blood flow response to 50 ng x kg(-1) of bradykinin in both age groups. HOE 140 administration was associated with an age-dependent increase in mean arterial pressure, with little effect on heart rate or renal vascular resistance. This study provides new information regarding the effects of kinins in modulating renal haemodynamics during postnatal maturation. We reject our hypothesis and conclude that the high renal vascular resistance of the newborn does not appear to result from age-dependent changes in the responsiveness of the renal vasculature to endogenous kinins.     

Comparison of renal responses to 5% saline infusions into vena portae and vena cava in conscious dogs

Indwelling catheters were placed in conscious dogs into the vena portae via a jejunal mesenteric vein several weeks prior to actual experiments. To compare a possible different response to different pathways of administration, 5% saline solution was infused either into vena portae or into vena cava at a rate of 0.05 ml/min/kg BW for 40 min.

1. Infusion of 5% sodium chloride into the vena portae, as well as into the vena cava caused a significant increase in urine flow, serum osmolality, sodium excretion rate and heat rate. The increase in urine flow was always due to an increase in osmolal clearance whereas free water clearance decreased consistantly. In some experiments plasma renin activity (PRA) was measured by radioimmunoassay. For both routes of administration the hypertonic saline infusion caused a decrease in PRA. At no time did any of these parameters display significant differences depending on route of application.
2. This means that the calculated differences between infused and excreted amounts of water and of sodium did not depend on the route of infusions.
3. A close relationship was found between initial urine osmolality and the length of the periods during which peak values of urine flow were observed.

These results do neither provide evidence for a hepatic osmoreceptor mechanism in dogs nor for the hypothesis that in conscious dogs the liver might control sodium excretion.     

Attention to endogenous and exogenous cues affects auditory localization

Three experiments examine attentional differences in auditory localization using either endogenous or exogenous visual cues. Participants were presented with visual cues on a computer screen and asked to localize auditory targets presented through headphones. In conditions in which the auditory and visual stimuli traveled in the same direction, participants showed illusory directional hearing (Hari in Neurosci Lett 189:29–30, 1995) in that the targets were perceived to travel through the head. In conditions in which the directions of the auditory and visual stimuli were conflicting, participants localized the auditory targets as traveling in the direction of the visual cues. These data suggest that visual capture plays a predominate role in the processes of auditory localization that occurs within the head. Additionally, endogenous response times were significantly greater than exogenous response times. We propose this is the result of additional time required to shift one’s attentional window in the endogenous condition.     

Cardiovascular responses to salt-loading in conscious domestic geese

1. The intravenous injection of large volumes of 0.5 M-NaCl that are usually used to induce nasal gland secretion in marine birds has been shown in geese to increase greatly plasma volume, cardiac output, heart rate and stroke volume at the time secretion commences after 2-8 min.2. There were no consistent changes in mean arterial blood pressure or in the distribution of the cardiac output to major organs except to the salt-glands whose share increased approximately fourteenfold. Salt-gland blood flow remained high for 10-20 min after cardiac output and heart rate had returned to nearly normal levels.3. The increases in plasma volume and venous return are unlikely to be the stimuli for salt-gland secretion because secretion was also initiated by giving artificial sea water into the proventriculus and this produced no changes in these variables at the time secretion commenced, 5-14 min later.4. At the start of secretion in orally loaded birds, the only detectable changes in the plasma were small increases in osmolality (from 1.3 to 4.6%), Na (from 0.3 to 6%) and Cl (from 1.3 to 7.1%) concentrations.     

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.     

IgE responses to exogenous and endogenous allergens in atopic dermatitis patients under long‐term systemic cyclosporine A treatment

Atopic dermatitis (AD) patients mount IgE antibody responses to a variety of environmental allergens and also to autoantigens. We analyzed serum samples from four AD patients who had received oral cyclosporine A (CyA) treatment for up to 17 months regarding IgE autoreactivity to nitrocellulose‐blotted human epithelial cell extracts and IgE levels to environmental allergens by quantitative ImmunoCap measurements. Skin inflammation was assessed by SCORAD. During full‐dose treatment, a strong reduction in T‐cell‐mediated skin symptoms was observed which reappeared when CyA treatment was reduced or stopped. The intensity of IgE autoreactivity seemed to follow skin inflammation as it was reduced during full‐dose treatment and increased upon inflammation. Interestingly, IgE levels to exogenous allergens were boosted by allergen exposure, declined thereafter, and seemed to be unaffected by CyA. Our data thus indicate that allergen‐specific IgE production is boosted by allergen contact and cannot be reduced by CyA‐mediated T‐cell suppression.