The antinatriuretic effect of dopaminergic blockade during volume expansion is independent of circulating atrial natriuretic factor

1. Ten normal subjects were subjected to 2 h water immersion with and without pharmacological dopaminergic blockade with either metoclopramide (group I) or domperidone (group II). 2. In group I, urinary sodium excretion showed a marked increase during water immersion alone, whereas it was blunted during water immersion plus dopaminergic blockade with metoclopramide (P less than 0.05 vs water immersion alone, n = 5). Plasma aldosterone was significantly suppressed by water immersion alone (P less than 0.05), but remained unchanged during water immersion plus metoclopramide. Plasma atrial natriuretic factor showed similar augmentation during water immersion alone and during water immersion plus metoclopramide. 3. Another five subjects (group II) were studied during water immersion alone and during water immersion plus dopaminergic blockade with domperidone. In this group the increase in urinary sodium excretion was similarly blunted by dopaminergic blockade. Plasma atrial natriuretic factor was equally elevated during water immersion alone and during water immersion plus domperidone, but aldosterone was suppressed by both water immersion alone and water immersion plus domperidone. 4. Our findings suggest that water immersion-induced atrial natriuretic factor release is independent of dopaminergic activity. Dopamine blockade is able to blunt significantly both water immersion-induced natriuresis and plasma aldosterone suppression, independently of the marked elevation of circulating atrial natriuretic factor, via a mechanism involving type 2 dopaminergic receptors.     

Aldosterone, atrial natriuretic factor and sodium intake as determinants of the natriuretic response to head-out water immersion in healthy subjects.

1. The effect of sodium intake on the natriuresis and hormonal changes induced by head-out water immersion was studied in seven normal subjects during head-out water immersion and on a control day while successively on 20 mmol of sodium/day and 100 mmol of sodium/day diets. The effects of head-out water immersion were compared with those seen on the control day for both diets. 2. The natriuresis on the 100 mmol of sodium/day diet was significantly greater than on the 20 mmol of sodium/day diet (natriuretic peak: 10.3 +/- 2.2 versus 3.9 +/- 1 mmol of sodium/h; P less than 0.01). The total sodium excretion during the 3 h of head-out water immersion was 26.2 +/- 2.0 mmol on the 100 mmol of sodium/day diet and 9.9 +/- 0.9 mmol on the 20 mmol of sodium/day diet (P less than 0.01). In contrast, the increase in the plasma atrial natriuretic factor level was similar on both diets (peak plasma atrial natriuretic factor level 23.1 +/- 1.9 versus 26.2 +/- 1 pg/ml; not significant). As expected, the baseline serum aldosterone level was higher on the 20 mmol of sodium/day diet and, despite a significant suppression, remained significantly higher at the end of the third hour of head-out water immersion (peak serum aldosterone level: 495 +/- 130 versus 197 +/- 26 pmol/l, P less than 0.06). Furthermore, there was an inverse relationship between the serum aldosterone level and the urinary sodium excretion at the time of peak natriuresis (r = -0.59, P less than 0.01). 3. We conclude that the effect of sodium intake on the natriuresis induced by head-out water immersion is more dependent upon anti-natriuretic agents, such as aldosterone, than on natriuretic factors, such as atrial natriuretic factor.     

Pharmacological, hemodynamic and autonomic nervous system mechanisms responsible for the blood pressure and heart rate lowering effects of pergolide in rats

In conscious spontaneously hypertensive rats, pergolide (50.0 micrograms/kg s.c.) produced a sustained decrease in tail artery pressure which was blocked by haloperidol (1.0 mg/kg s.c.) pretreatment. In anesthetized spontaneously hypertensive rats this effect was accompanied by a fall in total peripheral resistance inasmuch as pergolide did not significantly change cardiac output. In anesthetized normotensive rats, pergolide (30.0 micrograms/kg i.v.) also lowered blood pressure. This effect was not significantly modified by adrenalectomy, methysergide, idazoxan (alpha-2 adrenoceptor antagonist), vagotomy alone or plus ligation of carotid arteries or plus atenolol, but was entirely prevented by domperidone or sulpiride pretreatment and was reverted to a pressor response (due to stimulation of alpha adrenoceptors and 5-hydroxytryptamine receptors) by blockade of ganglionic transmission with chlorisondamine. Pergolide given either i.v. or into the cisterna magna or the lateral cerebral ventricle produced changes in blood pressure of the same magnitude. In intact or adrenalectomized rats, i.v. pergolide significantly lowered plasma norepinephrine concentration. Furthermore, in saline but not sulpiride-pretreated pithed rats, pergolide reduced the pressor responses and the accompanying increases in plasma norepinephrine evoked by electrical stimulation of the spinal cord. However, pergolide failed to modify the vascular reactivity to several pressor agents and lacked beta-2 and DA-1 dopamine receptor agonist properties. These results indicate that the decrease in blood pressure produced by pergolide can be accounted for by an inhibition of sympathetic tone resulting from stimulation of peripheral neuronal dopamine receptors. A possible central contribution remains to be substantiated. The pronounced bradycardia produced by pergolide (30.0 micrograms/kg i.v.) in anesthetized intact rats was partly reduced by vagotomy, methylatropine, domperidone, sulpiride, idazoxan, phentolamine or atenolol. The effects of pergolide in vagotomized rats were further diminished by domperidone but they were blocked by the combination of phentolamine or idazoxan plus domperidone. In rats pretreated with atenolol or in rats with the cervical section of spinal cord and the low level of heart rate increased with an isoprenaline infusion, the decrease in heart rate produced by pergolide was abolished by domperidone, methylatropine or idazoxan. In pithed rats, pergolide changed neither the base-line heart rate nor the tachycardia to exogenous norepinephrine nor the bradycardia evoked by carbachol or electrical stimulation of the peripheral cervical vagus.(ABSTRACT TRUNCATED AT 400 WORDS)     

Role of prostaglandins in the natriuresis of head-out water immersion in humans.

1. Prostaglandins may play a role in the natriuresis seen after acute circulatory challenges. To assess this role in head-out water immersion, we compared, in clearance studies, the effects of acute (24 h) and chronic (7 days) administration of indomethacin, an inhibitor of prostaglandin synthesis, on the renal response to head-out water immersion in six healthy subjects on a 200 mmol of sodium/day diet and on a 40 mmol of sodium/day diet. 2. Indomethacin caused a similar degree of sodium retention on each of these two diets. 3. During the 40 mmol of sodium/day diet, acute administration of indomethacin decreased sodium excretion before, as well as during, head-out water immersion; however, the relative increase caused by head-out water immersion was normal. After chronic administration of indomethacin, both baseline sodium excretion and the natriuresis induced by head-out water immersion were similar to those in control studies. 4. During the 200 mmol of sodium/day diet, indomethacin had no effect on baseline sodium excretion, nor on the natriuretic effect of head-out water immersion. 5. Head-out water immersion decreased tubular lithium reabsorption and increased diluting segment delivery. Despite opposite effects of indomethacin on these parameters, indomethacin did not prevent the tubular effects of head-out water immersion on either diet. However, indomethacin did prevent the marked increase in estimated renal plasma flow and the fall in filtration fraction that were observed during head-out water immersion in the absence of indomethacin (control). 6. Head-out water immersion was not associated with an increase in urinary excretion of prostaglandins.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dopamine receptor blockade does not affect the natriuresis accompanying sodium chloride infusion in dogs

Intravenous (IV) saline infusions cause parallel increments in urinary excretion of dopamine (DA) and sodium. Exogenous administration of DA exerts a natriuretic effect by action on DA receptors. The possibility that DA mediates the natriuretic response to saline infusion was studied by infusing 0.9% saline solution IV (60 ml/kg) in conscious dogs with and without selective blockade of DA1 and DA2 receptors. With no antagonist, the total increase in sodium excretion during the 120-minute saline infusion and the 60 minutes after the saline infusion was 99.5 +/- 7.6 mmol. The increase in total sodium excretion was not affected by IV infusion of the selective DA1 antagonist SCH 23390 in doses of 0.5 micrograms/kg/min and 5 micrograms/kg/min. The total increment in sodium excretion produced by saline was also unaltered by large doses (1 micrograms/kg/min and 10 micrograms/kg/min) of the selective DA2 antagonist domperidone. Our results do not support a role of DA as a mediator of saline-induced natriuresis in the dog.     

Renal and cardiovascular responses to water immersion in essential hypertension: is there a role for the opioidergic system?

Our study aimed at elucidating the effects of acute central hypervolemia induced by water immersion (WI) on renal hemodynamics, hormonal responses and on cardiovascular control in hypertensive patients, as well as at evaluating the possible role of the opioidergic system (OS) in determining these effects. Thirteen essential hypertensives were studied for 2 h before and for 2 h during WI. This was done twice, without and with i.v. injection of the OS antagonist naloxone. Before and during WI alone, glomerular filtration rate (GFR), effective renal plasma flow (ERPF), renal vascular resistance (RVR), mean arterial pressure (MAP), pulse interval (PI), spontaneous baroreflex sensitivity (BRS), Low frequency to High frequency (LF/HF) ratio in PI spectra, hematocrit, urinary sodium excretion, plasma renin activity (PRA) and aldosterone (PA) were assessed. Based on their response to WI, hypertensives were subdivided into two groups: ERPF+ (n = 7) in whom WI increased ERPF, and ERPF- (n = 6) in whom WI reduced ERPF. ERPF+ displayed a higher BRS than ERPF- at baseline and during WI. A suppression of PRA and PA and an increase in MAP and urinary sodium excretion were found in both groups. In ERPF+ naloxone caused RVR and MAP to increase during WI and this response was associated with a blockade of the increase in ERPF in this group, while BRS and natriuresis were unchanged. In ERPF- naloxone did not affect WI-induced MAP, ERPF, RVR and BRS changes, while it blunted sodium excretion. Our data provide the first evidence of a differentiate renal hemodynamic response to WI in hypertension; they also suggest that while OS may significantly potentiate the renal vasodilatory response to WI in ERPF+, it does not affect the natriuretic response nor the changes in systemic cardiovascular regulation induced by central hypervolemia.     

Domperidone, a DA2-specific dopamine antagonist, has no effect on the renal or haemodynamic response to atrial natriuretic peptide in man

1. Animal experiments have suggested that the renal effects of atrial natriuretic peptide (ANP) are dependent on dopaminergic activation, predominantly of the DA1-receptor. In man, there is evidence of dependence on the DA2-receptor for the natriuresis produced by central blood volume expansion. 2. Six normal volunteers underwent infusions of alpha-human ANP preceded by domperidone (a DA2-antagonist) or placebo. Eight volunteers underwent a 3 h period of 10 degrees head-down tilt also preceded by domperidone or placebo. 3. Both the ANP infusion and head-down tilt produced a significant diuresis and natriuresis, neither of which was antagonized by the presence of domperidone. 4. The ANP infusion significantly reduced diastolic blood pressure and produced significant increases in the Doppler-measured aortic blood velocity variables of peak velocity and maximal acceleration. Domperidone had an independent effect of increasing blood pressure but did not appear to have a specific interaction with the haemodynamic effects of ANP. 5. Head-down tilt reduced mean arterial pressure and heart rate and increased maximal acceleration. Again, an independent effect of domperidone was seen on blood pressure. Heart rate and maximal acceleration showed similar changes in the presence of domperidone. 6. Domperidone does not antagonize the renal or haemodynamic effects of ANP and if dopaminergic activation is necessary for the renal action of ANP it is unlikely to be mediated by the DA2-receptor.     

Urinary prostaglandin E and antidiuretic hormone during water immersion in man

In 10 normal subjects water immersion to the neck at 35 degrees C produced a highly significant natriuresis and diuresis. Urinary prostaglandin E levels did not change significantly throughout immersion. During the diuresis of water immersion a suppression of urinary antidiuretic hormone occurred.     

Effect of metoclopramide on dopamine-induced changes in renal function in healthy controls and in patients with renal disease

1. The effects of intravenous metoclopramide on baseline values and dopamine dose-response curves for renal haemodynamics and natriuresis were investigated in healthy volunteers and patients with renal disease. 2. Dopamine infusion alone, in doses ranging from 0.25 to 8 micrograms min-1 kg-1, resulted in a dose-dependent increase in effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) with a fall in filtration fraction (FF) in eight hydrated healthy volunteers and, to a lesser degree, in 12 patients with renal disease. An increase in natriuresis (urinary excretion of sodium, UNa+V), fractional excretion of sodium (FENa+) and diuresis (urine flow rate, UV) was found in both groups for doses of 2 micrograms min-1 kg-1 and higher. 3. Metoclopramide infusion did not alter baseline values of GFR, ERPF or FF, but shifted the dopamine dose-response curve for ERPF and FF in the healthy volunteers. Metoclopramide induced a fall in UNa+V and FENa+ in both groups (fall in baseline FENa+ from 1.52 to 0.71 during metoclopramide in healthy volunteers and from 1.23 to 0.56 in patients; P less than 0.01) and blunted the natriuretic response to subsequent dopamine infusion. The fall in UNa+V during metoclopramide infusion showed a strong correlation with baseline GFR (r = -0.944). In the patients, the response for the fractional excretions of beta 2-microglobulin and gamma-glutamyltransferase was comparable with that of FENa+. 4. Dopamine infusion induced a fall, and metoclopramide led to rise, in plasma aldosterone concentration. 5. We conclude that metoclopramide acts as a dopamine antagonist at the renal level in man.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dopamine blockade with domperidone: bridge between prophylactic and abortive treatment of migraine? A dose-finding study

The feasibility of a "last moment" prevention of migraine with the selective dopamine receptor blocker domperidone (Motilium) was evaluated in patients who experience typical, but minor prodromes several hours before the attack. Following a previous placebo-controlled trial, a dose-response study was done. In a randomized, double-blind cross-over setting, oral doses of 20 mg, 30 mg or 40 mg of domperidone were each given twice to 19 patients who were able to predict their attack several hours in advance. Taken at the very first appearance of the early warning symptoms, 20 mg, 30 mg and 40 mg prevented respectively 30%, 58% and 63% of the (imminent) attacks. Part of the attacks still occurring after domperidone, particularly after 20 mg, were reduced in severity. Irrespective of the dose given, the best response was observed when domperidone was taken 6 h, and even better, 12 h before the attack. Migraine-associated hypersensitivity of dopamine receptors might explain why dopamine blockade with domperidone is of benefit to the patient.     

Demonstration of specific dopamine-1 receptor-mediated coronary vasodilation in the anesthetized dog

This study was conducted to identify the vascular dopamine receptor subtype responsible for specific dopamine-mediated coronary vasodilation. The left circumflex coronary artery (LCX) of pentobarbital anesthetized, open chest dogs was isolated and perfused under either constant flow or constant pressure conditions with blood withdrawn from a cannulated left femoral artery. In animals subjected to constant flow LCX perfusion, after beta adrenoceptor blockade with nadolol (4 mg/kg), alpha-1 adrenoceptor blockade with prazosin (0.5 mg/kg) and alpha-2 adrenoceptor blockade with idazoxan (1.0 mg/kg), intracoronary (c) injection of dopamine (0.01-10 micrograms/kg) produced a dose-dependent decrease in LCX perfusion pressure which was unaltered by administration of the dopamine-2 receptor antagonist domperidone (10 micrograms/kg) but which was blocked completely by the dopamine-1 receptor antagonist SK&F R-83566 (5 micrograms/kg). Similarly, under conditions of constant pressure LCX perfusion and after combined beta, alpha-1 and alpha-2 adrenoceptor blockade, i.c. administration of dopamine produced a dose-related increase in LCX coronary blood flow which was inhibited by SK&F R-83566 but not by domperidone. Direct i.c. administration of the selective dopamine-1 receptor agonist, fenoldopam (1 microgram/kg), resulted in an increase in LCX coronary blood flow which was eliminated completely after administration of SK&F R-83566. Doses of the selective dopamine-2 receptor agonist, dipropyldopamine (0.1-30 micrograms/kg), effective in producing blood flow increases in the femoral vascular bed and which could be antagonized by domperidone, produced only minimal and inconsistent changes in LCX coronary blood flow. Our data demonstrate that direct, dopamine-mediated coronary vasodilation in vivo occurs via stimulation of a vascular receptor of the dopamine-1 subtype.     

Hyperresponsiveness to water immersion in sodium retaining cirrhotics: the role of atrial natriuretic factor

Cirrhotics do not respond uniformly to head-out water immersion (HWI). Some cirrhotics have an exaggerated natriuresis while others are unresponsive. We studied the humoral and urinary responses to HWI in 5 cirrhotics and compared this to 5 normals on the same 20 mM sodium intake. These cirrhotics had a documented tendency to salt and water retention but had minimal or no evidence of significant ascites. Plasma levels of atrial natriuretic factor (ANF) increased during immersion in both groups. However, the rise in plasma ANF from baseline during each hour of immersion was significantly greater in the cirrhotics (p less than 0.01), than in the normal volunteers. In these cirrhotics, HWI not only corrected the pre-immersion tendency to sodium retention, but by 3 hours had produced an exaggerated natriuretic response (p less than 0.05). It is possible that the greater risk of ANF in cirrhotics is responsible for this natriuretic response. However the reason for the larger rise in cirrhotics is unclear; presumably either a greater central redistribution of plasma volume occurs in cirrhotics following immersion, or there may be greater sensitivity of the ANF release system in cirrhotics.     

The dopaminergic regulation of plasma growth hormone secretion in normal subjects

The role of endogenous dopamine (DA) on plasma GH secretion was studied using domperidone (DA receptor blocker which does not cross blood brain barrier) in 16 normal subjects. After a bolus injection of domperidone (10 mg, i.v.), plasma PRL in 11 cases rose quickly and markedly from the basal level of 9.5 +/- 1.2 ng/ml (Mean +/- S.E.) to a maximum of 76.3 +/- 10.6 ng/ml at 30 min. In contrast, plasma GH in these cases showed a delayed and slight increases to domperidone injection where the values at 90 min and 120 min (3.5 +/- 0.8 ng/ml and 3.7 +/- 1.0 ng/ml) were significantly higher than those in control study (1.2 +/- 0.2 ng/ml and 1.0 +/- 0.1 ng/ml; p less than 0.05; n = 8). Domperidone infusion (0.22 mg/min/3 hr) was performed in the remaining 5 subjects. The plasma PRL responses were similar to those in the bolus injection of domperidone. These PRL responses were not modified when L-dopa was administered 30 min after the start of iv infusion of domperidone. Plasma GH showed slight but significant increases 135 min after the infusion compared to control study (4.3 +/- 1.2 ng/ml vs. 1.0 +/- 0.1 ng/ml; p less than 0.05). By the prior infusion of domperidone plasma GH responses to L-dopa was delayed and blunted, i.e., the occurrence of elevation and peak value of GH delayed by 15 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clebopride enhances contractility of the guinea pig stomach by blocking peripheral D2 dopamine receptor and alpha-2 adrenoceptor.

The mechanism of action of clebopride on the motility of guinea pig stomach was examined by the receptor binding assay for bovine brain membrane and by measuring gastric contractility and the release of acetylcholine from the stomach. The receptor binding assay revealed that clebopride bound to the D2 dopamine receptor with a high affinity and to the alpha-2 adrenoceptor and 5-HT2 serotonin receptor with relatively lower affinity, and not to D1 dopamine, alpha-1 adrenergic, muscarinic acetylcholine, H1 histamine, or opioid receptor. In strips of the stomach, clebopride at 10(-8) M to 10(-5) M enhanced the electrical transmural stimulation-evoked contraction and the release of acetylcholine. This enhancement was attributed to the blockade of the D2 dopamine receptor and alpha-2 adrenoceptor because: 1) Maximum responses obtained with specific D2 dopamine receptor antagonist, domperidone, and with specific alpha-2 adrenoceptor antagonist, yohimbine, were smaller than that with clebopride, and the sum of the effects of these two specific receptor antagonists is approximately equal to the effect of clebopride. 2) The facilitatory effect of clebopride was partially eliminated by pretreatment of the sample with domperidone or yohimbine, and the facilitatory effect of clebopride was not observed in preparations treated with the combination of domperidone and yohimbine. Clebopride also antagonized the inhibitory effects of dopamine and clonidine on the electrical transmural stimulation-evoked responses. These results indicate that clebopride acts on post ganglionic cholinergic neurons at D2 and alpha-2 receptors in this preparation to enhance enteric nervous system stimulated motility.     

Role of endothelins in hypertension

There are three peptides of endothelial origin, called endothelins (ETs), having different receptors that mediate a potent vasoconstrictor effect and also a mild vasodilation. Their renal effects are characterized by natriuresis in spite of the renal vasoconstriction. This effect, along with the stimulation of ETs by high sodium intake, suggests that ETs may be responsible for maintaining sodium balance when the renin angiotensin system is depressed. ET is activated in deoxycorticosterone acetate (DOCA) salt hypertension models and salt-sensitive hypertension. In humans, the role of ET seems to be similar to that shown in experimental animals; in both, ET participates in the regulation of salt metabolism. Salt-sensitive patients exhibit a blunted renal ET-1 response during sodium load. The role of ETs in humans has been investigated with use of nonspecific ET receptor blockers that inhibit the vasoconstriction and vasodilator components of ET. However, the effects of ET blockade should be investigated with ETA receptor blockers that mediate vasoconstriction alone. Effects of ET blockade should also be evaluated with respect to stimulation of oxidative stress and tissue damage, important mechanisms responsible for tissue fibrosis.     

Heart rate response to hypoxic exercise: role of dopamine D2-receptors and effect of oxygen supplementation

This study examined the effects of dopamine D(2)-receptor blockade on the early decrease in maximal heart rate at high altitude (4559 m). We also attempted to clarify the time-dependent component of this reduction and the extent to which it is reversed by oxygen breathing. Twelve subjects performed two consecutive maximal exercise tests, without and with oxygen supplementation respectively, at sea level and after 1, 3 and 5 days at altitude. On each study day, domperidone (30 mg; n=6) or no medication (n=6) was given 1 h before the first exercise session. Compared with sea level, hypoxia progressively decreased the maximal heart rate from day 1 and onwards; also, hypoxia by itself increased plasma noradrenaline levels after maximal exercise. Domperidone further increased maximal noradrenaline concentrations, but had no effect on maximal heart rate. On each study day at altitude, oxygen breathing completely reversed the decrease in maximal heart rate to values not different from those at sea level. In conclusion, dopamine D(2)-receptor blockade with domperidone demonstrates that hypoxic exercise in humans activates D(2)-receptors, resulting in a decrease in circulating levels of noradrenaline. However, dopamine D(2)-receptors are not involved in the hypoxia-induced decrease in the maximal heart rate. These data suggest that receptor uncoupling, and not down-regulation, of cardiac adrenoreceptors, is responsible for the early decrease in heart rate at maximal hypoxic exercise.     

Interaction of non-guanylate cyclase-linked atriopeptin receptor ligand and endopeptidase inhibitor in conscious rats

We examined the interaction of SC-46542 [des(Phe106, Gly107, Ala115, Gln116)-AP(103-126)], a non-guanylate cyclase-linked atriopeptin (AP) binding site ligand, with thiorphan, an inhibitor of endopeptidase 24.11, on mean arterial pressure, urine flow, urinary sodium excretion and plasma AP immunoreactivity in conscious rats. The coadministration of SC-46542 (16 micrograms/kg/min) and thiorphan (30 mg/kg i.v. bolus) produced a greater diuresis and natriuresis (but had no effect on mean arterial pressure) than administration of either compound alone; plasma APir increased 2-fold during coadministration of SC-46542 and thiorphan (from 325 +/- 46 to 676 +/- 86 pg/ml). Administration of SC-46542 or thiorphan alone had small or no effects on mean arterial pressure, urine flow, urinary sodium excretion or plasma APir. Converting enzyme inhibition did not contribute to the effects of thiorphan since coadministration of captopril plus SC-46542 produced effects similar to SC-46542 alone. When a near threshold infusion of AP(103-126) was combined with the coadministration of SC-46542 and thiorphan, there was a potentiation of the depressor, diuretic and natriuretic responses. Neither SC-46542 nor thiorphan alone had these effects. SC-46542 potentiated the depressor but not diuretic or natriuretic responses to low dose AP(103-126) infusion; thiorphan had little or no effect on the responses to low dose AP(103-126). We conclude that blockade of non-guanylate cyclase-linked AP binding sites with SC-46542 combined with inhibition of AP degradation by endopeptidase 24.11 with thiorphan increases diuresis and natriuresis more than inhibition of either system alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired sodium excretion in response to volume expansion induced by water immersion in insulin-dependent diabetes mellitus

The renal response to volume expansion produced by water immersion to the neck at 35 degrees C was examined in eight young normotensive uncomplicated insulin-dependent diabetic subjects and in eight matched normal control subjects. Both the diabetic and normal subjects manifested a renal response of natriuresis and kaliuresis on immersion, but the natriuretic response was reduced in the diabetic group. Thus the induced excretion of sodium over the 4 h of immersion was 40 +/- 5 mmol (mean +/- SEM) in the normal group compared with 22 +/- 4 mmol in the diabetic group (P less than 0.02). In the normal subjects creatinine clearance did not change during immersion compared with pre-immersion control values while in the diabetic group it rose from pre-immersion control values of 112 +/- 11 ml/min to a mean value of 127 +/- 11 ml/min during immersion (P less than 0.01). The diabetic subjects thus excreted less sodium despite an increased filtered load during water immersion. Fractional excretion of sodium was significantly reduced in the diabetic subjects compared with the normal control subjects (P less than 0.05). The suppression of plasma renin and aldosterone was similar in normal and diabetic groups. Tubular sodium retention could be an early functional change in the diabetic kidney, and be implicated in the development of diabetic nephropathy.     

Requirement of intact adenosine A1 receptors for the diuretic and natriuretic action of the methylxanthines theophylline and caffeine

Although the diuretic and natriuretic effects of the methylxanthines caffeine and theophylline are well established, the mechanisms responsible for these effects are unclear and may be related to inhibition of phosphodiesterases and/or antagonism of adenosine receptors. With regard to the latter, pharmacological blockade of A1 receptors can induce diuresis and natriuresis by inhibition of proximal tubular reabsorption. To elucidate the role of the A1 receptor in renal actions of methylxanthines, experiments were performed in A1 receptor knockout (A1R-/-) and littermate wild-type (A1R+/+) mice. Urinary excretion was determined in awake mice in metabolic cages over 3 h in response to theophylline (as theophylline2/ethylenediamine, 45 mg/kg), caffeine (45 mg/kg), or vehicle (0.9 ml/30 g b.wt. of 0.85% NaCl) given by oral gavage. Theophylline and caffeine elicited a diuresis and natriuresis (in absolute terms and related to urinary creatinine excretion) in A1R+/+ but not in A1R-/- mice. In a second series, the renal effect of intravenous application of theophylline (30 mg/kg) was determined in clearance experiments under anesthesia. This study revealed that the blunted diuretic and natriuretic effect of theophylline in A1R-/- mice was not due to different responses in blood pressure or glomerular filtration rate. The data indicate that an intact A1 receptor is necessary for caffeine- and theophylline-induced inhibition of renal reabsorption causing diuresis and natriuresis. This is consistent with the assumption that A1 receptor blockade mediates these effects.     

Cortical effects of anticipation and endogenous modulation of visceral pain assessed by functional brain MRI in irritable bowel syndrome patients and healthy controls

Visceral pain processing is abnormal in a majority of irritable bowel syndrome (IBS) patients. Aberrant endogenous nociceptive modulation and anticipation are possible underlying mechanisms investigated in the current study. Twelve IBS patients and 12 matched healthy controls underwent brain fMRI scanning during the following randomised stimuli: sham and painful rectal distensions by barostat without and with simultaneous activation of endogenous descending nociceptive inhibition using ice water immersion of the foot for heterotopic stimulation. Heterotopic stimulation decreased rectal pain scores from 3.7+/-0.2 to 3.1+/-0.3 (mean+/-SE, scale 0-5) in controls (p<0.01), but not significantly in IBS. Controls differed from IBS patients in showing significantly greater activation bilaterally in the anterior insula, SII and putamen during rectal stimulation alone compared to rectal plus heterotopic stimulation. Greater activation during rectal plus heterotopic versus rectal stimulation was seen bilaterally in SI and the right superior temporal gyrus in controls and in the right inferior lobule and bilaterally in the superior temporal gyrus in IBS. Rectal pain scores were similarly low during sham stimulation in both groups, but brain activation patterns differed. In conclusion, IBS patients showed dysfunctional endogenous inhibition of pain and concomitant aberrant activation of brain areas involved in pain processing and integration. Anticipation of rectal pain was associated with different brain activation patterns in IBS involving multiple interoceptive, homeostatic, associative and emotional areas, even though pain scores were similar during sham distension. The aberrant activation of endogenous pain inhibition appears to involve circuitry relating to anticipation as well as pain processing itself.