Increase In Osmolar Clearance Research Articles

Clonidine-induced increase in osmolar clearance and free water clearance via activation of two distinct alpha 2-adrenoceptor sites.

1. Clonidine, an alpha 2-adrenoceptor agonist, will increase urine flow rate in the anaesthetized rat by increasing both free water and osmolar clearance. In the present study, we investigated whether these effects of clonidine were mediated at two sites which could be distinguished pharmacologically in uninephrectomized male Sprague-Dawley rats. 2. Clonidine (1.0 nmol kg-1 min-1) infused into the renal artery increased osmolar and free water clearance. Following pretreatment with prazosin (0.15 mg kg-1, i.v.), an antagonist with reported selectivity for the alpha 2b-adrenoceptor subtype, the increase in free water but not osmolar clearance was decreased. Pretreatment with the opioid receptor antagonist, naltrexone (3.0 mg kg-1, i.v.) attenuated the increase in osmolar but not free water clearance. This disparate antagonism of clonidine by prazosin and naltrexone was consistent with two distinct sites. 3. We submit the hypothesis that the alpha 2a- and alpha 2b-adrenoceptor subtypes mediated the clonidine-induced osmolar and free water clearance. The blockade in free water clearance by prazosin indicated a possible role of the alpha 2b-adrenoceptor subtype whereas the alpha 2a-adrenoceptor subtype was considered as the site mediating the clonidine-induced increase in osmolar clearance. UK-14,304 (1.0 nmol kg-1 min-1), a mixed alpha 2-adrenoceptor/imidazoline receptor agonist with selectivity for the alpha 2a-subtype increased only osmolar clearance. This increase was blocked by naltrexone but not prazosin pretreatment. The imidazoline receptor was not involved, as naltrexone failed to alter the moxonidine (3.0 nmol kg-1-min-1) induced increase in osmolar clearance. These data suggested to us that the alpha 2a-/alpha 26-subtype hypothesis should be investigated more closely in future studies. 4. These findings indicate that the increase in osmolar and free water clearance following clonidine can be distinguished pharmacologically indicating that two sites were involved. Furthermore, we propose the hypothesis that the alpha 2a-adrenoceptor subtype mediated osmolar clearance whereas the alpha 2b-subtype mediated free water clearance. The prazosin-sensitive increase in free water clearance following clonidine suggested a possible role for the alpha 2b-subtype. The naltrexone-sensitive increase in osmolar clearance following clonidine and UK-14,304 (but not moxonidine) suggested a possible role of the alpha 2a-subtype. Clearly, this postulate requires further study.

Renal I1-Imidazoline Receptor-Selective Compounds Mediate Natnuresis in the Rat

In the present study, we investigated the renal actions of two compounds reported to interact with the imidazoline receptor: rilmenidine (I1-receptor selective, centrally acting antihypertensive) and agmatine (an endogenous clonidine-displacing substance). Rilmenidine (saline vehicle, 3 or 30 nmol/kg/min) or agmatine (saline vehicle, 3 or 30 nmol/kg/min) was infused directly into the renal artery of anesthetized (pentobarbitone) Sprague-Dawley rats (280-300 g) that had undergone a unilateral nephrectomy 7 to 10 days before the experiment. Rilmenidine produced an increase in urine flow rate at doses that failed to significantly alter blood pressure, creatinine clearance, or heart rate. The increase in urine flow rate was secondary to an increase in osmolar clearance, primarily composed of sodium. Free water clearance was not altered at these infusion rates. Agmatine also increased urine flow rate at doses that failed to alter blood pressure, creatinine clearance, and heart rate. The increase in urine flow rate was secondary to an increase in osmolar clearance, again primarily composed of sodium. The natriuretic action of rilmenidine and agmatine, at doses that do not lower blood pressure acutely, could be beneficial in the antihypertensive actions of these centrally acting agents.

Renal imidazoline preferring sites and solute excretion in the rat

1. Moxonidine has been found to have an approximately 600 fold greater affinity for I1 imidazoline preferring sites as compared to alpha 2-adrenoceptors in the rat kidney. The effects of an intrarenal infusion of moxonidine in an anaesthetized rat preparation were investigated and contrasted with the effects previously reported for alpha 2-adrenoceptor stimulation. 2. An intrarenal infusion of moxonidine (1, 3 and 10 nmol kg-1 min-1) produced an increase in urine flow rate and sodium excretion. Moxonidine increased urine volume through an increase in osmolar clearance rather than an increase in free water clearance as previously reported for alpha 2-adrenoceptor stimulation. 3. The effects of moxonidine also appeared to be unique from the effects of alpha 2-adrenoceptor stimulation. An imidazoline preferring site specific blocking dose of idazoxan (0.3 mg kg-1), but not an alpha 2-adrenoceptor specific blocking dose of rauwolscine (0.3 mg kg-1) attenuated the renal effects of moxonidine (3 nmol kg-1 min-1). Moreover, unlike alpha 2-adrenoceptor agonists, the effects of moxonidine were not altered by prior treatment with a V2 vasopressin receptor antagonist. 4. These results indicate differences between stimulation of alpha 2-adrenoceptors and I1 imidazoline preferring sites in the rat kidney and suggest a direct physiological function of renal imidazoline preferring sites.

Potentiation of the natriuretic effect of clonidine following indomethacin in the rat

Previous studies have demonstrated a diuretic effect of clonidine at low intrarenal infusion rates with a natriuretic effect being observed at high infusion rates (greater than or equal to 3 micrograms.kg-1.min-1). The natriuresis at high infusion rates may have been secondary to increased renal prostaglandin production. We therefore evaluated the effects of indomethacin (a cyclooxygenase inhibitor) on the response to clonidine in the anesthetized rat. Intrarenal infusions of saline (vehicle) or clonidine (0.1, 0.3, 1, and 3 micrograms.kg-1.min-1) were examined both in the presence and absence of pretreatment with indomethacin (5 mg/kg, i.p.). Clonidine produced a dose-related increase in urine volume and free water clearance at 0.3, 1, and 3 micrograms.kg-1.min-1 as compared with the vehicle group. Sodium excretion and osmolar excretion were increased only at the highest infusion rate investigated. Following indomethacin pretreatment, clonidine produced a greater increase in urine volume at each infusion rate investigated. The indomethacin pretreatment also resulted in a potentiation of the natriuretic effect of clonidine at all infusion rates. Interestingly, this was associated with an increase in osmolar clearance but not free water clearance. These effects of indomethacin were reversed by infusion of prostaglandin E2. An infusion of prostaglandin E2 attenuated the indomethacin-induced increase in both urine flow rate and sodium excretion, indicating that the effects of indomethacin were mediated by prostaglandin inhibition. These results suggest that endogenous prostaglandin production attenuates the renal effects of clonidine, and as well, that in the presence of alpha 2-adrenoceptor stimulation, prostaglandin E2 mediates an antidiuretic and antinatriuretic effect.

Renal Effects of the Non-Ionic Contrast Medium Iopentol after Intravenous Injection in Healthy Volunteers

Renal effects of the new non-ionic contrast medium iopentol in increasing doses were assessed and compared with the effects of physiologic saline. Twenty-four healthy male volunteers, allocated to three dose groups, were given iopentol intravenously in doses of 0.3, 0.6, and 1.2 g I/kg body weight, respectively. The highest dose group was also given physiologic saline separately as a control. The diuresis increased in all groups, most in the highest dose group, and with a concomitant fall of urine osmolality and increase in osmolar clearance. A slight decrease of serum osmolality, creatinine and urea occurred at 3 hours due to hemodilution. The glomerular filtration rate was unaffected by iopentol. The urinary excretion of albumin and beta 2-microglobulin was unchanged. However, urinary N-acetyl-beta-glucosaminidase and alkaline phosphatase increased significantly, most in the highest dose group. All changes were reversible.

Effects of verapamil alone and with captopril on blood pressure and bilateral renal function in Goldblatt hypertensive rats.

The effects of verapamil infusion alone and superimposed with captopril on arterial pressure and bilateral renal function were evaluated in 21 two-kidney, one-clip Goldblatt hypertensive rats and in 13 control rats. Verapamil significantly decreased arterial pressure of both hypertensive and control rats. Addition of captopril further reduced arterial pressure in hypertensive rats only. There were significant increases in glomerular filtration rate (GFR), urine flow and absolute and fractional excretory rates of sodium and potassium in the non-clipped kidney. In contrast, these renal indices decreased in the clipped kidney. Superimposed captopril during verapamil infusion did not significantly change function of the non-clipped kidney but further depressed function of the clipped kidney. In control rats, no significant change in GFR occurred in response to drugs. Renal excretion of water and sodium, but not potassium, increased after verapamil. However, the diuresis and natriuresis were less pronounced than those seen in the non-clipped kidney of hypertensive rats. There was a proportionate increase in osmolar clearance and free water reabsorption rate in the non-clipped kidney and the normal kidney. The linear relationship did not change after verapamil infusion. The results suggest that verapamil enhances the excretory function of the non-clipped kidney of Goldblatt hypertensive rats via increased GFR and decreased tubular reabsorption in the proximal and/or distal tubules despite its hypotensive action.

Site of renal action of xipamide

Xipamide, hydrochlorothiazide, and furosemide were given to normal volunteers on a double-blind basis. During maximal water diuresis, there was a reduction in free water clearance and an increase in osmolar clearance after administration of xipamide and hydrochlorothiazide, but not in the case of furosemide. During maximal hydropenia, both xipamide and hydrochlorothiazide increased free water reabosorption in a linear relationship to osmolar clearance, while furosemide increased osmolar clearance with little change in free water reabsorption. It was concluded, therefore, that, as with hydrochlorothiazide, the site of action of xipamide was on the distal convoluted tubule, and that of furosemide on the loop of Henle.

A bilateral antidiuresis to renal artery infusion of prostaglandin E1 in dogs treated with phenylbutazone.

1. In acute experiments, high levels of endogenous prostaglandins, provoked by operative stress, could obscure or alter the actions of infused prostaglandins on the kidney. For this reason we decided to compare the effects of infusing prostaglandin E(1) into the renal artery of the dog before and after the administration of phenylbutazone, a prostaglandin synthetase inhibitor.2. Infusion of prostaglandin E(1) into the left renal artery of the pre-phenylbutazone treated dog undergoing a mannitol diuresis increased renal plasma flow, glomerular filtration rate and the excretion of salt and water. The findings are in general agreement with those reported by others.3. Following phenylbutazone administration the vascular and saluretic actions of prostaglandin E(1) were unchanged but a reduced diuretic effect was observed. The response to a low dose of prostaglandin E(1) (0.05 mug/min) was reduced from 1.46 +/- 0.15 to 0.96 +/- 0.16 ml./min (P < 0.001) and the response to a high dose (0.5 mug/min) from 1.82 +/- 0.19 to 0.99 +/- 0.31 ml./min (P < 0.002).4. A significantly less dilute urine was excreted during prostaglandin infusion in the dog after phenylbutazone treatment than before. The reduction in the diuretic response was of the same order as the decrease in the free water clearance response, while the increase in osmolar clearance was unchanged.5. In water-loaded dogs treated with phenylbutazone, infusion of prostaglandin E(1) into the left renal artery had a biphasic effect on urine output from the left kidney. An initial diuretic response to a low dose of prostaglandin E(1) disappeared with the infusion of higher doses, and antidiuresis developed in the immediate post-infusion period.6. As prostaglandin was infused into the left kidney progressive antidiuresis was seen in the non-infused right kidney.7. It is concluded that endogenous prostaglandins do not obscure or alter the vascular and saluretic actions of intrarenal prostaglandin E(1). The findings question the proposed link between the vascular and saluretic actions of this compound.8. It is suggested that the reduced diuretic effect of prostaglandin E(1) in series no. 1, and the antidiuresis in the water-loaded dogs, are caused by the release of endogenous ADH. It is further suggested that phenylbutazone unmasks this release by removing the endogenous prostaglandins. If these deductions are correct, the findings support the anti-ADH role assigned to endogenous prostaglandins by Anderson, Berl, McDonald & Schrier (1975).

Mode of Action of Ethacrynic Acid in Congestive Heart Failure

The renal response to a single intravenous dose of ethacrynic acid was evaluated in ten patients with cardiac decompensation. Following infusion of the drug, a prompt increase in urine flow occurred lasting for approximately two hours. During this diuresis, renal function studies disclosed a fall in tubular reabsorption of water, sodium and chloride, and an increase in osmolar clearance. These findings are compatible with a blockade of coupled sodium chloride reabsorption in either the ascending loop of Henle or early distal tubule or both, but do not exclude a redistribution of intrarenal blood flow as contributing significantly to ethacrynic acid's mode of action. Distal tubular exchange between sodium and potassium-hydrogen does not seem to be affected by this diuretic.