In vivo effect of indomethacin to potentiate the renal medullary cyclic AMP response to vasopressin (original) (raw)
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Renal haemodynamic actions of pressor doses of lysine vasopressin in the rat
The Journal of Physiology, 1987
1. Dose-response effects of lysine vasopressin on renal haemodynamics were studied in conscious rats infused with 2-5 % (w/v) dextrose solution at 5'8 ml/h. 2. Lysine vasopressin was maximally antidiuretic in the absence of a significant pressor effect at a dose of 2-5 pmol h-' 100 g body weight-'. Doses of vasopressin greater than this induced a dose-dependent increase in arterial blood pressure. 3. The clearance of p-aminohippurate (PAH) was not significantly changed by vasopressin, even at pressor doses. Rats pre-treated with indomethacin to inhibit prostaglandin synthesis showed a decrease in PAH clearance during the infusion of vasopressin at a dose of 30 pmol h-' 100 g body weight-', and this suggests that the renal vasoconstrictor actions of vasopressin are attenuated by dilator prostaglandins. 4. Inulin clearance was unchanged by non-pressor doses of vasopressin but was decreased in a dose-dependent manner by pressor doses. A maximal effect was induced by a dose of 30 pmol h-' 100 g body weight-' which decreased inulin clearance from 3-23+0-76 (mean+s.E. of mean) to 1-60+0-37 ml/min (P < 0-02). A change in inulin clearance (from 3-42 +0-46 to 2-17 +0-33 ml/min, P < 0-01) was also observed in rats pre-treated with indomethacin and infused with vasopressin at the same dose. The magnitude of the change was not significantly different from that observed in rats which were not treated with indomethacin. 5. Control rats infused with dextrose showed a slight but significant increase in sodium excretion during the course of the experiment. A similar natriuresis was observed in rats infused with non-pressor doses of vasopressin but was considerably enhanced in rats infused with pressor doses of the peptide. The antidiuresis induced by vasopressin remained maximal in rats infused with pressor doses. 6. Potassium and osmolal outputs were unchanged by non-pressor doses of vasopressin but significantly increased during administration of pressor doses. 7. It is concluded that pressor doses of lysine vasopressin do not alter total renal perfusion in conscious rats when the prostaglandin system is intact. Glomerular filtration is, however, decreased in a dose-dependent manner by these amounts but the mechanism is unclear.
Acute Effect of Physiological Concentrations of Vasopressin on Rat Renal Function
Clinical and Experimental Pharmacology and Physiology, 1993
1. The antidiuretic, pressor and electrolyte transport effects of arginine vasopressin (AVP) were simultaneously evaluated in the anaesthetized water diuretic rat. Increasing concentrations of AVP (7.5, 75 and 750 ng/ kg bolus and per h), were used to produce plasma levels which approximate the physiological range (4.8 f2.4,35.7 f 12.5, 85.2f 16.1 pg/mL respectively).
British Journal of Pharmacology, 1998
The potential in¯uences of nitric oxide (NO) and prostaglandins on the renal eects of angiotensin II (Ang II) have been investigated in the captopril-treated anaesthetized rat by examining the eect of indomethacin or the NO synthase inhibitor, N o-nitro-L-arginine methyl ester (L-NAME), on the renal responses obtained during infusion of Ang II directly into the renal circulation. 2 Intrarenal artery (i.r.a.) infusion of Ang II (1 ± 30 ng kg 71 min 71) elicited a dose-dependent decrease in renal vascular conductance (RVC; 738+3% at 30 ng kg 71 min 71 ; P50.01) and increase in ®ltration fraction (FF; +49+8%; P50.05) in the absence of any change in carotid mean arterial blood pressure (MBP). Urine output (Uv), absolute (UNaV) and fractional sodium excretion (FENa), and glomerular ®ltration rate (GFR) were unchanged during infusion of Ang II 1 ± 30 ng kg 71 min 71 (+6+17%, +11+17%, +22+23%, and 75+9%, respectively, at 30 ng kg 71 min 71). At higher doses, Ang II (100 and 300 ng kg 71 min 71) induced further decreases in RVC, but with associated increases in MBP, Uv and UNaV. 3 Pretreatment with indomethacin (10 mg kg 71 i.v.) had no signi®cant eect on basal renal function, or on the Ang II-induced reduction in RVC (725+7% vs 738+3% at Ang II 30 ng kg 71 min 71). In the presence of indomethacin, Ang II tended to cause a dose-dependent decrease in GFR (738+10% at 30 ng kg 71 min 71); however, this eect was not statistically signi®cant (P=0.078) when evaluated over the dose range of 1 ± 30 ng kg 71 min 71 , and was not accompanied by any signi®cant changes in Uv, UNaV or FENa (721+12%, 718+16% and +36+38%, respectively). 4 Pretreatment with L-NAME (10 mg kg 71 min 71 i.v.) tended to reduce basal RVC (control 711.8+1.4, +L-NAME 77.9+1.8 ml min 71 mmHg 71 610 72), and signi®cantly increased basal FF (control +15.9+0.8, +L-NAME +31.0+3.7%). In the presence of L-NAME, renal vasoconstrictor responses to Ang II were not signi®cantly modi®ed (738+3% vs 735+13% at 30 ng kg 71 min 71), but Ang II now induced dose-dependent decreases in GFR, Uv and UNaV (751+11%, 741+14% and 731+17%, respectively, at an infusion rate of Ang II, 30 ng kg 71 min 71). When evaluated over the range of 1 ± 30 ng kg 71 min 71 , the eect of Ang II on GFR and Uv were statistically signi®cant (P50.05), but on UNaV did not quite achieve statistical signi®cance (P=0.066). However, there was no associated change in FENa observed, suggesting a non-tubular site of interaction between Ang II and NO. 5 In contrast to its eects after pretreatment with L-NAME alone, Ang II (1 ± 30 ng kg 71 min 71) failed to reduce renal vascular conductance in rats pretreated with the combination of L-NAME and the selective angiotensin AT 1 receptor antagonist, GR117289 (1 mg kg 71 i.v.). This suggests that the renal vascular eects of Ang II are mediated through AT 1 receptors. Over the same dose range, Ang II also failed to signi®cantly reduce GFR or Uv. 6 In conclusion, the renal haemodynamic eects of Ang II in the rat kidney appear to be modulated by cyclooxygenase-derived prostaglandins and NO. The precise site(s) of such an interaction cannot be determined from the present data, but the data suggest complex interactions at the level of the glomerulus.
Journal of Clinical Investigation - J CLIN INVEST, 1980
of unilateral ureteral obstruiction (UUO) of 24 h duration in rats is followed by severe renal vasoconstriction in the postobstructive kidney (POK). The present study examined possible roles of renal prostaglandins (PG) and thromboxanes (TX), as well as the renin-angiotensin system, in this vasoconstriction. Administration of the cyclooxygenase inhibitor indomethaciin, which blocks both PG and TX production, failed to improve POK hemodynamics in UUO rats. To explore the possible role of the TX compounds, which include the potent vasoconstrictor thromboxane A2 (TXA2), UUO rats were infused with imidazole, an agent that blocks synthesis of TX, but not of PG. Imidazole led to two-to threefold increases in the clearance of both inulin and p-aminohippuric acid by the POK. This effect of imidazole was abolished by indomethacin, suggesting that the amelioration of POK vasoconstriction by imidazole was a result of inhibition of vasoconstrictor TX synthesis (e.g. TXA2), with PG vasodilators (e.g. PGE2 or PGI2) still active. Urea, infused in a solution whose osmolality and voluime were identical to the imidazole infusion, failed to improve hemodynamics in the POK, making it unlikely that nonspecific effects of volume expansion or osmotic diuresis mediated the beneficial effect of imidazole. Further studies examined the possible role of the renin-angiotensin systems in the vasocoinstriction of the POK. UUO rats infused with the angiotensii II Ai al)stract of this work was published in 1978. Clin. Res.
Acta Physiologica Scandinavica, 1999
In preliminary experiments rats preinfused with hypertonic saline showed exaggerated natriuresis after an additional small volume expansion (SVE). This was systematically studied in anaesthetized Wistar rats prepared for clearance studies of the left kidney and measurements of medullary blood flow (MBF, laser-Doppler technique) and tissue electrical admittance (Y ), an index of interstitial ion concentration. The rats were preinfused i.v. with 3 mL of 5% NaCl during 90 min. A subsequent injection of isotonic saline, 0.5% of body weight, increased sodium excretion (U Na V ) from 2.1 0.5 to 4.5 1.1 lmol min ±1 and urine¯ow (V ) from 12.0 2.3 to 24.3 5.6 lL min ±1 (P < 0.02). The same volume of whole blood increased U Na V from 5.0 1.4 to 8.7 1.7 lmol min ±1 and V from 22.3 5.1 to 37.4 5.9 lL min ±1 (P < 0.01). The glomerular ®ltration rate, MBF and Y did not change. In rats preinfused with 0.9% saline no natriuresis was observed after SVE. To examine if prostaglandins (PG) were involved in SVE natriuresis, indomethacin (Indo), 5 mg kg ±1 or sodium meclophenamate (Meclo), 7.5 mg kg ±1 , were added to the injected 0.9% saline. Paradoxically, both PG synthesis inhibitors enhanced natriuresis to SVE. After Indo U Na V increased from 2.0 0.6 to 7.6 1.3 lmol min ±1 , signi®cantly more than after SVE alone (P < 0.001). At higher baseline U Na V, the increase with Meclo from 4.5 1.2 to 13.5 1.8 lmol min ±1 was signi®cantly higher than after whole blood infusion (P < 0.001). MBF decreased and Y increased after both inhibitors. Further studies are required to explain the enhancement of natriuresis after blockade of PG synthesis.
Pfl�gers Archiv European Journal of Physiology, 1975
Blood-perfused isolated dog kidneys demonstrate steady increases in blood flow and in water and sodium excretion which could be attributed to the accumulation of renal prostaglandins in the perfusing blood. This hypothesis was tested by adding indomethacin, a potent inhibitor of prostaglandins synthesis, to the perfusing blood. Indomethacin completely prevented the vasodilation observed in control kidneys, without affecting glomerular filtration rate. Urine volume was not modified but sodium excretion was enhanced while the steady free water clearance increment observed in the control kidneys was depressed by indomethaein. The sum of sodium and free water clearances which, in the absence of antidiuretie hormone, constitutes an index of the part of the filtered load of solutes which escapes proximal tubular reabsorption, was not modified by indomethacin. Finally, indomethaein partially maintained the osmotic cortico-papillary gradient which was abolished after 2 hrs perfusion in control kidneys. These data suggest that prostaglandins accumulation in the blood is probably the major cause of the vasodilation taking place in isolated blood-perfused kidneys. This vasodilation does not account for decreased proximal reabsorption but partially explains the ADH-resistant diabetes insipidus developing in the isolated kidney. l~oreover, indomethacin inhibits sodium reabsorption in the ascending limb of Henle's loop and increases water transport in the collecting duct.
1980
of unilateral ureteral obstruiction (UUO) of 24 h duration in rats is followed by severe renal vasoconstriction in the postobstructive kidney (POK). The present study examined possible roles of renal prostaglandins (PG) and thromboxanes (TX), as well as the renin-angiotensin system, in this vasoconstriction. Administration of the cyclooxygenase inhibitor indomethaciin, which blocks both PG and TX production, failed to improve POK hemodynamics in UUO rats. To explore the possible role of the TX compounds, which include the potent vasoconstrictor thromboxane A2 (TXA2), UUO rats were infused with imidazole, an agent that blocks synthesis of TX, but not of PG. Imidazole led to two-to threefold increases in the clearance of both inulin and p-aminohippuric acid by the POK. This effect of imidazole was abolished by indomethacin, suggesting that the amelioration of POK vasoconstriction by imidazole was a result of inhibition of vasoconstrictor TX synthesis (e.g. TXA2), with PG vasodilators (e.g. PGE2 or PGI2) still active. Urea, infused in a solution whose osmolality and voluime were identical to the imidazole infusion, failed to improve hemodynamics in the POK, making it unlikely that nonspecific effects of volume expansion or osmotic diuresis mediated the beneficial effect of imidazole. Further studies examined the possible role of the renin-angiotensin systems in the vasocoinstriction of the POK. UUO rats infused with the angiotensii II Ai al)stract of this work was published in 1978. Clin. Res.
American journal of physiology. Regulatory, integrative and comparative physiology, 2003
Recent results from our laboratories indicate that renal escape from AVP-induced antidiuresis is accompanied by marked downregulation of kidney aquaporin-2 (AQP2) and AVP V2 receptors. The present studies evaluated the effect of nitric oxide (NO) and PG synthesis blockade on escape from antidiuresis. dDAVP-infused rats were water loaded (WL) for 5 days. l-NAME, an NO synthesis inhibitor, or diclofenac, a cyclooxygenase inhibitor, was infused subcutaneously beginning 1 day before WL. As early as 2 days after WL, urine volume increased and urine osmolality decreased, indicating the onset of escape. Endogenous NO synthesis, measured as urinary NO2 + NO3 excretion, was significantly increased in the WL group compared with the non-WL controls during all 5 days of WL. l-NAME (20 mg. kg(-1). day(-1)) markedly decreased urine volume on days 4 and 5 of WL, indicating inhibition of the escape phenomenon. Kidney AQP2 protein was significantly increased by this dose of l-NAME as well. A lower d...
The Journal of Physiology, 1995
1. Modulation of the cortico-papillary electrolyte gradient by prostaglandins (PG) was studied in the kidney of anaesthetized rats. The intrarenal PG activity was varied by synthesis blockade with indomethacin (Ind) or meclophenamate (Me) and by intrarenal infusion of prostaglandin E2 (PGE2). 2. The intersttial electrolyte concentration in the medulla was continuously recorded in the kidney in situ as tissue electrical admittance (reciprocal impedance); the total renal blood flow (RBF), inulin clearance (Ci.) and renal excretion were measured simultaneously. 3. Indomethacin and Me (15 mg kg-' h-) increased tissue admittance 15-20% in the inner and 12-15% in the outer medulla (P < 0 001) whereas PGE2 (300 ng kg-' min-') decreased admittance 14 and 8%, respectively (P < 0 01). 4. Renal blood flow and Ci. were not affected by intrarenal PG activity changes. There was an increase in urine concentration after PG blockade and a delayed decrease after PGE2 infusion. 5. A joint analysis of the dynamics of medullary tissue admittance, renal haemodynamics and renal excretion provides evidence that PGs modify the medullary ionic hypertonicity by affecting NaCl transport in the ascending limb of the loop of Henle.