Exaggerated prostaglandin and thromboxane synthesis in the rabbit with renal vein constriction (original) (raw)
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Peptide-induced prostaglandin biosynthesis in the renal-vein-constricted kidney
Biochemical Journal, 1981
The ipsilateral kidney was removed from a rabbit 48h after unilateral partial renal-vein-constriction and was perfused with Krebs–Henseleit media at 37°C. Hourly administration of a fixed dose of bradykinin to the renal-vein-constricted kidney demonstrated a marked time-dependent increase in the release of bioassayable prostaglandin E2 and thromboxane A2 into the venous effluent as compared with the response of the contralateral control kidney. The renal-vein-constricted kidney produced up to 60 times more prostaglandin E2 in response to bradykinin after 6h of perfusion as compared with the contralateral kidney; thromboxane A2 was not demonstratable in the contralateral kidney. Inhibition of protein synthesis de novo in the perfused renal-vein-constricted kidney with cycloheximide lessened the hormone-stimulated increase in prostaglandin E2 by 94% and in thromboxane A2 by 90% at 6h of perfusion. Covalent acetylation of the renal cyclo-oxygenase by prior oral administration of aspiri...
Thromboxane mediates renal hemodynamic response to infused angiotensin II
Kidney International, 1991
Thromboxane mediates renal hemodynamic response to infused angiotensin II. Since we had found that angiotensin II (Ang II), but not phenylephrine (PE), increased the excretion of thromboxane (Tx) and raised mean arterial pressure (MAP) by a Tx-dependent mechanism, we tested the role of TxA2 in mediating Ang Il-induced changes in renal hemodynamics. For series 1, groups of anesthetized rats received an i.v. infusion of Ang 11(50 ng kg min'). When infused with a vehicle, Ang II increased MAP, renal vascular resistance (RVR) and the excretion of TxB2 factored by GFR. A PGH2-TxA2 receptor antagonist, SQ-29,548, or three days of pretreatment With a TxA2 synthase inhibitor UK-38,485, which reduced excretion of TxB2 by 80%, blunted the rise in MAP and RVR induced by Ang II. In contrast, three days of pretreatment with indomethacin did not alter the renal vascular response to Ang II. For series 2, groups of rats received Ang II at a higher rate (500 ng. kg min I) while the RPP was stabilized at + 11 to + 15 mm Hg with a suprarenal aortic clamp. SQ-29,548 and UK-38,485 both prevented Ang 11-induced reductions in GFR and blocked 80% of the increase in RVR. For series 3, infusions of phenylephrine at an equipressor dose to series 2 of 30 g kg min with control of RPP at +14 mm Hg also increased RVR but this was not blunted by SQ-29,548. In conclusion: I.) infusion of Ang II increases excretion of filtered TxB2, causes dose-dependent increases in RVR and, at high doses, reduces GFR. 2.) Inhibition of TxA2 synthesis or blockade of PGH2-TxA2 receptors prevents the fall in GFR and blunts 70 to 90% of the increase in RVR. 3,) These effects are independent of RPP, appear to be specific for Ang II, and are counteracted by release of vasodilator cyclooxygenase products. Angiotensin II (Ang II) is a powerful renal vasoconstrictor which, when infused in high doses, can reduce the glomerular filtration rate (GFR). There is evidence in a number of animal models of Ang 11-related hypertension of increased thromboxane A2 (TxA2) generation by the tissues and/or the kidneys and a reduction in blood pressure (BP), or renal vascular resistance (RVR), with drugs which blunt TxA2 generation or which block prostaglandin (PG) H2-TxA2 receptors. These models include the 2-kidney, 1-clip (2K,1C) renovascular rat [1-31, the spontaneously hypertensive rat (SHR) [4-6], the Dahl salt-sensitive rat [7], the Lyon genetically hypertensive rat [8] and the rat model of reduced renal mass [9-11]. Short-or long-term infusions of Ang II into anesthetized or conscious rats increases the renal excretion of TxB2 [12, 13]. Therefore, the present studies were
Circulation Research, 1989
The capacity of small arteries to respond to increased intravascular pressure may be altered in hypertension. In the kidney, hypertension is associated with a compensatory shift in the autoregulatory response to pressure. To directly determine the effects of established hypertension on the renal microvascular response to changes of perfusion pressure, we evaluated pressure-induced vasoconstriction in hydronephrotic kidneys isolated from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Vessel diameters of interlobular arteries (ILAs) and afferent and efferent arterioles were determined by computer-assisted videomicroscopy during alterations in renal arterial pressure (RAP) from 80 to 180 mm Hg. Increased RAP induced a pressure-dependent vasoconstriction in preglomerular vessels (afferent arterioles and ILAs), but not in postglomerular vessels (efferent arterioles). The calcium antagonist nifedipine prevented pressure-induced afferent arteriolar vasoconstrict...
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.
Journal of Clinical Investigation, 1992
8-epi-prostaglandin F2. (8-epi-PGF2.) and related compounds are novel prostanoid produced by a noncyclooxygenase mechanism involving lipid peroxidation. Renal ischemia-reperfusion injury increased urinary excretion of these compounds by 300% over baseline level. Intrarenal arterial infusion at 0.5, 1, and 2 ,gg/kg per min induced dose-dependent reductions in glomerular filtration rate (GFR) and renal plasma flow, with renal function ceasing at the highest dose. Micropuncture measurements (0.5 ,g/kg per min) revealed a predominant increase in afferent resistance, resulting in a decrease in transcapillary hydraulic pressure difference, and leading to reductions in single nephron GFR and plasma flow. These changes were completely abolished or reversed by a TxA2 receptor antagonist, SQ 29,548. Competitive radioligand binding studies demonstrated that 8epi-PGF2. is a potent competitor for I3HISQ 29,548 binding to rat renal arterial smooth muscle cells (RASM) in culture. Furthermore, addition of 8-epi-PGF2, to RASM or isolated glomeruli was not associated with stimulation of arachidonate cyclooxygenase products. Therefore, 8-epi-PGF2, is a potent preglomerular vasoconstrictor acting principally through TxA2 receptor activation. These findings may explain, in part, the beneficial effects of antioxidant therapy and TxA2 antagonism observed in numerous models of renal injury induced by lipid peroxidation.
The American Journal of Cardiology, 1987
The renal hemodynamic response to calcium entry blockade depends on the neural, hormonal and physiologic determinants influencing basal renal vascular tone. The effects of perfusion pressure per se on the renal vascular response of the rat kidney to diltiazem were evaluated using normal kidneys and hydronephrotic kidneys perfused extracorporally. In isolated perfused normal kidneys, diltiazem did not alter perfusate flow or glomerular filtration rate (GFR) when administered at a perfusion pressure of 100 mm Hg. In contrast, when diltiazem was administered at a perfusion pressure of 150 mm Hg, the calcium antagonists caused a striking increase in GFR, which was accompanied by an increase in renal perfusate flow. In the isolated perfused hydronephrotic rat kidney, elevation of perfusion pressure was associated with an increase in renal vascular resistance and a reduction in afferent arteriolar diameter. Diltiazem abolished the pressure-induced constriction of afferent arterioles and caused an increase in renal perfusate flow in hydronephrotic kidneys perfused at pressures above 100 mm Hg. These findings suggest that in the setting of increased renal perfusion pressure, diltiazem's effects on GFR are mediated in part by an inhibition of pressure-induced constriction of the afferent arteriole.
Clinical Science, 1980
1. Renal arterial injection of bolus doses of angiotensin II or noradrenaline, (0.06, 0.12 and 0.25 μg) caused renal vasoconstriction and decreased blood flow to the kidney in a dose-related manner in dogs anaesthetized by sodium pentobarbital. 2. The effect of angiotensin II and noradrenaline in lowering renal blood flow was reduced during renal arterial infusion of either bradykinin (10 ng min−1 kg−1) or prostaglandin E2 (4 ng min−1 kg−1). 3. Pretreatment of the dogs with an inhibitor of prostaglandin synthesis, sodium meclofenamate (5 mg/kg), blunted the inhibitory action of bradykinin, but not that of prostaglandin E2, on renal vascular reactivity to angiotensin II and noradrenaline. 4. These results indicate that bradykinin reduces the renal vasoconstriction induced by angiotensin II and noradrenaline in the dog by a mechanism dependent upon synthesis of prostaglandins.
Adrenergic stimulation of renal prostanoids in the Lyon hypertensive rat
Hypertension, 1991
Young, genetically hypertensive Lyon (LH) rats exhibited an increased renal in vivo turnover of norepinephrine and an elevated urinary excretion of thromboxane B 2 when compared with nonnotensive (LN) and low blood pressure (LL) controls. Therefore, the effects of norepinephrine (1.2 xlO" 8 to 9.6 xlO" 7 M) and of phenylephrine (5xlO~8 to 1.9x10"' M) on renal function and the urinary excretion of prostanoids were assessed in isolated perfused kidneys of 8-week-old LH, LN, and LL rats. In addition, the effects of norepinephrine were assessed before and during thromboxane A 2 /prostaglandin H 2 receptor blockade by AH23848 (4xlO~* M). Before drug infusion, LH kidneys differed from those of LN and LL controls by having an elevated renal vascular resistance and a decreased natriuresis and glomerular filtration rate; the urinary output of prostaglandin E 2 and F^, of 6-ketoprostaglandin F la , and of thromboxane B 2 was similar in the three strains. The constrictor effects of norepinephrine and phenylephrine were significantly increased in LH rat kidneys compared with LL but not with LN controls, and their pressure-natriuresis was markedly reduced. Norepinephrine and phenylephrine induced a 10-to 20-fold dose-dependent increase in the synthesis of the four prostanoids, which was more pronounced in LH than in LN and LL rats for thromboxane B 2 only. AH23848 infusion significantly reduced the vascular effects of norepinephrine and increased the natriuretic response of LH but not of LN and LL rat kidneys. In conclusion, isolated perfused kidneys from LH rats exhibit an increased production of thromboxane A 2 , which enhances the renal effects of norepinephrine and therefore could participate in the development of hypertension of the Lyon model. (Hypertension 1991;17:296-302) W e have previously observed that the urinary excretion of renal thromboxane (Tx) B2, used as an index of the renal synthesis of TxA^1-2 was increased in 5-and 9-week-old genetically hypertensive (LH) rats of the Lyon strain. 3 The same abnormality has also been described in vivo 4 and in vitro 5-6 in spontaneously hypertensive rats (SHR) of the Japanese strain. Because TxA 2 is a potent vasoconstrictor 7 and promotes platelet aggregation, 8 such an increase is likely to play a pathogenic role. This hypothesis is supported by the observation that TxA 2 synthesis inhibition or blockade of TxA 2 receptors delays the onset 9 or reduces 10 the severity of hypertension in SHR and in LH rats. 11 However,