Modulation of renin by thromboxane: studies with thromboxane synthase inhibitor, receptor antagonists, and mimetic

Welch, William J.; Wilcox, Charles S.; Dunbar, K. R.

doi:10.1152/ajprenal.1989.257.4.f554

Cited by 12 publications

(15 citation statements)

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“…This could indicate compensatory activation of other vasoconstrictive signals in TP Ϫ/Ϫ mice. The FF and RVR commonly increase during activation of the renin-angiotensin-aldosterone system, and we reported that inhibition of TP-Rs or TxA 2 synthase increases plasma renin activity (39). However, TP Ϫ/Ϫ mice had a normal level of ANG I and aldosterone and a normal regulation during ANG II infusion.…”

Section: Discussionmentioning

confidence: 88%

“…It is possible that an increased oxidative stress may account for the renal vasoconstriction, but the cause for the oxidative stress is obscure. Rats infused with TP-R antagonists do not have an increase in RVR or FF (37,39,41). Therefore, the increase in RVR and FF in TP Ϫ/Ϫ mice may be a consequence of a developmental defect in these mice.…”

Section: Discussionmentioning

confidence: 99%

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TP receptors regulate renal hemodynamics during angiotensin II slow pressor response

Kawada¹,

Dennehy²,

Solis³

et al. 2004

American Journal of Physiology-Renal Physiology

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/ajprenal. 00423.2003.-We investigated the hypothesis that thromboxane A 2 (TxA2)-prostaglandin H2 receptors (TP-Rs) mediate the hemodynamic responses and increase in reactive oxygen species (ROS) to ANG II (400 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 sc for 14 days) using TP-R knockout (TP Ϫ/Ϫ) and wild-type (ϩ/ϩ) mice. TP Ϫ/Ϫ had normal basal mean arterial blood pressure (MAP) and glomerular filtration rate but reduced renal blood flow and increased filtration fraction (FF) and renal vascular resistance (RVR) and markers of ROS (thiobarbituric acid-reactive substances and 8-isoprostane PGF 2␣) and nitric oxide (NOx). Infusion of ANG II into TP ϩ/ϩ increased ROS and thromboxane B 2 (TxB2) and increased RVR and FF. ANG II infusion into TP Ϫ/Ϫ mice reduced ANG I and increased aldosterone but caused a blunted increase in MAP (TP Ϫ/Ϫ: ϩ6 Ϯ 2 vs. TP ϩ/ϩ: ϩ15 Ϯ 3 mmHg) and failed to increase FF, ROS, or TxB 2 but increased NOx and paradoxically decreased RVR (Ϫ2.1 Ϯ 1.7 vs. ϩ2.6 Ϯ 0.8Blockade of AT1 receptor of TP Ϫ/Ϫ mice infused with ANG II reduced MAP (Ϫ8 mmHg) and aldosterone but did not change the RVR or ROS. In conclusion, during an ANG II slow pressor response, AT 1 receptors activate TP-Rs that generate ROS and prostaglandins but inhibit NO. TP-Rs mediate all of the increase in RVR and FF, part of the increase in MAP, but are not implicated in the suppression of ANG I or increase in aldosterone. TP Ϫ/Ϫ mice have a basal increase in RVR and FF associated with ROS. thromboxane A 2-prostaglandin H2 receptor; isoprostane; hypertension; renal vascular resistance SUBCUTANEOUS ANG II infusion at 400 ng⅐ kg Ϫ1 ⅐min Ϫ1 causes a slow pressor response accompanied by oxygen free radical (O 2 Ϫ ⅐) formation and increased filtration fraction (FF) and renal vascular resistance (RVR). The important role of increased O 2 Ϫ ⅐ formation from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the vasoconstrictor response to ANG II was first showed by Harrison and colleagues (15). We showed later that ANG II increased NADPH oxidase activity in the kidney and the expression of the p22 phox component in the renal afferent arteriole (6, 35). We and others also proposed a significant role for thromboxane A 2 (TxA 2 ) and other ligands for the TxA 2 -PGH 2 receptor (TP-R) in the pressor and renal hemodynamic response to ANG II (17, 18, 20 -22, 40, 42, 43). Under normal conditions, blood pressure (BP) is unaffected by a TxA 2 synthase inhibitor, TP-R blocker, or by TP-R gene knockout (13,28,40). However, during ANG II infusion, there is increased prostaglandin (PG) and TxA 2 generation (19), and blockade of TP-Rs blunts or prevents the pressor response and the increase in RVR (20 -22, 40, 43). However, the conclusion that TP-Rs have a critical role in the response to ANG II depends on the specificity of the drugs used. Therefore, this study was conducted in mice lacking functional TP-Rs by gene deletion.TP-Rs are expressed on systemic blood vessels and renal microvessels, glomeruli, mesangial cells, thick ascending limbs (TALs) of the loops of...

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

TP receptors regulate renal hemodynamics during angiotensin II slow pressor response

Kawada¹,

Dennehy²,

Solis³

et al. 2004

American Journal of Physiology-Renal Physiology

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“…However, Franco et al (17) found that local perfusion of the LH with drugs that block TXA2 synthesis or receptors did not alter the TGF responses. These differences may be explained because endogenous TXA2 was not produced in the perfused LH since this is not a major site of TXA2 synthesis (18 Potentiation ofTGF by U-46,619 is probably not related to renin release inasmuch intravenous infusion of U-46,619 into anesthetized rats reduced plasma renin activity (19). Moreover, even at much higher doses, renal hemodynamic responses to TXA2/PGH2 mimetics are unaffected by angiotensin antagonists (20).…”

Section: Resultsmentioning

confidence: 99%

Potentiation of tubuloglomerular feedback in the rat by thromboxane mimetic. Role of macula densa.

Welch¹,

Wilcox²

1992

J. Clin. Invest.

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Because endogenous thromboxane A2 (TXA2) potentiates the tubuloglomerular feedback response (TGF), we studied the mechanism of action of TXA2 by using a stable TXA2/prostaglandin (PG) H2 mimetic, U46,619. Intravenous infusion of U46,619 at 100 ng * kg-' . min-' reduced the GFR and the single-nephron (SN)GFR measured from the distal tubule (macula densa function intact), whereas the SNGFR measured from the proximal tubule (macula densa function interrupted) was not changed consistently. 10-100-fold higher rates of infusion of U46,619 were required to raise blood pressure or femoral vascular resistance. The regulation of glomerular capillary pressure (PGC) by TGF was assessed in anesthetized rats from changes in proximal stop flow pressure (PSF) and/or SNGFR during perfusion of the loop of Henle (LH) with artificial tubular fluid (ATF). Orthograde loop perfusion and retrograde perfusion of U46,619 into the macula densa segment reduced PSF. Responses to luminal U46,619 were blunted by a TXA2-PGH2 receptor antagonist. Orthograde loop perfusions with luminal U46,619 increased net Cl absorption, whereas coperfusion with furosemide (10-i M) blunted the response to U46,619 by 68%. These data indicated that the luminal U46,619 might increase the signal for TGF activation by increasing Cl reabsorption in macula densa cells. However, since 80±4% of IHIU-46,619 perfused via the LH was reabsorbed, peritubular capillaries (PTC) were perfused with U-46,619 to test additional extra-luminal actions. PTC perfusion with U-46,619 again increased TGF by reducing PSF selectively only while macula densa function was intact during perfusion of the LH with ATF. Conclusions: (a) TGF is potentiated by U46,619 given systemically, via the lumen of the LH by orthograde or retrograde perfusions or via the PTC; (b) at the lower doses tested, reduction of PGC and SNGFR by U46,619 depends on tubular fluid delivery and reabsorption by the macula densa; (c) potentiation ofTGF by U46,619 entails preglomerular vasoconstriction which may be elicited in part by an increased signal due to increased net chloride reabsorption in the LH and presumably macula densa cells and by an increased Parts of this report were presented in abstract form

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“…This result is in accordance with those of Jackson et al, 33 demonstrating that, in dogs, two different TXA 2 synthase inhibitors lowered the renin release induced by decreases in RPP. Conversely, Welch et al 10 reported that TXA 2 synthase inhibition elevated the plasma renin activity in anesthetized rats. However, it must be emphasized that in their experiment, the doses of TXA 2 synthase inhibitors that enhanced plasma renin were threefold higher than those that blocked TXA 2 synthesis.…”

Section: Discussionmentioning

confidence: 97%

“…Because the renin gene polymorphism in LH rats does not appear directly related to the blood pressure level, 8 we thought it of interest to assess the control of renin secretion by one of its major regulatory factors, the renal perfusion pressure (RPP). In addition, since in previous experiments we have shown that kidneys of LH rats synthesized an excess of thromboxane A 2 (TXA 2 ), 9 a vasoconstrictor prostanoid that may be involved in renin secretion, 10 the baroreceptor control of renin secretion was studied before and after blockade of TXA 2 /prostaglandin H 2 (PGH 2 ) receptors. All these experiments were conducted in isolated perfused kidneys from LH rats and its two control strains.…”

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confidence: 99%

Pressure independence of renin release by isolated kidneys of Lyon hypertensive rats.

Medeiros¹,

Vincent²,

Benzoni³

et al. 1992

Hypertension

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In the present work the influence of perfuslon pressure on renal functions and renin release was studied before and after the blockade of thromboxane A 2 /prostaglandin H 2 (TXA 2 /PGH 2 ) receptors using isolated kidneys from 7-week-old genetically hypertensive (LH), nonnotensive (LN), and low blood pressure (LL) rats of the Lyon strain. Kidneys were single pass perfused with Krebs-Henseleit solution with a gelatine derivative (Polygeline) added as an oncotic agent A servocontrolled system stabilized the renal perfusion pressure (RPP) at any chosen (±1 mm Hg) level. In baseline conditions (RPP, 90 mm Hg), LH (n=7) kidneys differed from LN (n=6) and LL (n=8) controls by increased vascular resistance, decreased glomerular filtration rate, and natriuresis. The LH kidney responses to stepwise changes in RPP (between 60 and 170 mm Hg) differed from those of LN and LL rats by a significantly lower perfusion flow, glomerular filtration rate, and natriuresis. Above all, the reduction in RPP, which induced a marked and highly reproducible renin release in LN and LL kidneys, was devoid of effects in LH kidneys. The blockade of TXAJ/PGHJ receptors by AH23848 (4x 10~' M) did not change the baseline (RPP, 90 mm Hg) functions of kidneys of the three strains. During changes in RPP, the responses of LN and LL kidneys were not modified, whereas LH kidneys exhibited significant increases in both glomerular filtration rate and natriuresis. Finally, AH23848 significantly decreased the renin release by kidneys of the three strains. It is concluded that renin release of LH isolated kidneys is independent of the perfusion pressure and that renal TXA 2 /PGH 2 receptor activation participates in the renin release and in the altered functions exhibited by kidneys of LH rats. Several recent experiments using kidney transplantation 12 have emphasized the primary role played by the kidney in the pathogenesis of genetic hypertension. Obviously, among the pressor factors originating in the kidney, the most important is the renin-angiotensin system. In Lyon genetically hypertensive (LH) rats, the plasma renin activity is normal in young animals and low in adult ones. 3 Similar findings have been reported in Japanese spontaneously hypertensive rats (SHR). 4 Despite these low levels of plasma renin, both models are highly sensitive to the blockade of the renin-angiotensin system. 5 -6 This demonstrates that, in genetically hypertensive rats, the low renin levels remain inappropriate and actively contribute to blood pressure elevation.Such an inappropriate renin secretion may reflect a polymorphism of the renin gene, as found in Dahl saJt-sensitive rats, 7 or an abnormal control by its physiological regulators. Because the renin gene polymorphism in LH rats does not appear directly related to the blood pressure level, 8 we thought it of interest to assessFrom the Department of Physiology and Clinical Pharmacology,

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Modulation of renin by thromboxane: studies with thromboxane synthase inhibitor, receptor antagonists, and mimetic

Cited by 12 publications

References 0 publications

TP receptors regulate renal hemodynamics during angiotensin II slow pressor response

TP receptors regulate renal hemodynamics during angiotensin II slow pressor response

Potentiation of tubuloglomerular feedback in the rat by thromboxane mimetic. Role of macula densa.

Pressure independence of renin release by isolated kidneys of Lyon hypertensive rats.

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