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H M Siragy

Publications and source records attributed to H M Siragy.

At least 37 records · Page 2Linked to original sources
PubMed1999

Angiotensin II and nitric oxide: a question of balance.

The vasoconstrictor peptide angiotensin II (Ang II) and the endogenous vasodilator nitric oxide (NO) have many antagonistic effects, as well as influencing each other's production and functioning. In the short-term, Ang II stimulates NO release, thus modulating the vasoconstrictor actions of the peptide. In the long-term, Ang II influences the expression of all three NO synthase (NOS) isoforms, while NO downregulates the Ang II Type I (AT1) receptor, contributing to the protective role of NO in the vasculature. Within the cardiovascular system, Ang II and NO also have antagonistic effects on vascular remodeling and apoptosis. In the kidney, the distribution of the NOS isoforms coincides with the sites of the components of the renin-angiotensin system. NO influences renin secretion from the kidney, and NO-Ang II interactions are important in the control of glomerular and tubular function. In the adrenal gland, NO has been shown to affect Ang II-induced aldosterone synthesis, while in the brain NO appears to influence Ang II-induced drinking behavior, although conflicting data have been reported. In this review, we focus on the diverse ways in which Ang II and NO interact, and on the importance of maintaining a balance between these two important mediators.

Adrenal Glands↗
PubMed1999

Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor.

The vast majority of the known biological effects of the renin-angiotensin system are mediated by the type-1 (AT1) receptor, and the functions of the type-2 (AT2) receptor are largely unknown. We investigated the role of the AT2 receptor in the vascular and renal responses to physiological increases in angiotensin II (ANG II) in mice with targeted deletion of the AT2 receptor gene. Mice lacking the AT2 receptor (AT2-null mice) had slightly elevated systolic blood pressure (SBP) compared with that of wild-type (WT) control mice (P < 0.0001). In AT2-null mice, infusion of ANG II (4 pmol/kg/min) for 7 days produced a marked and sustained increase in SBP [from 116 +/- 0.5 to 208 +/- 1 mmHg (P < 0.0001) (1 mmHg = 133 Pa)] and reduction in urinary sodium excretion (UNaV) [from 0.6 +/- 0.01 to 0.05 +/- 0.002 mM/day (P < 0.0001)] whereas neither SBP nor UNaV changed in WT mice. AT2-null mice had low basal levels of renal interstitial fluid bradykinin (BK), and cyclic guanosine 3', 5'-monophosphate, an index of nitric oxide production, compared with WT mice. In WT mice, dietary sodium restriction or ANG II infusion increased renal interstitial fluid BK, and cyclic guanosine 3', 5'-monophosphate by approximately 4-fold (P < 0.0001) whereas no changes were observed in AT2-null mice. These results demonstrate that the AT2 receptor is necessary for normal physiological responses of BK and nitric oxide to ANG II. Absence of the AT2 receptor leads to vascular and renal hypersensitivity to ANG II, including sustained antinatriuresis and hypertension. These results strongly suggest that the AT2 receptor plays a counterregulatory protective role mediated via BK and nitric oxide against the antinatriuretic and pressor actions of ANG II.

Angiotensin II↗
PubMed1999

Mechanism of action of angiotensin-receptor blocking agents.

Angiotensin II is the most active hormone of the renin-angiotensin system. In humans, two angiotensin receptors have been identified: AT(1) and AT(2). In adults, most of the effects of angiotensin II are mediated by the AT(1) receptor; the function of the AT(2) receptor is not yet well established. Angiotensin II has both systemic and local paracrine effects. Increased activity of angiotensin II and stimulation of the AT(1) receptor have been linked to the development of several cardiovascular and renal diseases, including hypertension, heart failure, left ventricular hypertrophy, and diabetic nephropathy. Over the past two decades, angiotensin-converting enzymes have been used to manage these diseases. However, the side effects and less-than- maximum therapeutic effects of angiotensin-converting enzyme inhibitors, particularly in the decrease of mortality associated with congestive heart failure, have led to the development of AT(1)-receptor blockers.

Angiotensin Receptor Antagonists↗
PubMed1999

Differential regulation of renal angiotensin subtype AT1A and AT2 receptor protein in rats with angiotensin-dependent hypertension.

-This study was designed to investigate distribution and regulation of the renal AT1A and AT2 subtype receptors in rats with either systemic angiotensin II (Ang II)-induced hypertension or acute phase renal hypertension (2-kidney, 1-clip [2K1C] or 2-kidney, 1-figure-of-8-wrap [2K1W]). In normal rat kidneys, positive immunostaining for the AT1A receptor was observed in the intrarenal vasculature, glomeruli, proximal and distal tubules, and collecting ducts. The AT2 receptor was localized mainly to the glomeruli. The AT1A but not AT2 receptor protein expression was significantly reduced in rats with 10-day systemic Ang II-induced hypertension. In both 7-day 2K1C and 3-day 2K1W rats, the AT1A receptor was significantly reduced in ischemic and contralateral kidneys compared with sham-operated control rats. Reduction in AT2 receptor expression was observed only in the ischemic kidneys in 2K1C and 2K1W renal hypertensive rats. These results demonstrate that the AT1A receptor is widely distributed in the glomerulus and all other nephron segments of the rat kidney. Renal AT1A but not AT2 receptor protein is downregulated in rats with Ang II-induced hypertension. In renal hypertensive rats, the AT1A receptor is bilaterally downregulated and the AT2 receptor is downregulated only in the ischemic kidney.

Acute Disease↗
PubMed1999

Protective role of the angiotensin AT2 receptor in a renal wrap hypertension model.

We evaluated the role of the renal angiotensin II type 2 (AT2) receptor in blood pressure regulation in rats with 2-kidney, 1 figure-8 wrap (Grollman) hypertension. Renal wrapping increased systolic blood pressure (SBP). Renal interstitial fluid (RIF) bradykinin (BK), nitric oxide end-products (NOX), and cGMP were higher in the contralateral intact kidney than in the wrapped kidney. In rats with Grollman hypertension, losartan normalized SBP and increased renal function, RIF BK, NOX, and cGMP only in contralateral kidneys. In contrast, PD 123319, a specific AT2-receptor antagonist, significantly increased SBP and decreased RIF BK, NOX, and cGMP in both kidneys. Combined administration of losartan and PD 123319 prevented the decrease in SBP and the increase in RIF BK, NOX, and cGMP levels observed with losartan alone. BK-receptor blockade caused a significant increase in RIF BK and a decrease in RIF NOX and cGMP in both kidneys similar to that observed during administration of PD 123319. In rats that underwent sham operation, RIF BK increased in response to angiotensin II, an effect that was blocked by PD 123319. These data demonstrate that angiotensin II mediates renal production of BK, which, in turn, releases nitric oxide and cGMP via stimulation of AT2 receptors. The increase in blood pressure and the decrease in renal BK, nitric oxide, and cGMP during AT2-receptor blockade suggests that the AT2 receptor mediates counterregulatory vasodilation in Grollman hypertension and prevents a further increase in blood pressure.

Analysis of Variance↗
PubMed1999

Compartmentalization of extracellular cGMP determines absorptive or secretory responses in the rat jejunum.

We examined potential mechanisms by which angiotensin subtype-2 (AT2) receptor stimulation induces net fluid absorption and serosal guanosine cyclic 3',5'-monophosphate (cGMP) formation in the rat jejunum. L-arginine (L-ARG) given intravenously or interstitially enhanced net fluid absorption and cGMP formation, which were completely blocked by the nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine methylester (L-NAME), but not by the specific AT2 receptor antagonist, PD-123319 (PD). Dietary sodium restriction also increased jejunal interstitial fluid cGMP and fluid absorption. Both could be blocked by PD or L-NAME, suggesting that the effects of sodium restriction occur via ANG II at the AT2 receptor. L-ARG-stimulated fluid absorption was blocked by the soluble guanylyl cyclase inhibitor 1-H-[1,2,4]oxadiazolo[4, 2-alpha]quinoxalin-1-one (ODQ). Cyclic GMP-specific phosphodiesterase in the interstitial space decreased extracellular cGMP content and prevented the absorptive effects of L-ARG. Angiotensin II (ANG II) caused an increase in net Na+ and Cl- ion absorption and 22Na+ unidirectional efflux (absorption) from the jejunal loop. In contrast, intraluminal heat-stable enterotoxin of Escherichia coli (STa) increased loop cGMP and fluid secretion that were not blocked by either L-NAME or ODQ. These findings suggest that ANG II acts at the serosal side via AT2 receptors to stimulate cGMP production via soluble guanylyl cyclase activation and absorption through the generation of NO, but that mucosal STa activation of particulate guanylyl cyclase causes secretion independently of NO, thus demonstrating the opposite effects of cGMP in the mucosal and serosal compartments of the jejunum.

Angiotensin II↗
PubMed1999

Increased renal vasodilator prostanoids prevent hypertension in mice lacking the angiotensin subtype-2 receptor.

The angiotensin subtype-1 (AT(1)) receptor mediates renal prostaglandin E(2) (PGE(2)) production, and pharmacological blockade of the angiotensin subtype-2 (AT(2)) receptor potentiates the action of angiotensin II (Ang II) to increase PGE(2) levels. We investigated the role of the AT(2) receptor in prostaglandin metabolism in mice with targeted deletion of the AT(2) receptor gene. Mice lacking the AT(2) receptor (AT(2)-null) had normal blood pressure that was slightly elevated compared with that of wild-type (WT) control mice. AT(2)-null mice had higher renal interstitial fluid (RIF) 6-keto-PGF(1alpha) (a stable hydrolysis product of prostacyclin [PGI(2)]) and PGE(2) levels than did WT mice, and had similar increases in PGE(2) and 6-keto-PGF(1alpha) in response to dietary sodium restriction and Ang II infusion. In contrast, AT(2)-null mice had lower PGF(2alpha) levels compared with WT mice during basal conditions and in response to dietary sodium restriction or infusion of Ang II. RIF cAMP was markedly higher in AT(2)-null mice than in WT mice, both during basal conditions and during sodium restriction or Ang II infusion. AT(1) receptor blockade with losartan decreased PGE(2), PGI(2), and cAMP to levels observed in WT mice. To determine whether increased vasodilator prostanoids prevented hypertension in AT(2)-null mice, we treated AT(2)-null and WT mice with indomethacin for 14 days. PGI(2), PGE(2), and cAMP were markedly decreased in both WT and AT(2)-null mice. Blood pressure increased to hypertensive levels in AT(2)-null mice but was unchanged in WT. These results demonstrate that in the absence of the AT(2) receptor, increased vasodilator prostanoids protect against the development of hypertension.

Angiotensin II↗
PubMed1998

Regulation of jejunal sodium and water absorption by angiotensin subtype receptors.

The purpose of this study was to determine the precise role of angiotensin subtype-1 (AT1) and -2 (AT2) receptors and the mechanisms by which they act to alter fluid transport in the rat jejunum. In rats on normal sodium intake, ANG II at low dose stimulated net jejunal fluid absorption, whereas at a high dose the peptide inhibited absorption. Low-dose ANG II-stimulated fluid absorption was blocked completely by the specific AT2 receptor antagonist PD-123319 (PD) but was unchanged by the AT1 receptor antagonist losartan (Los). The AT2 receptor agonist CGP-42112A, caused an inversely dose-dependent increase in fluid absorption, which also was totally prevented by PD but was unaltered by Los. Conversely, high-dose ANG II inhibition of absorption was blocked by Los but not by PD. In animals receiving normal sodium intake, neither Los nor PD alone altered fluid absorption. In sodium-restricted animals, however, Los alone increased absorption and PD alone inhibited absorption. In rats on normal sodium intake, low-dose ANG II increased jejunal interstitial and luminal (loop) fluid concentrations of cGMP. These increases in cGMP were blocked with PD but not with Los. 8-Bromoguanosine-3',5'-cyclic monophosphate administered via the mesenteric artery or the submucosal interstitial space markedly increased absorption, but it inhibited absorption when administered into the loop. High-dose ANG II decreased jejunal interstitial and loop fluid cAMP and increased PGE2. The increase in PGE2 was blocked by Los but not by PD. The data demonstrate that ANG II mediates jejunal sodium and water absorption by an action at the AT2 receptor involving cGMP formation. The data also show that ANG II inhibits absorption via the AT1 receptor by a mechanism that is both negatively coupled to cAMP and increases jejunal PGE2 production.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1998

Action of angiotensin receptor subtypes on the renal tubules and vasculature: implications for volume homeostasis and atherosclerosis.

Angiotensin-II (ANG-II) is a potent endocrine and paracrine hormone that functions in humans through two distinct G-protein-coupled transmembrane receptor subtypes (AT-1 and AT-2). ANG-II is found in nearly all tissues of the body including the brain, heart, kidneys, gonads, and gastrointestinal tract. Just as it is found in nearly every organ system of the body, so is it involved in an array of physiologic processes from fetal development to blood pressure control. ANG-II regulates blood pressure by controlling sodium reabsorption in the proximal tubule, altering the glomerular filtration rate and renal blood flow, and by modifying the production and release of aldosterone in the adrenal gland. Additionally, ANG-II is involved in several pathologic processes including the development of hypertension, cardiomyopathy, atherosclerosis, and diabetic nephropathy. It is able to exert influences in these widely varying processes by working together with multiple different second messenger systems including the MAP kinase pathway, nitric oxide production, and phospholipase C and D, and several arachidonic acid metabolites. This paper is a review of the current knowledge of ANG-II and its receptors in health and disease.

Animals↗
PubMed1998

Immunolocalization of subtype 2 angiotensin II (AT2) receptor protein in rat heart.

Angiotensin II exerts its effects on cardiovascular function and water and sodium homeostasis by interacting with plasma membrane receptors on target organs. The existence of subtype 2 angiotensin II (AT2) receptors in the rat heart has been demonstrated by ligand binding and reverse transcription-polymerase chain reaction. In the present study, the expression and localization of AT2 receptor protein in the rat heart was investigated using an antipeptide polyclonal antibody against the native rat AT2 receptor by light microscopic immunocytochemistry and Western blot analysis. In frozen tissue sections, positive immunostaining was observed in the myocardium and coronary vessels throughout the ventricle and atrium of neonatal and young rat hearts. Coronary vessels of the neonatal heart were more intensely stained compared with the surrounding myocardium. Positive immunoreactivity in the coronary vessels of young rats was localized to vascular endothelium but not in the smooth muscle cells. Preadsorption controls were all negative. Western blot analysis showed that the AT2 receptor protein (approximately 44 kDa) was detectable from the AT2 receptor-transfected COS-7 cells and neonatal rat cardiac myocytes but not from fibroblasts or young rat aortic smooth muscle cells. The neonatal rat heart expressed significantly more AT2 receptors than young rat heart. These data provide the first direct evidence for the expression and localization of AT2 receptor protein in the rat heart.

Angiotensin II↗
PubMed1997

The subtype 2 (AT2) angiotensin receptor mediates renal production of nitric oxide in conscious rats.

The angiotensin AT2 receptor modulates renal production of cyclic guanosine 3',5'-monophosphate (cGMP; J. Clin. Invest. 1996. 97:1978-1982). In the present study, we hypothesized that angiotensin II (Ang II) acts at the AT2 receptor to stimulate renal production of nitric oxide leading to the previously observed increase in cGMP. Using a microdialysis technique, we monitored changes in renal interstitial fluid (RIF) cGMP in response to intravenous infusion of the AT2 receptor antagonist PD 123319 (PD), the AT1 receptor antagonist Losartan, the nitric oxide synthase (NOS) inhibitor nitro--arginine-methyl-ester (-NAME), the specific neural NOS inhibitor 7-nitroindazole (7-NI), or Ang II individually or combined in conscious rats during low or normal sodium balance. Sodium depletion significantly increased RIF cGMP. During sodium depletion, both PD and -NAME caused a similar decrease in RIF cGMP. Combined administration of PD and -NAME decreased RIF cGMP to levels observed with PD or -NAME alone or during normal sodium intake. During normal sodium intake, Ang II caused a twofold increase in RIF cGMP. Neither PD nor -NAME, individually or combined, changed RIF cGMP. Combined administration of Ang II and either PD or -NAME produced a significant decrease in RIF cGMP compared with that induced by Ang II alone. Combined administration of Ang II, PD, and -NAME blocked the increase in RIF cGMP produced by Ang II alone. During sodium depletion, 7-NI decreased RIF cGMP, but the reduction of cGMP in response to PD alone or PD combined with 7-NI was greater than with 7-NI alone. During normal sodium intake, 7-NI blocked the Ang II-induced increase in RIF cGMP. PD alone or combined with 7-NI produced a greater inhibition of cGMP than did 7-NI alone. During sodium depletion, 7-NI (partially) and -NAME (completely) inhibited RIF cGMP responses to -arginine. These data demonstrate that activation of the renin- angiotensin system during sodium depletion increases renal nitric oxide production through stimulation by Ang II at the angiotensin AT2 receptor. This response is partially mediated by neural NOS, but other NOS isoforms also contribute to nitric oxide production by this pathway.

Angiotensin II↗
PubMed1997

The subtype 2 angiotensin receptor regulates renal prostaglandin F2 alpha formation in conscious rats.

The angiotensin AT1 receptor mediates renal prostaglandin (PG) E2 production through stimulation of phospholipase A2. Blockade of the AT2 receptor potentiates the angiotensin II-induced increase in PGE2 levels. In the kidney, PGE2 is converted to PGF2 alpha mainly by the enzyme PGE 9-ketoreductase. We hypothesized that the conversion of PGE2 to PGF2 alpha is inhibited by AT2 receptor blockade, resulting in the observed increase in PGE2 levels. Using a microdialysis technique, we monitored changes in renal interstitial fluid PGE2 and PGF2 alpha in response to 5 days of sodium depletion alone or a combination of sodium depletion and intravenous infusion of the AT1 receptor blocker losartan or the AT2 receptor blocker PD-123319 in conscious rats. We utilized the PGF2 alpha-to-PGE2 ratio as an indirect measure of the rate of renal PGF2 alpha formation. Sodium depletion increased PGE2, PGF2 alpha, and the PGF2 alpha-to-PGE2 ratio. During sodium depletion, losartan decreased PGE2 and PGF2 alpha and did not change the PGF2 alpha-to-PGE2 ratio. In contrast, PD-123319 increased PGE2, decreased PGF2 alpha, and decreased the PGF2 alpha-to-PGE2 ratio. These data demonstrate that activation of the renin-angiotensin system during sodium depletion physiologically increases renal conversion of PGE2 to PGF2 alpha. The increase in renal production of PGF2 alpha is mediated through stimulation of the angiotensin AT2 receptor.

Angiotensin II↗
PubMed1997

Intrarenal dopamine production and distribution in the rat. Physiological control of sodium excretion.

Dopamine (DA), produced by the renal proximal tubule, has been demonstrated as an intrarenal paracrine hormone mediating diuresis and natriuresis. The precise mechanism by which DA exerts its cell-to-cell action is not fully understood. In the present study, renal interstitial fluid (RIF) DA (by in vivo microdialysis) and urinary DA excretion (UDAV) were compared in anesthetized rats on either normal (0.28% NaCI, NS) or high (4.0% NaCI, HS) sodium balance and in response to acute gamma-L-glutamyl-L-dopa (gludopa) administration. Urine flow (UV) and sodium excretion (UNaV) in HS were greater than in NS rats. UDAV was increased in HS compared with NS rats. RIF DA was significantly lower in HS than NS rats. Gludopa at 3, 5, and 7.5 nmol/kg (IV bolus) produced a larger increase in UDAV than RIF DA. Only the highest dose of gludopa (7.5 nmol/kg), which resulted in a 7.3-fold increase in UDAV and 1.7-fold increase in RIF DA, was associated with significant diuresis and natriuresis. Cortical and medullary blood flow remained unchanged after gludopa (7.5 nmol/kg) administration, while angiotensin II (100 ng.kg-1.min-1) induced significant reduction in cortical and medullary blood flow. Prior bilateral renal denervation did not have a significant effect on basal DA levels (RIF DA and UDAV) or gludopa-induced DA production or natriuresis and diuresis. These data demonstrated that both chronic sodium loading and acute gludopa administration stimulated renal DA production and release predominantly into the tubule lumen, where DA had a direct tubule action in the control of UNaV. Renal DA production and its renal effects were not significantly regulated by renal sympathetic nerve activity.

Animals↗
PubMed1997

Bradykinin B2 receptor modulates renal prostaglandin E2 and nitric oxide.

Bradykinin and lys-bradykinin generated intrarenally appear to be important renal paracrine hormones. However, the renal effects of endogenously generated bradykinin are still not clearly defined. In this study, we measured acute changes in renal excretory and hemodynamic functions and renal cortical interstitial fluid levels of bradykinin, prostaglandin E2, and cGMP in response to an acute intrarenal arterial infusion of the bradykinin B2 receptor antagonist Hoe 140 (icatibant), cyclooxygenase inhibitor indomethacin, or nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) given individually or combined in uninephrectomized, conscious dogs (n=10) in low sodium balance. Icatibant caused a significant decrease in urine flow, urinary sodium excretion, and renal plasma flow rate (each P<.001). Glomerular filtration rate did not change during icatibant administration. Icatibant produced an unexpected large increase in renal interstitial fluid bradykinin (P<.0001) while decreasing renal interstitial fluid prostaglandin E2 and cGMP (each P<.001). Both indomethacin and L-NMMA when given individually caused significant antidiuresis and antinatriuresis and decreased renal blood flow (each P<.001). Glomerular filtration rate decreased during L-NMMA administration (P<.001) and did not change during indomethacin administration. Combined administration of icatibant and indomethacin or L-NMMA caused significant decreases in renal excretory and hemodynamic functions, which were not different from changes observed with icatibant alone. The failure of icatibant to change renal function after inhibition of cyclooxygenase and nitric oxide synthase activity suggests that the effects of kinin B2 receptor are mediated by intrarenal prostaglandin E2 and nitric oxide generation. The increase in renal interstitial fluid bradykinin during icatibant requires further study of possible alterations in kinin synthesis, degradation, or clearance as a result of B2 receptor blockade.

Animals↗
PubMed1997

Expression of the subtype 2 angiotensin (AT2) receptor protein in rat kidney.

In situ hybridization studies have suggested that the subtype 2 angiotensin (AT2) receptor gene is expressed in fetal and newborn rat kidney but is undetectable in the adult animals. In the present study, we investigated the expression of AT2 receptor protein in the fetal (days 14 and 19 of fetal life), newborn (day 1 postpartum), and adult (4-week-old and 3-month-old) rat kidney. Polyclonal anti-peptide antiserum was raised against the amino terminus of the native AT2 receptor. The selectivity of the antiserum was validated by recognition of the AT2 receptor in a stably transfected COS-7 cell line by Western blot and immunocytochemical analysis. As a positive control, the AT2 receptor signal was detected strongly in the adrenal gland. Positive immunohistochemical staining was observed in the mesenchymal cells and ureteric buds of the 14-day fetal kidney and in the glomeruli, tubules, and vessels in the 19-day fetal and newborn kidney. Glomeruli expressing the AT2 receptor were localized mainly in the outer layer of the renal cortex. In the young (4-week-old) and mature (3-month-old) adult rat on normal sodium intake, renal AT2 receptor immunoreactivity was present in glomeruli but substantially diminished compared with that of newborn rats. In both young and mature adult rats, dietary sodium depletion increased the renal AT2 receptor signal, mainly in the glomeruli and interstitial cells. Preimmune and preadsorption controls were negative. Western blot analysis detected a single 44-kD band in the fetal and newborn rat kidney and in the young and mature adult rat kidney. Dietary sodium depletion increased the density of the AT2 receptor band in mature adult rat kidneys. These data provide evidence that the AT2 receptor protein is expressed in the fetal and newborn rat kidney, diminishes in adult life, and is reexpressed in the adult in response to sodium depletion.

Adrenal Glands↗
PubMed1996

The subtype-2 (AT2) angiotensin receptor regulates renal cyclic guanosine 3', 5'-monophosphate and AT1 receptor-mediated prostaglandin E2 production in conscious rats.

The renal effects of angiotensin II(AII) are attributed to AT1 receptors. In contrast, the function of renal AT2 receptors in unknown. Using a microdialysis technique, we monitored changes in renal interstitial fluid (RIF) prostaglandin E2 (PGE2) and cyclic guanosine 3', 5'-monophosphate (cGMP) in response to dietary sodium (Na) depletion alone, or Na depletion or normal Na diet combined with the AT1 receptor blocker, Losartan, the AT2 receptor blocker, PD 123319 (PD), or angiotensin II, individually or combined in conscious rats. Na depletion significantly increased PGE2 and cGMP. During Na depletion, Losartan decreased PGE2 and did not change cGMP. In contrast, PD significantly increased PGE2 and decreased cGMP. Combined administration of Losartan and PD decreased PGE2 and cGMP. During normal Na diet, RIF PGE2 and cGMP increased in response to angiotensin II. Neither Losartan nor PD, individually or combined, changed RIF PGE2 or cGMP. Combined administration of angiotensin II and Losartan or PD produced a significant decrease in response of PGE2 and cGMP to angiotensin II, respectively. These data demonstrate that activation of the reninangiotensin system during Na depletion increases renal interstitial PGE2 and cGMP. The AT1 receptor mediates renal production of PGE2. The AT2 receptor mediates cGMP. AT2 blockade potentiates angiotensin-induced PGE2 production at the AT1 receptor.

Analysis of Variance↗
PubMed1996

Renin-angiotensin system modulates renal bradykinin production.

Previous studies have shown that sodium depletion is associated with an increase in renal kallikrein-kinin system activity. This system may play an important role in counterbalancing the renal effects of the renin-angiotensin system. In this study, we examined whether the renal renin-angiotensin system participates in the regulation of renal bradykinin (BK) levels during sodium depletion. We measured changes in renal excretory and hemodynamic function, renal interstitial fluid (RIF) BK, and RIF and urinary guanosine 3',5'-cyclic monophosphate (cGMP) and prostaglandin E2 (PGE2) in conscious uninephrectomized dogs (n = 5) in sodium metabolic balance (10 meq/day) in response to intrarenal arterial administration of the renin inhibitor ACRIP (0.2 microgram.kg-1.min-1) or angiotensin II AT1-receptor blocker losartan (100 ng.kg-1.min-1). ACRIP and losartan increased urine flow rate from 0.75 +/- 0.06 to 1.6 +/- 0.03 and 1.5 +/- 0.05 ml/min, respectively (each P < 0.001), and urine sodium excretion from 5.4 +/- 0.7 to 18.3 +/- 1.3 and 15.9 +/- 1.2 meq/min, respectively (each P < 0.001). Glomerular filtration rate and renal plasma flow increased only during losartan administration (P < 0.05). ACRIP decreased RIF BK by 48%, from 33.1 +/- 3.8 to 17.4 +/- 4.1 pg/min (P < 0.01). ACRIP decreased RIF cGMP by 38%, from 0.69 +/- 0.08 to 0.43 +/- 0.1 pmol/min (P < 0.01); urinary cGMP by 16%, from 0.63 +/- 0.05 to 0.53 +/- 0.02 pmol/min (P < 0.05); and RIF PGE2 by 46%, from 10.5 +/- 1.1 to 5.7 +/- 1.1 pg/min (P < 0.01). Urinary PGE2 was unchanged by ACRIP. Losartan decreased RIF PGE2 by 71%, from 10.8 +/- 0.6 to 3.1 +/- 0.6 pg/min (P < 0.01) but failed to change RIF BK, RIF cGMP, urinary cGMP, or urinary PGE2. These data suggest that the renin-angiotensin system tonically stimulates renal BK production and cGMP formation via a non-AT1 angiotensin receptor and renal PGE2 production via the AT1 receptor.

Angiotensin II↗