cyclic-gmp and candesartan

A positive association between renin-angiotensin system, especially AT1 receptor, and oxidative stress in the pathogenesis of hypertension and cardiovascular/renal diseases has been suggested. However, the role of oxidative stress, especially superoxide radicals in renal sodium handling in response to AT1 and AT2 receptors, is not known. Therefore, the present study was designed to investigate the role of NAD(P)H oxidase (NOX), a major superoxide radical producing enzyme, in AT1 and AT2 receptor function on natriuresis/diuresis in Sprague-Dawley rats. The rats under anesthesia were intravenously infused with NOX inhibitor apocynin (3.5 μg·kg(-1)·min(-1)), the AT1 receptor antagonist candesartan (100 μg/kg; bolus), and the AT2 receptor agonist CGP-42112A (1 μg·kg(-1)·min(-1)) alone and in combinations. Candesartan alone significantly increased urinary flow (UF; μl/30 min) by 53 and urinary Na excretion (U(Na)V; μmol/min) by 0.4 over basal. Preinfusion of apocynin had no effect on the net increase in UF or U(Na)V in response to candesartan. On the other hand, apocynin preinfusion caused profound increases in CGP-42112A-induced UF by 72, U(Na)V by 1.14, and fractional excretion of Na by 7.8. Apocynin and CGP-42112A alone did not cause significant increase in UF or U(Na)V over the basal. CGP-42112A infusion in the presence of apocynin increased urinary nitrite/nitrates and cGMP over basal. The infusion of candesartan, apocynin, and CGP-42112A alone or in combinations had no effect on the blood pressure or the glomerular filtration rate, suggesting tubular effects on natriuresis/diuresis. The data suggest that NOX may have an antagonistic role in AT2 receptor-mediated natriuresis/diuresis possibly via neutralizing nitric oxide and thereby influence fluid-Na homeostasis.

Topics: Acetophenones; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cyclic GMP; Glomerular Filtration Rate; Homeostasis; Male; NADPH Oxidases; Natriuresis; Nitric Oxide; Oligopeptides; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Sodium; Tetrazoles

Oxidative stress causes changes in angiotensin (Ang) type 1 receptor (AT1R) function, which contributes to hypertension. Ang II affects blood pressure via maintenance of sodium homeostasis by regulating renal Na(+) absorption through its effects on Na/K-ATPase (NKA). At low concentrations, Ang II stimulates NKA; higher concentrations inhibit the enzyme. We examined the effect of oxidative stress on renal AT1R function involved in biphasic regulation of NKA. Male Sprague-Dawley rats received tap water (control) and 30 mmol/L of L-buthionine sulfoximine (BSO), an oxidant, with and without 1 mmol/L of Tempol (antioxidant) for 2 weeks. BSO-treated rats exhibited increased oxidative stress, AT1R upregulation, and hypertension. In proximal tubules from control rats, Ang II exerted a biphasic effect on NKA activity, causing stimulation of the enzyme at picomolar and inhibition at micromolar concentrations. However, in BSO-treated rats, Ang II caused stimulation of NKA at both of the concentrations. The effect of Ang II was abolished by the AT1R antagonist candesartan and the mitogen-activated protein kinase inhibitor UO126, whereas the Ang type 2 receptor antagonist PD-123319 and NO synthase inhibitor N(G)-nitro-L-arginine methyl ester had no effect. The inhibitory effect of Ang II was sensitive to candesartan and N(G)-nitro-L-arginine methyl ester, whereas PD-123319 and UO126 had no effect. In BSO-treated rats, Ang II showed exaggerated stimulation of NKA, mitogen-activated protein kinase, proline-rich-tyrosine kinase 2, and NADPH oxidase but failed to activate NO signaling. Tempol reduced oxidative stress, normalized AT1R signaling, unmasked the biphasic effect on NKA, and reduced blood pressure in BSO-treated rats. In conclusion, oxidative stress-mediated AT1R upregulation caused a loss of NKA biphasic response and hypertension. Tempol normalized AT1R signaling and blood pressure.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Antioxidants; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Buthionine Sulfoximine; Cyclic GMP; Cyclic N-Oxides; Enzyme Inhibitors; Focal Adhesion Kinase 2; Hypertension, Renal; Kidney Tubules, Proximal; Male; Mitogen-Activated Protein Kinases; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Signal Transduction; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Sodium-Potassium-Exchanging ATPase; Spin Labels; Tetrazoles; Vasoconstrictor Agents

Renal volume regulation is modulated by the action of cyclooxygenases (COX) and the resulting generation of prostanoids. Epithelial expression of COX isoforms in the cortex directs COX-1 to the distal convolutions and cortical collecting duct, and COX-2 to the thick ascending limb. Partly colocalized are prostaglandin E synthase (PGES), the downstream enzyme for renal prostaglandin E(2) (PGE(2)) generation, and the EP receptors type 1 and 3. COX-1 and related components were studied in two kidney-one clip (2K1C) Goldblatt hypertensive rats with combined chronic ANG II or bradykinin B(2) receptor blockade using candesartan (cand) or the B(2) antagonist Hoechst 140 (Hoe). Rats (untreated sham, 2K1C, sham + cand, 2K1C + cand, sham + Hoe, 2K1C + Hoe) were treated to map expression of parameters controlling PGE(2) synthesis. In 2K1C, cortical COX isoforms did not change uniformly. COX-2 changed in parallel with NO synthase 1 (NOS1) expression with a raise in the clipped, but a decrease in the nonclipped side. By contrast, COX-1 and PGES were uniformly downregulated in both kidneys, along with reduced urinary PGE(2) levels, and showed no clear relations with the NO status. ANG II receptor blockade confirmed negative regulation of COX-2 by ANG II but blunted the decrease in COX-1 selectively in nonclipped kidneys. B(2) receptor blockade reduced COX-2 induction in 2K1C but had no clear effect on COX-1. We suggest that in 2K1C, COX-1 and PGES expression may fail to oppose the effects of renovascular hypertension through reduced prostaglandin signaling in late distal tubule and cortical collecting duct.

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Bradykinin; Cyclic GMP; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Hypertension, Renovascular; Kidney Cortex; Kidney Tubules, Collecting; Kidney Tubules, Distal; Loop of Henle; Male; Membrane Proteins; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP3 Subtype; Surgical Instruments; Tetrazoles

The role of local endogenous angiotensin II (Ang II) in endothelial function in resistance arteries was investigated using rabbit mesenteric resistance arteries. First, the presence of immunoreactive Ang II together with Ang II type-1 receptor (AT1R) and angiotensin converting enzyme (ACE) was confirmed in these arteries. In endothelium-intact strips, the AT1R-blocker olmesartan (1 microM) and the ACE-inhibitor temocaprilat (1 microM) each enhanced the ACh (0.03 microM)-induced relaxation during the contraction induced by noradrenaline (NA, 10 microM). Similar effects were obtained using CV-11974 (another AT1R blocker) and enalaprilat (another ACE inhibitor). The nitric-oxide-synthase inhibitor NG-nitro-L-arginine (L-NNA) abolished the above effect of olmesartan. In endothelium-denuded strips, olmesartan enhanced the relaxation induced by the NO donor NOC-7 (10 nM). Olmesartan had no effect on cGMP production (1) in endothelium-intact strips (in the absence or presence of ACh) or (2) in endothelium-denuded strips (in the absence or presence of NOC-7). In beta-escin-skinned strips, 8-bromoguanosine 3',5' cyclic monophosphate (8-Br-cGMP, 0.01-1 microM) concentration dependently inhibited the contractions induced (a) by 0.3 microM Ca2+ in the presence of NA+GTP and (b) by 0.2 microM Ca2++GTPgammaS. Olmesartan significantly enhanced, while Ang II (0.1 nM) significantly inhibited, the 8-Br-cGMP-induced relaxation. We propose the novel hypothesis that in these arteries, Ang II localized within smooth muscle cells activates AT1Rs and inhibits ACh-induced, endothelium-dependent relaxation at least partly by inhibiting the action of cGMP on these cells.

Topics: Acetylcholine; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Cell Membrane Permeability; Cyclic GMP; Enalaprilat; Endothelium, Vascular; In Vitro Techniques; Kinetics; Male; Mesenteric Arteries; Muscle, Smooth, Vascular; Nitroarginine; Rabbits; Receptor, Angiotensin, Type 1; Tetrazoles; Thiazepines; Vasodilation

We previously showed that CGP 42112 (an angiotensin type 2 [AT(2)] agonist) markedly reduces catecholamine biosynthesis by decreasing cGMP production mediated by AT(2), a subtype of Ang II receptor that is dominantly expressed in cultured porcine chromaffin cells. To elucidate the relationship of the 2 types of Ang II receptors, angiotensin type 1 (AT(1)) and AT(2), in the synthesis of catecholamine in adrenal medullary cells, we have examined the effect of Ang II plus CV-11974 (an AT(1) antagonist that selectively simulates AT(2) stimulation) and the effect of Ang II plus PD 123319 (an AT(2) antagonist that selectively simulates AT(1) stimulation) on catecholamine synthesis. We found that Ang II reduced cGMP production via AT(2), in a similar manner to that found with CGP 42112. Stimulation of AT(1) significantly upregulated protein kinase C activity. Tyrosine hydroxylase (TH) is a rate-limiting enzyme involved in the biosynthesis of catecholamine, and this catecholamine synthesis depends both on TH enzyme activity and on the levels of TH protein after TH gene transcription. We found that AT(2) stimulation significantly inhibited TH enzyme activity, whereas AT(1) stimulation significantly upregulated TH enzyme activity. The stimulatory effect of AT(1) was completely inhibited by Ro-32-0432 (a protein kinase C inhibitor) and PD 98059 (a MAP kinase kinase-1 [MEK-1] inhibitor). Pretreatment of cells with either 8-Br-cGMP (a membrane-permeable cGMP analog) or Zaprinast (a phosphodiesterase inhibitor) abolished the inhibitory effect of AT(2) on TH enzyme activity, indicating that the stimulatory effect of AT(2) may be mediated through a reduction in cGMP concentration. Similar to the effect on TH enzyme activity, AT(2) stimulation significantly reduced TH mRNA and protein levels and net catecholamine content below basal levels, whereas AT(1) stimulation increased them. We confirmed these findings by gel mobility shift assay. Our results show that stimulation of AT(2) reduces catecholamine biosynthesis via a decrease in cGMP levels. In contrast, stimulation of AT(1) stimulates catecholamine biosynthesis through activation of PKC. Thus, we conclude that AT(1) and AT(2) have counter-regulatory roles in the synthesis of catecholamine in adrenal medullary chromaffin cells.

Topics: Adrenal Medulla; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Catecholamines; Cells, Cultured; Cyclic GMP; Imidazoles; Phosphodiesterase Inhibitors; Protein Kinase C; Pyridines; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; RNA, Messenger; Swine; Tetrazoles; Tyrosine 3-Monooxygenase

We have previously demonstrated that CGP 42112 (AT(2) agonist > or =1 nM) markedly reduces catecholamine biosynthesis through AT(2), which is the major angiotensin II (AngII) receptor subtype in cultured porcine chromaffin cells. Also, we have shown that CGP 42112 (> or =1 nM) induces a reduction in cGMP production in these cells. The present study showed that AngII reduced cGMP production via AT(2) in a manner similar to that found with CGP 42112. AngII (1 nM) significantly increased catecholamine secretion from cultured porcine adrenal medullary chromaffin cells. The stimulation was significantly inhibited by PD 123319 (AT(2) antagonist). The stimulation was moderately, but significantly, attenuated by CV-11974 (AT(1) antagonist, > or =10 nM), suggesting an involvement of AT(1). Moreover, CGP 42112 (> or =10 nM) markedly increased catecholamine release from these cells. The stimulation by CGP 42112 was abolished by PD 123319, whereas CV-11974 had no effect, indicating that this response is also mediated by AT(2). We further examined whether extracellular Ca(2+) is involved in the stimulatory effect of AT(2) on catecholamine secretion. Removal of external Ca(2+) significantly suppressed either AngII plus CV-11974 (100 nM; which simulates specific AT(2) stimulation) or CGP 42112- induced catecholamine secretion. AngII plus CV-11974 or CGP 42112 caused a sustained increase in intracellular Ca(2+) ([Ca(2+)](i)), as determined in fura-2-loaded chromaffin cells in an extracellular Ca(2+)-dependent manner. In the presence of EGTA, the subsequent addition of AngII with CV-11974 and CGP 42112 did not cause any increase in [Ca(2+)](i) levels. Consistent with this finding, CGP 42112 (10 nM to 1 microM) did not alter inositol triphosphate (IP(3)) production, a messenger for mobilization of Ca(2+) from intracellular storage sites. In addition, the intracellular Ca(2+) chelator 1,2-bis(2-amino-phenoxy)ethane-N,N,N',N'- tetraacetic acid acetoxymethylester (BAPTA) did not affect CGP 42112-induced catecholamine release. We tested whether a decrease in cGMP was the cause of the stimulatory effect of AT(2) on catecholamine secretion. Pretreatment with 8-bromo-cGMP (1 mM) prevented the stimulatory effect of AngII plus CV-11974 and CGP 42112 on both catecholamine secretion and [Ca(2+)](i). When 8-bromo-cGMP was added after application of AngII plus CV-11974 or CGP 42112, [Ca(2+)](i) induced by these agents was gradually reduced toward the baseline values. Similarly, guanyli

Topics: Adrenal Medulla; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Calcium; Catecholamines; Cells, Cultured; Chromaffin Cells; Cyclic GMP; Extracellular Space; Imidazoles; Inositol 1,4,5-Trisphosphate; Intracellular Membranes; Oligopeptides; Pyridines; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Swine; Tetrazoles; Virulence Factors, Bordetella

Two distinct types of angiotensin II (AngII) receptors, AT1 and AT2, have been cloned. We have shown previously that stimulation of AT2 reduces intracellular cyclic guanosine monophosphate (cGMP) levels in cultured porcine chromaffin cells in which AT2 is the predominantly expressed receptor. However, it has not been determined whether AT1 or AT2 affects signal transduction pathways involving mitogen-activated protein kinases (MAPKs) and signal transducers and activators of transcription (STATs) in chromaffin cells. Also, it is unclear whether cGMP/protein kinase G (PKG) is involved in the regulation of MAPKs and STATs in these cells.. Chromaffin cells were derived from porcine adrenal medulla. The effects of AngII alone (representing physiological conditions), AngII plus CV-11974 (an AT1 antagonist, which simulates specific AT2 stimulation), AngII plus PD 123319 (an AT2 antagonist, which simulates specific AT1 stimulation), and 8-Br-cGMP (a membrane-permeable cGMP analogue) alone on MAPKs (ERKs, JNK, p-38 MAPK) and STATs (STATs 1, 3 and 5) activity were measured.. Phosphorylated MAPKs (extracellular signal-related kinases (ERKs), c-jun N-terminal kinase (JNK) and p38 MAPK) and STATs (STATs 1, 3 and 5) were measured by immunoprecipitation-Western blot analysis (IP-Western blot).. AT1 stimulation markedly increased expression of ERKs, JNK, p38 MAPK via Ca2+-dependent protein kinase C (PKC) isoforms (cPKC), as well as STATs 1, 3 and 5 in cultured porcine chromaffin cells. In contrast, AT2 stimulation markedly decreased the expression of these signaling molecules. Also, 8-Br-cGMP alone induced increases in ERKs, JNK, p38 MAPK, and STATs 1, 3 and 5. Because AT2 inhibits cGMP production, we speculate that AT2 may act to suppress cGMP production, which in turn reduces the activity of both MAPKs and STATs in chromaffin cells.. AT2 negatively regulates AT1 in signal transduction pathways in chromaffin cells.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Cells, Cultured; Chromaffin Cells; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; DNA-Binding Proteins; Drug Combinations; Enzyme Activation; Imidazoles; Isoenzymes; Milk Proteins; Mitogen-Activated Protein Kinases; Protein Kinase C; Pyridines; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Signal Transduction; STAT1 Transcription Factor; STAT3 Transcription Factor; STAT5 Transcription Factor; Swine; Tetrazoles; Trans-Activators

Angiotensin II subtype 2 receptor (AT(2)-R) is abundantly expressed in adrenal medullary chromaffin cells. However, the physiological roles of AT(2)-R in chromaffin cells remain to be clarified. Therefore, we investigated the effects of CGP42112 (AT(2)-R agonist) on catecholamine biosynthesis in cultured porcine adrenal medullary cells. We initially confirmed AT(2)-R was predominantly expressed in porcine adrenal medullary cells by [(125)I]-Ang II binding studies. CGP42112 (>==1 nM) significantly inhibited cGMP production from the basal value. Tyrosine hydroxylase (TH) is a rate-limiting enzyme in the biosynthesis of catecholamine, and its activity is regulated by both TH-enzyme activity and TH-synthesis. CGP42112 (>==1 nM) significantly inhibited TH-enzyme activity from the basal value. These inhibitory effects of CGP42112 on TH-enzyme activity and-cGMP production were abolished by PD123319 (AT(2)-R antagonist) while CV-11974 (AT(1)-R antagonist) was ineffective. We also tested whether decrease of cGMP is involved in the inhibitory effect of CGP42112 on TH-enzyme activity. Pretreatment of 8-Br-cGMP (membrane-permeable cGMP analogue) prevented the inhibitory effect of CGP 42112 on TH-enzyme activity. Similar to that of TH-enzyme activity, CGP42112 (>==1 nM) significantly reduced TH-mRNA and TH-protein level from the basal value, and these inhibitory effects were abolished by PD123319 but not CV-11974. These findings demonstrate that CGP 42112 reduces both TH-enzyme activity and TH-synthesis and that these inhibitory effects could be mediated by decrease of cGMP production.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Adrenal Medulla; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Binding, Competitive; Biphenyl Compounds; Catecholamines; Cells, Cultured; Chromaffin Cells; Cyclic GMP; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Induction; Imidazoles; Oligopeptides; Pyridines; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; RNA, Messenger; Swine; Tetrazoles; Tyrosine 3-Monooxygenase

We hypothesized that the cardioprotective effect of angiotensin II (AngII) type 1 receptor (AT(1)R) blockade during in vivo ischemia-reperfusion (IR) might be associated with an increase in AngII type 2 receptor (AT(2)R) protein, as well as 1,4,5-inositol trisphosphate type 2 receptor (IP(3)R) and protein kinase C(epsilon) (PKC(epsilon)) proteins and cyclic guanosine 3',5' monophosphate (cGMP).. We studied the effects of the AT(1)R blocker, candesartan, on in vivo left ventricular (LV) systolic and diastolic function and remodeling (echocardiogram/Doppler) and hemodynamics during canine reperfused anterior infarction (90-minute ischemia, 120-minute reperfusion), and ex vivo infarct size and AT(1)R/AT(2)R, IP(3)R, and PKC(epsilon) proteins (immunoblots), and cGMP (enzyme immunoassay). Compared with controls, candesartan (1 mg/kg intravenously over 30-minute preischemia) inhibited the AngII pressor response, decreased preload and afterload, improved LV systolic and diastolic function, limited LV remodeling, decreased infarct size (55% vs 27% risk; P <.000003), markedly increased AT(2)R, IP(3)R, and PKC(epsilon) proteins in the infarct zone, but not the AT(1)R protein, and increased infarct more than noninfarct cGMP.. The overall results suggest that cardioprotective effects of AT(1)R blockade on acute IR injury might involve AT(2)R activation and downstream signaling via IP(3)R, PKC(epsilon), and cGMP.

Topics: Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Calcium Channels; Cyclic GMP; Dogs; Female; Hemodynamics; Infusions, Intravenous; Inositol 1,4,5-Trisphosphate Receptors; Isoenzymes; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Protein Kinase C; Protein Kinase C-epsilon; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Tetrazoles; Ventricular Function, Left

Although ACE inhibitors can protect myocardium against ischemia/reperfusion injury, the mechanisms of this effect have not yet been characterized at the cellular level. The present study was designed to examine whether an ACE inhibitor, cilazaprilat, directly protects cardiac myocytes against hypoxia/reoxygenation (H/R) injury.. Neonatal rat cardiac myocytes in primary culture were exposed to hypoxia for 5.5 hours and subsequently reoxygenated for 1 hour. Myocyte injury was determined by the release of creatine kinase (CK). Both cilazaprilat and bradykinin significantly inhibited CK release after H/R in a dose-dependent fashion and preserved myocyte ATP content during H/R, whereas CV-11974, an angiotensin II receptor antagonist, and angiotensin II did not. The protective effect of cilazaprilat was significantly inhibited by Hoe 140 (a bradykinin B2 receptor antagonist), NG-monomethyl-L-arginine monoacetate (L-NMMA) (an NO synthase inhibitor), and methylene blue (a soluble guanylate cyclase inhibitor) but not by staurosporine (a protein kinase C inhibitor), aminoguanidine (an inhibitor of inducible NO synthase), or indomethacin (a cyclooxygenase inhibitor). Cilazaprilat significantly enhanced bradykinin production in the culture media of myocytes after 5.5 hours of hypoxia but not in that of nonmyocytes. In addition, cilazaprilat markedly enhanced the cGMP content in myocytes during hypoxia, and this augmentation in cGMP could be blunted by L-NMMA and methylene blue but not by aminoguanidine.. The present study demonstrates that cilazaprilat can directly protect myocytes against H/R injury, primarily as a result of an accumulation of bradykinin and the attendant production of NO induced by constitutive NO synthase in hypoxic myocytes in an autocrine/paracrine fashion. NO modulates guanylate cyclase and cGMP synthesis in myocytes, which may contribute to the preservation of energy metabolism and cardioprotection against H/R injury.

Topics: Adrenergic beta-Antagonists; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Bradykinin; Cell Hypoxia; Cells, Cultured; Cilazapril; Creatine Kinase; Cyclic GMP; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Guanidines; Indomethacin; Methylene Blue; Muscle Fibers, Skeletal; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine; Oxygen; Rats; Rats, Wistar; Staurosporine; Tetrazoles

1. The association between the stimulation of the angiotensin subtype 2 receptor (AT2-R) and the change in tissue levels of cyclic nucleotide was assessed on neointima formation in rat aorta following aortic balloon injury. 2. Tissue levels of guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate levels (cAMP) in the injured and uninjured aorta was determined by enzyme immunoassay at baseline and again 30 s after administration of 10(-7) M angiotension II. 3. Injured and uninjured aorta showed no difference in basal levels of cGMP. Angiotension II reduced the basal level of cGMP in the injured aorta only. 4. This decrease was blocked by a selective AT2-R antagonist (PD123319) and by a nonselective angiotensin II antagonist (angiotensin II antipeptide), but not by a selective angiotensin subtype 1 antagonist (CV-11974). 5. Stimulation with a selective AT2-R caused no change in the level of cAMP in the injured or uninjured aorta. 6. Results suggest that stimulation of AT2-R in proliferative neointima leads to a decreased tissue level of cGMP.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Aorta, Thoracic; Benzimidazoles; Biphenyl Compounds; Catheterization; Cyclic AMP; Cyclic GMP; Imidazoles; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Pyridines; Rats; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Tetrazoles; Tunica Intima