Angiotensin III ; Humans

PURPOSE: Angiotensin(ANG) II regulates tone of penile smooth muscle for erection. ANG III is a product converted from ANG II by aminopeptidase A. The effects of ANG III have not been clarified in the penile corpus cavernosum. The purpose of the present experiment was to determine whether the ANG III has regulatory function in the control of rabbit corpus cavernosum smooth muscle tone. MATERIALS AND METHODS: A strip of rabbit corpus cavernosum was mounted in an organ chamber to measure the isometric tension. We compared the effects of ANG III(10-7M to 10-5M), ANG II(10-8M to 10-6M) and ANG I(10-7M to 10-5M) on the contractility of the corpus cavernosum smooth muscle. RESULTS: ANG III, ANG II, and ANG I contracted corpus cavernosum smooth muscle strips dose-dependently. The contraction of smooth muscle induced by ANG III was 10 fold less by ANG II. Contractile response to ANG III was not attenuated by captopril(angiotensin converting enzyme inhibitor). Contractile response to ANG III was significantly inhibited by Dup 753 of 10-7M(type 1 specific ANG II receptor inhibitor) but not inhibited by PD 123,319 of 10-6M(type 2 specific ANG II inhibitor). CONCLUSIONS: The present results suggest that ANG III is involved in the regulation of corpus cavernosum smooth muscle tone, and contractile effect to ANG III produced via activation of type 1 ANG II (AT1) receptor. The rank order of potency of contraction was as follows, ANG II>ANG IIIANG I.
Angiotensin I* ; Angiotensin II* ; Angiotensin III* ; Angiotensins* ; Glutamyl Aminopeptidase ; Losartan ; Muscle, Smooth*

BACKGROUND: Angiotensin converting enzyme (ACE) is heavily expressed in the lung and plays a role in the metabolism of angiotensin II, bradykinin and substance P. Nitric oxides, including those produced by endothelial nitric oxide synthase (ecNOS), may regulate vascular and airway tone in the lung and influence various aspects of airway homeostasis. They are potentially involved in the pathogenesis of asthma, but the role of ACE and ecNOS gene in bronchial asthma is not completely understood. OBJECTIVE: To examine the possible involvement of ACE and ecNOS genes in the genetic basis for bronchial asthma, we investigated the association between genetic polymorphism and bronchial asthma, and its severity. METHOD: We determined the ACE and ecNOS genotypes by the polymerase chain reaction in 160 patients with bronchial asthma and 121 healthy subjects. Severity of asthma was classified by the guideline of NHLBI/WHO workshop. RESULTS: The frequency of the ID genotypes of ACE and bb genotype of ecNOS was highest in both groups, respectively. The distribution of ACE genotypes did not differ between the two groups (p=0.27). There was a higher frequency of the bb genotype of ecNOS in the asthma group than in the control population (p=0.004). In asthmatic patients, there were no differences in the distribution of ACE and ecNOS genotypes in different severity groups (p= 0.17, 0.06). CONCLUSION: These results suggest that the polymorphism of the ecNOS gene, not ACE gene, may be associated with development of asthma. But, the severity of asthma may not be influenced by polymorphisms of the ecNOS and ACE genes.
Angiotensin II ; Angiotensins* ; Asthma* ; Bradykinin ; Education ; Genotype ; Homeostasis ; Humans ; Lung ; Metabolism ; Nitric Oxide Synthase Type III* ; Oxides ; Peptidyl-Dipeptidase A* ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Substance P

Mitochondrial fission can occur via activation of dynamin-related protein 1 (Drp1), which participates in the mitochondrial membrane scission process. The present study was designed to investigate the effect of angiotensin II (AngII) on mitochondrial fission and fusion in human umbilical vascular endothelial cells (HUVECs). And we further inquire into whether Mdivi-1, a newly identified pharmacological inhibitor of Drp1, can prevent endothelial dysfunction induced by AngII. The HUVECs were treated with AngII alone or in combination with Mdivi-1. Western blot was used to detect protein expressions of Drp1, endothelial nitric oxide synthase (eNOS) and apoptosis-related enzymes. MitoTracker Red and JC-1 dye were used to detect mitochondrial morphology and membrane potential, respectively. DCFH-DA probe was used to access intracellular reactive oxygen species (ROS) generation. Transwell assay was used to evaluate cell migration. Annexin V/PI staining was used to assess cellular apoptosis. The results showed that, in cultured HUVECs, AngII (1 × 10mol/L, 12 h) treatment significantly upregulated the expression of Drp1 followed by increased apoptosis and decreased eNOS expression. The treatment of AngII resulted in a change in mitochondrial morphology from elongated to uniformly punctate organelles, which was accompanied by decreased mitochondrial membrane potential. Furthermore, Mdivi-1 significantly protected against AngII-induced endothelial dysfunction, as shown by increased mitochondrial membrane potential and eNOS expression, reduced ROS level, decreased apoptosis and migration ability. Taking together, our data suggest that inhibition of Drp1 with Mdivi-1 can restore AngII-induced endothelial dysfunction.
Angiotensin II ; Apoptosis ; Cells, Cultured ; Endothelial Cells ; Fluoresceins ; Humans ; Membrane Potential, Mitochondrial ; Microtubule-Associated Proteins ; Mitochondria ; Mitochondrial Proteins ; Nitric Oxide Synthase Type III ; Quinazolinones

BACKGROUND AND OBJECTIVES: The renin angiotensin system seems to play an important role in the development of cardiac and vascular hypertrophy in hypertension. The changes in pathology, and gene expressions of the angiotensin II receptor type 1A (ATIA) and angiotensin converting enzyme (ACE) were investigated in order to explore the effects of losartan in spontaneously hypertensive rat (SHR) models. MATERIALS AND METHODS: Twelve week-old male Wistar rats were grouped as follows: control (C) group, hypertension (H) group, and losartan (L) group in which SHR was treated with losartan (10 mg/kg/day). Western blot and reverse transcription-polymerase chain reaction analysis regarding seven genes such as endothelin-1, ACE, ATIA, neutrophil cytosolic factor, brain natriuretic peptide, troponin I, endothelial nitric oxide synthase were performed. RESULTS: Systolic blood pressure was significantly decreased in the L group compared with the H group in weeks 3 and 5. ACE and ATIA proteins in the L group were lower than H group in week 5. CONCLUSION: Losartan reduced blood pressure, cardiac hypertrophy and protein expressions of ACE and ATIA. Changes of protein expressions were more sensitive than changes in pathology. Further study is needed for the differing doses of losartan in SHR models.
Blood Pressure ; Blotting, Western ; Cardiomegaly ; Cytosol ; Endothelin-1 ; Gene Expression ; Humans ; Hypertension ; Hypertrophy ; Losartan ; Male ; Natriuretic Peptide, Brain ; Neutrophils ; Nitric Oxide Synthase Type III ; Peptidyl-Dipeptidase A ; Proteins ; Rats, Inbred SHR ; Rats, Wistar ; Receptors, Angiotensin ; Renin-Angiotensin System ; Troponin I

BACKGROUND: Apart from its blood pressure-lowering effect by blocking the renin-angiotensin-aldosterone system, telmisartan, an angiotensin II type 1 receptor blocker (ARB), exhibits various ancillary effects including cardiovascular protective effects in vitro. Nonetheless, the protective effects of telmisartan in cerebrocardiovascular diseases are somewhat variable in large-scale clinical trials. Dysregulation of endothelial nitric oxide (NO) synthase (eNOS)-derived NO contributes to the developments of various vascular diseases. Nevertheless, the direct effects of telmisartan on endothelial functions including NO production and vessel relaxation, and its action mechanism have not been fully elucidated. Here, we investigated the mechanism by which telmisartan regulates NO production and vessel relaxation in vitro and in vivo. METHODS: We measured nitrite levels in culture medium and mouse serum, and performed inhibitor studies and western blot analyses using bovine aortic endothelial cells (BAECs) and a hyperglycemic mouse model. To assess vessel reactivity, we performed acetylcholine (ACh)-induced vessel relaxation assay on isolated rat aortas. RESULTS: Telmisartan decreased NO production in normoglycemic and hyperglycemic BAECs, which was accompanied by reduced phosphorylation of eNOS at Ser¹¹⁷⁹ (p-eNOS-Ser¹¹⁷⁹). Telmisartan increased the expression of protein phosphatase 2A catalytic subunit (PP2Ac) and co-treatment with okadaic acid completely restored telmisartan-inhibited NO production and p-eNOS-Ser¹¹⁷⁹ levels. Of the ARBs tested (including losartan and fimasartan), only telmisartan decreased NO production and p-eNOS-Ser¹¹⁷⁹ levels, and enhanced PP2Ac expression. Co-treatment with GW9662 had no effect on telmisartan-induced changes. In line with in vitro observations, telmisartan reduced serum nitrite and p-eNOS-Ser¹¹⁷⁹ levels, and increased PP2Ac expression in high fat diet-fed mice. Furthermore, telmisartan attenuated ACh-induced rat aorta relaxation. CONCLUSION: We demonstrated that telmisartan inhibited NO production and vessel relaxation at least in part by PP2A-mediated eNOS-Ser¹¹⁷⁹ dephosphorylation in a peroxisome proliferator-activated receptor γ-independent manner. These results may provide a mechanism that explains the inconsistent cerebrocardiovascular protective effects of telmisartan.
Acetylcholine ; Animals ; Aorta ; Blotting, Western ; Catalytic Domain ; Endothelial Cells ; In Vitro Techniques ; Losartan ; Mice ; Mice, Obese ; Nitric Oxide Synthase Type III ; Nitric Oxide ; Okadaic Acid ; Peroxisomes ; Phosphorylation ; Protein Phosphatase 2 ; Rats ; Receptor, Angiotensin, Type 1 ; Relaxation ; Renin-Angiotensin System ; Vascular Diseases

BACKGROUNDRepeated attacks of bronchial asthma lead to different degrees of airway remodeling, the mechanism of which is not yet clear. Some evidences indicate that it is related to the excessive expression of some growth promotion factors. Angiotensin II is a polypeptide that may be involved in airway remodeling. To evaluate its role in airway remodeling in asthma, we observed the effects of an angiotensin II type 1 receptor antagonist (valsartan) on the expression of collagen III, collagen V, and transforming growth factor beta1 (TGF-beta1) mRNA and protein in the airway walls of sensitized rats.

METHODSForty Wistar rats were randomly divided into 5 groups: control group, sensitized group, and valsartan groups 1, 2, and 3. The rats in the sensitized group and in valsartan groups 1, 2, and 3 were sensitized and challenged with ovalbumin. Rats in control group were sensitized and challenged with 0.9% NaCl. Rats from valsartan groups 1, 2, and 3 were drenched with valsartan (10 microg, 20 microg, or 30 microg, respectively) at the time of the ovalbumin challenges. The expression of collagen III, collagen V, and TGF-beta1 protein were detected using immunohistochemical method in combination with image analysis methods. The expression of TGF-beta1 mRNA was detected by in situ hybridization.

RESULTSThe expression in the airways of collagen III and collagen V was significantly higher in rats from the sensitized group (7.73 +/- 0.81, 1.34 +/- 0.28) and from valsartan groups 1, 2, and 3 (5.73 +/- 0.64, 1.13 +/- 0.15; 4.96 +/- 0.51, 0.98 +/- 0.08; 4.43 +/- 0.35, 0.93 +/- 0.06, respectively) than those in the control group (2.65 +/- 0.38, 0.67 +/- 0.08, P < 0.05). In addition, collagen levels were significantly lower in valsartan groups 1, 2, and 3 than those from the sensitized group (P < 0.05). The expression of TGF-beta1 mRNA and protein in the airways was significantly higher in rats from the sensitized group (20.49% +/- 3.46%, 29.73% +/- 3.25%) and from valsartan groups 1, 2, and 3 (16.47% +/- 1.94%, 19.41% +/- 1.87%; 14.38% +/- 1.58%, 18.29% +/- 1.43%; 12.96% +/- 1.73%, 18.63% +/- 1.11%, respectively) than that from the control group (7.84% +/- 1.61%, 5.63% +/- 1.07%, P < 0.05). TGF-beta1 mRNA and protein levels were significantly lower in valsartan groups 1, 2, and 3 than that in the sensitized group (P < 0.05).

CONCLUSIONSAngiotensin II receptor antagonist valsartan can suppress synthesis of collagen III and collagen V by downregulating TGF-beta1 mRNA and protein expression. Valsartan can decrease airway remodeling and could play a role in asthma therapy.

Angiotensin Receptor Antagonists ; Animals ; Asthma ; physiopathology ; Bronchi ; metabolism ; Collagen Type III ; analysis ; Collagen Type V ; analysis ; Immunization ; Male ; Ovalbumin ; RNA, Messenger ; analysis ; Random Allocation ; Rats ; Rats, Wistar ; Tetrazoles ; pharmacology ; Transforming Growth Factor beta ; analysis ; Valine ; analogs & derivatives ; pharmacology ; Valsartan

To investigate the mutual relationship between angiotensin II (Ang II) and nitric oxide (NO) in paraventricular nucleus (PVN), Ang II receptor type Ia (AT1A), type Ib (AT1B), endothelial constitutive nitric oxide synthase (ecNOS), and neuronal constitutive nitric oxide synthase (ncNOS) mRNA levels of rat PVN were measured after unilateral carotid artery ligation. AT1A and AT1B mRNA levels were markedly elevated 6 hrs after unilateral carotid artery ligation. Losartan injection (10 microgram/0.3 microliter) into the PVN augmented of the increment of AT1A and AT1B mRNAs It also increased ecNOS gene expression. In addition, AT1B mRNA levels increased after N-nitro-L-arginine methyl ester (L-NAME) injection (50 microgram/0.3 microliter) into the PVN. These results suggest that Ang II and NO in the rat PVN may interplay, at least in part, through regulation of gene expression of ecNOS and AT1B, respectively.
Angiotensin II* ; Angiotensins* ; Animals ; Carotid Arteries ; Gene Expression ; Gene Expression Regulation ; Ligation ; Losartan ; Neurons ; Nitric Oxide Synthase ; Nitric Oxide Synthase Type III ; Nitric Oxide* ; Paraventricular Hypothalamic Nucleus* ; Rats* ; RNA, Messenger

Angiotensin II Type 1 Receptor Blockers ; therapeutic use ; Animals ; Benzimidazoles ; therapeutic use ; Hypertension ; blood ; drug therapy ; Male ; Nitric Oxide ; blood ; Nitric Oxide Synthase Type III ; blood ; Random Allocation ; Rats ; Rats, Inbred SHR ; Tetrazoles ; therapeutic use ; Urotensins ; blood

This study investigated the role of angiotensin II receptor blocker in atrial remodeling in rats with atrial fibrillation (AF) induced by a myocardial infarction (MI). MIs were induced by a ligation of the left anterior descending coronary artery. Two days after, the rats in the losartan group were given losartan (10 mg/kg/day for 10 weeks). Ten weeks later, echocardiography and AF induction studies were conducted. Ejection fraction was significantly lower in the MI rats. Fibrosis analysis revealed much increased left atrial fibrosis in the MI group than sham (2.22 +/- 0.66% vs 0.25 +/- 0.08%, P = 0.001) and suppression in the losartan group (0.90 +/- 0.27%, P 0.001) compared with the MI group. AF inducibility was higher in the MI group than sham (39.4 +/- 43.0% vs 2.0 +/- 6.3%, P = 0.005) and significantly lower in losartan group (12.0 +/- 31.6%, P = 0.029) compared with the MI. The left atrial endothelial nitric oxide synthase (NOS) and sarco/endoplasmic reticulum Ca(2+)-ATPase levels were lower in the MI group and higher in the losartan group significantly. The atrial inducible NOS and sodium-calcium exchanger levels were higher in the MI and lower in the losartan group significantly. Losartan disrupts collagen fiber formation and prevents the alteration of the tissue eNOS and iNOS levels, which prevent subsequent AF induction.
Angiotensin Receptor Antagonists/*therapeutic use ; Animals ; Atrial Fibrillation/*prevention & control ; Atrial Remodeling ; Disease Models, Animal ; Fibrosis ; Heart Failure/*etiology/ultrasonography ; Immunohistochemistry ; Losartan/*therapeutic use ; Male ; Myocardial Infarction/*complications/ultrasonography ; Nitric Oxide Synthase Type II/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Angiotensin/chemistry/metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism ; Sodium-Calcium Exchanger/metabolism