title: Angiotensin-(1-7)-dependent vasorelaxation of the renal artery exhibits unique angiotensin and bradykinin receptor selectivity.
abstract: Angiotensin-(1-7) [Ang-(1-7)] exhibits blood pressure lowering actions, inhibits cell growth, and reduces tissue inflammation and fibrosis which may functionally antagonize an activated Ang II-AT1receptor axis. Since the vascular actions of Ang-(1-7) and the associated receptor/signaling pathways vary in different vascular beds, the current study established the vasorelaxant properties of the heptapeptide in the renal artery of male Wistar male rats. Ang-(1-7) produced an endothelium-dependent vasodilator relaxation of isolated renal artery segments pre-contracted by a sub-maximal concentration of phenylephrine (PE) (3×10-7M). Ang-(1-7) induced vasodilation of the rat renal artery with an ED50of 3±1nM and a maximal response of 42±5% (N=10). The two antagonists (10-5M each) for the AT7/Mas receptor (MasR) [D-Pro7]-Ang-(1-7) and [D-Ala7]-Ang-(1-7) significantly reduced the maximal response to 12±1% and 18±3%, respectively. Surprisingly, the AT2R receptor antagonist PD123319, the AT1R antagonist losartan and B2R antagonist HOE140 (10-6M each) also significantly reduced Ang-(1-7)-induced relaxation to 12±2%, 22±3% and 14±7%, respectively. Removal of the endothelium or addition of the soluble guanylate cyclase (sGC) inhibitor ODQ (10-5M) essentially abolished the vasorelaxant response to Ang-(1-7) (10±4% and 10±2%, P <0.05). Finally, the NOS inhibitor LNAME (10-4M) reduced the response to 13±2% (p<0.05), but the cyclooxygenase inhibitor indomethacin failed to block the Ang-(1-7) response. We conclude that Ang-(1-7) exhibits potent vasorelaxant actions in the isolated renal artery that are dependent on an intact endothelium and the apparent stimulation of a NO-sGC pathway. Moreover, Ang-(1-7)-dependent vasorelaxation was sensitive to antagonists against the AT7/Mas, AT1, AT2and B2receptor subtypes.
authors.affiliation: Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, Kuwait.
authors.forename: Mariam H M
authors.initials: MHM
authors.lastname: Yousif
authors.affiliation: Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, Kuwait.
authors.forename: Ibrahim F
authors.initials: IF
authors.lastname: Benter
authors.affiliation: The Hypertension & Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: Debra I
authors.initials: DI
authors.lastname: Diz
authors.affiliation: The Hypertension & Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA. Electronic address: mchappel@wakehealth.edu.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Chappell
mesh_terms: D000803:Angiotensin I / Q000008:administration & dosage / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D065168:Bradykinin Receptor Antagonists / Q000008:administration & dosage; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D019808:Losartan / Q000008:administration & dosage; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism*; D010656:Phenylephrine / Q000008:administration & dosage; D000090063:Proto-Oncogene Mas; D011725:Pyridines / Q000008:administration & dosage; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D018002:Receptors, Bradykinin / Q000378:metabolism*; D012077:Renal Artery / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation / Q000235:genetics
chemical_list: D057911:Angiotensin Receptor Antagonists; D065168:Bradykinin Receptor Antagonists; C472420:D-Pro7-Ang-(1-7); D007093:Imidazoles; C000715470:MAS1 protein, human; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D018002:Receptors, Bradykinin; C073402:PD 123319; D010656:Phenylephrine; D009569:Nitric Oxide; D000803:Angiotensin I; D006162:Guanylate Cyclase; C118790:angiotensin I (1-7); D019808:Losartan; D019331:NG-Nitroarginine Methyl Ester
keywords: Angiotensin; Endothelium; Kidney; Renal artery; c-GMP,