Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The heptapeptide, angiotensin-(1-7), is an active member of the renin-angiotensin system. The present study was designed to characterize the role of endothelium in relaxations of large cerebral arteries to angiotensin-(1-7). Rings of canine middle cerebral arteries were suspended in organ chambers for isometric force recording. The levels of cyclic guanosine 3',5'-monophosphate (cGMP) were assessed by radioimmunoassay. During contraction to uridine 5'-triphosphate (UTP, 3x10(-6) to 10(-5) mol/l), angiotensin-(1-7) (10(-9) to 3x10(-5) mol/l) caused concentration-dependent relaxations in arteries with endothelium, but not in endothelium-denuded vessels. Angiotensin-(1-7) significantly increased formation of cGMP. Nitric oxide synthase inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME, 3x10(-4) mol/l), and selective soluble guanylate cyclase inhibitor, 1 H-[1,2, 4]oxadiazolo[4,3-a]quinozalin-1-one (ODQ, 3x10(-6) mol/l), abolished angiotensin-(1-7)-induced relaxations. Angiotensin receptor antagonists, losartan (10(-5) mol/l), PD 123319 (10(-5) mol/l), [Sar(1),Thr(8)]-angiotensin II (10(-5) mol/l) [Sar(1),Val(5), Ala(8)]-angiotensin II (10(-5) mol/l) or [7-D-Ala]-angiotensin 1-7 (10(-6) mol/l) did not affect these relaxations. However, angiotensin-converting enzyme inhibitor, captopril (10(-5) mol/l) augmented relaxations to angiotensin-(1-7). Finally, bradykinin B(2) receptor antagonist, [D-Arg(0),Hyp(3),Thi(5),D-Tic(7), Oic(8)]-bradykinin (HOE 140, 5x10(-8) mol/l) significantly reduced the effect of angiotensin-(1-7), while bradykinin B(1) receptor antagonist, des-Arg(9), [Leu(8)]-bradykinin (6x10(-9) mol/l) did not influence the vascular response to the heptapeptide. These findings indicate that (1) angiotensin-(1-7) produces relaxation of canine middle cerebral arteries by the release of nitric oxide from endothelial cells, (2) angiotensin receptors do not mediate endothelium-dependent relaxations to the heptapeptide, and (3) this effect appears to be dependent on activation of local production of kinins. Our studies support the concept that angiotensin-(1-7), as a natural vasodilator hormone, may counterbalance the hemodynamic actions of angiotensin II.
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PMID:Angiotensin-(1-7) causes endothelium-dependent relaxation in canine middle cerebral artery. 1091 12

Natriuretic peptide receptor (NPR) A is composed of an extracellular domain (ECD) with a ligand binding site, a single transmembrane region, a kinase homology domain, and a guanylyl cyclase domain. The natural agonists atrial and brain natriuretic peptides (ANP, BNP) bind and activate NPRA, leading to cyclic GMP production, which is responsible for their role in cardiovascular homeostasis. Previous studies suggested that stabilization of a dimeric form of NPRA by agonist is essential for receptor activation. However, ligand specificity and sequential steps of this dimerization process have not been investigated. We used radioligand binding, fluorescence resonance energy transfer homoquenching, and molecular modeling to characterize the interaction of human NPRA-ECD with ANP, BNP, the superagonist (Arg(10),Leu(12),Ser(17),Leu(18))-rANP-(1-28), the minimized analog mini-ANP and the antagonist (Arg(6),beta-cyclohexyl-Ala(8),d-Tic(16),Arg(17),Cys(18))-rANP-(6-18)-amide (A71915). ANP binds to preformed ECD dimers and spontaneous dimerization is the rate-limiting step of the ligand binding process. All the studied peptides, including A71915 antagonist, induce a dose-dependent fluorescence homoquenching, specific to dimerization, with potencies highly correlated with their binding affinities. A71915 induced more quenching than other peptides, suggesting stabilization by the antagonist of ECD dimer in a distinct inactive conformation. In summary, these results indicate that the ligand-induced dimerization process of NPRA is different from that for cytokine receptor model. Agonists or antagonists bind to preformed dimeric ECD, leading to dimer stabilization in an active or inactive conformation, respectively. Furthermore, the highly sensitive fluorescence assay designed to assess dimerization could serve as a powerful tool for further detailing the kinetic steps involved in natriuretic peptide receptor binding and activation.
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PMID:Role of extracellular domain dimerization in agonist-induced activation of natriuretic peptide receptor A. 1796 96