ABSTRACT
We assessed the possible link between endothelin receptor mediated phosphoinositide breakdown and NO/cGMP signaling pathways in rat arcuate nucleus-median eminence fragments (AN-ME), brain structures known to contain a rich plexus of nitric oxide synthase (NOS)-containing neurons and fibers, together with densely arranged endothelin ETB-receptors-like immunoreactive fibres. Our data show that ET-1, ET-3 and the ETB-receptors agonist, IRL 1620, increased inositol monophosphate (InsP1) accumulation, NOS activity and cGMP formation, in a similar degree. The stimulatory effect of ETs on InsP1 accumulation and cGMP formation was inhibited by the phospholipase C (PLC) inhibitor, neomycin, and the absence of extracellular calcium, suggesting that calcium is involved in endothelin receptor-induced PLC activation. The L-arginine analog, L-NAME, inhibited ET-1 or IRL1620-stimulated cGMP formation. The ETA receptor antagonists BQ 123, did not alter, while the ETB receptor antagonists BQ788 inhibited ETs-induced increase in the PI metabolism, NOS activity and cGMP generation. Our data indicate that in AN-ME, ETB receptor signals through receptor-mediated calcium dependent-stimulation of phosphoinositide breakdown and activation of NOS/cGMP signaling pathway.
Subject(s)
Arcuate Nucleus of Hypothalamus/physiology , Median Eminence/physiology , Phosphatidylinositols/metabolism , Receptor, Endothelin B/physiology , Signal Transduction/physiology , Animals , Calcium/metabolism , Cyclic GMP/metabolism , Endothelin B Receptor Antagonists , Endothelin-1/pharmacology , Endothelin-3/pharmacology , Endothelins/pharmacology , Enzyme Inhibitors/pharmacology , Male , NG-Nitroarginine Methyl Ester/pharmacology , Neomycin/pharmacology , Nitric Oxide/physiology , Nitric Oxide Synthase/physiology , Oligopeptides/pharmacology , Peptide Fragments/pharmacology , Piperidines/pharmacology , Protein Synthesis Inhibitors/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
Abstract. The aim of this study was to evaluate the role of AT1 angiotensin II receptor on the sympathetic response to the cold pressor test (CPT) in normotensive healthy volunteers. Eighty-two healthy volunteers were included in this double-blind, placebo-controlled study. Blood pressure and heart rate were determined before and one hundred and seventy five minutes after oral administration of placebo, losartan (50 mg), valsartan (80 mg) or eprosartan (600 mg). Immediately, the subjects underwent CPT and then the same hemodynamic parameters were measured. CPT increased arterial blood pressure (systolic, diastolic and mean) and HR in placebo-treated group. Pretreatment with a single dose of losartan, valsartan or eprosartan blunted CPT-induced pressor response, but not the rise in heart rate. Our results demonstrate that endogenous angiotensin II, through stimulation of AT1 receptor, supports sympathetic mediated stress-response in humans.
