Beta 2-adrenergic receptor and angiotensin II receptor modulation of sympathetic neurotransmission in human atria.
The aim of the present study was to investigate beta-adrenergic receptor and angiotensin II (Ang II) receptor modulation of norepinephrine release in human atria. Slices of human atrial appendages were incubated with [3H]norepinephrine, superfused with Krebs-Henseleit solution, and electrically stimulated in superfusion chambers. Pretreatment of the tissue with 6-hydroxydopamine (1.2 mmol/L) before the [3H]norepinephrine incubation to destroy sympathetic nerves reduced the uptake of radioactivity and abolished the stimulation-induced (S-I) outflow of radioactivity. Furthermore, S-I outflow of radioactivity was prevented by the addition of tetrodotoxin (1 mumol/L) to and omission of extracellular Ca2+ from the superfusion solution. Separation of [3H]norepinephrine from its metabolites revealed that the S-I outflow of radioactivity was mainly composed of intact [3H]norepinephrine. Thus, the S-I outflow of radioactivity was taken as an index of norepinephrine release. Isoproterenol (0.001 to 0.1 mumol/L) dose-dependently enhanced the S-I outflow of radioactivity. The concentration-response curve of isoproterenol was shifted to the right by the selective beta 2-adrenergic receptor antagonist ICI 118551 (0.01 and 0.1 mumol/L) but not by the beta 1-adrenergic receptor-selective antagonist atenolol (0.3 and 30 mumol/L). Ang II (0.001 to 1.0 mumol/L) also dose-dependently enhanced S-I outflow of radioactivity. The facilitatory effect of Ang II was blocked by either the peptide Ang II receptor antagonist saralasin (1.0 mumol/L) or EXP 3174 (0.1 mumol/L), the in vitro active form of the nonpeptide Ang II receptor antagonist losartan. The cell-permeable cAMP analogue 8-bromo-cAMP (30 to 300 mumol/L) dose-dependently enhanced S-I outflow of radioactivity.(ABSTRACT TRUNCATED AT 250 WORDS)
Rump
L C
LC
Innere Medizin IV, Universitätsklinik Freiburg, Germany.
Schwertfeger
E
E
Schaible
U
U
Fraedrich
G
G
Schollmeyer
P
P
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000494:pharmacology; D004338:Drug Combinations; D004558:Electric Stimulation; D006325:Heart Atria; D006329:Heart Conduction System / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008875:Middle Aged; D009638:Norepinephrine / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D011945:Receptors, Angiotensin / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000502:physiology*
D004338:Drug Combinations; D011943:Receptors, Adrenergic, beta; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D015124:8-Bromo Cyclic Adenosine Monophosphate; D007545:Isoproterenol; D009638:Norepinephrine