Prejunctional AT(1) receptor subtype-dependent modification of neurotransmitter releases in canine isolated splenic arteries.
1. The regulation by angiotensin II (Ang II) formed locally on nerve-stimulated purinergic and adrenergic components of double-peaked vasoconstrictions in the canine splenic artery and Ang II receptor subtypes involved were investigated. 2. The perfusion of the precursor angiotensin I (Ang I, 0.1-1 nm) did not affect the vasoconstrictor responses to noradrenaline (NA, 0.03-1 nmol) and adenosine 5'-triphosphate (ATP, 0.03-1 micromol). The second component vasoconstrictor response to nerve stimulation was dose dependently potentiated by Ang I (0.1-1 nm). The first peaked constriction was slightly, but insignificantly increased. The potentiating effects of Ang I were abolished by KRH-594 (10 nm), a selective AT(1) receptor antagonist, but not by PD 123319 (1-10 nm), an AT(2) receptor antagonist. KRH-594 (10 nm) or PD 123319 (10 nm) never affected the vasoconstrictions to either NA or ATP. 3. The treatment with KRH-594 (1-10 nm) produced a greater inhibition on the second peaked response than the first one, although both of them were dose dependently inhibited. PD 123319 (1-10 nm) did not affect the vasoconstrictor responses induced by nerve stimulation. 4. Inhibition of angiotensin-converting enzyme with 10 nm enalaprilat reduced the second peaked response, having no significant inhibition on the first peaked response. A higher dose of enalaprilat (100 nm) produced a greater inhibition of the second peak than the first one. It reduced the second peak by approximately 65%, while the first peak was decreased approximately 35%. After treatment with enalaprilat, Ang I (1 nm) failed to enhance the neuronal vascular response. Enalaprilat at doses used did not affect the vasoconstrictions to either NA or ATP. 5. The present results indicate that endogenously generated Ang II may produce a more marked potentiation of adrenergic transmission than purinergic transmission via activation of prejunctional AT(1) receptors.
Komiyama
J
J
Department of Molecular Pharmacology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
Yang
X-P
XP
Chiba
S
S
D000255:Adenosine Triphosphate / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D000803:Angiotensin I / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004558:Electric Stimulation; D015773:Enalaprilat / Q000494:pharmacology; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009638:Norepinephrine / Q000008:administration & dosage / Q000493:pharmacokinetics; D010477:Perfusion / Q000379:methods; D011725:Pyridines / Q000008:administration & dosage; D044140:Receptor, Angiotensin, Type 1 / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology; D013157:Splenic Artery / Q000166:cytology* / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D007093:Imidazoles; C108799:KRH 594; D018377:Neurotransmitter Agents; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D013830:Thiadiazoles; D000804:Angiotensin II; C073402:PD 123319; D000255:Adenosine Triphosphate; D000803:Angiotensin I; D015773:Enalaprilat; D009638:Norepinephrine