Dissociation of inhibitory effects of guanethidine on adrenergic and on purinergic transmission in isolated canine splenic artery.
The aim of this study was both to investigate the effects of progressive inhibition of adrenergic neurons by increasing concentrations of guanethidine (0.1-10 microM) on the double-peaked vasoconstrictor responses to electrical periarterial nerve stimulation in the isolated and perfused canine splenic artery, and to clarify whether release of noradrenaline is presynaptically separate from release of adenosine 5'-triphosphate (ATP). Double-peaked vasoconstrictions (biphases of vasoconstrictions) were consistently observed under the conditions of 30-s trains of pulses at 1-10 Hz frequencies. Guanethidine, at a lower concentration (0.1 microM) did not modify the first (1st) phase vasoconstriction at low frequencies (1-2 Hz), but markedly inhibited the second (2nd) responses. On the other hand, it slightly but significantly inhibited the double-peaked vasoconstrictor responses at high frequencies (6-10 Hz). Furthermore, a 10-fold increase of concentration of guanethidine (1 microM) almost completely inhibited the 2nd phase responses at any frequencies used but did not completely inhibit the 1st phase response. A further increased concentration of guanethidine (10 microM) failed to enhance the 1 microM guanethidine-induced inhibition. The 1 microM guanethidine-resistant 1st phase responses at any frequencies used (1-10 Hz) were sensitive to tetrodotoxin (30 nM). Treatment with 0.1 microM prazosin did not modify the 1st phase response at any frequencies used in the 1 microM guanethidine-treated preparation. The responses remaining after 1 microM guanethidine and 0.1 microM prazosin were completely suppressed by a subsequent application of 1 microM alpha,beta-methylene ATP at any frequencies used. The results indicated that guanethidine, an adrenergic neuron blocker, may exert a dominant inhibitory effect on adrenergic rather than on purinergic components of sympathetic nerve co-transmission, indicating that guanethidine-sensitive mechanisms may mainly contribute to determine noradrenaline secretion from neurosecretory vesicles rather than ATP secretion.
Yang
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XP
Department of Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan.
Chiba
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D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D018663:Adrenergic Agents / Q000494:pharmacology*; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D006145:Guanethidine / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000378:metabolism* / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D058919:Purinergic P2 Receptor Antagonists; D013157:Splenic Artery / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects
D018663:Adrenergic Agents; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D058919:Purinergic P2 Receptor Antagonists; D000255:Adenosine Triphosphate; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D009638:Norepinephrine; D011224:Prazosin; D006145:Guanethidine