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Comparative study of the actions of AP 5 A and α,β‐methylene ATP on nonadrenergic, noncholinergic neurogenic excitation in the guinea‐pig vas deferens
Author(s) -
MacKenzie Ian,
Kirkpatrick Karen A.,
Burnstock Geoffrey
Publication year - 1988
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1988.tb11578.x
Subject(s) - vas deferens , carbachol , excitatory postsynaptic potential , medicine , stimulation , endocrinology , chemistry , muscle contraction , depolarization , purinergic receptor , alpha (finance) , adenosine , inhibitory postsynaptic potential , surgery , construct validity , patient satisfaction
1 The agonistic and antagonistic effects of two nucleotide analogues, P 1 ,P 5 ‐di‐(adenosine‐5′) pentaphosphate (AP 5 A) and α,β‐methylene ATP (α,β‐Me ATP), have been compared in the guinea‐pig isolated vas deferens. 2 In organ bath studies, both AP 5 A and α,β‐Me ATP were approximately 100 times more potent than ATP in producing phasic contractions of the vas deferens smooth muscle. Repeated additions of either agonist (1–10 μ m ) produced desensitization to a subsequent addition of the test substance. AP 5 A and α,β‐Me ATP were approximately equipotent in the production of desensitization. 3 After desensitization had been produced in the vas deferens by AP 5 A or α,β‐Me ATP, excitatory responses elicited by ATP (100–150 μ m ) and nonadrenergic field stimulation (2–20 Hz) were blocked, whereas those elicited by carbachol (1–10μ m ) were augmented. 4 Intracellular electrical recordings demonstrated that AP 5 A and α,β‐Me ATP produced similar effects on membrane activity of the vas deferens. Concentration‐dependent depolarizations alone were produced by both substances until the voltage threshold for action potential discharge was attained; thereafter, action potential discharges were superimposed on the depolarization and an accompanying phasic contraction was recorded. Upon restoration of the membrane potential to its control value (5–10 min after addition of either AP 5 A or α,β‐Me ATP), excitatory junction potentials (e.j.ps) elicited by field stimulation (up to 3 Hz) and spontaneous e.j.ps were reduced by AP 5 A (> 0.1 μm) in a concentration‐dependent manner (as previously described for α,β‐Me ATP). 5 The antagonistic effects of AP 5 A on mechanical responses elicited by field stimulation were more quickly reversed on washout of AP 5 A than were the effects of α,β‐Me ATP, suggesting some dissimilarity in their mechanism of action at the receptor level. 6 The antagonistic effects of AP 5 A on the nonadrenergic contractile responses of the vas deferens were not produced by the structurally related P 1 ,P 4 ‐di‐(adenosine‐5′) tetraphosphate (AP 4 A) even with cumulative concentrations up to 200 μm 7 Desensitization of P 2 ‐purinoceptors can be produced by some nucleotide analogues such as AP 5 A and α,β‐Me ATP, whose activity may arise partly because of their structural conformation and stability.