Slow off-rate of prazosin accounts for deviations from competitive antagonism in the isolated perfused kidney of rat.
1. The kinetics of the interaction of prazosin with noradrenaline, administered by bolus injection and infusion, was examined in the isolated perfused rat kidney. 2. Prazosin (1-30 nM) competitively antagonized vasoconstrictor responses to infusion of noradrenaline (pA2 = 9.51) whereas antagonism toward bolus injections of noradrenaline deviated from competition. 3. In the presence of prazosin, responses to bolus injection of noradrenaline became biphasic whereas the kinetics of the responses to infusions of noradrenaline were unchanged. 4. In contrast, phentolamine (30-300 nM) competitively antagonized responses to bolus injection of noradrenaline without altering response kinetics and in coperfusion studies with prazosin, prevented prazosin from inducing biphasic responses to bolus injection of noradrenaline. 5. It is concluded that prazosin acts as a pseudoirreversible antagonist toward vasoconstrictor responses to bolus injections noradrenaline (non-steady state conditions) whereas steady state conditions and competitive kinetics are observed with infused noradrenaline.
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Institute of Pharmacology, Syntex Research, Palo Alto, CA 94304.
Clarke
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D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007700:Kinetics; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010477:Perfusion; D010646:Phentolamine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology*; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects
D011942:Receptors, Adrenergic, alpha; D009638:Norepinephrine; D011224:Prazosin; D010646:Phentolamine