atrial-natriuretic-factor and alpha-beta-methyleneadenosine-5--triphosphate

This study tested the hypothesis that neuromodulatory effects of atrial natriuretic factor (ANF) are mediated by an activation of potassium channels in the rabbit isolated vas deferens. The neuromodulatory effects of ANF were tested in the presence of the potassium channel inhibitors, tetraethylammonium, 4-aminopyridine, glibenclamide and charybdotoxin. The effects of the first three were ascertained by their prevention of neuromodulatory effects of a cromokalim enantiomer (BRL 38227), which opens ATP-sensitive potassium channels. The nonspecific potassium channel inhibitors, tetraethylammonium (2 mM) and 4-aminopyridine (2 mM) blocked inhibitory effects of both ANF and BRL 38227 on the electrically-induced adrenergic contraction in the rabbit vas deferens. Glibenclamide (10 microM), an inhibitor of ATP-sensitive potassium channels, failed to antagonize ANF effects, but blocked the actions of BRL 38227. Charybdotoxin (100 nM) is known to block large conductance calcium-activated potassium channels, and it attenuated the neuromodulatory effects of ANF; however, the effects of BRL 38227 were sustained in the presence of charybdotoxin. These results are consistent with the hypothesis that the neuromodulatory action of ANF is mediated by the activation of potassium conductances. The potassium channel involved is not an ATP-sensitive channel, because glibenclamide failed to alter the neuromodulatory activity of ANF. We hypothesize that ANF effects could be mediated by an activation of either calcium-activated or outward rectifying potassium channels.

Topics: 4-Aminopyridine; Adenosine Triphosphate; Animals; Atrial Natriuretic Factor; Benzopyrans; Charybdotoxin; Cromakalim; Glyburide; In Vitro Techniques; Male; Muscle Contraction; Norepinephrine; Potassium Channel Blockers; Potassium Channels; Prazosin; Pyrroles; Rabbits; Receptors, Adrenergic; Scorpion Venoms; Synaptic Transmission; Tetraethylammonium; Tetraethylammonium Compounds; Vas Deferens

ATP has been reported to increase basal and atrial natriuretic factor (ANF)-stimulated guanylate cyclase activity. The structural features of ATP involved in the activation of guanylate cyclase were examined by employing a variety of ATP analogs with modification either at the phosphate chain or at the ribose moiety. Among the natural adenine nucleotides, ATP and ADP were able to increase both basal and ANF-stimulated guanylate cyclase activities in rat lung membranes. AMP had no effect. ATP was more effective than AMPPCP (the non-hydrolyzable analog of ATP), and ADP was more effective than ADP beta S and AMPCP (the hydrolysis-resistant analogs of ADP) to increase basal and ANF-stimulated guanylate cyclase activities. Removal of the oxygen atom from the ribose moiety of ATP or ADP significantly reduced their potency. Thus, the length of the phosphate chain and the hydroxyl groups at the ribose moiety are both determinants for nucleotide mediated guanylate cyclase activation.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Atrial Natriuretic Factor; Dose-Response Relationship, Drug; Guanylate Cyclase; In Vitro Techniques; Lung; Male; Membranes; Rats; Rats, Inbred Strains; Thionucleotides