NUCLEOSIDE-INDUCED ARTERIOLAR CONSTRICTION - A MAST CELL-DEPENDENT RESPONSE

Adenosine (Ado) is a potent vasodilator that has occasionally been sho wn to cause vasoconstriction. Constrictor responses are generally attr ibuted to A(1)-receptor stimulation or interactions with the renin-ang iotensin system. We describe a previously unreported vasoconstrictor a ction of Ado and inosine (Ino) in hamster cheek pouch arterioles and e xamine the mechanism by which these nucleosides induce constriction. A rterioles were dissected from male Golden hamster cheek pouches, trans ferred to a 37 degrees C tissue chamber, and cannulated at both ends. Changes of luminal diameter in response to Ado were measured to genera te cumulative concentration-response curves. The concentration-respons e curves were biphasic: 10(-6) M Ado elicited an intense, transient co nstriction, and higher concentrations induced dilator responses. Pretr eatment with 8(p-sulfophenyl)theophylline, an Ado receptor antagonist, inhibited the dilator responses but did not alter the constriction. I nhibition of Ado uptake with S-(4-nitrobenzyl)-6-thio-inosine eliminat ed the constrictor response without altering dilator responses. Simila r effects were found after pretreatment with an Ado deaminase inhibito r erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride. Finally, Ino, a metabolite of Ado, induced constrictions of similar magnitude to those seen with Ado, but at higher concentrations. The constrictor response was focal in nature, suggesting discrete sites of action of Ado. Meth ylene blue staining after Ado application revealed degranulated mast c ells closely associated with the vessel wall, indicating a possible ro le for mast cell degranulation in the constrictor response. Supporting this idea were the observations that inhibition of degranulation by 1 0 mu M cromolyn blocked the constrictor response, and compound 48/80 ( a mast cell secretagogue) caused constriction similar to that elicited by Ado. We hypothesize that these constrictions are either due to upt ake and intracellular metabolism of the nucleosides or to activation o f a non A(1)/A(2)-receptor (e.g., the A(3)-receptor) with resultant de granulation and subsequent vasoconstriction.