Rp diastereomeric analogs of cAMP inhibit both cAMP- and cGMP-induced dilation of hamster mesenteric small arteries.
Cross talk between the adenosine (3',5'-cyclic monophosphate) (cAMP) and the guanosine (3',5'-cyclic monophosphate) (cGMP) signalling pathways in vascular smooth muscle may occur such that cAMP may act through cGMP-dependent protein kinase rather than cAMP-dependent protein kinase to induce relaxation of this tissue. Therefore, it was hypothesized that due to this crosstalk, competitive antagonists of cAMP may not show much selectivity in inhibition of cAMP- or cGMP-induced vasodilation. To test this hypothesis, the effects of Rp-diastereomeric phosphorothioate derivatives of cAMP, putative competitive antagonists of cAMP at cAMP-dependent protein kinase, were assessed on vasodilation induced by Sp-phosphorothioate derivatives of cAMP, dibutyryl cAMP, 8-Br cGMP and sodium nitroprusside. Hamster mesenteric arteries (200-400 microns i.d.) were cannulated and pressurized to 75 mm Hg and constricted to approximately 50% of maximum with 1 mumol/l phenylephrine. Vasodilators were then added in cumulative fashion and diameter responses recorded in the absence and presence of (Rp)-adenosine (3',5'-cyclic monophosphorothioate) (Rp cAMPs) or (Rp)-8-(parachlorophenylthio) adenosine (3',5'-cyclic monophosphorothioate) (Rp 8CPT cAMPs). Rp cAMPs (0.1-0.5 mmol/l) inhibited dilations induced by the cAMP agonists, (Sp)-adenosine (3',5'-cyclic monophosphorothioate) (Sp cAMPs) and dibutyryl cAMP, but also inhibited dilations induced by 8-Br cGMP and sodium nitroprusside (p < 0.05 and n > 4 for all). In a more detailed study we found that Rp 8CPT cAMPs against Sp 8CPT cAMPs (3.6 +/- 1.2) was similar to the pA2 for Rp 8CPT cAMPs against 8-Br cGMP (4.1 +/- 1.2) (p > 0.05, d.f. = 37). These data support the hypothesis that both cAMP and cGMP act through a common protein kinase to cause vasodilation and urge caution in the use of Rp-diastereomeric analogs of cyclic nucleotides to dissect out specific signal transduction pathways in blood vessels.
Jackson
W F
WF
Department of Biological Sciences, College of Arts and Sciences, Western Michigan University, Kalamazoo 49008, USA.
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology*; D006224:Cricetinae; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D008833:Microcirculation; D011494:Protein Kinases / Q000494:pharmacology*; D013237:Stereoisomerism; D013873:Thionucleotides / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
D004791:Enzyme Inhibitors; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; C016276:8-bromocyclic GMP; D003994:Bucladesine; D000242:Cyclic AMP; D011494:Protein Kinases; D006152:Cyclic GMP