Maturation depresses cGMP-mediated decreases in [Ca2+]i and Ca2+ sensitivity in ovine cranial arteries.
Because cerebrovascular cGMP levels vary significantly during maturation, we examined the hypothesis that the ability of cGMP to relax cerebral arteries also changes during maturation. In concentration-response experiments, potassium-induced tone in basilar arteries was significantly more sensitive to a nonmetabolizable cell-permeant cGMP analogue 8-(p-chlorophenylthio)-cGMP (8-pCPT-cGMP) in term fetal [-log one-half maximal concentration (EC(50)) = 4.4 +/- 0.1 M] than in adult (-log EC(50) = 4.0 +/- 0.1 M) ovine basilar arteries. Serotonin-induced tone also revealed significantly greater sensitivity to the cGMP analogue in fetal (-log EC(50) = 4.9 +/- 0.1 M) than in adult (-log EC(50) = 4.7 +/- 0.1 M) basilars. In fura 2-loaded preparations, 8-pCPT-cGMP had no significant effect on cytosolic calcium concentrations in potassium-contracted arteries but at 6 microM significantly reduced calcium only in fetal basilars (Delta = 33 +/- 8%). Higher 8-pCPT-cGMP concentrations reduced cytosolic calcium in both fetal and adult basilars. Similarly, in both potassium- and 5-hydroxytryptamine (5-HT)-contracted preparations, low concentrations of 8-pCPT-cGMP reduced myofilament calcium sensitivity only in fetal basilars (Delta = 29 +/- 6 and Delta = 42 +/- 10%, respectively), whereas higher concentrations reduced calcium sensitivity in both fetal and adult arteries. In beta-escin-permeabilized arteries, equivalent reductions in basal and agonist-enhanced myofilament calcium sensitivity were produced by much lower 8-pCPT-cGMP concentrations in fetal (172 and 61 microM, respectively) than in adult (410 and 231 microM, respectively) basilars. The mechanisms mediating cGMP-induced vasorelaxation appear similar in fetal and adult arteries, with the exception that they are much more sensitive to cGMP in fetal than adult arteries. These age-related differences in the sensitivity of cytosolic calcium concentration, basal, and agonist-enhanced myofilament calcium sensitivity to cGMP can easily explain why both potassium- and 5-HT-induced tone are more sensitive to cGMP in fetal than adult cerebral arteries.
Nauli
S M
SM
Department of Physiology, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California 92350, USA.
Zhang
L
L
Pearce
W J
WJ
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002536:Cerebral Arteries / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000502:physiology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D005260:Female; D005456:Fluorescent Dyes; D016257:Fura-2; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011247:Pregnancy; D012756:Sheep; D013873:Thionucleotides / Q000494:pharmacology*; D014664:Vasodilation / Q000502:physiology*
D005456:Fluorescent Dyes; D010975:Platelet Aggregation Inhibitors; D013873:Thionucleotides; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C055656:8-((4-chlorophenyl)thio)cyclic-3',5'-GMP; D006152:Cyclic GMP; D002118:Calcium; D016257:Fura-2