Enhanced vascular effects of cyclic GMP in septic rat aorta.
The modulation of vascular function by guanosine 3',5'-cyclic monophosphate (cGMP) in sepsis was examined in isolated rat aortas. Basal cGMP content was similar in aortas from sham-operated [3.6 +/- 0.8 (SE) pmol cGMP/mg protein] and from septic (3.2 +/- 1.0) rats. Acetylcholine-induced increases in cGMP content were significantly greater in aortas from sham (109.7 +/- 31.1) than aortas from septic rats (42.1 +/- 10.6). Maximal contractile performance by aortas from septic rats was impaired whether contractions were induced by the alpha 1-receptor agonist norepinephrine (497 +/- 49 mg tension/mg tissue vs. sham 749 +/- 43) or by KCl depolarization (265 +/- 31 vs. sham 613 +/- 79). Aortas from septic rats also exhibited a rightward-shifted dose response to norepinephrine. Inhibition of endogenous cGMP production by myoglobin or methylene blue treatment disproportionally improved responses by aortas from septic rats to both norepinephrine and KCl. In contrast, exposure of aortas to exogenous 8-bromo-cGMP engaged exaggerated vasodilatory responses in tissue from septic animals. Aortas from sham and septic rats contracted equally to stimulation by phorbol 12,13-dibutyrate. These findings indicate that reduced vascular contraction in sepsis is not mediated by altered cGMP levels, but rather that enhanced sensitivity to effects of cGMP may contribute to the disorder.
McKenna
T M
TM
Surgical Research Division, Naval Medical Research Institute, Bethesda, Maryland 20814-5055.
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D001424:Bacterial Infections / Q000378:metabolism / Q000503:physiopathology*; D001688:Biological Products / Q000037:antagonists & inhibitors; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009211:Myoglobin / Q000494:pharmacology; D009569:Nitric Oxide; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014661:Vasoconstriction / Q000187:drug effects
D001688:Biological Products; D009211:Myoglobin; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D011189:Potassium Chloride; D006152:Cyclic GMP; D008751:Methylene Blue; D009638:Norepinephrine