Impaired cyclic nucleotide‐mediated vasorelaxation may contribute to closure of the human umbilical artery after birth

Abstract

1 The mechanical and biochemical effects of agents that relax vascular smooth muscle either through elevation of guanosine 3':5'-cyclic monophosphate (cyclic GMP) or adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were compared in isolated ring preparations of human umbilical artery and rat aorta. Tone was established by preconstriction with 5-hydroxytryptamine. 2 The endothelium-dependent vasodilator calcium ionophore (A23187) (which stimulates endotheliumderived relaxing factor [EDRF] release and thus acts through soluble guanylyl cyclase), sodium nitroprusside (which stimulates soluble guanylyl cyclase directly), and atrial natriuretic peptide (which stimulates particulate guanylyl cyclase) relaxed rat aorta but not human umbilical artery.3 Sodium nitroprusside, 101aM, increased cyclic GMP levels from 10 to 390pmolmg-' protein at 2min in rat aorta, as compared with a slower, relatively attenuated rise from 5 to 116pmolmg-' protein after 15 min in human umbilical artery. The rise in cyclic GMP in the umbilical artery was not significantly augmented by the cyclic GMP phosphodiesterase inhibitor, MB22948. Atrial natriuretic peptide increased cyclic GMP levels in rat aorta but not in human umbilical artery. 4 Forskolin, 10 gLM, which stimulates both soluble and particulate adenylyl cyclase, maximally relaxed rat aorta and increased cyclic AMP levels from 15 to 379 pmol mg-'protein at 15 min, but did not significantly relax or increase cyclic AMP levels in human umbilical artery. After preincubation with the cyclic nucleotide phosphodiesterase inhibitor, IBMX, 10 JiM forskolin increased cyclic AMP levels to 1365 pmol mg-' protein at 30 min in human umbilical arteries, but these high levels were not accompanied by mechanical relaxation. 5 8-Bromo-cyclic GMP and 8-bromo-cyclic AMP which are lipophilic analogues of cyclic GMP and cyclic AMP, both maximally relaxed the rat aorta at a concentration of 10 JAM, but did not significantly relax the human umbilical artery. 6 The findings indicate that elevated cyclic nucleotide levels are not associated with mechanical relaxation of the post-partum human umbilical artery, as in other vessels such as rat aorta. This impaired response to cyclic nucleotides may contribute to closure of the umbilical artery after birth.

Endothelium-lndependent Relaxations to Acetylcholine and A23187 in the Human Umbilical Artery

“…Chaudhuri et al [20] reorted that the HUA relaxed to the NO donor SNAP; however, sensitivity, compared to cho rionic artery and bovine pulmonary artery strips, was low er. Our data and the data of Chaudhuri et al [20], how ever, are in apparent disagreement with those reported by Renowden et al [31 ] who reported the failure of the HUA to respond to sodium nitroprusside. We have not exten sively investigated the effects of sodium nitroprusside on our HUA preparations, however, in those few prepara tions in which the effects of sodium nitroprusside were tested, the relaxation was clearly apparent.…”

The small heat shock protein, HSPB6, in muscle function and disease

“…Unlike other vascular muscle tissues, HUASM is refractory to cyclic nucleotide-dependent vasorelaxation (Renowden et al 1992;Bergh et al 1995;Brophy et al 1997;Flynn et al 2005). Furthermore, activation of the cyclic nucleotidedependent signaling pathway does not lead to increased phosphorylation of HSPB6 in HUASM.…”

Small Heat Shock Proteins and Vasospasm in Human Umbilical Artery Smooth Muscle1

“…However, umbilical artery smooth muscle is uniquely refractory to relaxation induced by activators of cyclic nucleotide-dependent signaling pathways [2,5]. This suggests that umbilical artery vasospasm may be due to an imbalance between the responses to endogenous vasoconstrictors and vasorelaxants.…”

“…FAX: (706) 823-3949; e-mail: colleenb@mail.mcg.edu cyclic nucleotide concentrations lead to relaxation of smooth muscles are not known, increases in cAMP and cGMP activate cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG), respectively [3,4]. Increases in cAMP and cGMP have been demonstrated in umbilical artery smooth muscle in response to forskolin and sodium nitroprusside [2,5]. However, there is no increase in the phosphorylation of a 20-kDa cyclic nucleotide-dependent protein kinase substrate in umbilical artery smooth muscle treated with forskolin or sodium nitroprusside [2].…”