Universität zu Köln

Welter, Johannes, Pfitzer, Gabriele, Grisk, Olaf, Hescheler, Juergen and Lubomirov, Lubomir T. (2020). Epac-mediated relaxation in murine basilar arteries depends on membrane permeability of cyclic nucleotide analogues and endothelial aging. Gen. Physiol. Biophys., 39 (2). S. 157 - 169. BRATISLAVA: GENERAL PHYSIOL AND BIOPHYSICS. ISSN 1338-4325

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Abstract

Cerebral blood supply is finely tuned by regulatory mechanisms depending on vessel caliber the disruption of which contributes to the development of diseases such as vascular dementia, Alzheimer's and Parkinson 's diseases. This study scopes whether cAMP-mimetic-ligands relax young and aged murine cerebral arteries, whether this relates to the activation of PKA or Epac signaling pathways and is changed with advanced age. The hormone Urocortin-1 relaxed submaximally contracted young and old basilar arteries with a similar pD(2) and DmAx (similar to -8.5 and similar to 90% in both groups). In permeabilized arteries, PKA activation by 6-Bnz-cAMP or Epac activation by 8-pCPT-2'-O-Me-cAMP also induced relaxation with pD(2) of -6.3 vs. -5.8 in old for PKA-ligands, and -4.4 and -4.0 in old for Epac-ligands. Furthermore, aging significantly increased submaximal Ca2+-induced force. The effect of 8-pCPT-2'-O-Me-cAMP on intact arteries was attenuated by aging or nitric oxide synthase inhibition. No relaxing effect in both age-groups was observed after treatment with PKA-activator, Sp-6-Phe-cAMPS. In conclusion, our results suggest that in intact basilar arteries relaxation induced by cAMP-mimetics refers only to the activation of Epac and is impaired by smooth muscle and endothelial aging. The study presents an interesting option allowing therapeutic discrimination between both pathways, possibly for the exclusive activation of Epac in brain circulatory system.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Welter, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfitzer, Gabriele UNSPECIFIED UNSPECIFIED UNSPECIFIED Grisk, Olaf UNSPECIFIED UNSPECIFIED UNSPECIFIED Hescheler, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Lubomirov, Lubomir T. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-350948
DOI:	10.4149/gpb_2019055
Journal or Publication Title:	Gen. Physiol. Biophys.
Volume:	39
Number:	2
Page Range:	S. 157 - 169
Date:	2020
Publisher:	GENERAL PHYSIOL AND BIOPHYSICS
Place of Publication:	BRATISLAVA
ISSN:	1338-4325
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MYOSIN LIGHT-CHAIN; SMOOTH-MUSCLE; CA2+ SENSITIZATION; NITRIC-OXIDE; PHOSPHORYLATION; PHOSPHATASE; UROCORTIN; PROTEINS; KINASE; SITES Multiple languages Biochemistry & Molecular Biology; Biophysics; Physiology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/35094