Linked Life Data

1714013

Source:http://linkedlifedata.com/resource/pubmed/id/1714013

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
1991-9-11
pubmed:abstractText
Using a series of functional criteria, we wished to evaluate the K+ conductance mechanism and the cyclic GMP mechanism implicated in the actions of nicorandil (NIC) as a vasodilator. In rabbit isolated superior mesenteric artery, NIC exhibited two relaxation dose-response curves (DRCs): one with a lower IC50 of 4.8 x 10(-6) M for norepinephrine (NE 5 microM) contraction, and another with a higher IC50 of 1.4 x 10(-4) M for 80 mM K+ contraction. K+ channel blockers (TEA 1-10 mM), Ba2+ (0.1-0.5 mM), glyburide (1 microM), and increased [K+]ex (20 mM), all caused significant attenuations in the ability of NIC to relax NE contraction, but did not influence the ability of NIC to relax high-K+ contraction. Pretreatment with 5 microM methylene blue, a guanylate cyclase inhibitor, produced a pronounced inhibition of nitroglycerine (NTG) relaxation, but only a marginal inhibitory effect on the NIC relaxation DRC for NE contraction. Functional studies demonstrated that the inhibitory effect of NIC on NE-sensitive intracellular Ca2+ release occurred in the same concentration range as that required for relaxation of 80 mM K+ contractions (10(-5)-10(-3) M). Furthermore, NIC also caused increases in cellular cyclic GMP levels at this higher concentration range. Finally, NIC relaxation of NE contraction was not prone either to self-tolerance (30 mM NIC preexposure) or cross-tolerance (0.55 mM NTG preexposure) development. In contrast, a modest but significant degree of self-tolerance to NIC could be demonstrated under high-K+ contraction condition. These studies thus show the existence of both cellular mechanisms for NIC in the same vascular preparation and further show that these two mechanistic components are separate and independent. The K+ channel-dependent component occurs at lower concentrations, is blocked by K+ channel blockers, is not inhibited by methylene blue, is not associated with increases in cyclic GMP, and is not prone to tolerance development. In this, NIC resembles other K+ channel openers. The cyclic GMP-dependent component is evident at relatively higher concentrations, is associated with inhibition of [Ca2+]i release, is associated with increases in cyclic GMP levels, and is prone to tolerance development. In this, NIC resembles other nitrovasodilators. A combination of these characteristics of the actions of NIC may contribute to the differences in the acute versus chronic hemodynamic profile of NIC.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0160-2446
pubmed:author
pubmed:issnType
Print
pubmed:volume
17
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
903-12
pubmed:dateRevised
2003-11-14
pubmed:meshHeading
pubmed:year
1991
pubmed:articleTitle
Nicorandil-induced vasorelaxation: functional evidence for K+ channel-dependent and cyclic GMP-dependent components in a single vascular preparation.
pubmed:affiliation
Cardiovascular Diseases Research, Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
pubmed:publicationType
Journal Article