Abstract
The present experiments investigated whether endothelium-derived mediators modulate the effect of natriuretic peptides in porcine coronary arteries. Rings with and without endothelium were suspended in organ chambers for isometric tension recording. Concentration-relaxation curves to C-type natriuretic peptide (CNP) and atrial natriuretic peptide (ANP) were obtained during contractions to endothelin-1. Removal of the endothelium potentiated relaxations to both CNP and ANP. Nω-nitro-l-arginine methyl ester potentiated relaxations to natriuretic peptides only in arteries with endothelium. Sodium nitroprusside (SNP) inhibited the response to the natriuretic peptides only in the absence of the endothelium. In rings with endothelium, 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one (ODQ) and 4H-8-bromo-1,2,4-oxadiazolo[3,4-d]benz[b][1,4]oxazin-1-one (NS2028) potentiated CNP-mediated relaxations. Iberiotoxin (IBTX) reduced the response only in rings without endothelium. Glybenclamide inhibited the relaxations in both the presence and absence of endothelium. CNP-induced relaxations were reduced by 8-bromoguanosine 3′,5′-cGMP (8-bromo-cGMP) to the same extent in rings with and without endothelium. There was no significant difference between the increased cGMP content caused by CNP in porcine coronary arteries with or without endothelium. In patch-clamp studies in porcine coronary arterial smooth muscle cells, the natriuretic peptide-mediated enhancement of the IBTX-sensitive big conductance calcium-activated potassium channel (BKCa) amplitude was reversed by SNP and 8-bromo-cGMP. These findings demonstrate that, in the porcine coronary artery, the opening of BKCa and ATP-dependent potassium channels of the vascular smooth muscle contributes to CNP-mediated relaxations. Endothelium-derived and exogenous NO inhibit the direct relaxing effect of natriuretic peptides by desensitizing the response of the BKCas of the vascular smooth muscle to the generation of cGMP.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.166652.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- ANP
- atrial natriuretic peptide
- BKCa
- big conductance calcium-activated potassium channel
- CNP
- C-type natriuretic peptide
- EDHF
- endothelium-derived hyperpolarizing factor
- eNOS
- endothelial nitric-oxide synthase
- IBMX
- 3-isobutyl-1-methyl-xanthine
- IKCa
- intermediate conductance calcium-activated potassium channel
- l-NAME
- Nω-nitro-l-arginine methyl ester
- NO
- nitric oxide
- NPR
- natriuretic peptide receptor
- NS1619
- 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one
- NS2028
- 4H-8-bromo-1,2,4-oxadiazolo[3,4-d]benz[b][1,4]oxazin-1-one
- ODQ
- 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one
- SKCa
- small conductance calcium-activated potassium channel
- TRAM-34
- 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole
- UCL-1684
- ditrifluoroacetate hydrate [6,12,19,20,25,26-hexahydro-5,27:13,18:21,24-trietheno-11,7-metheno-7H-dibenzo[b,m][1,5,12,16]tetraazacyclotricosine-5,13-diium ditrifluoroacetate hydrate]
- SNP
- sodium nitroprusside
- S18886
- sodium 3-((6R)-6-{[(4-chlorophenyl)sulfonyl]amido}-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl]propanoate
- AUC
- area under the curve
- IBTX
- iberiotoxin [N-p-[2-(5-chloro-2-methoxybenzamido)ethyl]benzenesulfonyl-N′-cyclohexylurea,5-chloro-N-[4-(cyclohexylureidosulfonyl)phenethyl]-2-methoxybenzamide (glybenclamide)]
- TP receptor
- thromboxane-prostaglandin receptor.
- Received January 28, 2010.
- Accepted March 22, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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