Abstract
We recently demonstrated that U46619 (9-11-dideoxy-11α,9a-epoxymethano-prostaglandin F2a) evoked a medullary vasodilation and a reduction in blood pressure despite a potent cortical vasoconstriction in the anesthetized rat. The present study tested the hypothesis that nitric oxide (NO) and prostanoids contribute to U46619-induced increase in medullary blood flow (MBF). U46619 at 1, 3, and 5 μg/kg increased MBF (above basal values) by 16 ± 3, 45 ± 10, and 58 ± 8 perfusion units, respectively, and increased NO current in the medulla by 17 ± 4, 34 ± 7, and 60 ± 12 pA, respectively.Nω-l-Nitro-arginine methyl ester (5 mg/kg), the inhibitor of NO production, attenuated the increase in MBF (75 ± 8%, p < 0.05) as did indomethacin (10 mg/kg), the inhibitor of cyclooxygenase (38 ± 5%, p < 0.05), suggesting the involvement of NO and dilator prostanoids. H-Arg-Lys-Arg-Ala-Arg-Lys-Glu-OH, a synthetic peptide and selective inhibitor of cGMP-dependent protein kinase, attenuated U46619-induced medullary perfusion (52 ± 6%,p < 0.05), but H-89 ((N-[2-((p-bromocinnamyl)aminoethyl)]-5-isoquinolinesulfonamide hydrochloride), a cell-permeable, selective, and potent inhibitor of cAMP-dependent protein kinase A, was without effect. Glybenclamide, a KATP channel blocker, also blunted the increase by U46619 in MBF (58 ± 7%, p < 0.05). These data suggest that NO and prostanoids contribute to U46619-induced medullary perfusion and that the effects of these mediators are coupled to activation of protein kinase G and KATP channels but not protein kinase A.
Footnotes
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This work was supported by National Institutes of Health Grants HL59884 and HL03674. A.O.O. is an Established Investigator of the American Heart Association (Award # 0040119N). The facilities of the Research Center for Minority Investigators were used for these studies. The findings in this study were presented at the 55th Annual Fall Conference and Scientific Sessions of the Council for High Blood Pressure Research, September 22–25, 2001.
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DOI: 10.1124/jpet.102.040170
- Abbreviations:
- PG
- prostaglandin
- COX
- cyclooxygenase
- U46619
- 9-11-dideoxy-11α,9a-epoxymethano-prostaglandin F2a
- TxA2
- thromboxane A2
- ET
- endothelin
- NO
- nitric oxide
- l-NAME
- Nω-l-nitro-arginine methyl ester
- H-89
- (N-[2-((p-bromocinnamyl)aminoethyl)]-5-isoquinolinesulfonamide hydrochloride
- PKGI
- protein kinase G inhibitor (H-Arg-Lys-Arg-Ala-Arg-Lys-Glu-OH)
- MBF
- medullary blood flow
- MABP
- mean arterial blood pressure
- PE
- phenylephrine
- PU
- perfusion unit(s)
- Received June 20, 2002.
- Accepted September 20, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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