Abstract
Many vasoactive agents produce qualitatively similar effects on blood flow in the renal cortex and medulla, evoking reductions or increases in blood flow in both regions. We demonstrated previously that endothelin-1 (ET-1) is an exception because it evoked an increase in medullary perfusion despite a potent cortical vasoconstriction (Hercule and Oyekan, 2000). We report here that U46619 (11,9 epoxymethano-prostaglandin H2), a selective agonist of prostaglandin H2 (PGH2)/thromboxane A2 (TxA2) (TP) receptor, evokes similar effects as ET-1. In the pentobarbital-anesthetized (60 mg/kg) rat, 1, 3, and 5 μg/kg U46619 dose dependently reduced mean arterial blood pressure by −2 ± 4, −8 ± 10, and −31 ± 10 mm Hg, respectively; renal cortical blood flow (CBF) by −50 ± 11, −174 ± 45, and −349 ± 43 perfusion units (PU), respectively; but increased medullary blood flow (MBF) by 42 ± 16, 51 ± 18, and 61 ± 21 PU, respectively. Prostaglandin F2α, a TxA2 mimetic, produced similar effects as U46619. SQ29548 ([1S-[1α,2α(Z), 3α,4α]]-7-[3[[2-[(phenylamino)carbonyl[hydrazino] methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid) (0.1 mg/kg), an antagonist of PGH2/TxA2 (TP), blunted U46619-induced hemodynamic changes without affecting that produced by phenylephrine. BMS182874 [5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyd)-1-naphthalene sulfonamide] (40 mg/kg), an ETA-selective antagonist, blunted U46619-induced reduction in CBF by 54 ± 9% (p < 0.05) and the increase in MBF by 59 ± 18% (p < 0.05). Similarly, BQ788 (N-cis2,6-dimethylpiperidinocarbonyl-l-γ-methylleucyl-d-1-methoxycarbonyltryptophanyl-d-norleucine) (1 mg/kg), an ETB-selective antagonist, blunted the effects of U46619 on CBF and MBF by 19 ± 3% (p < 0.05) and 48 ± 19% (p < 0.05), respectively. Combined administration of BMS182874 and BQ788 further attenuated U46619-induced reduction in CBF by 67 ± 8% (p < 0.05) and that on MBF by 61 ± 18% (p < 0.05). Phosphoramidon (10 mg/kg), an endothelin converting enzyme inhibitor, markedly blunted U46619-induced changes on CBF and MBF (p < 0.05). These findings are the first to demonstrate that U46619, through activation of ETA and ETB receptors, elicits renal cortical vasoconstriction and medullary vasodilation in the rat.
Footnotes
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This work was supported by National Institutes of Health Grants RO1 HL59884 and UH1 HL03674. Dr. Oyekan is an Established Investigator of the American Heart Association (Award 0040119N). The facilities of the Research Center in Minority Institutions' program at Texas Southern University were used for these studies.
- Abbreviations:
- AII
- angiotensin II
- ET
- endothelin
- TxA2
- thromboxane A2
- PGH2
- prostaglandin H2
- TP
- PGH2/TxA2
- MABP
- mean arterial blood pressure
- CBF
- cortical blood flow
- PE
- phenylephrine
- PU
- profusion units
- MBF
- medullary blood flow
- CVR
- cortical vascular resistance
- MVR
- medullary vascular resistance
- U46619
- 11,9 epoxymethano-prostaglandin H2
- SQ29548
- [1S-[1α,2α(Z), 3α,4α]]-7-[3[[2-[(phenylamino)carbonyl[hydrazino] methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
- BMS182874
- 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyd)-1-naphthalene sulfonamide
- BQ788
- N-cis 2,6 -dimethylpiperidinocarbonyl-l-γ-methylleucyl-d-1-methoxycarbonyltryptophanyl-d-norleucine
- Received March 9, 2001.
- Accepted July 6, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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