The abnormal renal vasodilator response to D1-like receptor stimulation in conscious SHR can be normalized by AT1 blockade.
BACKGROUND
We previously showed that the renal vasodilator response to a D1-like receptor agonist is blunted in conscious SHR compared with WKY rats. The mechanism of this impaired dopaminergic responsiveness in SHR is unclear. An altered balance between the renin-angiotensin-aldosterone system (RAAS) and the dopaminergic system may be involved. To determine the interaction between the RAAS and the dopaminergic system in the blunted D1-like responsiveness in SHR, we studied the renal vasodilator response to the D1-like receptor agonist fenoldopam before and after 7 days of pretreatment with the AT1-receptor antagonist (AT1-A) L158,809 in conscious SHR and WKY rats.


METHODS
Effective renal plasma flow (ERPF) was measured by the clearance of I-hippuran. Mean arterial pressure (MAP) was measured via an intraarterial catheter.


RESULTS
Without pretreatment, MAP was reduced to comparable degrees by fenoldopam in WKY (-7 +/- 4%, ns) and SHR (-6 +/- 1%, P < 0.05). However, ERPF was significantly more increased (P < 0.006) by fenoldopam in WKY (+26 +/- 2%, P < 0.0001) than in SHR (+2 +/- 2%, ns). AT1-A treatment reduced MAP and increased ERPF and glomerular filtration rate significantly in both strains. Pretreatment with AT1-A significantly potentiated the fenoldopam-induced rise in ERPF in SHR, but not in WKY, without affecting the blood pressure responses in either strain. As a result, during pretreatment with an AT1-A, the rise in ERPF by fenoldopam was similar in both strains (SHR +25 +/- 2%, P < 0.0001; WKY +33 +/- 2%, P < 0.0001).


CONCLUSIONS
These results suggest that the RAAS accounts for the blunted renal vasodilator response to a D1-like receptor agonist in SHR. A dysbalance between the dopaminergic system and the RAAS may be involved in the abnormal renal hemodynamic regulation in SHR.
de Vries
P A Marcel
PA
Departments of Clinical Pharmacology, Groningen University Institute for Drug Exploration (GUIDE), State University, Groningen, The Netherlands. P.A.M.de.Vries@int.azg.nl
de Zeeuw
Dick
D
de Jong
Paul E
PE
Navis
Gerjan
G
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D018818:Fenoldopam / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000503:physiopathology*; D007677:Kidney Function Tests; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017447:Receptors, Dopamine D1 / Q000187:drug effects*; D017596:Renal Plasma Flow, Effective / Q000187:drug effects / Q000502:physiology; D013045:Species Specificity; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D017447:Receptors, Dopamine D1; D013777:Tetrazoles; C070967:L 158809; D018818:Fenoldopam