Effects of a nucleoside transporter inhibitor, dilazep, on renal microcirculation in rats.
Adenosine, one of the endogenous modulators in renal hemodynamics, has recently been shown to be a mediator of tubuloglomerular feedback (TGF). Dilazep augments endogenous adenosine actions by blocking its cellular uptake. Our purpose in the present study was to clarify the effects of dilazep on renal microcirculation and the TGF mechanism. Clearance and micropuncture experiments were performed in anesthetized rats. TGF responsiveness was assessed in superficial nephrons by measuring the changes of early proximal flow rate (EPFR) in response to loop perfusion at 0-40 nl/min with artificial tubular fluid (ATF). Under dilazep administration (0.3 mg/kg+0.3 mg/kg/h i.v.) systemic BP and GFR were decreased and renal plasma flow was unaltered; as a result, the filtration fraction tended to decrease (p=0.076). Renal vascular resistance was reduced, but not to a significant degree. The reduction in EPFR by loop perfusion was similar between controls (47 +/- 2%) and rats administered dilazep i.v. (44 +/- 5%). Intraluminal application of dilazep in ATF suppressed TGF-mediated EPFR reduction to by 46 +/- 4%, 43 +/- 7%, and 37 +/- 3% at dilazep concentrations of 10(-6), 10(-5), and 10(-4) mol/l, respectively. TGF suppression with 10(-4) mol/l dilazep was reversed by co-perfusion of 10(-5) mol/l DMPX, a selective adenosine A2 receptor antagonist. DMPX alone did not affect TGF response. In conclusion, these results indicate that systemic dilazep dilates postglomerular arterioles and does not affect TGF, and thus reduces GFR. A pharmacological concentration of dilazep applied to single nephrons clearly attenuates TGF, indicating afferent arteriolar vasodilatation. Extracellular adenosine augmented by dilazep dilates glomerular vessels at both afferent and efferent sites, probably via the activation of A2 receptors.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004109:Dilazep / Q000494:pharmacology*; D005246:Feedback; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007678:Kidney Glomerulus / Q000187:drug effects / Q000502:physiology; D007684:Kidney Tubules / Q000187:drug effects / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000502:physiology; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D033703:Nucleoside Transport Proteins / Q000037:antagonists & inhibitors*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects*
D033703:Nucleoside Transport Proteins; D004109:Dilazep