Clopidogrel Partially Counteracts Adenosine-5'-Diphosphate Effects on Blood Pressure and Renal Hemodynamics and Excretion in Rats

Malwina Monika Roszkowska-Chojecka; Agnieszka Walkowska; Janusz Sadowski; Leszek Dobrowolski

doi:10.1016/j.amjms.2018.04.013

Clopidogrel Partially Counteracts Adenosine-5'-Diphosphate Effects on Blood Pressure and Renal Hemodynamics and Excretion in Rats

Am J Med Sci. 2018 Sep;356(3):287-295. doi: 10.1016/j.amjms.2018.04.013. Epub 2018 Apr 27.

Authors

Malwina Monika Roszkowska-Chojecka¹, Agnieszka Walkowska¹, Janusz Sadowski¹, Leszek Dobrowolski²

Affiliations

¹ Department of Renal and Body Fluid Physiology, M. Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
² Department of Renal and Body Fluid Physiology, M. Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland. Electronic address: lesdobro@imdik.pan.pl.

PMID: 30293555
DOI: 10.1016/j.amjms.2018.04.013

Abstract

Background: Adenosine-5'-diphosphate (ADP) can influence intrarenal vascular tone and tubular transport, partly through activation of purine P2Y12 receptors (P2Y12-R), but their actual in vivo role in regulation of renal circulation and excretion remains unclear.

Methods: The effects of intravenous ADP infusions of 2-8mg/kg/hour were examined in anesthetized Wistar rats that were untreated or chronically pretreated with clopidogrel, 20mg/kg/24hours, a selective P2Y12-R antagonist. Renal blood flow (transonic probe) and perfusion of the superficial cortex and medulla (laser-Doppler fluxes) were measured, together with urine osmolality (U_osm), diuresis (V), total solute (U_osmV), sodium (U_NaV) and potassium (U_KV) excretion.

Results: ADP induced a gradual, dose-dependent 15% decrease of mean arterial pressure, a sustained increase of renal blood flow and a 25% decrease in renal vascular resistance. Clopidogrel pretreatment attenuated the mean arterial pressure decrease, and did not significantly alter renal blood flow or renal vascular resistance. Renal medullary perfusion was not affected by ADP whereas U_osm decreased from 1,080 ± 125 to 685 ± 75 mosmol/kg H₂0. There were also substantial significant decreases in U_osmV, U_NaV and U_KV; all these changes were attenuated or abolished by clopidogrel pretreatment. Two-weeks' clopidogrel treatment decreased V while U_osmU_osmV and U_NaV increased, most distinctly after 7 days. Acute clopidogrel infusion modestly decreased mean arterial pressure and significantly increased outer- and decreased inner-medullary perfusion.

Conclusions: Our functional studies show that ADP can cause systemic and renal vasodilation and a decrease in mean arterial pressure, an action at least partly mediated by P2Y12 receptors. We confirmed that these receptors exert tonic action to reduce tubular water reabsorption and urine concentration.

Keywords: Adenosine-5′-diphosphate; Clopidogrel; P2Y12 receptor; Renal blood flow; Urine concentration ability.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Diphosphate / pharmacology*
Animals
Blood Flow Velocity / drug effects
Blood Pressure / drug effects*
Clopidogrel / antagonists & inhibitors
Clopidogrel / pharmacology*
Dose-Response Relationship, Drug
Kidney Cortex* / blood supply
Kidney Cortex* / physiopathology
Kidney Medulla* / blood supply
Kidney Medulla* / physiopathology
Male
Rats
Rats, Wistar
Receptors, Purinergic P2 / metabolism
Receptors, Purinergic P2Y12
Vascular Resistance / drug effects*

Substances

P2ry12 protein, rat
Receptors, Purinergic P2
Receptors, Purinergic P2Y12
Adenosine Diphosphate
Clopidogrel