Acute cardiovascular effects of the calcimimetic R-568 and its enantiomer S-568 in rats.
Calcimimetics increase the sensitivity of the calcium sensing receptor (CaSR) to calcium ions (Ca(2+)) and allow for efficient control of uraemic hyperparathyroidism. Recent studies suggested an additional blood pressure-lowering action, the underlying mechanisms are as yet unknown. We infused R-568 and its enantiomer S-568, which has little activity at the CaSR, in anaesthetized rats. Mean arterial blood pressure (MAP) and heart rate (HR) were measured in the femoral artery; renal blood flow (RBF) and mesenteric blood flow (MBF) were measured locally. Infusion of R-568 at 0.7 mg/kg per 10 min into the femoral vein, a dose known to reduce levels of parathyroid hormone (PTH) and Ca(2+) in plasma, did not affect blood pressure or heart rate. Infusion of 2.1 mg/kg per 3 min of R-568 and S-568 into the femoral vein significantly reduced MAP by 26 +/- 4.5 and 23.7 +/- 3.1% and HR by 7.8 +/- 2.9 and 5.8 +/- 2.0%, respectively. Intra-arterial infusions of R-568 increased blood flow in a dose-dependent fashion. At plasma concentrations of 70 micromol/l R-568 and S-568 increased RBF by 17 +/- 3 and 15 +/- 3% and MBF by 28 +/- 5 and 29 +/- 5%. The effects on blood flow were greater in the mesenteric artery than in the renal artery, but not different between both compounds.The calcimimetic R-568 exerts acute, CaSR-independent, hypotensive effects via vasodilation and negative chronotropy at concentrations exceeding those required for modulation of PTH secretion.
Nakagawa
Kumiko
K
Division of Paediatric Nephrology, Centre for Paediatric and Adolescent Medicine, University of Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.
Parekh
Niru
N
Koleganova
Nadezda
N
Ritz
Eberhard
E
Schaefer
Franz
F
Schmitt
Claus Peter
CP
D000814:Aniline Compounds / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D010627:Phenethylamines; D011437:Propylamines; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D013152:Splanchnic Circulation / Q000187:drug effects*; D013237:Stereoisomerism
D000814:Aniline Compounds; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010627:Phenethylamines; D011437:Propylamines; D044169:Receptors, Calcium-Sensing