TY - JOUR T1 - The T- and L-Type Calcium Channel Blocker (CCB) Mibefradil Attenuates Leg Edema Induced by the L-Type CCB Nifedipine in the Spontaneously Hypertensive Rat: A Novel Differentiating Assay JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 723 LP - 731 DO - 10.1124/jpet.107.133892 VL - 325 IS - 3 AU - Terry C. Major AU - Shantanu Dhamija AU - Nicole Black AU - Serguei Liachenko AU - Brandy Morenko AU - Gregg Sobocinski AU - Carlin Okerberg AU - Paula Tinholt AU - Steven Madore AU - Mark C. Kowala Y1 - 2008/06/01 UR - http://jpet.aspetjournals.org/content/325/3/723.abstract N2 - Among the L-type calcium channel blockers (CCBs), particularly dihydropyridines like nifedipine [1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester], a common adverse effect is vasodilatory edema. Newer CCBs, such as the T- and L-type CCB, mibefradil [(1S,2S)-2-[2[[3-(2-benzimidazolylpropyl]methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl methoxyacetate dihydrochloride hydrate], demonstrate antihypertensive efficacy similar to that of their predecessors but seem to have a reduced propensity to cause edema. Using a magnetic resonance imaging (MRI) T2 mapping technique, we investigated the ability of mibefradil to reduce extracellular water accumulation caused by the L-type CCB, nifedipine, in the hindleg skeletal muscle of the spontaneously hypertensive rat. Mibefradil (10 mg/kg i.v.) and nifedipine (1 mg/kg i.v.) lowered mean arterial blood pressure by 97 ± 5 and 77 ± 4 mm Hg, respectively. MRI edema index (expressed as percentage increase of integral T2 over predrug control) was significantly higher with nifedipine (2606 ± 86%; p < 0.05) than with mibefradil (981 ± 171%) measured 30 to 60 min after the start of drug infusion. The hindleg edema caused by nifedipine was dose dependently decreased by coadministration of mibefradil (0, 0.3, or 3 mg/kg). The hindleg edema formation was not due to albumin leakage into the interstitial space based on immunostaining. However, a 4.2-fold increase in the arterial L-/T-type CC mRNA expression ratio was observed compared with the venous L/T ratio as shown by quantitative reverse transcription polymerase chain reaction. These results demonstrate the novel utility of MRI to measure extravascular water after acute exposure to CCBs and indicate that T-type CCB activity may reduce L-type CCB-induced vasodilatory edema in the skeletal muscle vasculature, possibly by a differential effect on arteriole and venule dilatation. The American Society for Pharmacology and Experimental Therapeutics ER -