title: 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.
abstract: 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) T(2) 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 T(2) 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.
authors.affiliation: Cardiovascular and Atherosclerosis Biology, Pfizer Global Research & Development, Pfizer, Inc., Groton, Connecticut, USA.
authors.forename: Terry C
authors.initials: TC
authors.lastname: Major
authors.forename: Shantanu
authors.initials: S
authors.lastname: Dhamija
authors.forename: Nicole
authors.initials: N
authors.lastname: Black
authors.forename: Serguei
authors.initials: S
authors.lastname: Liachenko
authors.forename: Brandy
authors.initials: B
authors.lastname: Morenko
authors.forename: Gregg
authors.initials: G
authors.lastname: Sobocinski
authors.forename: Carlin
authors.initials: C
authors.lastname: Okerberg
authors.forename: Paula
authors.initials: P
authors.lastname: Tinholt
authors.forename: Steven
authors.initials: S
authors.lastname: Madore
authors.forename: Mark C
authors.initials: MC
authors.lastname: Kowala
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000502:physiology*; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000502:physiology*; D004487:Edema / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005263:Femoral Artery / Q000378:metabolism; D006614:Hindlimb; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D020748:Mibefradil / Q000627:therapeutic use*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009543:Nifedipine / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley
chemical_list: D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D012333:RNA, Messenger; D020748:Mibefradil; D009543:Nifedipine