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, mibefradilride 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 Ϯ 5 and 77 Ϯ 4 mm Hg, respectively. MRI edema index (expressed as percentage increase of integral T 2 over predrug control) was significantly higher with nifedipine (2606 Ϯ 86%; p Ͻ 0.05) than with mibefradil (981 Ϯ 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.Calcium channel blockers comprise a class of powerful, well tolerated, and safe antihypertensive agents that are widely used either alone or as a key component of combination therapy for hypertension. It is unfortunate that a common adverse effect of calcium channel blockers (CCBs) is vasodilatory edema, which results in peripheral leg edema. Vasodilatory edema is related to several mechanisms, including arteriolar dilation (Hayashi et al., 2005), stimulation of the renin-angiotensin-aldosterone system (Schiffrin, 2003;He et al., 2005), and fluid volume retention (Messerli, 2002). The most widely held theoretical mechanism for this edema is a disproportionate decrease in arteriolar versus venular resistance, which increases hydrostatic pressure in the capillary circulation and drives fluid shifts into the interstitial compartment. Vasodilatory edema is common and dose-dependent with first generation CCBs such as verapamil and nifedipine (Messerli, 2002;Safak and Simsek, 2006). Once edema is present, it can be slow to resolve without intervention. A number of strategies exist to treat CCB-related edema, including switching CCB classes, reducing the dosage, adding known venodilators such as nitrates, or adding We declare no other so...

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