Effect and mechanism of cilnidipine in human internal mammary artery (IMA)

Abstract

We investigated the efficacy of cilnidipine (CIL), a novel dihydropyridine calcium channel antagonist that possesses stimulating properties on nitric oxide (NO)-cGMP pathway, in human IMA rings (n=66) with comparison to nifedipine (NIF) in organ chambers. Cumulative concentration (−10~−5.5 logM)-relaxation curves (n=6) for CIL with/without ODQ (cGMP inhibitor, 3 μM) and L-NNA (300 μM) and for NIF were established in rings precontracted with K+ (40 mM) or norepinephrine (NE, 10 μM). Concentration-contraction curves for K+ (10~100mM) were also reconstructed after incubation with plasma concentrations of CIL (−6.7 and −7.7 logM) or solvent for 30min. CIL and NIF caused nearly full relaxation (94.7±2.6% vs 100±0%, p>0.05) with similar EC50s (−8.90±0.90 vs −8.46±1.08 logM, p>0.05) on K+-precontracted IMA and limited relaxation (27.3±7.8% vs 39.8±4.6%; EC50: −7.15±0.44 vs −7.14±0.43 log M, p>0.05) against NE. Pretreatment with CIL (−6.7 logM) depressed the K+-induced contraction (59.7±6.7%, p<0.05) and right-shifted the curve (EC50: 95.0±21.5 vs 36.4±12.3 mM, p<0.01). ODQ significantly (39.2±4.7%, p<0.05) and L-NNA (45.8±7.8%, p>0.05) or endothelium-denudation (48.7±8.2%, p>0.05) slightly reduced the relaxation. Thus, CIL significantly inhibits contraction at plasma concentrations and induces relaxation through both endothelium-independent and -dependent mechanisms in the human IMA. (Supported by St. Vincent Medical Foundation, Portland, OR, USA & CUHK 2041164)