NP-252

The cardiovascular effects of 3-pyridine carboxylic acid 5-[(cyclopropylamino)carbonyl]-1,4-dihydro-2,6-dimethyl-4-(2-nitro phenyl) oxtyl ester (NP-252, CAS 132031-81-3) were examined in anesthetized closed- or open-chest dogs and Langendorff perfused rabbit hearts, and compared with those of nifedipine (NF) and nicardipine (NC). In anesthetized closed- and open-chest dogs, NP-252 (i.v.) selectively increased vertebral and coronary blood flow with a fall in mean blood pressure (MBP). These effects were nearly equipotent with those of NF and NC, but more durable. A similar effect was obtained by intraduodenal administration of NP-252. Also, NP-252 (i.v.) decreased MBP, total peripheral resistance (TPR), left ventricular pressure and dLVP/dtmax while cardiac output (CO) and stroke volume (SV) increased without apparent changes in heart rate and myocardial contractility index. Decreases in MBP and TPR by NP-252 were equipotent with NF and NC, whereas increases in CO and SV were more potent than those of the two drugs. These actions of NP-252 were longer than those of the reference agents. Further, in perfused rabbit hearts, NO-252 increased coronary perfusion flow (CPF), accompanying a slight negative inotropy. Its effect in CPF was equipotent with NF and 2 times less than that of NC, however the duration was much longer than those of the reference drugs. On the other hand, the negative inotropic effect of NP-252 was less than NF, but greater than that of NC. In the preparations controlled by pacing, NP-252 and NF lengthened atrio-His bundle conduction time, without affecting His bundle-ventricular conduction time. Lengthening effect of NP-252 was about 4 times less than that of NF. These results suggest that NP-252 acts more selectively on vascular smooth muscle than cardiac muscle, and has almost equipotent but markedly longer vasodilating actions as compared to NF and NC. It may be expected that NP-252 is a new generation of tissue specific and long acting Ca2+ antagonist.

NP-252, a new dihydropyridine derivative, and nifedipine non-competitively inhibited contractile responses to KCl and responses to Ca2+ in Ca(2+)-free medium containing KCl in rabbit aorta and renal, mesenteric, coronary and basilar arteries, mesenteric veins and vena cava. The effects of NP-252 in these smaller arteries and veins were much greater than those in aorta. However, a similar differential selectivity was not seen with nifedipine. In aorta, only NP-252 reduced total La3+ resistant 45Ca binding. However, the increases in bound 45Ca at La3+ resistant sites and 45Ca unidirectional influx due to KCl were inhibited by both NP-252 and nifedipine. The displacement of [3H]nitrendipine binding to rabbit aorta was monophasic for both NP-252 and nifedipine. In guinea-pig papillary muscles, NP-252 (greater than 10(-7) M) slightly decreased action potential duration, developed tension and slow action potentials. The cardiac effects of NP-252 were much less prominent than those of nifedipine. These results indicate that NP-252 inhibits voltage-operated Ca2+ channels in small arteries and veins much more effectively than those in aorta, and this tissue selectivity is more apparent for NP-252 than nifedipine.