Nondihydropyridine Calcium Antagonists Research Articles

Arterial vasodilator effects of the dihydropyridine calcium antagonist amlodipine alone and in combination with verapamil in systemic hypertension

The arterial vasodilator properties of the dihydropyridine calcium antagonist amlodipine were compared with the effects of vascular muscle cyclic guanosine monophosphate production by sodium nitroprusside and with the effects of a combined infusion of amlodipine and the nondihydropyridine calcium antagonist verapamil in 8 untreated patients with primary hypertension. Arterial vasodilatation was assessed by measurement of changes of forearm blood flow by mercury in Silastic straingauge plethysmography during brachial artery drug infusions. Forearm blood flow increased during amlodipine infusions (0.4 to 45 μg/min/100 ml forearm tissue) from 2.9 ± 1.7 to a maximum of 23.6 ± 7.6 ml min 100 ml (687%), while sodium nitroprusside caused an increase from 3.0 ± 1.8 to 16.2 ± 5.4 ml/min/100 ml (449%), attesting to the importance of transmembrane calcium influx for the maintenance of vascular tone. The addition of verapamil 40 μg/min/100 ml to an infusion of amlodipine 44.5 μg/min/100 ml resulted in a further increase of forearm blood flow, from 23.6 ± 7.6 to 34.4 ± 9.8 ml/min/100 ml (p < 0.05). The precise mechanisms of this finding have yet to be elucidated but may be due to interactions of the effects of the binding of these 2 chemically and pharmacologically different calcium antagonists to distinct binding sites at calcium channels. The clinical relevance of this observation for the treatment of coronary artery disease and systemic hypertension needs further study.

Cardiac versus coronary dilator effects of SD-3211, a new nondihydropyridine calcium antagonist, in isolated, blood-perfused dog hearts

Coronary and cardiac effects of SD-3211 were compared in isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node, and papillary muscle preparations of dogs. SD-3211 was administered intraarterially. In all preparations SD-3211 produced an increase in coronary blood flow. In SA node preparations, the drug produced a decrease in sinus rate, and in high doses atrial standstill occurred. The dose that produced a 15% decrease in sinus rate was about 5.6 times the dose that doubled coronary blood flow. In AV node preparations, when injected into the artery supplying the AV node, the drug produced an increase in AV conduction time, and in high doses second- or third-degree AV block occurred. The dose that produced a 15% increase in AV conduction time was about 1.6 times the dose that doubled coronary blood flow. In the same preparations the drug slightly increased AV conduction time only at high doses when injected into the artery supplying the His-Purkinje-ventricular system. In paced papillary muscle preparations, the drug produced a decrease in the force of contraction. The dose that produced a 50% decrease in the force of contraction of the paced papillary muscle was about 50 times the dose that doubled coronary blood flow. The drug was virtually ineffective on ventricular automaticity. In short, in doses that doubled coronary blood flow, SD-3211 depressed only AV nodal conduction. This cardiovascular profile differs from those of diltiazem and verapamil, which do not discriminate between coronary vasculature and the SA and the AV node.

The pharmacological profile off SD-3211, a novel nondihydropyridine calcium antagonist, in in vivo experiments

The pharmacological profile off SD-3211, a novel nondihydropyridine calcium antagonist, in in vivo experiments

The pharmacokinetic profile of amlodipine

Amlodipine, a dihydropyridine calcium antagonist, was synthesized in an attempt to develop a compound with a pharmacokinetic profile characteristic of this class, which would also have an increased oral bioavailability and extended clearance time. A single intravenous dose of 10 mg resulted in an absolute bioavailability of 64% and a calculated elimination half-life of 34 hours. The pharmacokinetic profile of oral doses showed similar changes. These results were significantly different from those seen with most other dihydropyridines (elimination half-life of 3 to 10 hours and absolute bioavailability of 10% to 30%) and nondihydropyridine calcium antagonists (elimination half-life 3 to 6 hours and low absolute bioavailability). With chronic oral dosing of amiodipine once daily for 14 days, support was provided for the linearity of amlodipine's pharmacokinetics and absence of such with chronic oral dosing with verapamil, diltiazem, and nifedipine. In the elderly population, elimination half-life of 5 mg oral doses is significantly prolonged (48 vs 35 hours; p < 0.025) suggesting decreased oral clearance or increased bioavailability. Comparison of the pharmacokinetics of amlodipine in patients with chronic stable angina pectoris with the profile in healthy volunteers suggested that clearance is not altered in patients with chronic stable angina, steady state being reached 6 to 12 hours after administration of the drug. In patients with cirrhosis, elimination half-life is significantly prolonged (60 vs 34 hours; p < 0.01) suggesting that there is a greater accumulation of amlodipine in patients with severe liver disease than in individuals with normal hepatic function. In patients with renal dysfunction such changes were not seen, suggesting that hepatic excretion is the dominant route. Neither food, digoxin (0.375 mg daily for 14 days), nor cimetidine (400 mg daily for 14 days) had any significant effect on the pharmacokinetic parameters determined for amlodipine. The results presented indicate that the pharmacokinetic profile of amlodipine is such that it is expected to be effective for the treatment of hypertension when administered once daily.

Cardiac versus vascular effects of a new dihydropyridine derivative, CV-4093. In vitro comparison with other calcium antagonists

The effects of CV-4093, a new dihydropyridine derivative, on isolated cardiovascular tissues were compared with those of several dihydropyridine and non-dihydropyridine calcium antagonists. CV-4093 effectively inhibited the contractions induced in canine femoral arteries by high [K +] 0 and Bay K 8644, but incompletely relaxed those induced by norepinephrine. CV-4093, 10 −6 M, abolished the electrically induced slow action potentials in guinea-pig papillary muscles partially depolarized by 25 mM K + solution and attenuated those induced by isoproterenol, histamine and Bay K 8644. The rank order of potency of dihydropyridine and non-dihydropyridine calcium antagonists in canine femoral arteries and veins precontracted with 120 m [K +] 0 was as follows: nisoldipine > nicardipine ⩾ nifedipine ⩾ CV-4093 > verapamil ⩾ diltiazem. Nisoldipine was the most potent and CV-4093 was the least potent among these drugs in terms of negative inotropic effect in normally polarized papillary muscles and negative chronotropic effect in right atria of guinea pigs. The rank order of potency for these cardiodepressant actions was nisodipine ⩾ nifedipine > nicardipine > verapamil > diltiazem ⩾ CV-4093. The duration of action potential in guinea-pig papillary muscles was shortened by nisoldipine and nifedipine, unchanged by nicardipine and CV-4093 and was slightly prolonged by verapamil and diltiazem. These results suggest that CV-4093 is a calcium antagonist with a highly selective vascular effect and little cardiodepressant action, and could be of value for the treatment of hypertension.

Voltage- and use-dependent block of the inward calcium current by MCI-176, a new non-dihydropyridine calcium antagonist, in canine ventricular muscles and single ventricular cells of the guinea-pig.

Effects of MCI-176, 2-(2,5-dimethoxyphenylmethyl)-3-(2-dimethylaminoethyl)-6-isopro pox y-4(3H)- quinazolinone hydrochloride, on action potentials of canine ventricular muscles and on membrane currents of single ventricular cells of the guinea-pig heart were studied with the microelectrode and the patch-clamp ("whole-cell recording") methods. In canine ventricular trabeculae, MCI-176 (10(-5)-10(-4) M) decreased the plateau potential, the action potential duration at 30%-repolarization and the maximum rate of rise of the action potential; and it also decreased the amplitude and the duration of the slow response action potential in a concentration-dependent manner. Those effects were much more apparent at higher stimulus frequency. Under voltage clamp condition of single ventricular cells of the guinea-pig heart, MCI-176 (3 x 10(-5) M) decreased the inward calcium current (ICa) by 25-30% when the membrane potential was held at the resting membrane potential, and the drug abolished it when the membrane potential was held at -30 mV. MCI-176 added at rest decreased ICa ("initial block") and reduced it further with repetitive depolarizations in a beat-to-beat fashion. MCI-176 facilitated the reduction of ICa by increasing the clamp pulse frequency. These results indicate that MCI-176 decreases ICa of mammalian ventricular muscles in a voltage- and use-dependent manner.

Inhibition of phospholipase A2 (PLA2) activity by nifedipine and nisoldipine is independent of their calcium-channel-blocking activity.

The effects of several calcium antagonists on phospholipase A2 (PLA2) activity were examined. Nifedipine and nisoldipine inhibited a cell-free preparation of PLA2 in a dose-dependent manner with maximal inhibition of 71-77% observed at 100 microM. More potent or equipotent dihydropyridine calcium antagonists such as nitrendipine and felodipine did not inhibit PLA2 activity. In addition, nondihydropyridine calcium antagonists such as diltiazem, verapamil, and cinnarazine failed to reduce PLA2 activity markedly. Nifedipine and nisoldipine also reduced PLA2 activity in intact mouse peritoneal macrophages where PLA2 activity was monitored by free [14C]arachidonic acid release from [14C]arachidonic acid-prelabeled cells. When levels of PGE2 and LTC4 were measured by radioimmunoassay, it was found that the synthesis of these two metabolites was concomitantly inhibited by nifedipine and nisoldipine. In vivo, nifedipine and nisoldipine inhibited tetradecanoylphorbol acetate (TPA) induced ear edema. UV irradiation of nifedipine and nisoldipine (which destroys the slow calcium-channel-blocking activity of these compounds) did not result in a loss of PLA2 inhibitory activity. In fact, in both instances the UV-irradiated forms of nifedipine and nisoldipine were slightly more potent PLA2 inhibitors than the parent compound alone. We therefore conclude that the ability of nifedipine and nisoldipine to inhibit PLA2 was direct and unrelated to their actions on slow calcium channels.

Differences in cardiovascular profile among calcium antagonists

Calcium antagonists constitute a group of organic compounds with diverse chemical structures. Although their main pharmacodynamic actions are vasodilatation and myocardial depression, they are not uniform in producing these effects. Based on comparison of the potencies in producing negative inotropic, chronotropic and dromotropic effects to the coronary vasodilator potency of individual calcium antagonists determined by use of isolated, blood-perfused papillary muscle, sinoatrial node and atrioventricular node preparations of dogs, calcium antagonists are classified into 2 major groups. The dihydropyridines, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, PN 200-110 (isradipine) and PY 108-068, are generally far more potent in producing coronary vasodilatation than in producing negative inotropic, chronotropic and dromotropic (first-degree atrioventricular block) effects, although there are minor differences among them. The non-dihydropyridine calcium antagonists, verapamil, diltiazem, KB-944, bepridil and MCl-176, are nearly equipotent in producing coronary vasodilatation and a negative dromotropic effect, although all of them are less potent in producing negative inotropy. The non-dihydropyridine calcium antagonists can be further divided into 2 subgroups. Verapamil, diltiazem and KB-944 are nearly equipotent in producing negative dromotropic and chronotropic effects. Bepridil and MCI-176 are less potent in producing negative chronotropy than in producing negative dromotropy.

P-223 - Effects of a new non-dihydropyridine calcium antagonist, MCI-176, on membrane currents of single ventricular cells of the guinea-pig

P-223 - Effects of a new non-dihydropyridine calcium antagonist, MCI-176, on membrane currents of single ventricular cells of the guinea-pig

Adenosine uptake sites in dog heart and brain; interaction with calcium antagonists

[ 3H] Nitrobenzylthioinosine (NBI) binding is characterized in dog heart and brain. Evidence is presented suggesting that [ 3H] NBI is binding to the adenosine uptake site in both tissues. Physiologic studies in open-chested dogs clearly demonstrate that NBI acts as a coronary vasodilator, consistent with an action at the adenosine uptake site. The binding is reversible, saturable and of high affinity 3K D = 0.78 ± .06 nM for heart and 0.52 ± .05 nM for brain). Both dipyridamole and hexobendine are high potency inhibitors of [ 3H] NBI binding in heart and brain while other antihypertensives and vasodilators such as propranolol and nitroglycerine have no effect. The inhibition of [ 3H] NBI binding observed with dipyridamole was competitive indicating that both agents are acting at the same site. The dihydropyridine calcium antagonists also inhibited binding with a lower potency than the adenosine uptake blockers. Non-dihydropyridine calcium antagonists were much less potent in this regard. The inhibition of [ 3H] NBI binding observed with the dihydropyridine calcium antagonists was non-competitive suggesting that the calcium channel and adenosine uptake site may be coupled to each other.

Calcium channel ‘agonist’ BAY K 8644 inhibits calcium antagonist binding to brain and PC12 cell membranes

BAY K 8644, a drug that elicits calcium-dependent muscle contraction, inhibits binding of the voltage-dependent calcium channel antagonist [ 3H]nitrendipine to brain and PC12 pheochromocytoma cell membranes. This effect is due to high-affinity ( K i = 4.5nM) competitive inhibition at the binding site for dihydropyridine calcium antagonists. Allosteric sites that mediate calcium channel blockade by non-dihydropyridine calcium antagonists are not similarly affected. Our findings indicate that BAY K 8644 is active at central, as well as peripheral, calcium channels and are compatible with a multi-state model of the voltage-dependent calcium channel in which antagonist drugs promote a closed state of the channel, while BAY K 8644 promotes an open state.