In Vitro Effects of Nifedipine, Nisoldipine, and Lacidipine on Rat Isolated Coronary Small Arteries
10
Citation
0
Reference
10
Related Paper
Abstract:
We investigated the effect of 1,4-dihydro-pyridine calcium antagonists (nifedipine, nisoldipine, and lacidipine) on serotonin (5-HT)- and KC1 (120 mM)-induced contractions of rat isolated septal coronary artery. The preparations showed the well-known biphasic response to KC1 depolarization. All three calcium antagonists were more potent in inhibiting the second, tonic phase compared to the first, transient phase, with pIC50 values of 7.17 ± 0.12/8.27 ± 0.07 (nifedipine), 7.93 ± 0.21/8.96 ± 0.06 (nisoldipine), and 8.28 ± 0.07/9.79 ± 0.04 (lacidipine) for suppressing the first and the second phase, respectively. Furthermore, the influence of the calcium antagonists on the 5-HT concentration-response curve was investigated. Nifedipine, nisoldipine, and lacidipine concentration dependently depressed the maximum effect of 5-HT on the coronary artery preparations without influencing the pEC50 of the 5-HT concentration-response curve. In conclusion, all three dihydropyridine calcium antagonists are potent and effective inhibitors of depolarization- or 5-HT-induced coronary artery contractions. Lacidipine, a new lipophilic compound, was the most potent one in inhibiting the depolarization-induced contraction, thereby showing a marked selectivity for the tonic phase compared to the initial phasic response.Keywords:
Nisoldipine
Lacidipine
This chapter contains sections titled: Introduction Dihydropyridine Calcium Channel-Blocking Agents Nifedipine Felodipine Isradipine Nimodipine Nisoldipine Amlodipine Lacidipine Lercanidipine Manidipine Lacidipine: A Long-Lasting Calcium Channel-Blocking Drug: Case Study The Lacidipine Project Synthesis The Pharmacological Profile of Lacidipine Conclusion
Lacidipine
Nisoldipine
Isradipine
Lercanidipine
Nimodipine
Amlodipine
Felodipine
Cite
Citations (3)
Abstract Dihydropyridine derivative calcium-channel blockers are widely used in the therapy of hypertension, angina pectoris and other cardiovascular diseases. Because the prototype of dihydropyridine derivatives, nifedipine, does not have the optimum pharmacokinetic and pharmacodynamic characteristics, attempts have been made to synthesize other drugs in this class with improved properties. The synthesis and biological activity of two new calcium-channel blockers, non-symmetrical (mebudipine) and symmetrical (dibudipine) analogues of nifedipine, is described herein. The pharmacological potencies of the compounds were evaluated by studying their effects on the contractions of isolated guinea-pig ileum and rat aortic rings. Results were compared with those obtained from nifedipine. The new analogues and nifedipine inhibited the contractile response of guinea-pig ileum to electrical stimulation and the pIC50 value of the compounds did not differ significantly from each other. The compounds also antagonized the contractile responses of K+-depolarized guinea-pig ileum to cumulative concentrations of calcium. The inhibitory effect of mebudipine was significantly higher than that of nifedipine whereas the inhibitory effects of dibudipine and nifedipine were not different. All three compounds relaxed KCl (40 mm)–treated isolated aortic rings; the pIC50 values for relaxation were: mebudipine > nifedipine > dibudipine. It is concluded that these new dihydropyridine derivatives are potent relaxants of vascular and ileal smooth muscles and therefore have high potential for use as antihypertensive and anti-anginal agents.
Cite
Citations (29)
We investigated the effect of 1,4-dihydro-pyridine calcium antagonists (nifedipine, nisoldipine, and lacidipine) on serotonin (5-HT)- and KC1 (120 mM)-induced contractions of rat isolated septal coronary artery. The preparations showed the well-known biphasic response to KC1 depolarization. All three calcium antagonists were more potent in inhibiting the second, tonic phase compared to the first, transient phase, with pIC50 values of 7.17 ± 0.12/8.27 ± 0.07 (nifedipine), 7.93 ± 0.21/8.96 ± 0.06 (nisoldipine), and 8.28 ± 0.07/9.79 ± 0.04 (lacidipine) for suppressing the first and the second phase, respectively. Furthermore, the influence of the calcium antagonists on the 5-HT concentration-response curve was investigated. Nifedipine, nisoldipine, and lacidipine concentration dependently depressed the maximum effect of 5-HT on the coronary artery preparations without influencing the pEC50 of the 5-HT concentration-response curve. In conclusion, all three dihydropyridine calcium antagonists are potent and effective inhibitors of depolarization- or 5-HT-induced coronary artery contractions. Lacidipine, a new lipophilic compound, was the most potent one in inhibiting the depolarization-induced contraction, thereby showing a marked selectivity for the tonic phase compared to the initial phasic response.
Nisoldipine
Lacidipine
Cite
Citations (10)
The antihypertensive effects of orally administered CD-349, (2-nitratopropyl-3-nitratopropyl-2,6-dimethyl-4-(3-nitrophen yl)- 1,4-dihydropyridine-3,5-dicarboxylate), a new dihydropyridine calcium-entry blocker, were evaluated in comparison with nifedipine in spontaneously hypertensive rats (SHR), renal hypertensive rats (RHR) and normotensive rats (NTR) all in a conscious state. CD-349 (0.3, 1.0 and 3.0 mg/kg) and nifedipine (1.0 mg/kg) produced a long-lasting decrease in mean arterial blood pressure (BP) and an increase in heart rate (HR) in all the rat groups; the effects of CD-349 were dose-dependent and greater in hypertensive rats than in NTR. As compared with nifedipine at the same dose of 1 mg/kg, the hypotensive effect of CD-349 was relatively slower in onset and longer-lasting, thereby suggesting that gastrointestinal absorption of CD-349 was slower than that of nifedipine. The increase in HR associated with the hypotension induced by CD-349 at 1 mg/kg was relatively transient in comparison with that induced by nifedipine at the same dose in both types of hypertensive rat. From these results, it is expected that CD-349 could be a useful antihypertensive drug.
Calcium channel blocker
Spontaneously hypertensive rat
Cite
Citations (1)
Derivative (finance)
Cite
Citations (0)
Low-density lipoprotein
Cite
Citations (9)
Summary We compared two newer dihydropyridine-calcium antagonists (lacidipine and nisoldipine) with the classic prototype of this group, nifedipine, in the rat working heart preparation. The hearts were paced at a frequency of 5 Hz and perfused with Tyrode's solution of 37°C. The following five parameters were determined: left ventricular pressure (LVP), maximal rate of pressure increase ( + dP/dtmax), aortic output (AO), coronary blood flow (CBF), and cardiac output (CO). First, dose-response curves were constructed; from these data the EC50 concentration for the three calcium antagonists was calculated. Subsequently, washout from the cardiac tissue for these three compounds was determined. The effects of lacidipine did not diminish during <90-min washout, whereas the effects of nifedipine disappeared completely in 10 min. The effects of nisoldipine, however, disappeared partly in 10 min. In separate experiments, the antiischemic activity of the three calcium antagonists was analyzed, using low-flow ischemia. The calcium antagonists were used in a concentration that produced a 60% reduction in contractile force (EC60). Nifedipine and nisoldipine caused significant improvement in functional recovery. The antiischemic properties of lacidipine could not be shown because of its slow kinetic properties with accumulation in the membrane phase and slow kinetics with the channel. Nisoldipine and lacidipine appear to be more potent calcium antagonists as compared with nifedipine, whereas lacidipine displays a clearly different kinetic pattern in comparison to nifedipine and nisoldipine. In particular, the extremely slow onset and very long duration of action of lacidipine are of interest.
Nisoldipine
Lacidipine
Washout
Cite
Citations (5)
The Ca 2+ ‐antagonistic properties of lacidipine were investigated in patch‐clamp guinea‐pig ventricular myocytes. In basal conditions, 0.1 μm lacidipine reduced the action potential duration, associated with a decrease in the L‐type calcium current ( I ca,L ) to 66 ± 4% of the control value, without a change in the current‐voltage relationship. Sodium current and background potassium currents were not affected. All the effects reached a steady state within 2 min. The Ca 2+ ‐antagonistic effect of lacidipine was voltage‐dependent: a marked negative shift (about 20 mV) of the steady‐state inactivation curve was observed with long (10 s) conditioning prepulses, but not with short (350 ms) prepulses. The onset of and recovery from the voltage‐dependent effect caused by 0.1 μm lacidipine were significantly slower when compared to those of equiactive concentrations of nimodipine (0.5 μm) and nisoldipine (0.1 μm). I Ca,L measured after prepulses at —40 mV lasting 500 ms or less was unchanged (95 ± 5% of maximum current value) while it was reduced to 49±10% by nimodipine and 43 ± 9% by nisoldipine ( P <0.05 vs lacidipine for both). Similarly, the recovery from block in the presence of lacidipine was slower than with nimodipine and nisoldipine. After a prepulse of 1 s at —80 mV, I Ca,L recovered up to 54 ± 2% of the maximum current value in the presence of lacidipine, and up to 91 ±3% and 93 ± 5% in the presence of nimodipine and nisoldipine, respectively ( P <0.05 vs lacidipine). Blockade of I Ca,L by lacidipine was use‐dependent. After ten 200 ms long pulses (1 Hz) from −80 mV, I Ca,L was reduced to 55 ± 7% of the current measured at the first pulse. In the presence of nimodipine and nisoldipine, I Ca,L elicited by the tenth pulse amounted to 93 ± 3% and 80 ± 6% of the first pulse value, respectively ( P <0.05 vs lacidipine). Lacidipine did not cause use‐dependent blockade of I ca,L in cells stimulated with 10 ms long pulses. These results demonstrate that lacidipine selectively inhibits I Ca,L in isolated cardiomyocytes and suggest that this effect occurs mainly through binding to the inactivated Ca 2+ channels.
Lacidipine
Nisoldipine
Nimodipine
Cite
Citations (15)
Antibodies with high affinity and specificity for the 1,4-dihydropyridine Ca2+-channel blockers have been produced in rabbits by immunization with dihydropyridine-protein conjugates. Anti-dihydropyridine antibodies were found to specifically bind [3H]nitrendipine, [3H]-nimodipine, [3H]nisoldipine, and [3H]PN 200-110 (all 1,4-dihydropyridine Ca2+-channel blockers) with high affinity, while [3H]verapamil, [3H]diltiazem, and [3H]trifluoperazine were not recognized. The average dissociation constant of the [3H]nitrendipine-antibody complex was 0.06 (+/- 0.02) X 10(-9) M for an antiserum studied in detail and ranged from 0.01 to 0.24 X 10(-9) M for all antisera. Inhibition of [3H]nitrendipine binding was specific for the 1,4-dihydropyridine Ca2+-channel modifiers and the concentrations required for half-maximal inhibition ranged between 0.25 and 0.90 nM. Structurally unrelated Ca2+-channel blockers, calmodulin antagonists, inactive metabolites of nitrendipine, and UV-inactivated nisoldipine did not modify [3H]nitrendipine binding to the anti-dihydropyridine antibodies. Dihydropyridines without a bulky substituent in the 4-position of the heterocycle were able to displace [3H]nitrendipine binding, but the concentrations required for half-maximal inhibition were greater than 800 nM. In summary, anti-dihydropyridine antibodies have been shown to have high affinity and specificity for the 1,4-dihydropyridine Ca2+-channel blockers and to exhibit dihydropyridine binding properties similar to the membrane receptor for the 1,4-dihydropyridine Ca2+-channel blockers.
Nitrendipine
Nisoldipine
Cite
Citations (7)
[Objective] To evaluate the effects of the lacidipine combined extended release nifedipine on hypertensive patients.[Methods]158 cases of hypertensive patients were collected in our hospital,and were divided into extended release nifedipine group,lacidipine and extended release nifedipine group.The duration of treatment was 6 months.Diastolic blood pressure(DBP),systolic blood pressure(SBP),heart rate(HR),intima-media thickness of the common carotid artery(IMTcca),IMT of the bifurcating coronary artery(IMTbif),IMT of the internal carotid artery(IMTica),left ventricular spetum thickness(LVST),left ventricular end-diastolic posterior wall thickness(LVPWT),LV internal diameter (LVID),left ventricular mass index(LVMI),flow-mediated brachial artery dilation(FMD),high-sensitivity C-reactive protein(hs-CRP)were observed in all patients.[Results]Six months medical treatment revealed that SBP of lacidipine and extended release nifedipine group was significantly diminished from 159.4 mmHg to 127.1 mmHg,and that of Extended Release Nifedipine group was down from 99.7 mmHg to 78.4mmHg(P﹤0.05).The levels of IMTs of the lacidipine and extended release nifedipine group were significantly lower.However,whereas the IMTs of Extended Release Nifedipine group did not show any significant changes(P﹥0.05).Compared with extended release nifedipine group,the hs-CRP was also lower.Lacidipine and extended release nifedipine group significantly improved the condition of heart.[Conclusion]lacidipine and extended release nifedipine group leads to a significant reduction of BP of patients with hypertension as well as to a decrease in markers of inflammation during a relatively short period(6 months).
Lacidipine
Brachial artery
Cite
Citations (0)