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Koki Shigenobu - One of the best experts on this subject based on the ideXlab platform.

  • Pathophysiological significance of T-type Ca2+ channels: T-type Ca2+ channels and drug development.
    Journal of Pharmacological Sciences, 2019
    Co-Authors: Hikaru Tanaka, Koki Shigenobu
    Abstract:

    Abstract T-type Ca2+ channels are present in cardiovascular, neuronal, and endocrine systems; and they are now receiving attention as novel therapeutic targets. Many drugs and compounds non-specificaly block T-type Ca2+ channels. Certain dihydropyridine compounds, such as Efonidipine, have blocking activity on both L-type and T-type Ca2+ channels which possibly underlies their excellent clinical profiles such as minimum reflex tachycardia and renal protection. Selective inhibitors of T-type Ca2+ channels, such as non-hydrolyzable mibefradil and R(−)-Efonidipine, are powerful pharmacological tools for further studies and may lead to the development of novel therapeutic strategies.

  • species difference in the contribution of t type calcium current to cardiac pacemaking as revealed by r Efonidipine
    Journal of Pharmacological Sciences, 2008
    Co-Authors: Hikaru Tanaka, Iyuki Namekata, Yayoi Tsuneoka, Chisa Komikado, Koki Shigenobu, Hideki Nakamura, Mariko Suzuki, Akira Takahara
    Abstract:

    Abstract The contribution of the T-type Ca2+ current to cardiac pacemaking was examined in isolated right atrial tissue from the mouse, guinea pig, and rabbit using a specific blocker, R(−)-Efonidipine. At 10−6 M, R(-)-Efonidipine produced negative chronotropy, which was prominent in the mouse and small but significant in the guinea pig. No effect was observed in the rabbit. Microelectrode recordings revealed that R(-)-Efonidipine significantly prolongs the pacemaker (phase 4) depolarization of the sinoatrial-node action potential in the mouse and guinea pig. These results provide the first pharmacological evidence that the contribution of T-type Ca2+ current to cardiac pacemaking differs among experimental animal species.

  • Efonidipine hydrochloride a dual blocker of l and t type ca2 channels
    Cardiovascular Drug Reviews, 2006
    Co-Authors: Hikaru Tanaka, Koki Shigenobu
    Abstract:

    : T-type Ca(2+) channels have properties different from those of the L-type and are involved in cardiac pacemaking and regulation of blood flow, but not in myocardial contraction. Efonidipine is an antihypertensive and antianginal drug with dihydropyridine structure that was recently found to block both L- and T-type Ca(2+) channels. In isolated myocardial and vascular preparations, Efonidipine has potent negative chronotropic and vasodilator effects but only a weak negative inotropic effect. In experimental animals and patients, reduction of blood pressure by the drug was accompanied by no or minimum reflex tachycardia leading to improvement of myocardial oxygen balance and maintenance of cardiac output. Efonidipine increased glomerular filtration rate without increasing intraglomerular pressure. By relaxing both the afferent and efferent arterioles, Efonidipine markedly reduced proteinuria. Thus, Efonidipine, an L- and T-type dual Ca(2+) channel blocker, appears to have an ideal profile as an antihypertensive and antianginal drug with organ-protective effects in the heart and kidney.

  • Efonidipine Hydrochloride: A Dual Blocker of L‐ and T‐Type Ca2+ Channels
    Cardiovascular Drug Reviews, 2006
    Co-Authors: Hikaru Tanaka, Koki Shigenobu
    Abstract:

    : T-type Ca(2+) channels have properties different from those of the L-type and are involved in cardiac pacemaking and regulation of blood flow, but not in myocardial contraction. Efonidipine is an antihypertensive and antianginal drug with dihydropyridine structure that was recently found to block both L- and T-type Ca(2+) channels. In isolated myocardial and vascular preparations, Efonidipine has potent negative chronotropic and vasodilator effects but only a weak negative inotropic effect. In experimental animals and patients, reduction of blood pressure by the drug was accompanied by no or minimum reflex tachycardia leading to improvement of myocardial oxygen balance and maintenance of cardiac output. Efonidipine increased glomerular filtration rate without increasing intraglomerular pressure. By relaxing both the afferent and efferent arterioles, Efonidipine markedly reduced proteinuria. Thus, Efonidipine, an L- and T-type dual Ca(2+) channel blocker, appears to have an ideal profile as an antihypertensive and antianginal drug with organ-protective effects in the heart and kidney.

  • the r enantiomer of Efonidipine blocks t type but not l type calcium current in guinea pig ventricular myocardium
    Journal of Pharmacological Sciences, 2004
    Co-Authors: Hikaru Tanaka, Iyuki Namekata, Chisa Komikado, Hideaki Shimada, Kentaro Takeda, Toru Kawanishi, Koki Shigenobu
    Abstract:

    Abstract In guinea pig ventricular cardiomyocytes, the R (−)-enantiomer of Efonidipine concentration-dependently blocked T-type Ca 2+ current with 85% inhibition at 1 μ M. In contrast, R (−)-Efonidipine (1 μ M) had no effect on the L-type Ca 2+ current and Ca 2+ transient in cardiomyocytes and contractile force in papillary muscles. Thus, R (−)-Efonidipine is a highly selective blocker of the T-type Ca 2+ current in native myocardia.

Hikaru Tanaka - One of the best experts on this subject based on the ideXlab platform.

  • Pathophysiological significance of T-type Ca2+ channels: T-type Ca2+ channels and drug development.
    Journal of Pharmacological Sciences, 2019
    Co-Authors: Hikaru Tanaka, Koki Shigenobu
    Abstract:

    Abstract T-type Ca2+ channels are present in cardiovascular, neuronal, and endocrine systems; and they are now receiving attention as novel therapeutic targets. Many drugs and compounds non-specificaly block T-type Ca2+ channels. Certain dihydropyridine compounds, such as Efonidipine, have blocking activity on both L-type and T-type Ca2+ channels which possibly underlies their excellent clinical profiles such as minimum reflex tachycardia and renal protection. Selective inhibitors of T-type Ca2+ channels, such as non-hydrolyzable mibefradil and R(−)-Efonidipine, are powerful pharmacological tools for further studies and may lead to the development of novel therapeutic strategies.

  • effects of s Efonidipine on the rabbit sinus node action potential and calcium channel subunits cav1 2 cav1 3 and cav3 1
    European Journal of Pharmacology, 2010
    Co-Authors: Hikaru Tanaka, Iyuki Namekata, Toru Ogawa, Yayoi Tsuneoka, Chisa Komikado, Akira Takahara, Naoko Iidatanaka, Hiroko Izuminakaseko, Hiromichi Tsuru, Satomi Adachiakahane
    Abstract:

    Abstract The effect of S (+)-Efonidipine on sinus node action potential and calcium channel α-subunits was examined. The slope of the phase 4 depolarization of isolated rabbit sinus node tissue was significantly reduced by S (+)-Efonidipine (1 μM), slightly reduced by nifedipine (1 μM), but was not affected by R (−)-Efonidipine. S (+)-Efonidipine (1 μM), inhibited the expressed Ca V 1.2, Ca V 1.3 and Ca V 3.1 channel currents by 75.7%, 75.3% and 94.0%, nifedipine 84.0%, 43.2% and 14.9%, and R (−)-Efonidipine 30.0%, 19.6% and 92.8%, respectively. Thus, the prolongation of the phase 4 depolarization of the rabbit sinus node by S (+)-Efonidipine may be explained by blockade of the Ca V 1.3 channel current.

  • Effects of S(+)-Efonidipine on the rabbit sinus node action potential and calcium channel subunits CaV1.2, CaV1.3 and CaV3.1
    European Journal of Pharmacology, 2010
    Co-Authors: Hikaru Tanaka, Iyuki Namekata, Toru Ogawa, Yayoi Tsuneoka, Chisa Komikado, Akira Takahara, Hiromichi Tsuru, Naoko Iida-tanaka, Hiroko Izumi-nakaseko, Satomi Adachi-akahane
    Abstract:

    Abstract The effect of S (+)-Efonidipine on sinus node action potential and calcium channel α-subunits was examined. The slope of the phase 4 depolarization of isolated rabbit sinus node tissue was significantly reduced by S (+)-Efonidipine (1 μM), slightly reduced by nifedipine (1 μM), but was not affected by R (−)-Efonidipine. S (+)-Efonidipine (1 μM), inhibited the expressed Ca V 1.2, Ca V 1.3 and Ca V 3.1 channel currents by 75.7%, 75.3% and 94.0%, nifedipine 84.0%, 43.2% and 14.9%, and R (−)-Efonidipine 30.0%, 19.6% and 92.8%, respectively. Thus, the prolongation of the phase 4 depolarization of the rabbit sinus node by S (+)-Efonidipine may be explained by blockade of the Ca V 1.3 channel current.

  • Effects of S(+)-Efonidipine on the rabbit sinus node action potential and calcium channel subunits Ca(V)1.2, Ca(V)1.3 and Ca(V)3.1.
    European journal of pharmacology, 2010
    Co-Authors: Hikaru Tanaka, Iyuki Namekata, Toru Ogawa, Yayoi Tsuneoka, Chisa Komikado, Akira Takahara, Hiromichi Tsuru, Naoko Iida-tanaka, Hiroko Izumi-nakaseko, Satomi Adachi-akahane
    Abstract:

    The effect of S(+)-Efonidipine on sinus node action potential and calcium channel α-subunits was examined. The slope of the phase 4 depolarization of isolated rabbit sinus node tissue was significantly reduced by S(+)-Efonidipine (1 μM), slightly reduced by nifedipine (1 μM), but was not affected by R(-)-Efonidipine. S(+)-Efonidipine (1 μM), inhibited the expressed Ca(V)1.2, Ca(V)1.3 and Ca(V)3.1 channel currents by 75.7%, 75.3% and 94.0%, nifedipine 84.0%, 43.2% and 14.9%, and R(-)-Efonidipine 30.0%, 19.6% and 92.8%, respectively. Thus, the prolongation of the phase 4 depolarization of the rabbit sinus node by S(+)-Efonidipine may be explained by blockade of the Ca(V)1.3 channel current.

  • species difference in the contribution of t type calcium current to cardiac pacemaking as revealed by r Efonidipine
    Journal of Pharmacological Sciences, 2008
    Co-Authors: Hikaru Tanaka, Iyuki Namekata, Yayoi Tsuneoka, Chisa Komikado, Koki Shigenobu, Hideki Nakamura, Mariko Suzuki, Akira Takahara
    Abstract:

    Abstract The contribution of the T-type Ca2+ current to cardiac pacemaking was examined in isolated right atrial tissue from the mouse, guinea pig, and rabbit using a specific blocker, R(−)-Efonidipine. At 10−6 M, R(-)-Efonidipine produced negative chronotropy, which was prominent in the mouse and small but significant in the guinea pig. No effect was observed in the rabbit. Microelectrode recordings revealed that R(-)-Efonidipine significantly prolongs the pacemaker (phase 4) depolarization of the sinoatrial-node action potential in the mouse and guinea pig. These results provide the first pharmacological evidence that the contribution of T-type Ca2+ current to cardiac pacemaking differs among experimental animal species.

Minoru Horie - One of the best experts on this subject based on the ideXlab platform.

  • Long-term effect of Efonidipine therapy on plasma aldosterone and left ventricular mass index in patients with essential hypertension
    Hypertension Research, 2009
    Co-Authors: Takayoshi Tsutamoto, Toshinari Tanaka, Masanori Fujii, Takashi Yamamoto, Keizo Nishiyama, Masayuki Yamaji, Chiho Kawahara, Minoru Horie
    Abstract:

    A certain percentage of aldosterone (ALD) breakthrough generally occurs in patients with hypertension and chronic heart failure and is an important issue during long-term treatment with angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB). It has been reported that Efonidipine decreases the plasma levels of ALD. However, the long-term effects of Efonidipine on the plasma levels of ALD and the left ventricular mass index (LVMI) remain unknown in patients with hypertension. Sixty stable outpatients with essential hypertension who had received amlodipine and ACE-I or ARB for more than 1 year were randomized into two groups (amlodipine group ( n =30): continuous amlodipine treatment at a stable dose; Efonidipine group ( n =30): amlodipine (5 mg day^−1) was changed to Efonidipine at a dose of 40 mg day^−1). There was no difference in their baseline characteristics including the LVMI and plasma levels of ALD. In the amlodipine group, there were no significant changes in blood pressure, LVMI or plasma levels of ALD for 18 months. In the Efonidipine group, blood pressure did not change after replacement of amlodipine with Efonidipine, although there was a significant decrease in the plasma levels of ALD after 6 months. The decrease in ALD was sustained for 18 months and LVMI was significantly decreased after 18 months (121±25 vs. 114±21 g m^−2, P

  • long term effect of Efonidipine therapy on plasma aldosterone and left ventricular mass index in patients with essential hypertension
    Hypertension Research, 2009
    Co-Authors: Takayoshi Tsutamoto, Toshinari Tanaka, Masanori Fujii, Takashi Yamamoto, Keizo Nishiyama, Masayuki Yamaji, Chiho Kawahara, Minoru Horie
    Abstract:

    Long-term effect of Efonidipine therapy on plasma aldosterone and left ventricular mass index in patients with essential hypertension

  • comparison of the effects of Efonidipine and amlodipine on aldosterone in patients with hypertension
    Hypertension Research, 2007
    Co-Authors: Toshinari Tanaka, Takayoshi Tsutamoto, Hiroshi Sakai, Masanori Fujii, Takashi Yamamoto, Minoru Horie
    Abstract:

    To prevent cardiovascular disease, targeting aldosterone synthesis and release may be clinically important. Aldosterone production in the adrenal gland is mediated mainly by the T-type calcium channel in vitro. Efonidipine inhibits both L- and T-type Ca channels. To compare the effects of Efonidipine on neurohumoral factors with those of amlodipine, an L-type Ca channel blocker, we studied 40 essential hypertensive outpatients. Forty patients who had been administered amlodipine for more than 1 year were treated with Efonidipine for 6 months in place of amlodipine. Substituting Efonidipine for amlodipine had no significant effect on clinic systolic blood pressure or the plasma levels of brain natriuretic peptide, norepinephrine or active renin. However, the heart rate was significantly decreased (72.0±1.3 vs. 69.8±1.3 beats/min, p<0.01) and the plasma aldosterone level was also significantly decreased after Efonidipine treatment (97.7±7.9 vs. 79.7±5.6 pg/mL, p<0.0001). Changes in the aldosterone level correlated with the baseline value before the replacement of amlodipine by Efonidipine (r=−0.769, p<0.0001). These findings indicate that at the effective antihypertensive doses of Efonidipine and amlodipine, Efonidipine significantly decreases heart rate and plasma aldosterone level compared with those under amlodipine treatment in hypertensive patients.

  • Comparison of the Effects of Efonidipine and Amlodipine on Aldosterone in Patients with Hypertension
    Hypertension Research, 2007
    Co-Authors: Toshinari Tanaka, Takayoshi Tsutamoto, Hiroshi Sakai, Masanori Fujii, Takashi Yamamoto, Minoru Horie
    Abstract:

    To prevent cardiovascular disease, targeting aldosterone synthesis and release may be clinically important. Aldosterone production in the adrenal gland is mediated mainly by the T-type calcium channel in vitro . Efonidipine inhibits both L- and T-type Ca channels. To compare the effects of Efonidipine on neurohumoral factors with those of amlodipine, an L-type Ca channel blocker, we studied 40 essential hypertensive outpatients. Forty patients who had been administered amlodipine for more than 1 year were treated with Efonidipine for 6 months in place of amlodipine. Substituting Efonidipine for amlodipine had no significant effect on clinic systolic blood pressure or the plasma levels of brain natriuretic peptide, norepinephrine or active renin. However, the heart rate was significantly decreased (72.0±1.3 vs . 69.8±1.3 beats/min, p

Takao Saruta - One of the best experts on this subject based on the ideXlab platform.

  • Disparate effects of calcium antagonists on renal microcirculation.
    Hypertension Research, 2020
    Co-Authors: Koichi Hayashi, Takahiko Nagahama, Murray Epstein, Takao Saruta
    Abstract:

    : Although calcium antagonists reduce systemic blood pressure, the effects of calcium antagonists on renal preglomerular and postglomerular microcirculation have been suggested to differ. In the present study we examined the vasodilator action of dihydropyridine-type calcium antagonists, including nifedipine, nicardipine, amlodipine, and Efonidipine, on afferent and efferent arterioles during angiotensin II (A-II)- and norepinephrine (NE)-induced renal vasoconstriction. Isolated perfused hydronephrotic kidneys were used to directly visualize renal microcirculatory response to calcium antagonists. Both A-II and NE caused marked vasoconstriction of afferent (A-II, 27 +/- 2% decrement; NE, 28 +/- 2% decrement) and efferent arterioles (A-II, 25 +/- 4% decrement; NE, 22 +/- 2% decrement). The subsequent addition of nifedipine, nicardipine, and amlodipine reversed the afferent arteriolar vasoconstriction in a dose-dependent manner, and elicited complete vasodilation at 10(-6) M. In contrast, efferent arteriolar vasoconstriction was relatively refractory to the dilator action of these calcium antagonists; maximal dilation observed at 10(-6) M was 21 +/- 1% (A-II) and 22 +/- 3% (NE) for nifedipine, 25 +/- 3% (A-II) and 20 +/- 6% (NE) for nicardipine, and 39 +/- 6% (A-II) and 37 +/- 3% (NE) for amlodipine. In striking contrast, Efonidipine dilated not only afferent arterioles, but also efferent arterioles in a dose-dependent manner. At 10(-6) M, Efonidipine completely inhibited the afferent (A-II, 89 +/- 7% reversal; NE, 99 +/- 8% reversal) and efferent arteriolar vasoconstriction (A-II, 93 +/- 4% reversal; NE, 87 +/- 9% reversal). These findings clearly demonstrate that calcium antagonists dilate the afferent arteriole. Unlike the effects on the afferent arteriole, efferent arteriolar responsiveness to calcium antagonists differ, depending on the type of calcium antagonist. The Efonidipine-induced efferent arteriolar vasodilation is probably not related to voltageoperated calcium channels, and may act, in concert with blood pressure lowering effect, to ameliorate glomerular capillary hypertension.

  • The Effects of Calcium Channel Blockers on Nuclear Factor Kappa B Activation in the Mesangium Cells
    Hypertension Research, 2020
    Co-Authors: Matsuhiko Hayashi, Yasuyoshi Yamaji, Yuichi Nakazato, Takao Saruta
    Abstract:

    : It has been reported that calcium channel blockers (CCBs) have an inhibitory action on cell growth and transcriptional changes induced by cytokines and hormones. In this study, we examined the effects of CCBs on nuclear factor kappa B (NFkappaB), which plays a key role in the intracellular signaling of various growth factors and cytokines. The activity of NFkappaB was determined by luciferase assay with the transfection of the reporter gene, which has six NFkappaB-recognizing sequences in the upstream of herpes simplex virus thymidine kinase promoter. In cultured human mesangial cells, increased intracellular calcium concentration by calcium ionophore, A23187, showed a stimulatory effect on the phorbor 12-myristate 13-acetate (PMA)-induced activation of NFkappaB, while L-type calcium channel agonist, Bay K 8644, did not have any significant effects on either basal or PMA-stimulated activity of NFkappaB. At a higher concentration (10 microM), nifedipine, verapamil, or Efonidipine showed an inhibitory effect on the activation of NFkappaB by PMA and A23187, while at a lower concentration (1 microM), only Efonidipine showed a significant inhibitory effect. From these results, we conclude that CCBs have an inhibitory effect on NFkappaB via the independent pathway of an L-type calcium channel and that the potency of this effect is variable among L-type calcium channel blockers.

  • Pathophysiological Significance of T-type Ca2+ Channels: Role of T-type Ca2+ Channels in Renal Microcirculation
    Journal of Pharmacological Sciences, 2019
    Co-Authors: Koichi Hayashi, Shu Wakino, Koichiro Homma, Naoki Sugano, Takao Saruta
    Abstract:

    Abstract Since conventional Ca2+ antagonists, with predominant blockade of L-type voltage-dependent Ca2+ channels, elicit preferential dilation of afferent arterioles, they might ostensibly aggravate glomerular hypertension. Recently, novel Ca2+ antagonists, with inhibitory action on L-/T-type Ca2+ channels, have been reported to dilate both afferent and efferent arterioles. The present review attempted to characterize the renal action of these Ca2+ antagonists and evaluated the consequences following the treatment with these agents. In contrast to conventional Ca2+ antagonists (e.g., nifedipine), novel antagonists (e.g., benidipine, Efonidipine) potently dilated afferent and efferent arterioles; their action on efferent arterioles appeared to be mediated by the T-type Ca2+ channel blockade, probably through the inhibition of the intracellular Ca2+ release. The comparison of the anti-proteinuric action in subtotally nephrectomized rats showed that Efonidipine exerted more prominent action than nifedipine. Furthermore, Ca2+ antagonists with T-type Ca2+ inhibitory action inhibited renin/aldosterone release and proinflammatory process. Finally, patients with chronic renal disease given a 48-week Efonidipine treatment showed reduced proteinuria, and this effect was seen even when mean arterial blood pressure failed to become less than 100 mmHg. Collectively, T-type Ca2+ channel blockade provides beneficial action in renal injury. Various mechanisms serve to protect against renal injury, including systemic/glomerular hemodynamic action and non-hemodynamic mechanisms.

  • impact of renal function on cardiovascular events in elderly hypertensive patients treated with Efonidipine
    Hypertension Research, 2010
    Co-Authors: Koichi Hayashi, Takao Saruta, Yoshio Goto, Masao Ishii
    Abstract:

    Impact of renal function on cardiovascular events in elderly hypertensive patients treated with Efonidipine

  • Role of Actions of Calcium Antagonists on Efferent Arterioles – with Special References to Glomerular Hypertension
    American Journal of Nephrology, 2003
    Co-Authors: Koichi Hayashi, Hiroo Kumagai, Shu Wakino, Keiji Fujiwara, Yuri Ozawa, Takao Saruta
    Abstract:

    Although calcium antagonists are used as a first-line antihypertensive agent, controversy attends the renal microvascular effects of calcium antagonists. Since calcium antagonists elicit predominant vasodilation of the afferent arteriole, they might ostensibly aggravate glomerular hypertension. Recently, novel types of calcium antagonists have been developed, some of which are reported to dilate efferent as well as afferent arterioles. The present review attempted to characterize the renal microvascular action of calcium antagonists, and evaluated the consequences of renal injury following the treatment with these antagonists. In contrast to predominant afferent arteriolar action of conventional calcium antagonists (e.g. nifedipine, nicardipine, amlodipine and diltiazem), novel antagonists (e.g. manidipine, nilvadipine, benidipine and Efonidipine) potently dilated both afferent and efferent arterioles. The vasodilator action on efferent arterioles appears to be mediated in part by the blockade of T-type calcium channels, particularly through the inhibition of the intracellular calcium release mechanism. The comparison of the anti-proteinuric action of calcium antagonists in subtotally nephrectomized rats showed that Efonidipine and enalapril, both possessing vasodilator action on efferent arterioles, exerted more prominent action than other calcium antagonists. Finally, in patients with chronic renal disease, a 48-week treatment with Efonidipine reduced proteinuria, and this effect was seen even when the mean arterial blood pressure failed to reach below 100 mm Hg. In conclusion, although calcium antagonists potently inhibit afferent arteriolar constriction, efferent arteriolar responses to these agents vary, depending on the types of calcium antagonists used. These divergent actions of these agents on the efferent arteriole may alter differently the glomerular hemodynamics, and could affect the final outcome of underlying renal diseases.

Haruko Masumiya - One of the best experts on this subject based on the ideXlab platform.

  • frequency dependent blockade of t type ca2 current by Efonidipine in cardiomyocytes
    Life Sciences, 2000
    Co-Authors: Haruko Masumiya, Hikaru Tanaka, Yoshio Tanaka, Junya Kase, Koki Shigenobu
    Abstract:

    Abstract Efonidipine is a dihydropyridine Ca 2 + antagonist with inhibitory effects on both L-type and T-type Ca 2 + channels and potent bradycardiac activity especially in patients with high heart rate. In the present study, we examined the frequency dependence of Efonidipine action on the T-type Ca 2 + channel in isolated guinea-pig ventricular myocytes. The potency of Efonidipine to inhibit the T-type Ca 2 + current was higher under higher stimulation frequencies. The IC 50 values were 1.3×10 −8 , 2.0×10 −6 and 6.3×10 −6 M under stimulation frequencies of 1, 0.2 and 0.05 Hz, respectively. The reduction of T-type Ca 2 + current amplitude was not accompanied by change in the time course of current decay. Efonidipine (10 μM) inhibited T-type Ca 2 + current elicited by depolarization from holding potentials ranging from −90 to −30 mV by about 30%; the voltage-dependence of steady-state inactivation was not changed by the drug. Efonidipine slowed the recovery from inactivation following an inactivating prepulse. In conclusion, Efonidipine was shown to have frequency-dependent inhibitory effects on the T-type Ca 2 + channel, which could be explained by slow dissociation of the drug from the inactivated state of the channel.

  • possible requirement of phosphonate moiety for Efonidipine effects on the sino atrial node action potential
    Life Sciences, 2000
    Co-Authors: Haruko Masumiya, Hikaru Tanaka, Tomoyuki Matsuda, Yoshio Tanaka, Koki Shigenobu
    Abstract:

    Abstract The effects of Efonidipine, a 1,4-dihydropyridine phosphonate, and structurally related compounds on rabbit sino-atrial node action potential were examined with microelectrodes. 3NIC5NZ has a phosphonate moiety identical to that of Efonidipine at the C5 position of the dihydropyridine ring and a side chain identical to nicardipine at C3, while 3NZ5NIC has C5 and C3 side chains identical to nicardipine and Efonidipine, respectively. All four compounds decreased the slope and prolonged the early and late phases of pacemaker depolarization. The selectivity for the late phase against the early phase was in the order of Efonidipine > 3NIC5NZ ⪢ nicardipine > 3NZ5NIC. Thus, the phosphonate moiety at C5 position of the may be important for the characteristic prolongation of the late phase pacemaker depolarization by Efonidipine.

  • inhibition of myocardial l and t type ca2 currents by Efonidipine possible mechanism for its chronotropic effect
    European Journal of Pharmacology, 1998
    Co-Authors: Haruko Masumiya, Hikaru Tanaka, Toshinori Shijuku, Koki Shigenobu
    Abstract:

    Abstract Effects of Efonidipine, a dihydropyridine phosphonate Ca2+ channel antagonist, on the guinea-pig heart were compared with those of nifedipine. In the sino-atrial node, 1 μM Efonidipine produced increase in cycle length accompanied by prolongation of the phase 4 depolarization which was not prominent with 0.1 μM nifedipine. In ventricular myocytes, both Efonidipine and nifedipine produced inhibition of the L-type Ca2+ current, nifedipine being tenfold more potent than Efonidipine. Efonidipine also inhibited the T-type Ca2+ current at higher concentrations but nifedipine did not. Both Ca2+ channel antagonists had no or only a weak effect on K+ currents. In addition, 40 μM Ni2+, which selectively inhibited the T-type Ca2+ current, had no effect on myocardial Ca2+ transients and contractile force. In conclusion, Efonidipine was shown to have inhibitory effects on both L- and T-type Ca2+ currents, which may contribute to its high negative chronotropic potency.

  • effects of ca2 channel antagonists on sinus node prolongation of late phase 4 depolarization by Efonidipine
    European Journal of Pharmacology, 1997
    Co-Authors: Haruko Masumiya, Hikaru Tanaka, Koki Shigenobu
    Abstract:

    Abstract Effects of various Ca 2+ channel antagonists on the action potential configuration of rabbit sino–atrial node tissue were examined with standard microelectrode techniques. All Ca 2+ channel antagonists decreased the maximum rate of phase 0 depolarization ( V max ) and increased the cycle length. The potency order to increase the cycle length was nisoldipine=verapamil>nifedipine=clentiazem>Efonidipine>diltiazem. The potency order to decrease V max and to shift the threshold potential to a positive direction was the same as that to increase the cycle length, indicating that the major mechanism of negative chronotropism was inhibition of the L-type Ca 2+ current. All Ca 2+ channel antagonists except Efonidipine shifted the maximum diastolic potential to the positive direction, decreased the action potential amplitude and prolonged the action potential duration. The effects of nifedipine were slightly weaker than those of other drugs when compared at equally bradycardiac concentrations. These differences may reflect differences in drug effects on currents other than the L-type Ca 2+ current. A characteristic feature of Efonidipine was selective suppression of the later phase of pacemaker depolarization with no effect on action potential amplitude and duration. Similar suppression of the later phase was observed with 50 μ M Ni 2+ , which is reported to inhibit the T-type, but not L-type, Ca 2+ current. Thus, Efonidipine appears to suppress selectively the later phase of pacemaker depolarization through inhibition of both L- and T-type Ca 2+ currents, which may be the underlying mechanism for its reported potent negative chronotropic but weak inotropic activity.

  • myocardial and vascular effects of Efonidipine in vitro as compared with nifedipine verapamil and diltiazem
    General Pharmacology-the Vascular System, 1996
    Co-Authors: Hikaru Tanaka, Haruko Masumiya, Toshiyuki Sekine, Toshinori Sijuku, Motoko Sugahara, Haruyori Taniguchi, Miyuki Terada, Wataru Saito, Koki Shigenobu
    Abstract:

    Abstract 1. 1. Effects of Efonidipine on isolated myocardial and aortic preparations were compared with those of nifedipine, verapamil and diltiazem. 2. 2. All drugs produced concentration-dependent negative chronotropic effects on isolated guinea-pig atrial preparations. The potency order was Efonidipine⩾nifedipine>diltiazem⩾verapamil, EC 30 values being 3.08×10 −8 M , 3.48× 10 −8 M , 1.27×10 −7 M and 1.47×10 −7 M , respectively. 3. 3. Nifedipine, verapamil and diltiazem produced concentration-dependent negative inotropic effects on isolated guinea-pig left atrial preparations. The potency order was nifedipine>verapamil>diltiazem, EC 30 values being 4.94× 10 −8 M , 1.49×10 −7 M and 8.03×10 −7 M , respectively. Efonidipine, even at 1 μM produced no inotropic effect: 10 μM Efonidipine decreased the contractile force by about 20%. 4. 4. All drugs concentration-dependently attenuated the KCl-induced contraction of isolated rat aortic ring preparation. The potency order was nifedipine>Efonidipine>verapamil>diltiazem, EC 30 values being 2.98× 10 −9 M , 1.24×10 −8 M , 3.96×10 −8 M and 2.13×10 −7 M , respectively. 5. 5. Thus, Efonidipine was demonstrated to be a potent vasodilator with negative chronotropic but minimal negative inotropic activity, which may be of benefit in the treatment of cardiovascular disorders.