Inhibition of T-Type and L-Type Ca&lt;sup&gt;2+&lt;/sup&gt; Currents by Aranidipine, a Novel Dihydropyridine Ca&lt;sup&gt;2+&lt;/sup&gt; Antagonist

Masumiya, Haruko; Tanaka, Yoshio; Tanaka, Hikaru; Shigenobu, Koki

doi:10.1159/000028381

Cited by 19 publications

(9 citation statements)

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“…Interestingly, these antagonists possess inhibitory action on T-type and L-type voltage-dependent calcium channels. [12][13][14] Recently, …”

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confidence: 99%

“…Interestingly, these antagonists possess inhibitory action on T-type and L-type voltage-dependent calcium channels. [12][13][14] Recently, ␣1H subunits of T-type calcium channels have been reported to exist in the efferent as well as the afferent arteriole. 15 Although T-type calcium channels have been reported to play an important role in cardiac pacemaker cells 12 and endocrine tissues, 16 no study has examined the functional role of T-type calcium channels in vascular smooth muscle cells.…”

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Effect of T-Type Selective Calcium Antagonist on Renal Microcirculation

et al. 2001

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Abstract-Although calcium antagonists exert preferential vasodilation of renal afferent arterioles, we have recently demonstrated that nilvadipine and efonidipine, possessing both L-type and T-type calcium channel blocking action, reverse the angiotensin (Ang) II-induced afferent and efferent arteriolar constriction. In the present study, we investigated the role of T-type calcium channels in mediating the Ang II-induced efferent arteriolar tone using the selective T-type calcium channel blocker mibefradil. Isolated perfused hydronephrotic rat kidneys were used for direct visualization of renal microcirculation. Administration of Ang II (0.3 nmol/L) caused marked constriction of afferent (from 13.5Ϯ0.6 to 9.2Ϯ0.6 m, PϽ0.01, nϭ6) and efferent (from 11.5Ϯ1.0 to 7.4Ϯ0.7 m, PϽ0.01, nϭ5) arterioles. Mibefradil (1 mol/L) dilated both vessels, with 82Ϯ11% and 72Ϯ7% reversal of afferent and efferent arterioles, respectively. Similarly, nickel chloride (100 mol/L) caused dilation of both arterioles, similar in magnitude in afferent (68Ϯ10%, nϭ7) and efferent (80Ϯ7%, nϭ7) arterioles. To eliminate the possibility that the mibefradil-induced dilation was mediated by L-type channel blockade, mibefradil was administered in the presence of nifedipine (1 mol/L). Thus, nifedipine caused modest efferent arteriolar dilation (30Ϯ6% reversal, nϭ9), and subsequent addition of mibefradil elicited further dilation of this vessel (80Ϯ4%, PϽ0.01 versus nifedipine). Furthermore, mibefradil reversed the Ang II-induced efferent arteriolar constriction even in the presence of nifedipine and phentolamine. These findings demonstrate that T-type calcium antagonists markedly dilate the Ang II-induced efferent arteriolar constriction, but the action is not mediated by inhibition of catecholamine release. This potent activity would contribute to the efferent arteriolar response to nilvadipine and efonidipine and may offer benefit in light of glomerular hemodynamics. Key Words: mibefradil Ⅲ afferent arteriole Ⅲ efferent arteriole Ⅲ T-type calcium channel Ⅲ calcium antagonists Ⅲ renal microcirculation A growing body of evidence has accrued that the calcium antagonist, a blocker of L-type voltage-dependent calcium channels, exerts potent renal vasodilatory action in the face of systemic hypotension. 1 This unique action is frequently accompanied by an elevation in glomerular filtration rate and filtration fraction. 2,3 To elucidate the mechanism for calcium antagonist-induced alterations in renal hemodynamics, several lines of recent investigations indicate that the calcium antagonist elicits predominant dilation of the afferent arteriole but modest action on the efferent arteriole. 4 -6 These observations are endorsed by the fact that L-type voltagedependent calcium channels prevail functionally in the afferent arteriole but are silent in the efferent arteriole. 7,8 Such a preferential role of voltage-dependent calcium channels in the afferent arteriole thus favors the elevation in glomerular filtration rate by the calcium antagonist. 2,3 In contra...

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“…Interestingly, these antagonists possess inhibitory action on T-type and L-type voltage-dependent calcium channels. [12][13][14] Recently, …”

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confidence: 99%

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confidence: 99%

Effect of T-Type Selective Calcium Antagonist on Renal Microcirculation

et al. 2001

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“…29,30 Other T-and L-type CCBs have also been reported to dilate both afferent and efferent arterioles in rat models. 31,32 In this study, efonidipine, but not amlodipine, significantly reduced multiple components of the renin-angiotensin-aldosterone system. For example, both angiotensin II and aldosterone are potent constrictors of efferent arterioles, and these contractions are attenuated by T-type CCBs, but not L-type CCBs.…”

Section: Discussionmentioning

confidence: 53%

Combination therapy with irbesartan and efonidipine for attenuation of proteinuria in Dahl salt-sensitive rats

2010

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Angiotensin receptor blockers (ARBs) or T-and L-type calcium channel blockers (CCBs) are useful for glomerular protection; however, the protective effects of combination therapy remain unclear. In this study, Dahl salt-sensitive rats were fed a high-salt diet and were treated daily with placebo, irbesartan (60 mg kg À1 ), efonidipine (30 mg kg À1 ), irbesartan (60 mg kg À1 )+efonidipine (30 mg kg À1 ), amlodipine (3 mg kg À1 ), or irbesartan (60 mg kg À1 )+amlodipine (3 mg kg À1 ) for 4 weeks. Significant reductions in systolic blood pressure were seen in the irbesartan-, efonidipine-and amlodipine-treated groups compared with the placebo-treated group; a further significant reduction was seen in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group. Compared with the placebo-treated group, proteinuria was significantly lower in the irbesartan-and efonidipine-treated groups, but not in the amlodipine-treated group. Furthermore, a significant attenuation of proteinuria in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group was observed; this effect was not observed in the irbesartan+amlodipine-treated group. The glomerulosclerosis index was significantly attenuated by all active treatments except amlodipine. The glomerulosclerosis index in the irbesartan+efonidipine-treated group, but not in the irbesartan+amlodipine-treated group, was significantly lower than that in the irbesartan-treated group. Significant attenuations of gene expressions of p22 phox , transforming growth factor-b, monocyte chemoattractant protein-1 and collegen I were observed in the irbesartan-and efonidipine-treated groups, but not in the amlodipine-treated group. Values for these parameters were reduced to control levels in the irbesartan+efonidipine-treated group. Combination therapy with ARB and T-and L-type CCB might produce a powerful renal protective effect. INTRODUCTIONKidneys have an important role not only in the homeostasis of water and electrolyte balance but also in the regulation of blood pressure. Angiotensin II is a crucial peptide for regulating blood pressure by slow and rapid pressor responses. The main functions of slow response are augmentation of sodium reabsorption in the proximal tubules and release of aldosterone from the adrenal cortex, whereas the main functions of rapid response are direct contractile response in peripheral resistance arteries and enhancement of peripheral noradrenergic neurotransmission. Therefore, blockade of angiotensin II is a useful antihypertensive strategy. In addition, angiotensin II directly increases mesangial matrix formation by stimulating transforming growth factor (TGF)-b expression. 1 Inhibition of angiotensin II function induces dilation of efferent arterioles, and this mechanism contributes to amelioration of glomerular hypertension, resulting in a decrease in mesangial matrix formation. 2 Therefore, blockade of angiotensin II is also useful for preventing glomerular injury.Calcium channel blockers (CCBs), such as angi...

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“…[70] It has been found that mibefradil decreased both afferent and efferent arteriolar resistance in SHR kidneys, using the micropuncture technique. [71] Efferent arteriolar dilation by calcium antagonists that possess the blocking activity on T-type calcium channels, such as mibefradil, efonidipine, nilvadipine and aranidipine, [72,73] has been demonstrated. Thus, a critical role of T-type calcium channels in mediating the efferent arteriolar tone has been suggested.…”

Section: Effects On Renal Hemodynamicsmentioning

confidence: 99%

Calcium Antagonists and Renal Failure Progression

Robles

2008

Renal Failure

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Although tighter blood pressure control is considered the main mechanism for preventing the progression of chronic renal failure, angiotensin-converting enzyme inhibitors and angiotensin receptors blockers seem to have an additional organ protective role. The effects of calcium antagonists in renal disease are not so clearly defined. Calcium antagonists have pleiotropic effects that might contribute to protect the kidney, such as attenuating mesangial entrapment of macromolecules, countervailing the mitogenic effect of platelet-derived growth factors and platelet-activating factors, and suppressing mesangial cell proliferation. They could also act as free radical scavengers and inhibit the renal effects of endothelin. Some evidence has been accumulated demonstrating that certain new dihydropyridinic calcium antagonists may affect postglomerular as well as preglomerular vessels, resulting in decreased filtration fraction and nephroprotective effect as renin-angiotensin axis-blocking drugs. Though there are few reports on the clinical renal effects of new calcium antagonists, they have rendered promising results. Manidipine does not increase proteinuria as do some classic calcium antagonists, and lercanidipine combined with renin-angiotesin axisblocking drugs reduce proteinuria. Both drugs have been shown to decrease microalbuminuria when administered alone.

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Inhibition of T-Type and L-Type Ca<sup>2+</sup> Currents by Aranidipine, a Novel Dihydropyridine Ca<sup>2+</sup> Antagonist

Cited by 19 publications

References 17 publications

Effect of T-Type Selective Calcium Antagonist on Renal Microcirculation

Effect of T-Type Selective Calcium Antagonist on Renal Microcirculation

Combination therapy with irbesartan and efonidipine for attenuation of proteinuria in Dahl salt-sensitive rats

Calcium Antagonists and Renal Failure Progression

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