Effect of T-Type Selective Calcium Antagonist on Renal Microcirculation

Abstract

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...

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

“…Nickel could also block this response; however, the concentrations required (1 mM) would be expected to block almost all Ca 2ϩ channels. Similar results were obtained with rat isolated perfused hydronephrotic kidneys: either 1 M mibefradil or 100 M nickel (a relatively selective dose) dilated afferent and efferent arterioles constricted with ANG II (314). Selectivity of mibefradil for T-type channels was demonstrated by coadministration with the L-type blocker nifedipine.…”

Effects of Benidipine on Glomerular Hemodynamics and Proteinuria in Patients with Nondiabetic Nephropathy.

“…In contrast, benidipine, with stronger effects on (22). The L type has been found in afferent but not in efferent arterioles (23).…”

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

“…16 By contrast, novel types of Ca channel blockers, including efonidipine and benidipine, which possess T-type Ca channel blocking activity, 27,28 confer a greater benefit on renal function. 23,[29][30][31] Of interest, efonidipine possesses renal protective action via efferent arteriolar dilation, [17][18][19][20] the inhibition of Rho kinase 32 and, possibly, the inhibition of aldosterone activity. 33,34 Our present observations therefore imply a distinct therapeutic applicability of Ca channel blockers in CKD.…”

“…Upon obtaining informed consent, physicians were allowed to give information on patient profiles to the JATOS Central Registration Office, which subsequently assigned the subjects to two systolic BP target arms (strict-treatment group; o140 mm Hg, and mild-treatment group; 140 to o160 mm Hg) by computer-assisted random allocation. 12 Antihypertensive therapy with efonidipine (20-60 mg per day), a long-acting Ca channel blocker with renal afferent and efferent arteriolar dilator action, [16][17][18][19][20] was given to all patients, and if the target systolic BP was not achieved, additional antihypertensive agents, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics and b-blockers, were administered.…”