Effect of T-type selective calcium antagonist on renal microcirculation: Studies in the isolated perfused hydronephrotic kidney

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 13.5±0.6 to 9.2±0.6 μm, P<0.01, n = 6) and efferent (from 11.5± 1.0 to 7.4±0.7 μm, P<0.01, n=5) arterioles. Mibefradil (1 μmol/L) dilated both vessels, with 82±11% and 72±7% reversal of afferent and efferent arterioles, respectively. Similarly, nickel chloride (100 μmol/L) caused dilation of both arterioles, similar in magnitude in afferent (68±10%, n = 7) and efferent (80± 7%, n = 7) 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 μmol/L). Thus, nifedipine caused modest efferent arteriolar dilation (30±6% reversal, n=9), and subsequent addition of mibefradil elicited further dilation of this vessel (80±4%, P<0.01 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.