The role of T-type calcium channels in elderly human vascular function: A pilot randomized controlled trial

Abstract

Endothelial dysfunction develops with age and may precede cardiovascular disease. Animal data suggest that T-type calcium channels play an important role in endothelial function, but data from humans are lacking. This study included 15 healthy, sedentary, elderly males for a double blinded, randomized controlled trial. For 8 weeks, they were given 40 mg/day of either efonidipine (L- and T-type calcium channel blocker (CCB)) or nifedipine (L-type CCB). Vascular function was evaluated by graded femoral arterial infusions of acetylcholine (ACh; endothelium-dependent vasodilator) and sodium nitroprusside (endothelium-independent vasodilator) both with and without co-infusion of N-acetylcysteine (NAC; antioxidant). We measured leg blood flow and mean arterial pressure and calculated leg vascular conductance to evaluate the leg vascular responses. Despite no significant change in blood pressure in either group, we observed higher leg blood flow responses (Δ 0.43 ± 0.45 l/min, P = 0.006) and leg vascular conductance (Δ 5.38 ± 5.67 ml/min/mmHg, P = 0.005) to intra-arterial ACh after efonidipine, whereas there was no change in the nifedipine group, and no differences between groups. We found no upregulation of endothelial nitric oxide synthase in vastus lateralis muscle biopsies within or between groups. Smooth muscle cell responsiveness was unaltered by efonidipine or nifedipine. Intravenous co-infusion of NAC did not affect endothelium-dependent vasodilatation in either of the CCB groups. These results suggest that 8 weeks' inhibition of T- and L-type calcium channels augments endothelium-dependent vasodilatory function in healthy elderly males. Further studies are required to elucidate if T-type calcium channel inhibition can counteract endothelial dysfunction.

Keywords: acetylcholine receptor; blood vessels; cardiovascular; endothelium; hypertension.

FIGURE 1

Study protocol. Catheters were placed in the femoral artery and vein, and a muscle biopsy was obtained from the contralateral vastus lateralis. The experiment began with supine rest for 20 min (baseline) followed by femoral arterial infusion of acetylcholine (ACh) at two infusion rates (ACh 1: 25 µg/min/kg leg mass, ACh2: 100 µg/min/kg leg mass) followed by 20 min of supine rest. Likewise, sodium nitroprusside (SNP) was infused at two rates (SNP1: 0.5 µg/min/kg leg mass, SNP2: 2.0 µg/min/kg leg mass). Then an intravenous N‐acetylcysteine (NAC) loading dose for 20 min (125 mg/min/kg total body mass) was initiated followed by maintenance dose (25 mg/min/kg total body mass), which was continued for the rest of the experiment and during the same doses of ACh and SNP, as before NAC. Leg blood flow and intravascular blood pressure were measured at the end of each infusion trial marked by black arrows.

FIGURE 2

Leg blood flow. (a) Nifedipine versus efonidipine by the difference in leg blood flow between pre‐trial and post‐trial at baseline and during femoral arterial infusions of acetylcholine 25 µg/min/kg leg mass (ACh1), acetylcholine 100 µg/min/kg leg mass (ACh2), sodium nitroprusside 0.5 µg/min/kg leg mass (SNP1) and sodium nitroprusside 2 µg/min/kg leg mass (SNP2). (b) Nifedipine versus efonidipine by the differences in leg blood flow between pre‐trial and post‐trial during baseline and during ACh1 and ACh2 with co‐infusion of N‐acetylcysteine 25 mg/min/kg total body mass (NAC). (c) The leg blood flow responses from baseline within nifedipine group at pre‐ and post‐treatment. (d) The leg blood flow responses from baseline within efonidipine group at pre‐ and post‐treatment. Bars represent means, and whiskers represent SD. n = 5 (nifedipine) versus n = 7 (efonidipine).

FIGURE 3

Mean arterial pressure. (a) Nifedipine versus efonidipine by the difference in mean arterial pressure (MAP) between pre‐trial and post‐trial at baseline and during femoral arterial infusions of acetylcholine 25 µg/min/kg leg mass (ACh1), acetylcholine 100 µg/min/kg leg mass (ACh2), sodium nitroprusside 0.5 µg/min/kg leg mass (SNP1) and sodium nitroprusside 2 µg/min/kg leg mass (SNP2). (b) Nifedipine versus efonidipine by the differences in MAP between pre‐trial and post‐trial during baseline and during ACh1 and ACh2 with co‐infusion of N‐acetylcysteine 25 mg/min/kg total body mass (NAC). (c) The MAP responses from baseline within nifedipine group at pre‐ and post‐treatment. (d) The MAP responses from baseline within efonidipine group at pre‐ and post‐treatment. Bars represent means, and whiskers represent SD. n = 5 (nifedipine) versus n = 7 (efonidipine).

FIGURE 4

Leg vascular conductance. (a) Nifedipine versus efonidipine by the difference in leg vascular conductance (LVC) between pre‐trial and post‐trial at baseline and during femoral arterial infusions of acetylcholine 25 µg/min/kg leg mass (ACh1), acetylcholine 100 µg/min/kg leg mass (ACh2), sodium nitroprusside 0.5 µg/min/kg leg mass (SNP1) and sodium nitroprusside 2 µg/min/kg leg mass (SNP2). (b) Nifedipine versus efonidipine by the differences in LVC between pre‐trial and post‐trial during baseline and during ACh1 and ACh2 with co‐infusion of N‐acetylcysteine 25 mg/min/kg total body mass (NAC). (c) The LVC responses from baseline within nifedipine group at pre‐ and post‐treatment. (d) The LVC responses from baseline within efonidipine group at pre‐ and post‐treatment. Bars represent means, and whiskers represent SD. n = 5 (nifedipine) versus n = 7 (efonidipine).

FIGURE 5

Muscle content of endothelial nitric oxide synthase (eNOS). There was no difference within or between groups in muscle content of eNOS, n = 3 (nifedipine) versus n = 5 (efonidipine).

FIGURE A1

Systolic blood pressure. (a) Nifedipine versus efonidipine by the difference in systolic blood pressure between pre‐trial and post‐trial at baseline and during femoral arterial infusions of acetylcholine 25 µg/min/kg leg mass (ACh1), acetylcholine 100 µg/min/kg leg mass (ACh2), sodium nitroprusside 0.5 µg/min/kg leg mass (SNP1) and sodium nitroprusside 2 µg/min/kg leg mass (SNP2). (b) Nifedipine versus efonidipine by the differences in systolic blood pressure between pre‐trial and post‐trial during baseline and during ACh1 and ACh2 with co‐infusion of N‐acetylcysteine 25 mg/min/kg total body mass (NAC). (c) The systolic blood pressure responses from baseline within nifedipine group at pre‐ and post‐treatment. (d) The systolic blood pressure responses from baseline within efonidipine group at pre‐ and post‐treatment. Bars represent means, and whiskers represent SD. n = 5 (nifedipine) versus n = 7 (efonidipine).

FIGURE A2

Diastolic blood pressure. (a) Nifedipine versus efonidipine by the difference in diastolic blood pressure between pre‐trial and post‐trial at baseline and during femoral arterial infusions of acetylcholine 25 µg/min/kg leg mass (ACh1), acetylcholine 100 µg/min/kg leg mass (ACh2), sodium nitroprusside 0.5 µg/min/kg leg mass (SNP1) and sodium nitroprusside 2 µg/min/kg leg mass (SNP2). (b) Nifedipine versus efonidipine by the differences in diastolic blood pressure between pre‐trial and post‐trial during baseline and during ACh1 and ACh2 with co‐infusion of N‐acetylcysteine 25 mg/min/kg total body mass (NAC). (c) The diastolic blood pressure responses from baseline within nifedipine group at pre‐ and post‐treatment. (d) The diastolic blood pressure responses from baseline within efonidipine group at pre‐ and post‐treatment. Bars represent means, and whiskers represent SD. n = 5 (nifedipine) versus n = 7 (efonidipine).