Background/Aims: Vitamin D receptor activators (VDRAs) may suppress renin expression and VDR-mediated renin inhibitors may offer a novel mechanism to control the RAS. Methods: We delineated the effects of paricalcitol and calcitriol on PTH, renin, and iCa²⁺ in C57/BL6 mice administered vehicle, paricalcitol, or calcitriol (0.01, 0.03, 0.10, 0.33, 1.0 µg/kg s.c.) 3 days/week for 9 days. Results: Paricalcitol produced PTH suppression from 0.03 to 1.0 µg/kg (values between 9.7 ± 3.3 and 20.7 ± 4.7 pg/ml; vehicle = 88.0 ± 16.9) and elicited dose-dependent reductions in renin/GAPDH expression at 0.33 and 1.0 µg/kg (0.037 ± 0.002, 0.027 ± 0.003; vehicle = 0.054 ± 0.003) but produced no increases iCa²⁺ at any dose tested. Calcitrol produced PTH suppression at all doses tested (between 6.4 ± 1.2 and 29.5 ± 17.2 pg/ml) and renin suppression at 0.10, 0.33, and 1.0 µg/kg (0.029 ± 0.002, 0.031 ± 0.003, and 0.038 ± 0.02). However, at 0.33 and 1.0 mg/kg, calcitriol produced increases iCa²⁺ (1.31 ± 0.03 and 1.48 ± 0.02 mmol/l; vehicle = 1.23 ± 0.02 mmol/l). Conclusions: Paricalcitol produces significant, dose-dependent suppression of renin expression in the absence of hypercalcemia at doses 10-fold above those necessary for PTH suppression. Calcitriol also produced suppression of renin at doses at least 10-fold above those required for PTH suppression, but increases in iCa²⁺ were observed at doses only 3-fold above those necessary to elicit renin suppression.

The pharmacological profile of the novel dihydropyridine K channel opener (KCO), (9R)-9-(3-iodo-4-methylphenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (A-325100), is described in numerous in vitro assays. Furthermore, the cardiovascular effects of A-325100 are characterized in both the anesthetized and conscious dog. In vitro, A-325100 selectively activated KATP currents and potently relaxed vascular smooth muscle (IC50 between 7.69x10 M and 7.78x10 M), an effect that was abolished by glyburide. Moreover, A-325100 did not interact with L-type Ca2+ channels at concentrations up to 30 microM. In anesthetized dogs A-325100 produced a dose-dependent reduction in systemic vascular resistance and mean arterial pressure concomitant with dose-dependent increases in dP/dtmax and heart rate. In conscious telemetry-instrumented dogs oral administration of A-325100 produced a similar response profile, including dose-dependent reductions in MAP and increases in heart rate and dP/dtmax. When concentration-dependent changes in MAP, heart rate, and dP/dtmax were compared relative to circulating plasma concentrations, A-325100 produced similar effects in both the anesthetized and conscious dog. In conclusion, the present study provides the first pharmacological description of the novel and selective tricyclic dihydropyridine KCO, A-325100. When studied in vivo, A-325100 produced similar concentration-dependent cardiovascular effects in both models consistent with its mode of action and independent of route of administration. Thus, these data demonstrate that the hemodynamic effects of vasoactive compounds, such as KCOs, can be effectively profiled in both the conscious and anesthetized dog.