Calcium supplementation and calcium channel blockers are known to have antihypertensive effects in similar subsets of hypertensive patients, as well as in spontaneously hypertensive rats (SHR). To investigate this apparent paradox, we placed 12-week-old SHR on one of three dietary levels of calcium (0.2, 0.4, or 0.8%), as well as on one of four doses of nifedipine (0, 50, 150, or 300 mg/kg food) for 8 weeks. We performed a similar experiment using four verapamil doses (0, 300, 900, or 1,800 mg/kg food). In the nifedipine experiment, two-way analysis of variance showed significant independent antihypertensive effects of both nifedipine (p less than or equal to 0.0001) and calcium (p less than 0.0001) and significant interaction (p = 0.0034), the latter suggesting a synergistic effect. In the verapamil experiment, both calcium and verapamil again had significant independent antihypertensive effects (p = 0.006 and p = 0.004, respectively), but there was no significant interaction. Although the effects of the calcium supplement or calcium antagonist alone were significant, such hypotensive responses were not optimal or predictable or clearly dose-dependent. However, the combination of a calcium supplement and calcium antagonist resulted in predictable or dose-dependent effects, and the optimal effect was reflected in the reduction of the SHR pressure to normal range for Wistar-Kyoto (WKY) rats. These results appear to indicate that supplementary calcium and calcium channel blockers act by different mechanisms in lowering blood pressure (BP), and that the combination of those differing mechanisms of action may have potential therapeutic benefit.