Recent interest has centred on the role of divalent cations in hypertension, particularly in relation to the renin-angiotensin system. This study was undertaken to determine the hypotensive effect of magnesium administration in relation to the state of activation of the renin-angiotensin system. The mean blood pressure (MBP) and heart rate (HR) response to either the acute intravenous administration of a pharmacological dose of MgSO4or vehicle was determined in conscious mineralocorticoid-salt (DOCA-salt, low-renin) and two-kidney, one clip renovascular, high-renin hypertensive rats. Baseline MBP was higher in the renovascular than in the DOCA-salt rats, while there was no difference in HR or serum Mg concentration between the two. Following administration of MgSO4, serum Mg increased equally in both the DOCA-salt (1.4 ± 0.8 to 4.9 ± 0.16 mEq/l;P< 0.001) and in the renovascular rats (1.8 ± 0.14 to 4.4 ± 0.27 mEq/l;P< 0.001). Magnesium administration significantly lowered MBP over the 1-h infusion in the DOCA-salt (167 ± 8 to 145 ± 5 mmHg,P< 0.001) but not the renovascular hypertensive rats (191 ± 5 to 183 ± 4, NS). We conclude that the blood pressure lowering effect of Mg is related, in part, to the state of activation of the renin-angiotensin system. The mechanism of this differential effect remains to be determined.