Garlic reduces blood pressure (BP) in two-kidney, one-clip (2K-1C) rats, and enhances nitric oxide (NO) synthesis in in vivo and in vitro experiments. NO is an important modulator of BP in the 2K-1C model. This study investigated the role of NO in the BP-lowering effect of garlic in the 2K-1C model. BP readings (mm Hg) were obtained from 2K-1C rats in 4 groups treated intraperitoneally for 2 wk with either normal saline (NS), garlic, L-nitroarginine-methylester (L-NAME), or L-NAME+garlic (n=4x5). BP was determined using the tail-cuff method and compared with data of 4 similarly treated groups of normal (unclipped) rats (NRs). The BP readings of NR groups were 120+/-3 mm Hg for the NS-treated group, 120+/-2 mm Hg for the garlic-treated group, 167+/-3 mm Hg for the L-NAME treated group (higher than NS or garlic, P<0.001) and 128+/-5 mm Hg for the garlic+L-NAME-treated group (lower than L-NAME, P<0.001). The BP readings of 2K-1C rat groups were: for the NS group, 169+/-6 mm Hg (higher than NRs, P<0.001); for the garlic group, 116+/-7 mm Hg (lower than NS, P<0.001); for the L-NAME group: 184+/-8 mm Hg (higher than garlic, P<0.001), and for the L-NAME+garlic group: 130+/-6 mm Hg (lower than garlic or NS, P<0.001). The data show that L-NAME increases the BP of both NRs and 2K-1C rats, with the rise more evident in the NRs (39 vs. 9%, respectively). Garlic counteracts the hypertensive effect of L-NAME in NRs as well as 2K-1C rats. We conclude that the BP-lowering effect of garlic in the rat 2K-1C model may be partly mediated through the NO pathway.