Nimodipine-induced hypotension but not nitroglycerin-induced hypotension preserves long- and short-term memory in adult mice.

BACKGROUND

Acute hypotension may be implicated in cognitive dysfunction. L-type calcium channel blockers in the setting of hypoxia are protective of learning and memory. We tested the hypothesis that hypotension induced by nimodipine (NIMO) and nicardipine (NICA) would be protective of long- and short-term memory compared to hypotension induced by nitroglycerin (NTG).

METHODS

Forty Swiss-Webster mice (30 to 35 g, 6 to 8 weeks) were randomized into 4 groups for i.p. injection immediately after passive avoidance (PA) learning on day 0: (1) NTG (30 mg/kg); (2) NICA (40 mg/kg); (3) NIMO (40 mg/kg); and (4) saline. PA training latencies (seconds) were recorded for entry from a suspended platform into a Plexiglas tube where a shock (0.3 mA; 2-second duration) was automatically delivered. On day 2 latencies were recorded during a testing trial during which no shock was delivered. Latencies >900 seconds were assigned this value. Lower testing latency is indicative of an impairment of long-term associative memory. Forty-nine additional mice were randomized into similar groups for object recognition testing (ORT) and given i.p. injections on day 0. ORT measures short-term memory by exploiting the tendency of mice to prefer novel objects where a familiar object is present. On day 5 during training, 2 identical objects were placed in a circular arena and mice explored both for 15 minutes. A testing trial was conducted 1 hour later for 3 minutes after a novel object replaced a familiar one. Mice with intact memory spend about 65% of the time exploring the novel object. Mice with impaired memory devote equal time to each object. Recognition index (RI) is defined as the ratio of time spent exploring the novel object to time spent exploring both objects was the measure of memory. Mean arterial blood pressure (MAP), cerebral bloodflow, and body and brain oxygenation (PO(2)) studies were done in separate groups of mice to determine the dosages for matched degrees of hypotension and the physiological profile of each treatment.

RESULTS

The median PA latencies for the different conditions were as follows: NTG (219.5 ± 93.5 second semi-interquartile range [SIQR]), NICA (372.5 ± 75.5 second SIQR), NIMO (540 ± 200 second SIQR) and saline (804 ± 257.5 second SIQR). Rank methods were used to analyze the PA latencies for significant differences. NTG latency was significantly shorter than NIMO latency (P = 0.012) and saline latency (P = 0.006), but not NICA latency (P = 0.126). ORT RI values showed a similar pattern. We found that NTG RI (47.2 ± 5.9% SEM) was different from NIMO RI (60.2 ± 4.6% SEM, P = 0.031) and different from saline RI (66.9 + 3.7% SEM, P = 0.006). Physiological experiments showed that MAP decreased to 45 to 50 mm Hg in all animals who became minimally responsive to external stimuli within 10 to 15 minutes of injection. Intergroup differences for MAP, body and brain oxygenation, and cerebral bloodflow were not statistically significant.

CONCLUSION

Acute hypotension induced by NIMO was protective of 2 categories of memory formation relevant to the clinical posttreatment period. Both immediate long-term associative memory consolidation as measured by the PA learning paradigm and delayed short-term working memory function as measured by the ORT paradigm were significantly improved compared to matched levels of hypotension induced by NTG. These results indicate the utility of further investigation of l-type calcium channel blockers as a potential means of preserving cognition in the setting of hypotensive and low flow states.