The aim of the present study was to ascertain whether the possible occurrence of overproduction of inducible nitric oxide synthase (iNOS)-dependent nitric oxide (NO) in the brain and inflammatory cytokines in the peripheral blood exhibited during heat stroke can be reduced by prior administration of Shengmai San, a Chinese herbal medicine. Aminoguanidine, an iNOS inhibitor, was evaluated at the same time as a reference (positive control). Urethane-anesthetized rats were exposed to heat stress (ambient temperature of 43°C) to induce heat stroke. Control rats were exposed to 24°C. Mean arterial pressure and cerebral blood flow after the onset of heat stroke were all significantly lower than in control rats. However, cerebral iNOS immunoreactivity and NO levels were all greater after the onset of heat stroke. The serum levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α were all increased after the onset of heat stroke. Shengmai San (1.2 g/ml per rat) or aminoguanidine (30 μmol/ml per rat) was administered orally, daily, and consecutively for 7 days before the initiation of heat stress; and this significantly attenuated the heat stress-induced arterial hypotension, cerebral ischemia, and increased levels of brain iNOS-dependent NO production and serum cytokines formation. Shengmai San shared with the aminoguanidine almost the same efficacy in reducing iNOS-dependent NO and cytokines overproduction during heat stroke. These results suggest that Shengmai San or aminoguanidine protects against heat stroke-induced arterial hypotension and cerebral ischemia by inhibition of iNOS-dependent NO overproduction in the brain and excessive accumulation of several inflammatory cytokines in the peripheral blood stream.
The Japanese Pharmacological Society 2005