The aim of this study was to test our hypotheses that AT_1A receptors play a role in the pathogenesis of cold-induced hypertension (CIH) and in the cold-induced increase in drinking responses to angiotensin II (AngII). Two groups of wild-type (WT) and 2 groups of AT_1A receptor gene knockout (AT_1A-KO) mice were used (6/group). Blood pressures (BP) of the four groups were similar during the control period at room temperature (25°C). After the control period, 1 group of WT and 1 group of AT_1A-KO mice were exposed to cold (5°C), while the remaining groups were kept at 25°C. BP of the cold-exposed WT group elevated significantly within 1 week of exposure to cold and increased gradually to a maximum level by week 5. However, there was only a slight increase in BP of the cold-exposed AT_1A-KO group. The maximal cold-induced increase in BP (BP) is significantly less in AT_1A-KO group (11±3 mmHg) than in WT group (49±6 mmHg), indicating that AT_1A receptor deficiency attenuates cold-induced elevation of BP. Interestingly, both WT and AT_1A-KO mice developed cardiac and renal hypertrophy to the same extent. AT_1A-KO caused a significant increase in urine and plasma levels of NO, indicating that the renin-angiotensin system inhibits NO formation probably via AT_1A receptors. Cold exposure inhibited eNOS protein expression and decreased urine and plasma levels of NO, which may be mediated partially by AT_1A receptors. AT_1A-KO completely abolished the cold-induced increase in drinking responses to AngII. Conclusions: (1) AT_1A receptors play an essential role in the pathogenesis of CIH but not cardiac hypertrophy; (2) the role of AT_1A receptors in CIH may be mediated partially by its inhibitory effect on the NO system; (3) the cold-induced increase in drinking responses to AngII is mediated by AT_1A receptors.