To elucidate the central roles of histamine receptors in cardiovascular regulatory system, systolic, mean, and diastolic blood pressures (BPs) and heart rate (HR) were examined in conscious H1 receptor gene knockout (H1KO) mice, H2 receptor gene knockout (H2KO) mice, H1 and H2 receptor gene double knockout (DKO) mice, and their respective control mice by the tail-cuff system. Histamine, histamine-trifluoromethyl-toluidine derivative (HTMT, an H1 agonist), dimaprit (an H2 agonist), and immepip (an H3 agonist) were intrathecally administered to these KO mice and control mice. Basal BPs and HR were not different among these three KO mice and their control or wild-type mice. Intrathecal administration of histamine significantly increased BPs and decreased HR in control mice. The increases in BPs were produced by histamine in H1KO and H2KO mice and by HTMT and dimaprit in C57BL mice. The pressor responses by HTMT and dimaprit in C57BL mice were greater than those by histamine in H1KO and H2KO mice, although the same decreases in HR were induced by histamine in C57BL and H1KO mice and by dimaprit in C57BL mice. The selective stimulation of H3 receptors by immepip produced a consistent decrease in BPs in control mice. These results obtained with the exogenous selective agonists of three histamine receptors suggest that the pressor responses to histamine are mediated through the stimulation of both H1 and H2 receptors, whereas the atropine-sensitive decrease in heart rate is mainly due to H2 receptors which activate the vagal output to the heart.
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