Histamine receptors in the digital artery of the ‘warm acclimatized’ fallow deer (Dama dama)

Anthony Milton, Lee Meakin, Sanjin Idriz and Brian Callingham. Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD. U.K.

The vasoreactivity of the digital artery of the fallow deer (Dama dama) changes in response to the external temperature to which the animal is exposed. In cold weather, the artery spontaneously increases its resting tone and loses all sensitivity to nitric oxide (NO). The importance of this is that it is a temperature induced and not a seasonal induced change, as was described by Milton, Carr, Luby, Scarlett, White and Callingham in 1999. They proposed that this change in the temperature-dependent reactivity of the digital artery was a mechanism of cold adaptation, to conserve heat and energy production. This would enable the fallow deer to extend its foraging area. The digital arteries of Dama dama appear to be devoid of acetylcholine receptors, however histamine produces a nitric oxide (NO) dependent relaxation in this tissue. Histamine, in high concentrations, also produces vasoconstriction. The dual response to histamine has now been further investigated to determine which histamine receptor types are involved.

Fallow deer of both sexes, aged approximately 18 months and weighing between 34 – 45 kg, were killed for venison according to E.U. red meat regulations. Digital artery rings were prepared as previously described (Milton et al 1999). The experiments were carried out in the early part of 2004, during which time the minimum air temperature was rarely below 0 °C. All of the arteries responded to the endothelium-independent vasorelaxant sodium nitroprusside (SNP) indicating that the reactivity of the vessels corresponded to their being ‘warm acclimatized’ as opposed to ‘cold acclimatized’. In artery rings from 8 deer (n = 8), submaximally contracted with phenylephrine (1 x 10 -6 M), histamine (1 x 10-8 – 1 x 10-2 M) produced a biphasic relaxation; an immediate transient relaxation followed by a sustained relaxation. L-NAME 10-4 M inhibited the second phase without any effect on the immediate relaxation. In contrast, the H 1 antagonist doxepin (10 -8 M)significantly inhibited both phases(p= 0.001, n = 8). The H2 antagonist tiotidine (10-6 M) was without effect (n = 8). It is possible that the initial relaxation is due to opening of K+ channels, whereas the second phase is due to NO release. Increasing concentrations of external K+ (4.7 mM to 70.0 mM KCl) blocked the initial relaxation without affecting the contraction except at very high concentrations. However the potassium channel antagonists apamin (10-6 M) and charybdotoxin (10-7 M) had no effect on the relaxation.

Following the removal of the endothelium, histamine produced a dose related contraction. (EC50 of 1.18 x 10-4 ± 1.01x10-5M). Doxepin (10-8 M) produced a rightward shift in the dose response curve. (EC50 increased 10-fold to 1.36x 10-3 ± 1.29x 10-4M). This is highly significant with p < 0.01(n = 8) with no further shift with tiotidine (10-6 M), or clobenpropit (10-6 M), an H3 antagonist. However, the contraction produced by the H3 agonist imetit (10-3 and 10-4 M) was reduced by clobenpropit.

In conclusion, we believe that histamine causes an endothelial H1 mediated relaxation involving EDNO and EDHF, and an H1 mediated contraction involving H1 receptors on the smooth muscle. In addition, the possibility exists that H3 receptors are also involved.

Milton , A.S et al. (1999) J.therm. Biol. 24, 465-470.