Analysis of an H₁ receptor-mediated, zinc-potentiated vasoconstrictor action of the histidyl dipeptide carnosine in rabbit saphenous vein

Abstract

1. The contractile action of the dipeptide carnosine (β-alanyl-L-histidine), active as a Zn·carnosine complex (Zn·Carn), was investigated in isolated rings of rabbit saphenous vein (RSV) and was found to be antagonized by the H₁ antagonist mepyramine.

2. Mepyramine-sensitive, histamine-induced contractures in RSV, were smaller (73±0.1%) and less well sustained than carnosine-induced contractures.

3. Schild plot values for mepyramine antagonism were, for carnosine-induced contractures; pA₂=7.97±0.12, slope=1.33±0.06 (r=0.793) and for histamine-induced contractures; pA₂=8.48±0.07, slope=0.63±0.05, r=0.957).

4. Serotonergic antagonists methiothepin and ketanserin, antagonize both carnosine- and histamine-induced contractures in RSV, probably reflecting coincidental inhibition at the H₁-receptor.

5. Carnosine, with Zn present, can inhibit the H₁-specific binding of [³H]-mepyramine to isolated guinea-pig cerebellar membranes (log IC₅₀s−2.78±0.02, −3.93±0.03 and −4.64±0.03 at 10, 30 and 80 μM Zn respectively; values corrected for the Zn-specific inhibition which has a logIC₅₀ of −4.20).

6. In the radioligand binding assay, the effect of carnosine can be described as a function of Zn·Carn concentration with an apparent logIC₅₀ of −5.61. This value is consistent with that obtained from the functional studies on RSV.

7. Histamine-induced contractures have an indomethacine-sensitive component (27.2±8.3% of control response), not apparent with carnosine-induced contractures.

8. Like histamine, carnosine evoked an H₂-mediated (cimetidine-sensitive) relaxation in the presence of mepyramine, but was less potent (10.8±3.1% residual tension at 10 mM carnosine compared with 13.4±7.5% at 0.1 mM histamine).

9. Carnosine, like mepyramine, can 'reveal' the H₂-mediated relaxation of histamine providing further evidence that carnosine binds at the H₁ receptor.

10. We conclude that carnosine can act at the smooth muscle H₁-receptor to provoke vasoconstriction and that it also has the potential to act at H₁-receptors in CNS.

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