Role of endothelium and nitric oxide in histamine-induced responses in human cranial arteries and detection of mRNA encoding H₁- and H₂-receptors by RT-PCR

Abstract

1. Histamine induces relaxation of human cranial arteries. Studies have revealed that the relaxant histamine H₁-receptor predominates in human cerebral and the H₂-receptor in temporal arteries, while H₁- and H₂-receptors are of equal importance in the middle meningeal artery. The purpose of the present study was to examine the role of the endothelium and nitric oxide in histamine-induced responses and to show the presence of mRNA encoding H₁- and H₂-receptors in human cranial arteries.

2. Electrophoresis of polymerase chain reaction (PCR) products from human cerebral, middle meningeal and temporal arteries, demonstrated products corresponding to mRNA encoding both H₁- and H₂-receptors in arteries with and without endothelium. The amplified PCR products were sequenced and showed 100% homology with the published sequences of these histamine receptors.

3. A sensitive in vitro system was used to study vasomotor responses to histamine. In precontracted cerebral, middle meningeal and temporal arteries with and without endothelium, histamine caused a concentration-dependent relaxation with I_max values between 87% and 81% and pIC₅₀ values between 8.14 and 7.15. In arteries without endothelium the histamine-induced relaxation was significantly less potent (I_max values between 87% and 66% and pIC₅₀ values between 7.01 and 6.67) than in cranial arteries with an intact endothelium.

4. The addition of histamine to arteries without endothelium and pretreated with the histamine H₂-antagonist, cimetidine (10⁻⁵ M), caused a concentration-dependent contraction of the cranial arteries with E_max values between 86% and 29% and pEC₅₀ values between 7.53 and 6.77. This contraction was blocked by the histamine H₁-receptor antagonist, mepyramine (10⁻⁷ M), and even turned into a relaxation with I_max values between 84% and 14% and pIC₅₀ values between 7.42 and 5.86.

5. The nitric oxide synthase inhibitor N^G-nitro-L-arginine methyl ester (L-NAME, 3×10⁻⁵ M) significantly inhibited the relaxant response to histamine in cerebral and temporal arteries (pIC₅₀ values between 7.43 and 7.13). The combined treatment with L-NAME (3×10⁻⁵ M) and cimetidine (10⁻⁵ M) caused a further displacement of the concentration-response curve (pIC₅₀ values between 7.14 and 6.57) and decreased the maximum relaxant responses in all three cranial arteries (I_max values between 62% and 39%).

6. In conclusion, this is the first study which show mRNA encoding histamine H₁- and H₂-receptors in human cranial arteries. The results indicate that histamine-induced relaxation of human cranial arteries is partially mediated via an endothelial H₁-receptor coupled to the production of nitric oxide and partially via a H₂-receptor associated with the smooth muscle cells. In addition, there is evidence for a contractile H₁-receptor in the smooth muscle cells in these arteries.

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