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.
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 Imax 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 (Imax values between 87% and 66% and pIC50 values between 7.01 and 6.67) than in cranial arteries with an intact endothelium. 4. This 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 Emax 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 Imax values between 84% and 14% and pIC50 values between 7.42 and 5.86. 5. The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 3 x 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 x 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 (Imax 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.
Jansen-Olesen
I
I
Department of Biological Sciences, Royal Danish School of Pharmacy, Copenhagen 0, Sweden.
Ottosson
A
A
Cantera
L
L
Strunk
S
S
Lassen
L H
LH
Olesen
J
J
Mortensen
A
A
Engel
U
U
Edvinsson
L
L
D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002927:Cimetidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology* / Q000502:physiology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006801:Humans; D008576:Meningeal Arteries / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011969:Receptors, Histamine H1 / Q000235:genetics* / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000235:genetics* / Q000378:metabolism; D013699:Temporal Arteries / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
D004791:Enzyme Inhibitors; D006635:Histamine H2 Antagonists; D012333:RNA, Messenger; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D009569:Nitric Oxide; D002927:Cimetidine; D006632:Histamine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester