Altered serotonin receptor subtypes mediate coronary microvascular hyperreactivity in pigs with chronic inhibition of nitric oxide synthesis.
BACKGROUND
We previously reported that chronic inhibition of nitric oxide synthesis by administration of N omega-nitro-L-arginine methyl ester (L-NAME) causes microvascular hyperreactivity to 5-hydroxytryptamine (5-HT) and vascular structural changes in pigs in vivo. In the present study, we investigated the relative contributions of 5-HT receptor subtypes to microvascular hyper-reactivity in this animal model.


RESULTS
Coronary vasomotor response was studied in 16 pigs treated with oral L-NAME for 4 weeks (L group) and in 11 control pigs (C group). Intracoronary administration of 5-HT at 30 micrograms/kg decreased coronary blood flow (CBF) in the two groups. The decrease in CBF by 5-HT was greater (P < .01) in the L group than in the C group. The decrease in CBF by 5-HT in the C group was blocked completely by pretreatment with ketanserin, a 5-HT2 antagonist. In contrast, the augmented decrease in CBF by 5-HT in the L group was only partly inhibited by ketanserin alone and was blocked completely by ketanserin and methiothepin, a 5-HT1/5-HT2 antagonist. The decrease in CBF caused by prostaglandin F2 alpha and the increase in CBF caused by nitroglycerin were comparable between the two groups and were not affected by the 5-HT antagonists.


CONCLUSIONS
These results suggest that the 5-HT-induced microvascular hyperreactivity may be mediated by relative changes in affinity for 5-HT receptors or de novo expression of 5-HT1 receptors in microvascular smooth muscle cells in our animal model.
Kadokami
T
T
Research Institute of Angiocardiology, Kyushu University School of Medicine, Japan.
Egashira
K
K
Kuwata
K
K
Fukumoto
Y
Y
Kozai
T
T
Yasutake
H
H
Kuga
T
T
Shimokawa
H
H
Sueishi
K
K
Takeshita
A
A
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects*; D015237:Dinoprost / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008719:Methiothepin / Q000494:pharmacology; D008833:Microcirculation / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D005996:Nitroglycerin / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects*
D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014665:Vasodilator Agents; D012701:Serotonin; D008719:Methiothepin; D001120:Arginine; D007650:Ketanserin; D015237:Dinoprost; D019001:Nitric Oxide Synthase; D005996:Nitroglycerin; D019331:NG-Nitroarginine Methyl Ester