Ketanserin-induced baroreflex enhancement in spontaneously hypertensive rats depends on central 5-HT(2A) receptors.
1. Ketanserin may influence baroreflex function by blocking 5-HT(2A) receptors and/or alpha(1)-adrenoceptors through central and/or peripheral mechanisms. 2. In the present study, we tested the hypothesis that the baroreflex sensitivity (BRS)-enhancing effects of ketanserin are mediated by central 5-HT(2A) receptors in spontaneously hypertensive rats (SHR). 3. Using a conjugate of a monoclonal antibody to the serotonin reuptake transporter (SERT) and the toxin saporin (anti-SERT-SAP), which specifically eliminates the neurons that express SERT, the effects of ketanserin (0.3 and 3.0 mg/kg, i.g.) on BRS, blood pressure (BP), heart period (HP) and blood pressure variability (BPV) were compared between conscious intact SHR and SHR pretreated with anti-SERT-SAP. 4. Immunochemistry showed that, 2 weeks after intracerebroventricular injection of the toxin, 5-HT expression was strikingly attenuated in the brain, whereas values of BRS, BPV and BP were similar to those in the sham group. In intact SHR, 0.3 mg/kg ketanserin significantly improved BRS (191% control) and reduced BPV without affecting BP; at 3.0 mg/kg, ketanserin significantly increased BRS (197% control) and decreased BPV and BP. In toxin-pretreated SHR, only the high dose of ketanserin improved BRS (132% control), neither of the ketanserin doses reduced BPV, but both significantly decreased BP. 5. We conclude that the BRS-enhancing effects of ketanserin are mediated largely by central 5-HT(2A) receptors, whereas the antihypertensive effect of ketanserin persists even after destruction of serotonergic neurons in the central nervous system.
Shen
Fu-Ming
FM
Department of Pharmacology, Second Military Medical University, Shanghai, China.
Wang
Jin
J
Ni
Can-Rong
CR
Yu
Jian-Guang
JG
Wang
Wei-Zhong
WZ
Su
Ding-Feng
DF
D000818:Animals; D000911:Antibodies, Monoclonal; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017704:Baroreflex / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000922:Immunotoxins / Q000633:toxicity; D007650:Ketanserin / Q000494:pharmacology* / Q000627:therapeutic use; D009699:N-Glycosyl Hydrolases / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010940:Plant Proteins / Q000633:toxicity; D051381:Rats; D011918:Rats, Inbred SHR; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D012701:Serotonin / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D050486:Serotonin Plasma Membrane Transport Proteins / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000959:Antihypertensive Agents; D000922:Immunotoxins; D010940:Plant Proteins; D044402:Receptor, Serotonin, 5-HT2A; D054789:Ribosome Inactivating Proteins, Type 1; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D007650:Ketanserin; D009699:N-Glycosyl Hydrolases; D000076985:Saporins