Yia 03-03 Effect Of Gabapentin, Ligand Of Alpha 2 Delta Subunit Of Voltage-dependent Calcium Channels, On Blood Pressure And Baroreflex Sensitivity In Spontaneously Hypertensive Rats: The Influence Of Guanethidine-induced Sympathectomy

Objective: Voltage-dependent calcium channels (VDCCs) play an important role in two major abnormalities observed in spontaneously hypertensive rats (SHR) - hyperactivity of sympathetic nervous system (SNS) and enhanced Ca2+ influx to vascular smooth muscle cells (VSMC). α2δ subunit of VDCC, which promotes surface trafficking and modulates the biophysical properties of VDCC, was identified as a critical component of increased L-type VDCC calcium currents in arterial myocytes of SHR. On the other hand, N-type VDCCs control a neurotransmitter release in the peripheral sympathetic nervous system and play an important role in sympathetic hyperactivity in SHR. Design and Method: Our study was aimed to determine the effect of α2δ ligand (gabapentin) on blood pressure (BP) and baroreflex sensitivity in intact or sympathectomized adult SHR and WKY rats. Baroreflex sensitivity was studied in conscious rats using increasing doses of vasoactive drugs (sodium nitroprusside and phenylephrine). The sympathectomy was induced by daily intraperitoneal injection of guanethidine for 2 weeks. Results: Acute gabapentin administration lowered BP more in SHR than WKY, the difference being augmented by restraint stress. Sympathetic reflex tachycardia occurred only after nifedipine (L-type VDCC blocker) but not after ω-conotoxin GVIA (N-type VDCC blocker) or gabapentin administration. Acute gabapentin or ω-conotoxin GVIA administration totally abolished the sympathetic component (without affecting the vagal component) of baroreflex sensitivity in both strains in contrast to a nonsignificant effect of nifedipine. Guanethidine-induced sympathectomy lowered BP and HR in both rat strains. BP decrease after acute intravenous administration of gabapentin was prevented by sympathectomy which also abolished the effect of gabapentin on baroreflex sensitivity. Conclusions: Similar effects of gabapentin and ω-conotoxin GVIA suggest that acute administration of α2δ ligand gabapentin could reverse sympathetic hyperactivity in genetic hypertension. These results also demonstrate that cardiovascular response to gabapentin could be increased by stress-induced SNS activation and diminished by sympathectomy. Conclusions: Partially supported by GACR_14–16225P and GACR_16–10349Y.