GYKI-12743

Cutaneous microcirculatory changes were measured by laser-Doppler flowmetry in response to electrical stimulation of sympathetic efferent fibres of the rat's saphenous nerve. After perineural capsaicin (2%) pretreatment, electrical stimulation of the peripheral stump of the cut saphenous nerve evoked a reduction in blood flow (vasoconstriction) followed by a minimal enhancement. This late vasodilatation was further reduced by resiniferatoxin (1 microg/kg i.v.), and vasoconstriction was abolished by guanethidine (8 mg/kg i.v.), indicating the involvement of sensory and sympathetic fibres in the respective responses. The vasoconstrictor response was analysed after blockade of antidromic vasodilatation by combined capsaicin-resiniferatoxin pretreatment. alpha-Adrenoceptor antagonists (1 mg/kg phentolamine, 0.5 mg/kg prazosin and 1 mg/kg GYKI-12743 (RS-2-(3)N-(2-benzo;1,4i-dioxanyl)-methylamino(propyl)-3(2H) -piridazinone hydrochloride) inhibited, but did not eliminate the blood flow reduction evoked by 3 Hz stimulation. At 10 Hz stimulation significant inhibition was obtained only with GYKI-12743. No inhibition was observed with propranolol (10 microg/kg) on any occasion. A functional neuropeptide Y antagonist, alpha-trinositol (D-myo-inositol-1,2,6-trisphosphate, PP56; 50 mg/kg i.v.), markedly diminished the vasocontrictor response remaining after treatments with the alpha-adrenoceptor blocking agents. Inhibition was more pronounced at 10 Hz. Since 3 Hz corresponds to an average, and 10 Hz approaches the maximal firing rate of the sympathetic efferents, these results emphasise the significant role of neuropeptide Y in regulation of the cutaneous microcirculation by sympathetic fibres under physiological circumstances, particularly during high activity.