Olcegepant blocks neurogenic and non-neurogenic CGRPergic vasodepressor responses and facilitates noradrenergic vasopressor responses in pithed rats

Background and Purpose: Olcegepant (BIBN4096BS) is a selective non-peptide CGRP receptor antagonist with acute antimigraine properties. Since systemic vascular tone is modulated by perivascular (primary sensory CGRPergic and sympathetic) nerves, this randomized study investigated in pithed rats the effect of acute i.v. treatment with olcegepant on the neurogenic and non-neurogenic: (i) CGRPergic vasodepressor responses; and (ii) noradrenergic vasopressor responses. The pithed rat is an experimental model predictive of systemic (cardio) vascular side effects. Experimental Approach: Seventy-five male Wistar rats (divided into 15 groups, n = 5 each) were pithed, artificially ventilated and prepared for: (i) spinal stimulation (T9-T12; 0.56-5.6 Hz) of the sensory CGRPergic vasodepressor outflow or i.v. bolus injections (0.1-1 μg·kg-1) of α-CGRP, substance P or acetylcholine, which induced frequency-dependent or dose-dependent vasodepressor responses; or (ii) spinal stimulation (T7-T9; 0.03-3 Hz) of the sympathetic vasopressor outflow or i.v. bolus injections (0.03-3 μg·kg-1) of noradrenaline, which produced frequency-dependent or dose-dependent vasopressor responses. Key Results: Olcegepant (1000 and 3000 μg·kg-1, i.v.) dose-dependently blocked the vasodepressor responses to sensory nerve stimulation or i.v. α-CGRP, without affecting those to substance P or acetylcholine. Whereas it potentiated the vasopressor responses to sympathetic nerve stimulation or i.v. noradrenaline. Conclusions and Implications: Olcegepant (i.v.) selectively blocked the neurogenic and non-neurogenic CGRPergic vasodepressor responses. This blockade by olcegepant potentiated the neurogenic and non-neurogenic noradrenergic vasopressor responses in pithed rats, an effect that might result in an increased vascular resistance and, consequently, in a prohypertensive action.

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