Trigeminal nerve ganglion stimulation-induced neurovascular reflexes in the anaesthetized cat: Role of endothelinBreceptors in carotid vasodilatation

Autor: Andrew A. Parsons, Nambi Aiyar, Eliot H. Ohlstein, A. Jackie Hunter, Pravin Raval, John D. Elliott, Sharon Bingham
Rok vydání: 1999
Předmět:
Zdroj: British Journal of Pharmacology. 126:485-493
ISSN: 0007-1188
DOI: 10.1038/sj.bjp.0702306
Popis: The effects of intravenous administration of endothelin (ET) receptor antagonists SB-209670 (0.001–10.0 mg kg−1), SB-217242, SB-234551 (0.01–10.0 mg kg−1) and BQ-788 (0.001–1.0 mg kg−1) were investigated on trigeminal nerve ganglion stimulation-induced neurovascular reflexes in the carotid vasculature of the anaesthetized cat. Comparisons were made with sumatriptan (0.003–3.0 mg kg−1) and α-CGRP8–37 (0.001–0.1 mg kg−1). Trigeminal nerve ganglion stimulation produced frequency related increases in carotid blood flow, reductions in carotid vascular resistance and non-frequency related increases in blood pressure. Guanethidine (3 mg kg−1, i.v.) blocked trigeminal nerve ganglion-induced increases in blood pressure but had no effect on changes in carotid flow or resistance. Maximal reductions in carotid vascular resistance was observed at 10 Hz, and this frequency was selected to investigate the effects of drugs on trigeminal nerve ganglion stimulation-induced responses in guanethidine treated cats. Saline, α-CGRP8–37 SB-209670 and BQ-788 had little or no effect on resting haemodynamic parameters. SB-217242 (10 mg kg−1, n=3) produced a 56% reduction in arterial blood pressure whereas SB-233451 (10 mg kg−1, n=3) produced a 30% reduction in carotid vascular resistance. Sumatriptan produced dose-related reductions in resting carotid flow and increases (max. 104% at 0.3 mg kg−1, n=5) in vascular resistance. SB-209670 (n=6–7), SB-217242 (n=3) and BQ-788 (n=3) produced inhibition of trigeminal nerve ganglion stimulation-induced reductions in carotid vascular resistance. Saline, SB-234551, α-CGRP8–37 and sumatriptan had no effect. These data demonstrate ETB receptor blockade attenuates the vasodilator effects of trigeminal nerve ganglion stimulation in the carotid vascular bed of guanethidine pretreated anaesthetized cats. Keywords: SB-209670, SB-234551, SB-217242, trigeminal nerve ganglion, ETB receptor, sumatriptan, neurovascular reflex Introduction Electrical stimulation of the trigeminal nerve ganglion produces increases in blood flow (Goadsby & Duckworth, 1987; Goadsby & Edvinsson, 1993; 1994; Lambert et al., 1984), protein extravasation (Markowitz et al., 1987; Saito et al., 1988) and increases in brain stem cFos, but not c-jun and jun-D (Uhl et al, 1991; Shepheard et al., 1995). These experimental models have supported the concept of neurogenic inflammation as a mechanism for the development of migraine headache (Moskowitz & MacFarlane, 1993). Stimulation of sensory fibres appears to account for all the extravasation response (Markowitz et al., 1987) and detailed investigation has shown that sumatriptan and other 5-HT1B/1D agonists inhibit these effects (Buzzi & Moskowitz, 1990; Connor et al., 1997; Martin et al., 1997; Williamson et al., 1997). A variety of NK-1 receptor antagonists also inhibit trigeminal nerve ganglion stimulation-induced extravasation in rats (Lee et al., 1994; O'Shaughnessy & Connor, 1994; Phebus et al., 1997; Shepheard et al., 1993, 1995). Some species differences do exist as the NK-1 antagonist, GR82334 blocks neurogenic inflammation in rats and guinea-pigs, whereas the calcitonin gene-related peptide (CGRP) receptor antagonist αCGRP8–37 is effective in guinea-pigs, but not rats (O'Shaughnessy & Connor, 1994). Other agents that inhibit neurogenic extravasation include endothelin receptor antagonists (Brandli et al., 1995), sumatriptan analogues (Lee & Moskowitz, 1993) and a variety of other receptor agonists (Matsubara et al., 1992). However, a number of agents which show activity in this model, such as bosentan (May et al., 1996), CP-122288 (Roon et al., 1997) and LY-303870 (Goldstein et al., 1997) have not shown efficacy as acute migraine therapies in the clinic. Trigeminal nerve ganglion stimulation also produces a reflex activation of autonomic ganglia which are involved in a reflex vasodilatation of the carotid vascular bed in the cat (Lambert et al., 1984). Stimulation of the trigeminal nerve ganglion produces release of both sensory (CGRP) and parasympathetic (vasoactive intestinal polypeptide, VIP) neurotransmitters (Buzzi et al., 1991; Goadsby & Edvinsson, 1994), but does not appear to involve the sympathetic nervous system (Lambert et al., 1984). This interaction between afferent and efferent nervous systems is well documented in trigeminal nerve ganglion stimulation-induced reductions in common carotid vascular resistance in the cat (Lambert et al., 1984). Section of the VII nerve (parasympathetic) or pre-treatment with hexamethonium inhibited these reflex pathways (Lambert et al., 1984) which utilize VIP as the final mediator (Goadsby & MacDonald, 1985). A similar neurovascular reflex also operates in the intracranial circulation of the cat (Goadsby & Duckworth, 1987). In the rat, trigeminal fibres containing substance P and CGRP are present in parasympathetic ganglia forming basket-like arrangements with neurons (Suzuki et al., 1989a) and provide an anatomical basis for this neurovascular reflex. This pathway may also have clinical implications as inhibition of parasympathetic nerve has been suggested to mediate the antimigraine actions of intranasal lidocaine (Maizels et al., 1996). It is known that sumatriptan produces complete inhibition of trigeminal nerve ganglion-induced extravasation in rats (Buzzi & Moskowitz, 1990), inhibits trigeminal nerve-ganglion-induced increases pial blood flow in cats (Goadsby & Edvinsson, 1993) and increases resting carotid vascular resistance (Perren et al., 1989) in cats. In contrast, sumatriptan has little effect on trigeminal nerve ganglion-induced neurovascular reflexes involving the parasympathetic nerve in cats (Lambert & Michalicek, 1996). As endothelin-1 has been found in sensory nerves (Franco-Cereceda et al., 1991; Giaid et al., 1989) and ET receptor antagonists inhibit trigeminal nerve ganglion stimulation-induced extravasation (Brandli et al., 1995) and block cranial arterial vasodilatation (Maurice et al., 1997; Nilsson et al., 1997), the aims of the present studies were to explore the effects of endothelin receptor blockade on trigeminal nerve ganglion-induced neurovascular reflexes in comparison to the effects of sumatriptan and α-CGRP8–37 on these responses. Some of these results have been published in abstract form (Raval et al., 1996; 1997).
Databáze: OpenAIRE
Externí odkaz: