Tachykinins (Substance P, Neurokinin A, Neuropeptide K, and Neurokinin B) in the Cerebral Circulation: Vasomotor Responses in vitro and in situ

Abstract

Summary:The vasomotor responses of tachykinins have been studied in the cerebral vasculature of human, pig, cat, and guinea pig, Substance P (SP), neurokinin A (NKA), neurokinin B (NKB), and neuropeptide K (NPK) induced concentration-dependent relaxations of pre con tracted cerebral arteries in all species when examined by a sensitive in vitro technique, In addition, the relaxant responses to SP, NKA, and NKB were studied in cat pial arterioles by peptide microapplication in situ. In human pial vessels, the order of relaxant potency was SP > N KB > NKA > NPK; in the pig middle cerebral artery, there was no difference in potency between the tachykinins; in the cat middle cerebral artery, SP = NKB > NKA = NPK; and in the guinea pig basilar artery, SP :» NPK = NKA > NKB. Responses induced by SP, NKA, and NKB in the cat were comparable in vitro and in situ. Removal of the endothelium abolished relaxation induced by all four tachykinins. The relaxant responses of guinea It is well recognized that substance P (SP), which is a peptide involved in the mechanisms of nocicep tion, also produces strong relaxation of cerebral ar teries in vitro and in situ (Edvinsson et al. , , 1982. SP is present in afferent nerve fibers (Edvins son et al. , 1981(Edvins son et al. , , 1982(Edvins son et al. , , 1983 originating in trigem inal nerve cell bodies that supply cerebral blood vessels (Liu-Chen et al. , 1983a,b). The trigemino cerebrovascular system has been thought to initiate Received October 22, 1990; revised December 13, 1990; ac cepted February 1, 1991. Address correspondence and reprint requests to I. Jansen at Department of Experimental Research, University of Lund, Malmo General Hospital, S-214 01 Malmo, Sweden.Ab b revi ati ons used : CGRP, calcitonin gene-related peptide; 5-HT, 5-hydroxytryptamine; NKA; neurokinin A; NPK, neuro peptide K; NKB, neurokinin B; PPT, preprotachykinin; PGF2a, prostaglandin F2a; SP, substance P. 567pig basilar arteries to SP, NKA, and NPK were compet itively antagonized by the SP antagonist Spantide. How ever, Spantide lowered the I max of the NKB concentra tion-response curve without any rightward shift, suggest ing action at a different site than the other tachykinins. In the guinea pig basilar artery, the relaxation seems to be exerted via a N K -1 receptor subtype while the receptor subtype is more unclear in cerebral arteries from human, cat, and pig. It is concluded that relaxations induced by SP, NKA, NKB, and NPK are dependent on the endo thelium, and are antagonized either competitively or non competitively by the SP antagonist Spantide. The origin of tachykinins acting through the endothelium is dis cussed. Key Words: Cerebral arteries-In vitro pharma cology-In situ-Substance P-Neurokinin A Neuropeptide K-Neurokinin B-Cat-Guinea pig Pig-Human. (Nawa et al. , 1983(Nawa et al. , , 1984Krause et al. , 1985). a-PPT A contains SP while f3-PPT A and T-PPT A contain both SP and NKA.NPK is a prolonged form of NKA and is derived from f3-PPT A. NKB is derived from PPT B, which is g...

Neurokinin‐induced changes in pial artery diameter in the anaesthetized guinea‐pig

“…This, however, contrasts with the finding (Jansen et al, 1991) that in cat pial arteries, neurokinin A (0.01-1 JAM), a high affinity NK2 receptor agonist produced only dilatation. This apparent anomaly may suggest that species differences exist but seems more likely to reflect the poor selectivity of neurokinin A for NK2 receptors (Guard & Watson, 1991).…”

“…In the present study, substance P markedly dilated guinea-pig pial arteries when injected perivascularly, an effect consistent with its vasodilator activity in a variety of species, both in vitro and in situ (Regoli et al, 1989;Jansen et al, 1991;Stubbs et al, 1992). Moreover, the potency with which substance P increased pial artery diameter in the guinea-pig was similar to that observed in cat cerebral vessels (Edvinsson et al, 1981;Jansen et al, 1991). Such a vasodilatation could activate trigeminal nerve endings and via the initiation of local axon reflexes lead to the sensation of pain (Humphrey & Feniuk, 1991).…”

Increase of meningeal blood flow after electrical stimulation of rat dura mater encephali: mediation by calcitonin gene‐related peptide

“…The same stimuli probably also release substance P (Edvinsson et al, 1983) that is stored in a smaller proportion of dural nerve fibres (von During et al, 1990;Messlinger et al, 1993) where it may largely be co-localized with CGRP (O'Connor & van der Kooy, 1988), possibly in the same vesicles (Gulbenkian et al, 1986). Substance P has been shown in different species (man, guinea-pig, cat) to act as a powerful vasodilator on isolated intracranial arteries including the middle meningeal artery in vitro (Jansen et al, 1991;1992) and on cerebral arterioles of the cat in situ (Jansen et al, 1991). In our preparation, however, recent experiments have revealed that meningeal blood flow is not significantly changed by topical administration of substance P and the substance P analogue septide at concentrations of up to 10-3 M (unpublished results).…”

Neurobiology in primary headaches

“…of all nerve cell bodies contain CGRP and CGRP mRNA [50,187]. CGRP and SP are potent vasodilators in vivo and in vitro, the former being 10-1000 times more potent [45,58,59,106,136]. Several studies have suggested that SP is involved in plasma extravasation from postcapillary venules in the dura mater during primary headache attacks [131].…”

“…δ-preprotachykinin produces SP only, whereas proteolytic cleavage of β-and δ-preprotachykinin produces SP [59,106] and a second tachykinin neurokinin A (NKA). The cerebrovascular distribution of NKA resembles that of SP and coexistence of SP and NKA in cell bodies of sensory ganglia and in perivascular nerve fibers have been demonstrated [31,41].…”