neurokinin-a and Hypotension

Vascular NK-1 and NK-2 tachykinin receptors in the rat and the guinea pig were characterized pharmacologically by using available agonists and antagonists exhibiting varying degrees of selectivity for these receptors. Because the anesthetized guinea pig has unusually low blood pressure, these animals were pithed and vagotomized and infused, throughout the experimental procedure, with norepinephrine (6 micrograms/kg/min). This treatment raised their blood pressure to a level appropriate for the determination of dose-hypotensive response curves. The NK-1 receptor agonists substance P (SP) and septide (0.004 to 1 microgram/kg iv) decreased carotid artery blood pressure in a dose-dependent manner in both species, but they were more potent (13- and 33-fold, respectively) in guinea pigs than in rats. The NK-2 receptor agonist [beta Ala8]-NKA(4-10) (0.06 to 1 microgram/kg) also dose-dependently lowered blood pressure in the pithed guinea pig with noradrenaline-supported blood pressure, although it failed to do so in the same rat preparation. RP 67580, a selective NK-1 antagonist, antagonized the SP- or septide-induced hypotensive response in rats, but not in guinea pigs. Conversely, RPR 100893, a novel NK-1 receptor antagonist chemically related to RP 67580, dose-dependently inhibited hypotension induced by SP, and even more, that induced by septide only in guinea pigs. In the latter species, neither RP 67580 nor RPR 100893 affected decreases in blood pressure induced by [beta Ala8]-NKA(4-10). These decreases were, however, inhibited by the NK-2 receptor antagonist SR 48968. The selectivity of this compound for the latter receptor was confirmed by its failure to affect SP- or septide-induced hypotension in either guinea pigs or rats. These results confirm that the hypotensive responses to SP and septide are mediated by NK-1 receptors in the two species studied. However, functional NK-2 receptors appear to be present in the vascular bed of the guinea pig but not that of the rat, since in the former species the hypotensive responses induced [beta Ala8]-NKA(4-10) were inhibited by SR 48968 but not by the NK-1 receptor antagonists studied. This conclusion is, to our knowledge, drawn here for the first time from clear-cut pharmacological results.

Topics: Animals; Benzamides; Blood Pressure; Guinea Pigs; Hypotension; Indoles; Isoindoles; Male; Neurokinin A; Neurokinin-1 Receptor Antagonists; Peptide Fragments; Piperidines; Pyrrolidonecarboxylic Acid; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Substance P

1. We compared the effects of two novel tachykinin receptor antagonists, FK888 (selective at the tachykinin NK1 receptor) and FK224 (dual antagonist at NK1 and NK2 tachykinin receptors) on stimulus-evoked airway plasma exudation, bronchoconstriction and systemic hypotension in guinea-pigs in vivo. Plasma exudation was induced by substance P (SP), synthetic tachykinin receptor agonists, platelet activating factor (PAF), electrical stimulation of the cervical vagus nerves or by inhalation of cigarette smoke. Changes in airway tone and in carotid artery blood pressure (BP) were induced by synthetic tachykinin agonists, PAF and vagal stimulation. 2. Both FK224 and FK888 dose-dependently inhibited SP-induced plasma exudation in the lower trachea and main bronchi (ID50 values respectively of 1.1 and 0.1 mumol kg-1 in lower trachea, and of 0.5 and 0.1 mumol kg-1 in main bronchi) with complete inhibition at both airway levels at 10 mumol kg-1 for FK224 and at 2 mumol kg-1 for FK888. 3. The NK1-selective tachykinin receptor agonist, [Sar9,Met(O2)11]substance P ([Sar]SP), induced plasma exudation, a response which was blocked by both FK888 and FK224. The NK2-selective agonist, [beta-Ala8]neurokinin A-(4-10) ([beta-Ala]NKA), did not induce plasma exudation: neither FK888 nor FK224 affected this lack of response to [beta-Ala]NKA. 4. [beta-Ala]NKA induced bronchoconstriction, a response which was blocked by FK224 but which was completely unaffected by FK888. [Sar]SP induced a small but significant bronchoconstriction which was completely inhibited by both tachykinin antagonists. 5. In animals pretreated with capsaicin to deplete sensory neuropeptides, PAF induced both plasma exudation and bronchoconstriction. Neither response to PAF was inhibited by either FK888 or FK224.6. Both FK888 and FK224 inhibited plasma exudation induced by vagus nerve stimulation or by cigarette smoke, with FK888 more potent than FK224.7. FK224 inhibited non-cholinergic bronchoconstriction induced by vagal stimulation, whereas FK888,at doses inhibiting vagally-induced plasma exudation, did not.8. Decreases in BP induced by SP or [Sar]SP were blocked by both FK888 and FK224. In contrast,neither antagonist had any significant inhibitory effect on the decrease in BP induced by vagal stimulation (in the presence of atropine) or PAF. [beta-Ala]NKA did not decrease BP and neither tachykinin antagonist had any significant effect on this lack of response.9. We conclude that in guinea-pig airways, pla

Topics: Animals; Blood Pressure; Bronchoconstriction; Capsaicin; Dipeptides; Electric Stimulation; Evans Blue; Exudates and Transudates; Guinea Pigs; Hypotension; Indoles; Male; Neurokinin A; Peptide Fragments; Peptides, Cyclic; Platelet Activating Factor; Receptors, Neurokinin-2; Receptors, Neurotransmitter; Respiratory Mechanics; Smoking; Substance P; Vagus Nerve