Tachykinin-mediated respiratory effects in conscious guinea pigs: modulation by NK1 and NK2 receptor antagonists

Kudlacz, Elizabeth M.; Logan, Deborah E.; Shatzer, S. A.; Farrell, Amy M.; Baugh, Larry E.

doi:10.1016/0014-2999(93)90927-a

Cited by 14 publications

(5 citation statements)

References 22 publications

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“…There was a small but significant increase in sSNA immediately after administration of WIN 51708. The exact cause of this unknown, but it may be due to a partial agonist activity of WIN 51708, as has been demonstrated previously in other tachykinin antagonists (16,37).…”

Section: Discussionmentioning

confidence: 82%

NK1 receptor activation in rat rostral ventrolateral medulla selectively attenuates somato-sympathetic reflex while antagonism attenuates sympathetic chemoreflex

Makeham¹,

Goodchild²,

Pilowsky³

2005

American Journal of Physiology-Regulatory, Integrative and Comp

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The effects of activation and blockade of the neurokinin 1 (NK1) receptor in the rostral ventrolateral medulla (RVLM) on arterial blood pressure (ABP), splanchnic sympathetic nerve activity (sSNA), phrenic nerve activity, the somato-sympathetic reflex, baroreflex, and chemoreflex were studied in urethane-anesthetized and artificially ventilated Sprague-Dawley rats. Bilateral microinjection of either the stable substance P analog (pGlu5, MePhe8, Sar9)SP(5-11) (DiMe-SP) or the highly selective NK1 agonist [Sar9, Met (O(2))11]SP into the RVLM resulted in an increase in ABP, sSNA, and heart rate and an abolition of phrenic nerve activity. The effects of [Sar9, Met (O(2))11]SP were blocked by the selective nonpeptide NK1 receptor antagonist WIN 51708. NK1 receptor activation also dramatically attenuated the somato-sympathetic reflex elicited by tibial nerve stimulation, while leaving the baroreflex and chemoreflex unaffected. This effect was again blocked by WIN 51708. NK1 receptor antagonism in the RVLM, with WIN 51708 significantly attenuated the sympathoexcitatory response to hypoxia but had no effect on baseline respiratory function. Our findings suggest that substance P and the NK1 receptor play a significant role in the cardiorespiratory reflexes integrated within the RVLM.

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Section: Discussionmentioning

confidence: 82%

NK1 receptor activation in rat rostral ventrolateral medulla selectively attenuates somato-sympathetic reflex while antagonism attenuates sympathetic chemoreflex

Makeham¹,

Goodchild²,

Pilowsky³

2005

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Tachykinins, including substance P and neurokinin A, produce a number of airway effects that contribute to respiratory diseases and associated symptoms, including dyspnea. 21 Kudlacz and colleagues 21 found that the administration of aerosolized substance P to conscious guinea pigs produced respiratory alterations and induced dyspnea, both of which were inhibited by a neurokinin receptor antagonist.…”

Section: Discussionmentioning

confidence: 98%

Inhaled morphine for palliation of dyspnea in end-stage cystic fibrosis

Hayes

Anstead²,

Warner³

et al. 2010

American Journal of Health-System Pharmacy

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“…, 1993; Kudlacz, Logan, Shatzer, Farrell & Baugh, 1993; Boni, Ballati & Evangelista, 1995). Also, although the tachykinin NK 1 ‐receptor antagonist CP 99994 had no effect on capsaicin‐induced bronchospasm in isolated lung and intact guinea‐pig (Bertrand, Nadel, Graf & Geppetti, 1993; Kudlacz et al. , 1993; Robineau et al.…”

Section: Discussionmentioning

confidence: 99%

“…The predominant mechanism in capsaicin‐ or resiniferatoxin‐induced airway obstruction occurs indirectly through the stimulation of the tachykinin NK 2 ‐receptors in perfused isolated lung (Lilly, Besson, Israel, Rodger & Drazen, 1994) or intact guinea‐pig (Satoh, Lou, Lee & Lundberg, 1992; Foulon et al. , 1993; Kudlacz, Logan, Shatzer, Farrell & Baugh, 1993; Boni, Ballati & Evangelista, 1995). Also, although the tachykinin NK 1 ‐receptor antagonist CP 99994 had no effect on capsaicin‐induced bronchospasm in isolated lung and intact guinea‐pig (Bertrand, Nadel, Graf & Geppetti, 1993; Kudlacz et al.…”

Section: Discussionmentioning

confidence: 99%

Increased blocking activity of combined tachykinin NK₁‐ and NK₂‐receptor antagonists on tachykinergic bronchomotor responses in the guinea‐pig

Corboz¹,

Fernandez²,

Rizzo³

et al. 2003

Auton Autocoid Pharmacol

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1. The present study compared the effect of the administration of tachykinin NK1- and NK2-receptor antagonists alone and in combination on exogenous and endogenous tachykinin-induced contractions using three different guinea-pig airway preparations: isolated bronchus, isolated perfused lung and in vivo. 2. In the isolated bronchi, the tachykinin NK1-receptor antagonist CP 99994 (0.01-1 microM) produced concentration-dependent inhibition of contractions induced the tachykinin NK1-receptor agonists substance P (SP) and [Met-OMe11] SP ([Met-OMe11]SP), whereas the tachykinin NK2-receptor antagonist SR 48968 (0.1 microM) had no effect. SR 48968 (0.001-0.01 microM) concentration-dependently inhibited contractions induced by the tachykinin NK2-receptor agonists neurokinin A (NKA) and [beta-Ala8]-neurokinin A (4-10) ([betaAla8]-NKA) whereas CP 99994 (0.1 microM) did not inhibit the contractions. The contractile activity of capsaicin, an agent that releases endogenous tachykinins from sensory C-fibres, was inhibited in a concentration dependent manner by SR 48968 (0.001-0.03 microM) but not by CP 99994 (0.1 microM). Combination of CP 99994 and SR 48968 caused increased inhibitory effects on the concentration-response curves to SP, [Met-OMe1l]SP, NKA, [beta-Ala8]-NKA and capsaicin. 3. In isolated perfused lungs, SR 48968 concentration (0.01-10 microM) dependently inhibited NKA-, [beta-Ala8]-NKA- and capsaicin-induced bronchoconstriction whereas CP 99994 (30 microM) had no effect on SP-, NKA-, [beta-Ala8]-NKA- and capsaicin-induced bronchoconstriction. Combination of inactive concentrations of CP 99994 and SR 48968 produced an increased inhibitory effect on all previous stimuli-induced bronchoconstriction. 4. In in vivo guinea-pig studies, intravenous and oral pretreatment with SR 48968 (0.01-1 mg kg(-1) i.v. and 0.1-3 mg kg(-1) p.o., respectively), but not with CP 99994 (1 mg kg(-1) i.v. and 0.3-30 mg kg(-1) p.o., respectively), produced a dose-dependent inhibition of the bronchoconstrictor responses induced by NKA, [beta-Ala8]-NKA and capsaicin. CP 99994 intravenously (0.3 mg kg(-1)) and orally (3-10 mg kg(-1)) inhibited SP-induced bronchoconstriction only. Intravenous and oral low dose combinations of CP 99994 and SR 48968 produced an increased inhibition of SP-, NKA-, [beta-Ala8]-NKA- and capsaicin-induced bronchoconstriction, respectively. The present data indicate that combined tachykinin NK1- and NK2-receptor antagonist treatment compared with single antagonist treatment, using CP 99994 and SR 48968, produced an augmented blockade of tachykinin NK1-, NK2- and capsaicin-mediated contractions in guinea pig airways. These findings support the hypothesis that a dual NK1- and NK2-receptor antagonist may provide an advantage over single activity tachykinin NK1- or NK2-receptor antagonists in pulmonary obstructive diseases.

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Tachykinin-mediated respiratory effects in conscious guinea pigs: modulation by NK1 and NK2 receptor antagonists

Cited by 14 publications

References 22 publications

NK1 receptor activation in rat rostral ventrolateral medulla selectively attenuates somato-sympathetic reflex while antagonism attenuates sympathetic chemoreflex

NK1 receptor activation in rat rostral ventrolateral medulla selectively attenuates somato-sympathetic reflex while antagonism attenuates sympathetic chemoreflex

Inhaled morphine for palliation of dyspnea in end-stage cystic fibrosis

Increased blocking activity of combined tachykinin NK₁‐ and NK₂‐receptor antagonists on tachykinergic bronchomotor responses in the guinea‐pig

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Tachykinin-mediated respiratory effects in conscious guinea pigs: modulation by NK1 and NK2 receptor antagonists

Cited by 14 publications

References 22 publications

NK1 receptor activation in rat rostral ventrolateral medulla selectively attenuates somato-sympathetic reflex while antagonism attenuates sympathetic chemoreflex

NK1 receptor activation in rat rostral ventrolateral medulla selectively attenuates somato-sympathetic reflex while antagonism attenuates sympathetic chemoreflex

Inhaled morphine for palliation of dyspnea in end-stage cystic fibrosis

Increased blocking activity of combined tachykinin NK1‐ and NK2‐receptor antagonists on tachykinergic bronchomotor responses in the guinea‐pig

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Product

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Increased blocking activity of combined tachykinin NK₁‐ and NK₂‐receptor antagonists on tachykinergic bronchomotor responses in the guinea‐pig