A novel positive inotropic substance enhances contractility without increasing the Ca2+ transient in rat myocardium

Ferroni, C.; Hano, Osamu; Ventura, Carlo; Lakatta, Edward G.; Klockow, Michael; Spurgeon, Harold A.; Capogrossi, Maurizio C.

doi:10.1016/0022-2828(91)90068-w

Cited by 36 publications

(24 citation statements)

References 13 publications

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“…Measurement of ϩdF/dt is often used as an index of contractility (9,23,24). To estimate possible contractility changes in isometric lymphatic vessels induced by SP, ϩdF/dt and the rate of change in force decline (ϪdF/dt) were computed for each acquired force point in the spontaneous contraction/ relaxation cycle, after which the peak ϩdF/dt and ϪdF/dt values during each cycle were determined.…”

Section: Resultsmentioning

confidence: 99%

Modulation of lymphatic muscle contractility by the neuropeptide substance P

Davis¹,

Lane²,

Davis³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Davis MJ, Lane MM, Davis AM, Durtschi D, Zawieja DC, Muthuchamy M, Gashev AA. Modulation of lymphatic muscle contractility by the neuropeptide substance P. Am J Physiol Heart Circ Physiol 295: H587-H597, 2008. First published June 6, 2008 doi:10.1152/ajpheart.01029.2007.-Substance P (SP) is a neuropeptide associated with sensory innervation of lymphoid tissue and a suspected modulator of lymphatic function in inflammation. Only a few studies have examined the effects of SP on lymphatic contraction, and it is not clear to what extent SP acts directly on the lymphatic muscle and/or endothelium or indirectly through changes in intraluminal filling pressure secondary to increases in capillary permeability/ filtration. We tested the effects of SP on the spontaneous contractions of rat isolated mesenteric lymphatic vessels under isometric and isobaric conditions, hypothesizing that low concentrations would stimulate lymphatic pumping by enhancing lymphatic muscle contraction in a manner complementary to the effect of increased preload. Under isometric conditions, SP (10 nM) dramatically enhanced lymphatic chronotropy and inotropy. Unlike guinea pig lymphatics, SP actions were not blocked by cyclooxygenase or PLA2 inhibition. In the absence of SP, ramp increases in isometric preload resulted in ϫϳ1.6 increases in contraction amplitude (Amp) and ϫϳ1.7 increases in frequency (Freq). SP increased Freq by ϫϳ2.4, Amp by ϫϳ1.9, and the Amp-Freq product (AFP) by ϫϳ3.5. Under isobaric conditions, the pressure elevation from 0.5 to 10 cmH2O in the absence of SP decreased Amp by ϫϳ0.6 and increased Freq by ϫϳ1.8. SP caused a modest increase in Amp, a robust increase in Freq at all pressures, and shifted the AFP-pressure relationship upward and leftward. Therefore, SP has substantial positive inotropic and chronotropic effects on rat lymphatic muscle, improving pump efficiency independent of the effects of preload and broadening of the working range of the lymphatic pump. neurokinin; edema; inflammation; lymphatic pump; inotropy; chronotropy; thromboxane A2 SUBSTANCE P (SP) is an 11-amino acid neuropeptide (36) often associated with cells of lymphoid tissue (15,19,21,22,46,47). SP is released from enteric nerves, sensory nerves, and inflammatory cells (27,41,45,52). Correspondingly, SP receptors are expressed on endothelium and muscle of blood and lymphatic vessels, on nerves innervating those vessels, and on associated immune and inflammatory cells (31,36,44).SP appears to have both direct and indirect effects on vascular targets. For example, SP is a powerful stimulator of endothelium-dependent nitric oxide production (28), evoking vasodilation and increasing local blood flow. In addition, SP enhances vascular permeability (18,25) and stimulates the release of cytokines and chemokines (4, 36) that would indirectly elicit vasodilation and increase vascular permeability. These vascular effects of SP would collectively increase flow/ pressure in capillaries and post-capillary venules and lead to increases in transcapillary fluid ...

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Section: Resultsmentioning

confidence: 99%

Modulation of lymphatic muscle contractility by the neuropeptide substance P

Davis¹,

Lane²,

Davis³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…The compound EMD 53998 (developed by Merck) is a potent positive inotrope 77 . Further work clarified that separate enantiomers of EMD 53998 have different mechanisms of action 78 .…”

Section: Myosin Regulatory Chain Phosphorylationmentioning

confidence: 99%

Targeting the sarcomere to correct muscle function

Hwang

Sykes

2015

Nat Rev Drug Discov

110

122

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“…This effect did not depend on whether the measurements were performed at neutral pH ( = 7.35) or with acidosis (pH = 6.8) (60). Since PDE I11 inhibition is known not to improve systolic function in the rat, the dose-dependent increase in peak systolic pressure in isolated rat hearts after EMD 53998 must be considered as additional evidence for Ca2+ sensitization (25).…”

Section: Effects On Musclementioning

confidence: 94%