Remote cardioprotection by direct peripheral nerve stimulation and topical capsaicin is mediated by circulating humoral factors

Abstract

We have previously shown that remote ischemic preconditioning by limb ischemia (rIPC) or intra-arterial adenosine releases a dialyzable cardioprotective circulating factor(s), the release of which requires an intact neural connection to the limb and is blocked by pretreatment with S-nitroso-N-acetylpenicillamine (SNAP). Remote cardioprotection can be induced by other forms of peripheral stimulation including topical capsaicin, but the mechanisms of their signal transduction are incompletely understood. Rabbits were anesthetized by intravenous pentobarbital, intubated and ventilated, then randomized (4-7 animals in each group) to receive sham procedure, rIPC (4 cycles of 5 min lower limb ischemia, 5 min reperfusion), direct femoral nerve stimulation, topical capsaicin, pretreatment with intra-arterial SNAP + capsaicin, pretreatment with topical DMSO (a sensory nerve blocker) + topical capsaicin, or pretreatment with intra-arterial SNAP + femoral nerve stimulation, topical DMSO alone, or intra-arterial SNAP alone. Blood was then rapidly drawn from the carotid artery to produce the plasma dialysate which was used to perfuse a naïve heart from an untreated donor rabbit. The infarct size and recovery of LV-developed pressure and end-diastolic pressure were measured after 30 min of global ischemia and 120 min of reperfusion. Compared to sham, dialysate from rIPC, femoral nerve stimulation, and topical capsaicin groups all produced significant cardioprotection with significantly reduced infarct size, and improved the post-ischemic cardiac performance. Cardioprotection was not seen in the topical DMSO-capsaicin, SNAP + capsaicin, and SNAP + FNS groups. These results confirm the central role of peripheral nerves in the local signal transduction of remote cardioprotection. Direct electrical or peripheral neural stimulation evokes the release of cardioprotective substances into the bloodstream, with comparable effects to that of rIPC induced by limb ischemia.

Molecular Basis of Cardioprotection

“…37 440,441 induced activation of sensory fibers in the peripheral organ (1) activate the autonomic cardiac innervation through the central nervous system, and (2) release an as yet unidentified humoral factor (Figure 4). The activation of the peripheral sensory fibers involves activation of the PKCγ isoform.…”

“…432,444 Of importance, humoral transfer of protection with plasma or dialysate obtained after the peripheral preconditioning cycles to another individual or individual heart, even across species, is possible and highlights the functional importance of the humoral transfer signal. 433,440,441 The humoral transfer signal appears to be of a molecular weight <15 kDa and hydrophobic. There are data to support a role of NO, 64 stromal cell-derived factor-1α, …”

Thermal Degradation Kinetics of Capsaicin on Blanching-Brine-Calcium Pretreatment Red Chili Pepper Drying

“…It also is a major compound of capsaicinoids (alkaloid) that are widely applied in pharmaceutical and clinical product [7]. As one of the natural products, it was reported that capsaicin has therapeutic properties currently employed as antitumor [8], anti-mutagenic [9], antioxidant compounds [7], antimicrobial [3], anticancer [10], cardio-protection [11], antiobesity [12], anti-diabetic [13], and antiinflammatory effect [14].…”

Remote Limb Perconditioning and Postconditioning

“…Moreover, both topical capsaicin on the abdomen (via activation of C fiber afferents) and femoral nerve stimulation elicited release of the protective humoral factors in the circulation and reduced infarct size. 25,26 Denervation of afferents with pretreatment with capsaicin abolished the protective effect of remote limb postconditioning in a focal cerebral ischemia model. 19 In an in vivo study in mice, both femoral vein occlusion and sciatic and femoral transection abolished the cardioprotective effect of remote limb preconditioning, implying the requirement for both humoral and neural pathways.…”