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.

Remote ischemic preconditioning (rIPC) induced by transient limb ischemia (li-rIPC) leads to neurally dependent release of blood-borne factors that provide potent cardioprotection. We hypothesized that transcutaneous electrical nerve stimulation (TENS) is a clinically relevant stimulus of rIPC. Study 1: seven rabbits were subjected to lower limb TENS; six to li-rIPC, and six to sham intervention. Blood was drawn and used to prepare a dialysate for subsequent analysis of cardioprotection in rabbit Langendorff preparation. Study 2: 14 healthy adults underwent upper limb TENS stimulation on one study day, 10 of whom also underwent li-rIPC on another study day. Blood was drawn before and after each stimulus, dialysate prepared, and cardioprotective activity assessed in mouse Langendorff preparation. The infarct size and myocardial recovery were measured after 30 min of global ischemia and 60 or 120 min of reperfusion. Animal validation: compared to control, TENS induced marked cardioprotection with significantly reduced infarct size (TENS vs. sham p < 0.01, rIPC vs. sham p < 0.01, TENS vs. rIPC p = ns) and improved functional recovery during reperfusion. Human study: compared to baseline, dialysate after rIPC (pre-rIPC vs. post-rIPC, p < 0.001) and TENS provided potent cardioprotection (pre-TENS vs. post-TENS p < 0.001) and improved myocardial recovery during reperfusion. The cardioprotective effects of TENS dialysates were blocked by pretreatment of the receptor heart with the opioid antagonist naloxone. TENS is a novel method for inducing cardioprotection and may provide an alternative to the limb ischemia stimulus for induction of rIPC clinically.

Changes unresponsive to increasing blood pressure occurring during decompression and bone resection (type II) responded well to osteotomy closure. Unresponsive changes during osteotomy closure (type III) were treated successfully with opening the osteotomy, cage adjustment, and less correction.