Influence of Beta Blocker on Cardiac Rehabilitation Program

OBJECTIVE: The purpose of this study was to evaluate the beta blocker effect on excercise ability and hemodynamics after cardiac rehabilitation program (CRP). METHOD: Thirty-two patients with coronary artery disease were divided into two groups: 16 patients in the beta blocker group and 16 patients in the control group. CRP with aerobic exercise was done for 6 weeks. Before and after CRP, a symptom limited graded exercise test was done. RESULTS: The maximal exercise time and the maximal oxygen uptake were significantly higher, and the percentage of maximal oxygen uptake and the rating of perceived exertion were significantly lower after CRP as compared to those parameters before CRP in both groups (p 0.05). The submaximal heart rate and submaximal rate pressure product (RPP) were significantly lower after CRP as compared to those before CRP in both groups (p<0.05). After CRP, the maximal heart rate and the submaximal RPP were significantly lower in the beta blocker group than in control (p<0.05). CONCLUSION: A beta blocker can be widely used in CRP without having a negative effect on exercise capacity in the patients with coronary artery disease.

Loss of the Spinal GABAergic System Is Involved in Chronic Central Pain Following a Spinal Cord Injury; Behavioral and Electrophysiological Evidences / 대한마취과학회지

BACKGROUND: Allodynia, hyperalgesia, and spontaneous pain are symptoms characterized by chronic central pain which was frequently observed following a spinal cord injury (SCI). However, the underlying mechanism has not been fully understood. This study was conducted to investigate whether the loss of the GABAergic system in the spinal dorsal horn was involved in the development of central pain following a spinal cord injury. METHODS: SCI was induced by a hemisection of the spinal cord at T13 in adult male Sprague-Dawley rats. Mechanical allodynia was tested by measuring paw withdrawal frequency in response to repeated applications of a von Frey hair to the plantar surface of the hind-paw. Single neuronal activity of the dorsal horn neurons (L4 L6) was recorded extracellularly using a carbon filament-filled glass microelectrode (2 4 MOhm). The drugs were intrathecally or topically administrated on the spinal surface for behavioral and electrophysiological experiments, respectively. RESULTS: After a left spinal hemisection at T13, behavioral signs of mechanical allodynia developed on both hind-paws and responsiveness of spinal dorsal horn neurons increased on both sides of the spinal dorsal horn. GABA receptor agonists including GABAA and GABAB receptor subtypes suppressed mechanical allodynia on both sides of hind-paws and decreased responsiveness of spinal dorsal horn neurons on both sides of spinal cord. CONCLUSIONS: These results indicate that a loss of the GABAergic system within the spinal cord plays a key role on the development of central pain following a spinal cord injury.

Adrenergic sensitivity of uninjured C-fiber nociceptors in neuropathic rats

We investigated the adrenergic sensitivity of afferent fibers in the L4 dorsal roots of rats with a unilateral ligation of the L5-L6 spinal nerves. About 12% of nociceptive fibers on the affected side were excited by sympathetic stimulation or by intra-arterial injection of norepinephrine which did not affect A beta-fiber activity. Sympathetic excitation of nociceptive fibers was suppressed by alpha 1-antagonist prazosin, while it was unaffected by alpha 2-antagonist yohimbine. Most of these fibers were excited by intra-arterial injection of alpha 1-agonist phenylephrine, without being affected by an injection of alpha 2-agonist clonidine. Sympathetic excitation was blocked by lidocaine applied near the receptive fields of recorded fibers. The results suggested that some nociceptors remaining intact after partial nerve injury become sensitive to sympathetic activity by the mediation of alpha 1-adrenoceptors in the peripheral endings.

A Study on the Development of M.D.-Ph.D. Program / 한국의학교육

This study is to develop M.D.-Ph.D. program of medical school in Korea. The authors examined the related literature focusing on the current status and problems of training biomedical scientists. Next step was to make a collection of data related to American M.D.-Ph.D. program. The search for the materials was made through February 2000. The developed M.D.-Ph.D. program was modified and revised by the experts in the area and through public speech. The results of the study are as follows; first, the validity of M.D.-Ph.D. program was convicted by the need of interdisciplinary study, social needs, current problems of medical education and financial problems. Second, the development M.D.-Ph.D. program consists of educational period, admission procedure, entree examination, curriculum and its administration, degrees, school registration management, medical license examination, grants and problems related to military service. The expectations of the results are; first, M.D.-Ph.D. program will make Korea one of the leading countries in biomedical scientists and medical knowledge, and will activate the interdisciplinary research. Second, M.D.-Ph.D. program will facilitate to revise the educational problems of graduate school of medicine and medical schools.

The involvement of K+ channels and the possible pathway of EDHF in the rabbit femoral artery

Experiments were designed to characterize the cellular mechanisms of action of endothelium-derived vasodilator substances in the rabbit femoral artery. Acetylcholine (ACh, 10(-8)-10(-5) M) induced a concentration-dependent relaxation of isolated endothelium-intact arterial rings precontracted with norepinephrine (NE, 10(-6) M). The ACh-induced response was abolished by the removal of endothelium. NG-nitro-L-arginine (L-NAME, 10(-4) M), an inhibitor of NO synthase, partially inhibited ACh-induced endothelium-dependent relaxation, whereas indomethacin (10(-5) M) showed no effect on ACh-induced relaxation. 25 mM KCl partially inhibited ACh-induced relaxation by shifting the concentration-response curve and abolished the response when combined with L-NAME and NE. In the presence of L-NAME, ACh-induced relaxation was unaffected by glibenclamide (10(-5) M) but significantly reduced by apamin (10(-6) M), and almost completely blocked by tetraethylammonium (TEA, 10(-3) M), iberiotoxin (10(-7) M) and 4-aminopyridine (4-AP, 5 x 10(-3) M). The cytochrome P450 inhibitors, 7-ethoxyresorufin (7-ER, 10(-5) M) and miconazole (10(-5) M) also significantly inhibited ACh-induced relaxation. Ouabain (10(-6) M), an inhibitor of Na+, K(+)-ATPase, or K(+)-free solution, also significantly inhibited ACh-induced relaxation. ACh-induced relaxation was not significantly inhibited by 18-alpha-glycyrrhetinic acid (18 alpha-GA, 10(-4) M). These results of this study indicate that ACh-induced endothelium-dependent relaxation of the rabbit femoral artery occurs via a mechanism that involves activation of Na+, K(+)-ATPase and/or activation of both the voltage-gated K+ channel (Kv) and the large-conductance, Ca(2+)-activated K+ channel (BKCa). The results further suggest that EDHF released by ACh may be a cytochrome P450 product.

Effects of electrical stimulation of brainstem nuclei on dorsal horn neuron responses to mechanical stimuli in a rat model of neuropathic pain

The aim of the present study is to examine the brainstem sites where the electrical stimulation produces a suppression of dorsal horn neuron responses of neuropathic rats. An experimental neuropathy was induced by a unilateral ligation of L5-L6 spinal nerves of rats. Ten to 15 days after surgery, the spinal cord was exposed and single-unit recording was made on wide dynamic range (WDR) neurons in the dorsal horn. Neuronal responses to mechanical stimuli applied to somatic receptive fields were examined to see if they were modulated by electrical stimulation of various brainstem sites. Electrical stimulation of periaqueductal gray (PAG), n. raphe magnus (RMg) or n. reticularis gigantocellularis (Gi) significantly suppressed responses of WDR neurons to both noxious and non-noxious stimuli. Electrical stimulation of other brainstem areas, such as locus coeruleus. (LC) and n. reticularis paragigantocellularis lateralis (LPGi), produced little or no suppression. Microinjection of morphine into PAG, RMg, or Gi also produced a suppression as similar pattern to the case of electrical stimulation, whereas morphine injection into LC or LPGi exerted no effects. The results suggest that PAG, NRM and Gi are the principle brainstem nuclei involved in the descending inhibitory systems responsible for the control of neuropathic pain. These systems are likely activated by endogenous opioids and exert their inhibitory effect by acting on WDR neurons in the spinal cord.

The changes of immunoreactivity for CGRP and SP in the spinal cord and DRG according to the distance between the DRG and injury site of a peripheral neuropathic rat

Peripheral nerve injury sometimes leads to neuropathic pain and depletion of calcitonin gene related-peptide (CGRP) and substance P (SP) in the spinal cord. However, the pathophysiological mechanisms for depletion of CGRP and SP following the neuropathic injury are still unknown. This study was performed to see whether the distribution of immunoreactivity for CGRP and SP in the superficial dorsal horn and dorsal root ganglia (DRG) was related to the distance between the DRG and injury site. To this aim, we compared two groups of rats; one group was subjected to unilateral inferior and superior caudal trunk transections at the level between the S3 and S4 spinal nerves (S34 group) and the other group at the levels between the S1 and S2, between S2 and S3 and between S3 and S4 spinal nerve (S123 group). The transections in both groups equally eliminated the inputs from the tail to the S1-3 DRG, but the distance from the S1/S2 DRG to the injury site was different between the two groups. Immunostaining with SP and CGRP antibody was done in the S1-S3 spinal cord and DRG of the two groups 1 and 12 weeks after the injury. The results obtained are as follows: 1. The immunoreactivity for CGRP and SP in the ipsilateral superficial dorsal horn and DRG decreased 1 and 12 weeks after neuropathic nerve injury. 2. The immunoreactive area of SP and CGRP in the S1 dorsal horn was smaller in the S123 group than in the S34 group, whereas that in the S3 dorsal horn was not significantly different between the two groups. The number of SP- immunoreactive DRG cells decreased on the neuropathic side as compared to the sham group's in all DRGs of experimental groups except the S1 DRG of the S34 group. These results suggest that the amounts of SP and CGRP in the dorsal horn and DRG following neuropathic injury inversely decrease according to the distance between the DRG and injury site.

Effects of iontophoretically applied naloxone, picrotoxin and strychnine on dorsal horn neuron activities treated with high frequency conditioning stimulation in cats

Transcutaneous electrical nerve stimulation(TENS), acupuncture-needling, and electroacupuncture are useful non-ablative methods in medical practice for relief of pain. These procedures appear to work by causing an increased discharge in afferent nerve fibers which in turn modifies the transmission of impulses in pain pathways. It is known that the mechanism of analagesic effect via these maneuvers are variable depending on the stimulating parameters. For example, the endogenous opioid system is profoundly related to the mechanism when a peripheral nerve stimulation is applied with parameters of low frequency and high intensity. However, when stimulated with parameters of high frequency and high intensity, the reduced activity of dorsal horn neurons is only slightly reversed by a systemic administration of naloxone, a specific opiate antagonist. Thus, the present study was performed to investigate the neurotransmitter that concerns the mechanism of peripheral nerve stimulation with parameters of high frequency and high intensity. We used an iontophoretic application of antagonists of possible related neurotransmitters. The dorsal horn neuron activity which was evoked by squeezing the peripheral cutaneous receptive field, was recorded as an index of pain with a microelectrode at the lumbo-sacral spinal cord. Naloxone, picrotoxin and strychnine were applied at 200nA during a period of conditioning nerve stimulation. We observed the effects of these drugs on the change of dorsal horn neuron activities. The main results of the experiment can be summarized as follows. The spontaneous activity of dorsal horn neurons increased in the presence of glutamate and decreased with GABA. It did not change with naloxone, picrotoxin or strychnine. When naloxone was applied iontophoretically during peripheral nerve stimulation, there was no statistically significant analgesic effect compared with that of the control group. When picrotoxin was applied iontophoretically during peripheral nerve stimulation, the analgesic effect was reduced. When strychnine was applied, the analgesic effect was reduced but did not show a statistically significant difference with the control group. These results suggested that the GABAergic system may have been partially related in the analgesic action of peripheral nerve stimulation with parameters of high frequency and high intensity.

Intracellular acidosis decreases the outward Na(+)-Ca2+ exchange current in guinea pig ventricular myocytes

The Na(+)-Ca2+ exchange transport operating in outward mode has been suggested to cause Ca2+ entry during reperfusion or reoxygenation, exchanging extracellular Ca2+ for intracellular Na+ that has accumulated during ischemia or cardioplegia. During cardioplegia, however, an increase in Ca2+ entry via this mechanism can be decreased due to increased intracellular H+ activity and a decrease in cellular ATP content. In this study giant excised cardiac sarcolemmal membrane patch clamp technique was employed to investigate the effect of cytosolic pH change on the Na(+)-Ca2+ exchanger, excluding the effect of ATP, in guinea pig cardiac myocytes. The outward Na(+)-dependent current, which has a characteristics of Hill equation, was decreased as pH was decreased in the range of 7.5-6.5. The current density generated by the Na(+)-Ca2+ exchange transport was 56.6 +/- 4.4 pA/pF (Mean +/- S.E.M.) at pH 7.2 and decreased to 42.9 +/- 3.0 pA/pF at pH 6.9. These results imply that Na(+)-Ca2+ exchange transport, operating in a reverse mode during cardioplegia, decreases due to increased intracellular H+, and further suggest that consequent intracellular Na+ accumulation is one of aggravating factors for Ca2+ influx during reoxygenation or reperfusion.

Mechanism of transmission and modulation of renal pain in cats: effects of transcutaneous electrical nerve stimulation on renal pain

Transcutaneous electrical nerve stimulation (TENS) has widely been employed as a method of obtaining analgesia in medical practice. The mechanisms of pain relief by TENS are known to be associated with the spinal gate control mechanism or descending pain inhibitory system. However, most of the studies concerning the analgesic effects and their mechanisms for TENS have dealt with somatic pain. Thus, in this experiment, we investigated the analgesic effects of TENS on renal pain as a model of visceral pain, and the characteristics of the dorsal horn cells with renal inputs. The renal pain was induced by acute occlusion of the ureter or renal artery. The main results are summarized as follows: 1) The renal nerve was composed of A beta, A delta and C fiber groups; the thresholds for each group were 400-800 mV, 1.1-1.5 V, and 2.1-5.8 V, respectively. 2) The dorsal horn cells tested received A and/or C afferent fibers from the kidney, and the more C inputs the dorsal horn cells had, the greater was the response to the stimuli that elicited the renal pain. 3) 94.9% of cells with renal input had the concomitant somatic receptive fields on the skin; the high threshold (HT) and wide dynamic range (WDR) cells exhibited a greater responses than low threshold (LT) cells to the renal pain-producing stimuli. 4) TENS reduced the C-responses of dorsal horn cells to 38.9 +/- 8.4% of the control value and the effect lasted for 10 min after the cessation of TENS. 5) By TENS, the responses evoked by acute occlusion of the ureter or renal artery were reduced to 37.5 +/- 9.7% and 46.3 +/- 8.9% of the control value, respectively. This analgesic effects lasted 10 min after TENS. 6) The responses elicited by squeezing the receptive fields of the skin were reduced to 40.7 +/- 7.9% of the control value and the effects lasted 15 min after TENS. These results suggest that most of dorsal horn cells with renal inputs have the concomitant somatic inputs and TENS can alleviate the renal pain as well as somatic pain.

Effect of Teramethylammonium on the Release of Endothelium-Derived Relaxing Factor in Rabbit Thoracic Aorta

Teramethylammonium(TMA) in one of the synthetic compounds of nicotine that act at ganglionic site. The major action of TMA consists of initial stimulation followed by a more persistent depression of all autonomic ganglia by binding to a cholinergic receptor. It is well believed that the level of membrane potential in arterial smooth muscle is an important regulator of tension development. Depolarization and hyperpolarization by only few millivolts results in significant changes in tension. In general, the agents of vascular smooth muscle induce vascular relaxaion. The present study was undertaken to elucidate the effect of TMA on vascular contractility in the isolated rabbit thoracic aorta with or without endothelial cell, and mechanisms involved in the change of vascular contractility by TMA. The results obtained are summarized as follows ; 1) In the presence of endothelial cell, TMA induced a relaxtion of the aorta precontracted with norepinephrine but induced a contraction in the aorta without endothelial cells, indicating that in the rabbit aorta, relaxations produced by TMA were the endothelium-dependent. 2) The addition of inhibitor such as methylene blue, hemoglobin, hydroquinone and p-bromophenacyl bromide during the TMA-induced relaxation reversed the contractile tension to a level similar to or higher than that before the addition of TMA in rabbit thoracic aorta.This relaxation effect of TMA suggest that the TMA-inducdd relaxation in rabbit aorta is due to the release of endotheline derived relaxing factor(EDRF). 3) Relaxation induced by TMA was antagonized by atropine and thus the TMA does seem to act on the muscarinic receptors. 4) TMA reduced the norepinephrine-induced Ca++ influx into rabbit smooth muscle membrane. From the above results, it may be concluded that TMA-induced vacular relaxation in rabbit aorta is due to the release of EDRF. Mechanism involved in the relaxation induced by TMA may be the stimulation of soluble guanylate cyclase and increased tissue cGMP concentrations.

Compartmental analysis of RBC circulation through the rabbit kidney

This experiment involved 12 rabbits of both sexes, weighing 2.1 kg. After anesthesia, the kidneys were exposed, isolated and cannulated in the renal artery, ureter and sometimes in the vein as well. The kidney were perfused through the renal artery with Krebs-Henseleit solution, which were then filtered to be free of particles, gased with 95% O2-5% CO2, and kept at 37 degrees C. We measured RBCs concentrations by means of Coulter Counter in the venous outflow collected, and plotted them against the volume perfused. Using 2 different flow rates, 9 ml/min (group I) and 19 ml/min (group II), we found that the RBCs decreased in a multiexponential decay fashion and a biophysical model for each flow rate was constructed. These models indicated that there were more cell stores (2.20 x 10(10)) in the fast compartment of group II than in group I (1.72 x 10(10)). This difference is not statistically significant, but certainly coincides with urine flow collected from ureter cannula during perfusion. Our present data clearly suggest that in order to clear 99% blood cells out of 10-12 gm rabbit kidneys, at least 3-6 ml of cell free perfusate is required while clearing the whole blood cells out of human kidneys (200-240 gm) may need 600 ml or more. Thus, we recommend that at least 600 ml of perfusate should be used to clear most of the blood cells in the renal vasculature before renal transplantation is performed.

The Effect of D-phenylalanine on the Analgesia Produced by Peripheral Nerve Conditioning Stimulation in the Cat

An effect of D-phenylalanine on the pain inhibitory mechanism of prolonged electrical stimulation of the peripheral nerve was studied in decerebrate cats and spinal cats. The response of spinal neurons was elicited either by electrical stimulation of the ipsilateral common peroneal nerve and tibial nerve. The single-unit activity of motor neurons which represent the flexion reflex was recorded from a filament of ventral rootlet divided from either the L7, S1 or S2 ventral root, and activity of dorsal horns cells was recorded with a microelectrode at the lumbosacral cord The conditioning stimuli which provocate the pain inhibitory mechanism of the common peroneal or tibial nerve was applied with repetitive, low frequency (2Hz), at a suprathreshold intensity for C fiber, for 30-45 minutes. The results of the experiment are summarized as follows: 1. Applying conditioning stimuli produced a powerful inhibition of the responses which was provocated by noxious stimuli in either the decerebrate or the spinal cat without any statistical difference, and this effect can be observed for 15 minutes after the cessation of the conditioning stlmuli 2. This response was reversed completely by systemic injection of a specific opiate antagonist, naloxone. It suggests that the conditioning stimulus of the peripheral nerve can produce the endogenous opiate related pain inhibitory effect as the spinal mechanism. 3. The conditioning stimuli can produce the analgesic effect by means of supression of the activity of the dorsal horn cell which was related to the pain response in the decerebrate cat. The same result could be observed in flexion reflex. 4. D-phenylalanine, a putative inhibitor of carboxypeptidase which degradates the endogenous opiate-enkephalin, was studied in this experiment under the hypothesis that D-phenylalanine will emphasize or prolongate the action of enkephalin. But, intravenously injected D-phenylalanine did not potentiate the inhibitory effect of the conditioning stimuli of the peripheral nerve. From the above result, it is speculated that the electrical stimulation of the peripheral nerve is directly mediated by an endogenous opiate related analgesia, and the site of the analgesic action resides mainly in spinal cord level. But these data could not support the gypothesis that antinociceptive effect of D-phenylalanine results frm the potentiation of endogenously released enkephalin.

Relationship Between Dorsal Horn Cell Activity and Electrical Stimulation of Peripheral Nerve with Special Reference of Stimulatory Parameters

Transcutaneous electrical nerve stimulation (TENS), acupuncture-needling, and electroacu! Puncture are useful non-ablative methods in medical practice for relief of acute and chronic r pain These procedures appear to work by causing an increased discharge in afferent nerve fibers which in turn modifies the transmission of impulses in pain pathways. The present study was performed to evaluate the analgesic effects of peripheral nerve stimulation with different stimulatory parameters in decerebrated cats and spinalized cats. And we studied the effects of naloxone, a specific opiate antagonist, on analgesia produced by 50 Hz, C intensity conditioning stimulation. The electrical response of.spinal neurons was elicited either by electrical stimulation of the ipsilateral common peroneal nerve or tibial nerve, and then the single unit activity of the dorsal horn cell was recorded with a carbon filament-filled glass microelectrode at the lumbosacral spinal cord. The conditioning stimuli which provoke the pain inhibitory mechanism were applied to the cornmon peroneal nerve or tibial nerve with a relatively high frequency (25, 50, 200Hz) for 15, 30, and 60 seconds at suprathreshold intensity for A delta or C fiber. The results of the experiment are summarized as follows: 1. Peripheral conditioning stimulation at C strength showed larger analgesic effects than those produced by stimulation at A delta strength. And analgesic effects produced by conditioning stimulation for 30sec were greater than those produced by stimulation for 15sec, but showed no statistically significant difference from those produced by stimulation for 60 sec. 2. Analgesic effects produced by 50Hz conditioning stimulation were greater than thoseproduced by 25Hz stimulation. But 200Hz stimulation showed a lesser analgesic effect than 50 or 25Hz conditioning stimulation. 3. The analgesic effect produced by 50Hz conditioning stimulation was only slightly affected by naloxone, a specific opiate antagonist, indicating that involvement of an endogenous opiate system was minimal. 4. The analgesic effect produced by conditioning stimulation in decerebrated cats was nearly the same as in spinal cats suggesting that the neural circuitry responsible for the analgesic action seems to reside mostly within the spinal cord. From the above results, it is concluded that 1) frequency of stimulation is important for an efficient analgesia, i.e., stimulation with excessively high frequency decreases the analgesic effect, 2) the analgesic effect produced by high frequency conditioning stimulation may be minimally mediated by an endogenous opiate system, and 3) the site of analgesic action resides mainly in the spinal cord.

The Effect of Thyrotropin Releasing Hormone on somatosensory Evoked Potentials in Cats with Spinal Cord Injury

The therapeutic goal for the spinal injury has been focused on preventing the secondary ischemic changes because of the poor regeneration of human spinal cord. Naloxone, an antagonist of endogenous opiates, has been clinically used for the purpose of preventing ischemic change and improving the recovery of neurological function after spinal injury. Recently, thyrotropin releasing hormone(TRH), a hypothalamic hormone inducing the thyrotropin secretion in anterior pituitary gland, has been known as a potent stimulator of cardiovascular functions in shock and the neurologic recovery in injuries of central nervous system, however, its underlying mechanism is still obscure. The present study was designed to determine whether TRH was also effective to improve the experimentally induced spinal injury as naloxone did, Somatosensory evoked potentials(SEPs) have used as an index for recovery of neurological function after the spinal injury which was induced by the 400gm.cm contusion of the T-7 spinal level in cats. The results are summarized as follows : 1. SEPs abolished soon after spinal contusion were reappeared 3 hours after injury when either of naloxone(10mg/kg) or TRH(4mg/kg) was administrated intravenously. Its recovery was completed after 24 hours. 2. The recovery rates of SEPs after treatments of naloxone and TRH were 62.5% and 64.7% of experimental animals, respectively. In conclusion, the present studies confirm the therapeutic benefit of TRH in experimental spinal injury and demonstrate that it is superior to treatment with naloxone. Further studies would be needed to explain the underlying mechanism of TRH effects.