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The relationship between atherosclerosis and fat soluble vitamin, especially vitamin E is reviewed on the basis of oxidised modification of low density lipoprotein (LDL). Data now support the notion that the oxidised LDL is present in the blood and arterial wall and antioxidant drugs such as probucol and vitamin E, beta-carotene, may prevent the progression of atherosclerosis. LDL alpha-tocopherol levels are generally correlated to the plasma concentrations and supplementation with alpha-tocopherol increases its content in LDL. There is a significant correlation between the LDL alpha-tocopherol level and the resistance to oxidative modification. Epidemiological data also shows the relation between low levels of plasma vitamin E and the increased incidence of coronary heart disease. Clinical application of vitamin E should be clarified in detail to inhibit the progression of atherosclerosis.

The blood compatibility of the jellyfish valve was studied. Artificial heart (AH) blood pumps incorporating jellyfish valves were connected to 18 goats as total artificial hearts (TAHs) and pumped for 1 to 125 days without anticoagulant or antiplatelet drugs. No thrombus was formed on the valve membrane or around the valve seat. Scanning electron microscopy showed almost no platelet deposition or microfibrin clot formation on the valve membrane, including its central region; the spokes of the valve seat were also free from platelet and microfibrin clots. No calcification was observed during these tests, and plasma free hemoglobin was between 2 and 7 mg/dl. The jellyfish valve revealed good blood compatibility, even without anticoagulant use.

Atrial natriuretic peptide (ANP) was administered intravenously to three goats at a dose of 0.1 micrograms/kg/min for 40 min both before total artificial heart (TAH) placement and at 1, 7, and 14 postoperative weeks to determine whether exogenous ANP exhibits the same effect on animals with TAHs as it does on normal animals. No significant changes in the increases in plasma levels of ANP and cyclic guanosine monophosphate (c-GMP) were observed during ANP administration after TAH insertion. In preoperative animals, urine volume and urinary sodium excretion increased greatly during ANP administration, but this natriuretic effect was strongly suppressed in TAH animals. The changes in the decreases in arterial pressure and in central venous pressure (CVP) or right atrial pressure that occurred during the administration of ANP were not significant either pre- or post-operatively. Thus, only the natriuretic effect of ANP on the kidney was significantly suppressed in TAH animals, which might be due to some down-regulation of ANP receptors in the kidney, the production of some antagonists of ANP, sympathetic hypertonicity, or the elevation of CVP.

For percutaneous observation of lesions near the spinal cord and percutaneous spinal laser surgery under the visual field, we studied a method and approach to the spinal cord and intraspinal surgical procedures with laser using a newly developed, small-diameter laser endoscope. The subarachnoid and epidural spaces of a goat were punctured using a 17-gauge epidural needle, and the endoscope (diameter 0.7 mm) was inserted through the needle. The spinal cord and surrounding tissue were observed. Next, an endoscope (diameter 1.5 mm) was inserted into the subarachnoid space, and the quality of the picture and manageability of the endoscope were examined. The Xe:Cl excimer laser was irradiated to a nerve root through a 0.4 mm optical fiber for laser transmission through this endoscope. The spinal cord, nerve roots, and arachnoid were clearly observed through this endoscope. The pulsation of the artery accompanying a root was seen clearly, and the quality of the picture of the endoscope was thought to be sufficient for diagnosis. The nerve root was cut within 30 seconds by excimer laser, and the possibility of laser surgery was demonstrated. Although it was shown that this endoscope could be a useful diagnostic and therapeutic tool, improvement in the manageability of the tip of the endoscope was considered to be important for a clinically usable endoscope.

In man ketanserin tartrate reduces plasma LDL cholesterol. To clarify the mechanism of this effect the effect of ketanserin on 3-hydroxy-3-methylglutaryl (HMG) CoA reductase and LDL receptor activity in cultured human skin fibroblasts has been examined. After incubation with ketanserin for 14 h HMG CoA reductase activity was decreased in a dose-dependent manner up to 300 ng/ml (550 nM) without changing the free cholesterol content in the cells. Ketanserin increased specific binding and specific internalization of 125I-LDL dose-dependently. There was a significant inverse relationship between the percentage changes in HMG CoA reductase and LDL receptor activity. It appears that ketanserin induces up-regulation of LDL receptor activity by direct suppression of HMG CoA reductase, and this may be one mechanism by which plasma LDL-cholesterol is reduced by ketanserin.

Ketanserin tartrate (ketanserin) is a new antihypertensive drug that is a selective 5HT2 serotonergic receptor antagonist and at high concentrations antagonizes the alpha 1-adrenergic receptor. Several reports have indicated that ketanserin clinically decreases plasma low density lipoprotein (LDL) cholesterol. In order to clarify the mechanisms of this LDL cholesterol reduction by ketanserin, we investigated the effects of ketanserin on 3-hydroxy, 3-methylglutaryl coenzyme A(HMG CoA) reductase activity to cultured human skin fibroblasts. We also studied the effects of ritanserin (a 5HT2 serotonergic receptor antagonist) and prazosin HCl (an alpha 1-adrenergic receptor antagonist) on HMG CoA reductase activity in cultured human skin fibroblasts. Human skin fibroblasts were cultured in Dulbecco's modified Eagle's (DME) medium containing 10% fetal calf serum. Before the cells reached confluence, the medium was changed to DME containing 10% lipoprotein-deficient serum. After incubation for 48-72 hours, the drugs under investigation were added to the medium. The cells were incubated for 14 hours and harvested after washing with phosphate buffered saline. In our study, ketanserin decreased HMG CoA reductase activity in a dose-dependent manner up to 300 ng/ml (550 nM). Prazosin also decreased HMG CoA reductase activity in a dose-dependent manner up to 40 ng/ml (95 nM); ritanserin decreased HMG CoA reductase activity at concentrations of 100 nM and 200 nM. These findings suggest that the combination of alpha 1-adrenergic receptor and 5HT2 serotonergic receptor antagonist effects of ketanserin inhibits HMG CoA reductase activity and that this suppression is probably one of the mechanisms for the plasma LDL cholesterol reduction resulting from ketanserin treatment.

By fixing the function of one ventricle, a total right heart bypass model can clarify the function and regulatory mechanism of the natural heart, and the etiology of abnormal hemodynamics in TAH animals such as increased CVP blood pressure and hepatic congestion. The pulmonary artery of a right heart bypass in a goat was clamped proximally; the pulmonary circulation was thus supplied entirely by the artificial heart and the systemic circulation by the natural heart. This model enabled studies of long-term effects of an artificial right heart on systemic circulation at a right heart output of 80-100 ml/kg/min; the response of the natural left heart to changes in output of the right heart; and the response of the natural left heart and artificial right heart to treadmill exercise. It was found that only slight increase in CVP or no increase in blood pressure was observed during the experiment (112 days); a rapid increase in output of the RAH resulted in an increase in left atrial pressure, stroke volume and output of the left ventricle, and a decrease in its heart rate at rest; and significant increase in both artificial right heart and natural left heart output and heart rates were observed during treadmill exercise, despite the marked decrease in left atrial pressure. The above results suggest that the increase in CVP and blood pressure in total artificial heart animals are not due to factors involving the artificial right heart, and that although left ventricular function acts in accordance with Starling's law at rest, this is no longer true during treadmill exercise.

A practical model (Model-1) of a jellyfish valve was developed, which was composed of a valve seat and a flexible membrane. The valve seat has 12 spokes to hold the membrane, and is made of solution-cast polyurethane coated with segmented polyurethane or Cardiothane. The flexible membrane is 200 microns thick, and made of segmented polyurethane or Cardiothane by a casting method. The valves were built into a sac type blood pump. In mock circulation tests, this jellyfish valve revealed performance superior to Bjork-Shiley (B-S) valves. No stagnation point was observed in the flow visualization study, and durability testing is ongoing beyond 7.5 months. The valves were used in animal artificial heart experiments for up to 112 days with good performance. No thrombi were formed on the valve membrane or around the spokes. Although a ring thrombus was observed behind the valve, it would be prevented by perfect adhesion of the valve seat to the blood pump. The plasma free hemoglobin level was less than 2 mg/dl during these experiments. These results suggest that a jellyfish valve (Model-1) is useful in ventricular assist devices, and in short-term bridge use of a total artificial heart.

The present study examined the influence of spinally administered fentanyl on the spontaneous and noxiously evoked activity of wide dynamic range (WDR) neurons in the dorsal horn of decerebrate, spinal cord-transected cats. This work was performed in order to evaluate the dose-response relationship, time course, and naloxone reversibility of fentanyl suppression of neurons that are involved with the transmission of information about pain. Extracellular single neuron recordings were obtained from 18 WDR neurons in the lumbar enlargement. These neurons were activated by a radiant heat stimulus on the footpads of the hindpaw. Fentanyl (10, 15, 25 micrograms in 0.5 ml of physiologic saline) was placed on the spinal cord following control studies of each neuron and the effect was observed. In 12 cats, 31 min after fentanyl administration, naloxone (0.1 mg) was administered intravenously, and its effect on the fentanyl suppression was determined. All three doses of fentanyl suppressed both the spontaneous and evoked activity of all the neurons studied. Thirty minutes after fentanyl the mean evoked activity was reduced to 47, 23, and 11% of control values by 10, 15, and 25 micrograms, respectively. The spontaneous activity was reduced to similar levels. Intravenous naloxone (0.1 mg) caused a significant reversal of the fentanyl suppression. The results of the present study indicate that fentanyl causes a naloxone-reversible, dose-dependent suppression of noxiously evoked WDR neuron activity. Such results support the concept that fentanyl is acting through a specific drug-receptor interaction. The onset of neuronal suppression occurred more rapidly, and the duration of the suppression was longer following fentanyl than that seen following spinal morphine. The onset and duration of this suppression correlates well with human clinical data, providing further evidence that alterations of WDR neuronal activity may be important in the production of spinal opioid analgesia.

In six open-chest dogs, electrocardiogram- (ECG) controlled pulmonary arterial occlusion was performed during the control period and during the infusions of serotonin and histamine. A temporal series of instantaneous pulmonary capillary pressure and the longitudinal distributions of vascular resistance and compliance were evaluated in the intact left lower lung lobe. In the control period, we found a significant phasic variation of pulmonary capillary pressure (Pc) with the cardiac cycle. The ratio of arterial to venous resistances (Ra/Rv) was 6:4, and the ratio of arterial to capillary compliances (Ca/Cc) was 1:11. During the infusions of serotonin and histamine, Pc showed similar phasic variations, despite significant hemodynamic changes induced by these agents. Serotonin predominantly increased Ra, whereas histamine predominantly increased Rv. The ratio of Rv to the total resistance decreased significantly from 0.42 to 0.32 during the infusion of serotonin and increased significantly to 0.62 during the infusion of histamine. The data suggest that phasic Pc determined by ECG-controlled arterial occlusion reflects the pulsatility in the pulmonary microvascular bed under control conditions and after alterations of the pulmonary vascular resistance by serotonin and histamine.

This study was designed to determine if spinally administered epinephrine is capable of suppressing noxiously evoked activity of wide dynamic range (WDR) neurons in the dorsal horn of the spinal cord. Extracellular activity was recorded from single WDR neurons in the dorsal horn of decerebrate, spinal cord-transected (T-12) cats. Activity was evoked by the presentation of a noxious radiant heat stimulus (51 degrees C) to the cells' receptive fields on the hind paws. Evoked activity was monitored both before and after the spinal administration of either 50 micrograms (n = 6) or 100 micrograms (n = 6) epinephrine. Both doses of epinephrine produced a significant suppression of noxiously evoked activity, which was dose-dependent. In addition, the 100-microgram dose produced a suppression that was of longer duration than that seen following the 50-microgram dose. Recovery from suppression was recorded following both the 50- and 100-microgram dose. These results indicate that spinally administered epinephrine is capable of suppressing noxiously evoked activity of WDR neurons in the dorsal horn of the spinal cord. Since WDR neurons have been identified as cells of origin for the spinothalamic tract, such an action may block the central transmission of afferent pain information. This may be a mechanism by which spinally administered epinephrine enhances the duration or intensity of spinal anesthesia produced by local anesthetics and may also explain spinal analgesia resulting from the spinal administration of adrenergic agonists. Interactions between spinally administered epinephrine and spinally administered opioids also were studied.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of intravenously administered fentanyl (25 micrograms/kg, n = 9; 50 micrograms/kg, n = 5) and alfentanil (12.5 micrograms/kg, n = 5; 25 micrograms/kg, n = 7) on the noxiously evoked, single-unit activity of cells in the nucleus reticularis gigantocellularis (NRGC) were studied in decerebrate cats. Only cells of the NRGC excited exclusively by supramaximal electrical stimulation of A delta fibers (noxious stimulation) of the superficial radial nerve were studied. The noxiously evoked activity of all cells in the NRGC was suppressed by the administration of opioids (by 58 and 88% for fentanyl, 25 micrograms/kg and 50 micrograms/kg, respectively; by 35 and 78% for alfentanil 12.5 micrograms/kg and 25 micrograms/kg, respectively). Fentanyl and alfentanil effects were antagonized by the intravenous administration of naloxone. These results indicate that opioid suppression of noxiously evoked activity is seen in neurons located in the brainstem, and thus suppression of brainstem neurons may be important in the production of fentanyl and alfentanil analgesia.

Electrophysiological studies were performed to see the effects of lidocaine on the conduction system, particularly sinus node and atrium in 40 patients of SSS, using HBE recordings, rapid atrial pacing and atrial extrastimulus technique. Sinus cycle length, PA (P'A), AH, HV intervals, calculated SACT, and refractory periods of atrium, AV node and His-Purkinje system did not change after lidocaine. Only maximum CSRT was significantly increased with lidocaine. These results were not affected by pretreatment of atropine. In conclusion, the combining rapid atrial pacing with lidocaine may be useful to manifest the masked sinus node abnormalities. It was suggested that lidocaine directly depressed sinus node automaticity in SSS patients, without affecting perinodal tissue. Therefore, lidocaine should be used with caution in patients with known or suspected SSS.

Short-latency somatosensory evoked potential (SEP) was serially monitored in head-injured patients and its clinical significance was evaluated in relation to auditory brain stem response (ABR), prognosis and other parameters such as intracranial pressure (ICP). SEP, ABR, and ICP were monitored serially and automatically in 16 patients with acute head injury. Glasgow Coma Scale (GCS) score was equal to or less than 8 in 14 cases. High dose barbiturate therapy was performed in 7 cases and intracranial hematoma was removed operatively in 14 cases. SEP was recorded from C3'or C4'-Fz leads on the lesion side following stimulation of the contralateral median nerve, and the difference between the two potentials (N20, N13) defined as central conduction time (CCT) was followed at a basic time interval of 10-20 min. The patients were divided into 3 groups according to N20 finding and the prognosis of each group was analyzed. The final outcome (assessed 6 months after injury) was graded according to Glasgow Outcome Scale as follows: good (good recovery, moderate disability), poor (severe disability, persistent vegetative state), death (death). Three patients with no CCT change showed good recovery (table, 11). Out of 7 patients with no N20 on admission, 5 died due to severely increased ICP and the prognosis for the other 2 cases was poor. The last group consisted of 6 patients in whom CCT varied during hospitalization. In 3 out of these 6 cases N20 finally disappeared due to increased ICP and they died in the acute stage.(ABSTRACT TRUNCATED AT 250 WORDS)