Coronary vasodilator reserve in young dogs with moderate right ventricular hypertrophy.

The effects of experimental right ventricular (RV) pressure overload and RV hypertrophy on coronary vasodilator reserve in young animals is not well established. Therefore, we measured coronary vasodilator reserve in the right ventricle of dogs from 7 to 12 months old with moderate RV hypertrophy due to pulmonary artery banding performed 3 to 7 days after birth. In the 5 dogs with pulmonary artery banding, substantial RV hypertension developed (RV pressure at rest, 73 +/- 11 mm Hg) as did RV hypertrophy (ratio of RV free wall/left ventricular free wall weight, 1.86 +/- 0.41 gm/kg). The reactive hyperemic response following brief coronary occlusions was used as an index of coronary vasodilator reserve. The ratios of peak reactive hyperemic response to resting flow, however, were not significantly different in the 5 banded dogs compared with 7 control animals (3.6 +/- 1.0 versus 2.6 +/- 0.6); this implies that the extent of vasodilator reserve was similar with or without moderate RV hypertrophy. In addition, myocardial blood flow, as determined using radioactive microspheres, was not significantly different at rest: 0.57 +/- 0.09 ml/min per gram in the banded dogs versus 0.48 +/- 0.12 ml/min per gram in the controls. Uniform transmural distribution of blood flow was maintained during infusion of isoproterenol, which was used to increase myocardial oxygen requirements in both groups. Minimum coronary vascular resistance was significantly lower in the banded than the control dogs (1.5 +/- 0.6 versus 6.2 +/- 2.3; p less than 0.01). This difference suggests that the cross-sectional area of the right coronary vascular bed increased with the development of RV hypertrophy.

Norepinephrine plus phentolamine improves regional blood flow during experimental low cardiac output syndrome.

A complication of cardiac surgical procedures is postoperative low cardiac output syndrome. Treatment with norepinephrine plus phentolamine (N + P) is beneficial, but the effect of these agents on regional organ blood flow has not been evaluated. Therefore, in 6 dogs with long-term instrumentation, pentobarbital was infused to simulate low cardiac output (32 + 10% of the conscious control level). Infusions of N + P at 0.2, 0.5, and 1.0 microgram/kg/min restored cardiac pump performance to conscious control levels. Regional blood flows, determined with tracer-labeled microspheres, were substantially reduced in the low cardiac output state but increased to values not markedly different from control levels in all organs studied except stomach fundus during infusion of N + P. The pressure-work index, an indirect measure of myocardial oxygen consumption, did not increase to more than the conscious level except at the highest dose. The data demonstrate that simultaneous infusion of N and P is capable of successfully improving cardiac pump performance with restoration of vital organ perfusion and without evidence of excessive myocardial oxygen consumption.

Long term potentiation in the magnocellular medial geniculate nucleus of the anesthetized cat.

Long term potentiation (LTP) has been suggested as a mechanism in learning. The magnocellular division of the medial geniculate nucleus (MGm) is known to develop discharge plasticity rapidly during behavioral learning. The ability of the MGm also to develop long term potentiation was studied in cats under barbiturate anesthesia. Monosynaptic responses elicited in the MGm by periodic (0.2 Hz) stimulation of the brachium of the inferior colliculus (BIC) developed significant increases in amplitude and decreases in latency, which were maintained for at least 1 h, following brief high frequency stimulation of the BIC. Antidromic responses recorded in the inferior colliculus were unchanged. These findings provide a link between learning-induced physiological plasticity and LTP, and demonstrate that the auditory system can develop long term potentiation.

Changes in sciatic nerve and spinal cord function induced by a CNS viral infection.

Electrophysiologic response characteristics of mouse sciatic nerve and spinal cord were investigated following CNS infection with the temperature-sensitive (ts) vesicular stomatitis virus (VSV) mutant G31 KS5. Measurements were obtained before clinical symptoms of the virus-induced CNS disease appeared. Sciatic nerve peak conduction velocities were not different between virus and control inoculated groups. For all control groups, sciatic nerve response (SNR) recovery, characterized by the amplitude ratio of double pulse-evoked responses, followed a facilitation-depression time course. By 4 days after VSV inoculation, the time course of SNR recovery changed with the SNR amplitude ratios significantly depressed compared to control. Crossed spinal responses (CSRs) were measured from one sciatic nerve in response to stimulation of the contralateral sciatic nerve. For all control groups, CSR recovery, as characterized by area ratios calculated from single and double pulse evoked responses, followed a facilitation-depression time course. By 5 days after VSV inoculation, the time course of CSR recovery changed with the CSR area ratios significantly depressed compared to control. The results show that simple electrophysiologic techniques can be used to detect virus-induced changes in sciatic nerve and spinal cord previously undetectable by clinical measures.

Postnatal alpha-methylphenylalanine treatment effects on adult mouse locomotor activity and avoidance learning.

Neonatal mice were injected for five days with a combination of alpha-methylphenylalanine and phenylalanine to determine the influences of excess phenylalanine during development upon the behavior of these mice as adults. Spontaneous activity, bolus production, passive avoidance learning, simple active avoidance learning and complex active avoidance learning were tested in mice treated at two different postnatal periods. The results show that the treatments during development produced adult behavioral alterations compared to controls. The effects were most pronounced in mice treated in the postnatal period immediately after birth. The behavioral effects can be summarized as increased emotionality and generalized, stimulus-induced activity as well as decreased passive avoidance performance and complex active avoidance performance. These behavioral deficits are consistent with those usually reported in various models of human phenylketonuria.

Amplitude modulator-demodulator system for recording electroencephalographic signals with a standard 1/4 inch magnetic tape deck.

Circuit diagrams and a sample oscilloscopic tracings are provided for a simple modulator-demodulator system which permits the recording of low frequency bioelectric phenomena with an entertainment type tape recorder. The system is economical and easy to use. Several of the systems have been used successfully in routine laboratory applications for more than a year.

Triethyltin toxicity as a model for degenerative disorders.

Triethyltin (TET) toxicity in mice was examined as a model for certain degenerative disorders. Spontaneous and elicited behavioral tests, electrophysiological measures and nervous system protein characterizations were used to study anomalies resulting from TET treatments. TET animals exhibited lowered spontaneous locomotor activity levels, increased sciatic nerve excitation threshold and conduction velocities, and increased power levels in the slower frequency components of their electroencephalograms. Performance in an active avoidance task suggest that the gross ultrastructural changes commonly seen in TET intoxication are not primarily responsible for the observed neurophysiological changes. Possible sites of action of TET, in both the peripheral and central nervous systems, that would produce these neurophysiological changes and the relationship of these changes to the behavioral symptoms are discussed.

The effect of space and parabolic flight on macrophage hematopoiesis and function.

We used weak electric fields to monitor macrophage spreading in microgravity. Using this technique, we demonstrated that bone marrow-derived macrophages responded to microgravity within 8 s. We also showed that microgravity differentially altered two processes associated with bone marrow-derived macrophage development. Spaceflight enhanced cellular proliferation and inhibited differentiation. These data indicate that the space/microgravity environment significantly affects macrophages.

Subendocardial segment length shortening at lateral margins of ischemic myocardium in dogs.

The lateral borders of an infarcted area are sharply delineated in terms of perfusion, but functional impairment extends a limited distance into adjacent nonischemic myocardium. To determine the distribution of functional impairment we arrayed three ultrasonic dimension gauges to measure two subendocardial segment lengths in series. The center crystal, placed at the perfusion boundary (PB) between left anterior descending and circumflex arteries, radiated ultrasound to receiver crystals 7-17 mm to either side of the PB. The locations of the functional measurements relative to the PB were determined with myocardial blood flow (microsphere) "maps" constructed from multiple small tissue samples obtained circumferentially. On the nonischemic side of the PB, segment shortening (dL) increased from 2.00 +/- 0.37 mm during control conditions to 2.20 +/- 0.43 mm (P less than 0.05) after left circumflex coronary occlusion. Similar results were obtained in four conscious chronically instrumented dogs, supporting the conclusion that segment function adjacent to the ischemic margin is well preserved after coronary occlusion. On the ischemic side of the PB, dL decreased from 2.24 +/- 0.54 to 0.42 +/- 0.39 mm (P less than 0.01). By adding the data from the two segments in series, a combined measurement of dL across heterogeneously perfused myocardium was derived that decreased by 38% from control. The level of shortening represented an integral of normal and abnormal motion that was proportional to the mean reduction in blood flow (-44%) in all of the muscle spanned by the crystals. We conclude that subendocardial segment lengths "average" shortening in the muscle they subtend when arrayed across the perfusion boundary.

Failure of superoxide dismutase and catalase to alter size of infarction in conscious dogs after 3 hours of occlusion followed by reperfusion.

Superoxide dismutase (SOD) and catalase (CAT), enzymes that degrade superoxide anion and hydrogen peroxide, respectively, reduce size of infarction in anesthetized, open-chest dogs subjected to coronary occlusion followed by reperfusion. To evaluate potential protective effects of these enzymes in conscious animals, three groups of dogs were instrumented at sterile surgery with a hydraulic occluder on the left circumflex (LCX) coronary artery, sonomicrometers to measure regional wall thickness, and catheters to monitor arterial and left ventricular pressures. Ten to 14 days after surgery, the animals were sedated with morphine sulfate (0.5 mg/kg). The LCX artery was occluded for 3 hr by inflation of the hydraulic cuff. Infusions of SOD (n = 7), CAT (n = 6), or saline (control group, n = 7) were begun 15 min before reperfusion and lasted for 45 min of reperfusion. The doses of SOD and CAT were 5 mg/kg, dissolved in 60 ml of saline, and infused at a rate of 1 ml/min. Myocardial blood flow was measured with tracer-labeled microspheres (15 micron diameter) before occlusion, after 5 to 10 min of occlusion, after 150 min of occlusion, and 5 to 10 min after reperfusion. Size of infarction was measured 24 hr later by dual-perfusion staining with Evans blue and triphenyl tetrazolium. Size of infarction (expressed as a percentage of area at risk) did not differ significantly among the three groups: control, 32 +/- 17% (mean +/- SD); SOD, 38 +/- 17%; CAT, 27 +/- 17%. Hemodynamic parameters and myocardial blood flows (measured before infusion of any agents) were not significantly different among the three groups. Serum SOD levels in SOD-treated dogs were 19 +/- 2 micrograms/ml at the onset of reperfusion and 29 +/- 3 micrograms/ml at the end of the infusion. Blood assays collected after infusion showed a monoexponential decay of SOD levels with a half-life of 22 +/- 6 min. We conclude that myocardial protection by SOD or CAT is model dependent. In conscious dogs subjected to 3 hr of coronary occlusion followed by reperfusion, SOD and CAT failed to alter size of infarction.

Effect of aortic constriction on the functional border zone.

To evaluate how aortic constriction affects nonischemic myocardium adjacent to the perfusion boundary (the "functional border zone"), we measured systolic wall thickening (dWT) with sonomicrometers in eight anesthetized, open-chest dogs. The locations of the wall thickening measurements relative to the perfusion boundary (PB) were determined with myocardial blood flow (microspheres) maps constructed from multiple, small tissue samples. In nonischemic myocardium more than 10 mm from the PB produced by circumflex coronary occlusion, dWT increased significantly from 2.57 +/- 0.62 (mean +/- SD) to 3.24 +/- 0.73 mm (P less than 0.01). Within 10 mm of the PB, however, dWT did not change significantly (2.48 +/- 0.79 to 2.38 +/- 0.66 mm, NS). When the aorta was mechanically constricted, peak systolic pressure increased approximately 50%. Wall thickening decreased to the same relative degree in nonischemic muscle less than 10 mm and more than 10 mm from the perfusion boundary. By fitting sigmoid curves to the data, we estimated the extent of nonischemic dysfunction. It averaged 26 +/- 6 degrees (6-8 mm of endocardial circumference) during coronary occlusion alone and it was not significantly different (29 +/- 11 degrees) after aortic constriction. Thus elevated afterload affects nonischemic myocardium uniformly and does not increase the size or relative severity of the functional border zone.

Changes in contractility fail to alter the size of the functional border zone in anesthetized dogs.

The functional border zone is nonischemic myocardium that exhibits reduced function adjacent to an ischemic area. To determine if the functional border zone can be modified by pharmacologic interventions that alter contractility, we infused isoproterenol (0.04-0.10 micrograms/kg/min) or administered propranolol (2 mg/kg) during circumflex coronary occlusion in nine anesthetized, open-chest dogs. We measured systolic wall thickening on both sides of the perfusion boundary, which was delineated with myocardial blood flow (microsphere) maps constructed from small tissue samples. By fitting sigmoid curves to the composite systolic wall thickening data after coronary occlusion, we modeled the distribution of functional impairment across the perfusion boundary. Defined as the distance from the perfusion boundary to 97.5% of the nonischemic asymptote of the sigmoid fits, the functional border zone was 31 degrees of circumference after coronary occlusion alone. Isoproterenol increased +dP/dt by 58% and augmented nonischemic systolic wall thickening without changing the lateral extent of the functional border zone (32 degrees). Propranolol reduced +dP/dt by 24% and depressed nonischemic systolic wall thickening, but the size of the functional border zone remained limited to 28 degrees. Within the functional border zone, wall thickening was significantly but only moderately reduced (-28%) compared with thickening in nonischemic myocardium more than 10 mm away from the perfusion boundary. The ratio of nonischemic border zone to central nonischemic area wall thickening remained the same with each intervention. We conclude that the dimensions of the functional border zone are fixed early after coronary occlusion and that inotropic interventions do not modify the extent or relative severity of nonischemic regional dysfunction.

The distribution of functional impairment across the lateral border of acutely ischemic myocardium.

To evaluate the degree and lateral extent of dysfunction in nonischemic myocardium adjacent to ischemic muscle, we measured systolic wall thickening with sonomicrometers during circumflex coronary occlusion in 12 anesthetized, open-chest dogs. The locations of the wall thickness measurements relative to the perfusion boundary were determined with myocardial blood flow (microspheres) maps constructed from multiple, small tissue samples. Five minutes after circumflex occlusion, systolic wall thickening in the central ischemic zone decreased from 3.00 +/- 0.61 (mean +/- SD) mm to -0.61 +/- 0.36 mm (P less than 0.01). In nonischemic myocardium greater than 10 mm from the perfusion boundary, systolic wall thickening increased from 2.56 +/- 0.57 to 3.24 +/- 0.72 mm (P less than 0.01). In nonischemic myocardium within 10 mm of the perfusion boundary, systolic wall thickening was slightly but significantly reduced compared with control (2.72 +/- 0.80 to 2.44 +/- 0.79 mm, P less than 0.05), supporting the concept of regional dysfunction in nonischemic myocardium at the lateral borders of an ischemic area. Sigmoid curves were fitted to the data to model changes in wall thickening as a continuous function of distance from the perfusion boundary. This allowed estimation of the extent of dysfunction into nonischemic myocardium which averaged less than 8 mm (approximately 30 degrees of endocardial circumference) at one border. The level of functional impairment in this zone was relatively modest, and systolic wall thickening in the immediate border area was reduced more than 50% from control only in tissue characterized by a blood supply of mixed ischemic and nonischemic origin. We conclude that a functional border zone exists lateral to an acutely ischemic area, but measurement of regional function produces relatively small exaggeration of the size of the acutely ischemic zone if severe reduction in mechanical performance is used to define the extent of the ischemic area.

The functional border zone in conscious dogs.

Studies focusing on the functional border zone have been performed largely with anesthetized, open-chest preparations. Therefore, we instrumented 14 dogs at sterile surgery with sonomicrometers arrayed to measure systolic wall thickening across the perfusion boundary produced by circumflex coronary occlusion. We fitted sigmoid curves to the data to model the distribution of wall thickening impairment as a function of distance from the perfusion boundary, which was delineated with myocardial blood flow (15 micron diameter microspheres) maps. Using this approach, we defined the functional border zone as the distance from the perfusion boundary to 97.5% of the sigmoid curve's nonischemic asymptote. The lateral extent of the functional border zone, measured 10 min and 3 hr after occlusion, was 32 and 28 degrees of circumference, respectively. To evaluate the severity of nonischemic dysfunction, we measured average systolic wall thickening within the functional border zone. It was reduced from 3.69 +/- 1.10 (mean +/- SD) mm to 2.98 +/- 1.07 mm (p less than .01) and 2.74 +/- 1.12 mm (p less than .01) early and late after coronary occlusion. Thus, a narrow functional border zone was evident during circumflex coronary occlusion in conscious dogs. Its lateral extent was limited to approximately 30 degrees (similar to findings in open-chest, anesthetized dogs), severe dysfunction was restricted to the immediate vicinity of the perfusion boundary, and the average severity of nonischemic dysfunction within the functional border zone was mild.

Dissociation between epicardial and transmural function during acute myocardial ischemia.

The relationship between epicardial and transmural function (measured with sonomicrometers) was examined in 13 anesthetized open-chest dogs. Systolic wall thickening was used as a standard of integrated transmural function to compare with epicardial function measured as segment shortening parallel to surface fibers. Three levels of coronary inflow restriction were produced by using decrements in systolic wall thickening as an index of changes in the transmural distribution of myocardial blood flow (microspheres) in myocardium perfused by the left anterior descending artery (anterior-apical group, n = 7) or circumflex artery (posterior-basal group, n = 6). Levels 1 and 2 were characterized by reductions in systolic wall thickening of 35% and 80%, respectively, and marked decreases in deep myocardial blood flow. In the subepicardium, myocardial blood flow was minimally affected at levels 1 and 2 and there was no change in posterior-basal epicardial segment shortening, but anterior segment shortening decreased significantly (by 21% and 37%, respectively). At level 3 myocardial blood flow was reduced transmurally, producing systolic wall thinning and marked epicardial dysfunction in both groups. Parallel epicardial segment shortening underestimated the extent of transmural dysfunction in both groups at levels 1 and 2 but the degree of underestimation was greatest in the posterior-basal group. Anterior-apical segment shortening was impaired at levels 1 and 2, whereas posterior-basal segment shortening was unaffected, suggesting that significant regional variability exists in the epicardial response to nontransmural ischemia.