Biomedical subjects
Publications and source records attributed to M Korth.
Saccadic eye movements were examined by means of infrared reflection oculography in 8 patients having myotonic dystrophy and in 65 control subjects. In 7 patients typical alterations of the saccades could be observed. In comparison with the normal controls the saccades were significantly hypometric, of longer duration, of lower peak velocity, and showed a typical pattern of velocity and acceleration.
The typical pattern-onset-offset stimulus (stimulus A) consisting of local luminance increases and decreases was broken down into stimuli presenting only local luminance increases (stimulus B) or only local luminance decreases (stimulus C). With stimulus B the onset ERGs are luminance responses. With stimulus C the onset ERGs are pattern-related responses showing a spatial band-pass function. With stimulus A the response is a linear addition of responses to stimuli B and C. The simultaneously recorded VEP is a pattern-related response with all three stimuli (A-C).
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Recent studies suggest that inhibition of Na+,K(+)-ATPase may contribute to the positive inotropic action of the imidazopyridine sulmazole. Therefore, we investigated the effect of sulmazole and its stereoisomers and for comparison the effect of the cardioactive steroid dihydroouabain (DHO) on intracellular Na+ activity by means of Na(+)-sensitive microelectrodes. In the resting papillary muscle of the guinea pig, (+/-)-sulmazole increased intracellular Na+ activity (aiNa) within 15-20 minutes by 0.5 +/- 0.1 (n = 3), 1.3 +/- 0.1 (n = 7), 2.7 +/- 0.2 (n = 6), and 4.9 +/- 0.5 (n = 6) mM at 60, 100, 300, and 1,000 microM, respectively. (+)-Sulmazole was more effective than the racemate; aiNa was increased by 1.2 +/- 0.3, 2.1 +/- 0.3, and 4.0 +/- 0.2 mM at 60, 100, and 300 microM, respectively (n = 2 for each concentration). In the contracting papillary muscle (0.2 Hz), (+)- and (+/-)-sulmazole (600 and 1,000 microM) produced a maximum positive inotropic effect that exceeded that of DHO by 11% and 8%, respectively. As an inotropic agent, (+)-sulmazole was almost twice as potent as the racemate. The maximum direct inotropic effect of (-)-sulmazole (1,000 microM) amounted to only 14% of the DHO maximum and was, in contrast to the racemate and (+)-sulmazole, antagonized by 3 microM carbachol. (-)-Sulmazole did not affect aiNa.(ABSTRACT TRUNCATED AT 250 WORDS)
1. The effect of carbachol on force of contraction, contraction duration, intracellular Na+ activity and cyclic AMP content was studied in papillary muscles of the guinea-pig exposed to isoprenaline or the phosphodiesterase inhibitor 3-isobutyl, 1-methyl xanthine (IBMX). The preparations were obtained from reserpine-pretreated animals and were electrically driven at a frequency of 0.2 Hz. 2. Isoprenaline (10 nM) and IBMX (100 microM) produced comparable positive inotropic effects of 9.8 and 9.7 mN, respectively. Carbachol (3 microM) attenuated the inotropic effects by 82% (isoprenaline) and by 79% (IBMX). The shortening of contraction duration which accompanied the positive inotropic effect of isoprenaline (by 14.9%) and of IBMX (by 22.4%) was not significantly affected by 3 microM carbachol. 3. The positive inotropic effect of 10 nM isoprenaline and of 100 microM IBMX was accompanied by an increase in cellular cyclic AMP content of 58 and 114%, respectively. Carbachol (3 microM) failed to reduce significantly the elevated cyclic AMP content of muscles exposed to either isoprenaline or IBMX. 4. In the quiescent papillary muscle, isoprenaline (10 nM) and IBMX (100 microM) reduced the intracellular Na+ activity by 28 and 17%, respectively. This decline was not influenced by the additional application of 3 microM carbachol. 5. The results demonstrate that muscarinic antagonism in guinea-pig ventricular myocardium exposed to cyclic AMP-elevating drugs is restricted to force of contraction. The underlying mechanism does not apparently involve the cytosolic signal molecule cyclic AMP.
The spatial distribution of intracellular Ca2+ concentration was determined by fluorescent digital imaging microscopy in fura-2-loaded quiescent cardiac myocytes isolated from guinea pig ventricle. Fluorescent ratio images revealed discrete as well as clustered bright fluorescent spots ("hot spots"), which occupied approximately 20-50% of an individual cell's area. The fluorescent intensity and the area of the hot spots were increased by agents that deplete Ca2+ in the sarcoplasmic reticulum, namely, ryanodine (20-40 nM) and caffeine (5-15 mM). However, when cells were exposed to agents that deplete mitochondrial Ca2+, such as the protonophore, carbonyl cyanide m-chlorophenyl-hydrazone (CCCP, 100-300 nM), or the inhibitor of electron transport, antimycin A (4-40 nM), the fluorescent intensity and the area of the hot spots were reduced. These results indicate that the spatial distribution of intracellular Ca2+ concentration in the ventricular myocytes of guinea pig is quite heterogeneous. The ability of CCCP and antimycin A, but not of caffeine and ryanodine, to reduce the fluorescent intensity in the hot spots implies that Ca2+ compartmentation in the mitochondria is largely responsible for the intracellular Ca2+ heterogeneity seen in the present study.
Pattern-onset ERGs obtained with color contrast (red-green, blue-yellow) and luminance contrast (green "black") square-wave-stripe patterns (spatial frequency 0.3 c/deg, 32 degree field) were studied in larger groups of normal and glaucomatous (chronic open-angle glaucoma) eyes. Colored stimuli were generated in a two-channel Maxwellian-view system using grating monochromators. In producing isoluminant lights of different colors, the peak latency of the response was used as a criterion. Luminance-contrast responses always have significantly smaller amplitude and shorter peak latency than color-contrast responses. This can be explained by the smaller number and shorter latency of the non-color-coded phasic anglion cells and by the larger number and longer latency of the color-coded tonic cells. Glaucomatous eyes respond with significantly smaller amplitudes at all contrast conditions tested; however, this response reduction is most pronounced with red-green patterns. Peak latencies are not significantly altered in glaucomatous eyes. Since red-green patterns are most appropriate in showing glaucoma damage in the pattern ERG, the largest absolute losses seem to occur among the large red-green antagonistic group of ganglion cells.
The pattern-evoked electroretinogram was recorded to pattern onset-offset and pattern reversal stimuli in two color-normal subjects with either luminance contrast of black-red (600 nm) and black-green (526 nm) square-wave stripe patterns or color contrast red-green patterns. The size of the onset response shows a spatial tuning with luminance contrast patterns and only a simple low-pass filter function with color contrast patterns. The peak latency of the response to luminance contrast increases with increasing spatial frequency but stays constant with color contrast patterns. The size of the reversal responses, however, shows only a low-pass filter function under both contrast conditions. The peak latency to luminance contrast shows a slight increase and to color contrast it remains constant with increasing spatial frequency. The differences noted under the various stimulus conditions must take into account the possible effects of different luminance modulation depths of onset and reversal stimuli, the modulation transfer function of the eye, and the activity of luminance-antagonistic and color-antagonistic receptive fields.
Pattern-onset electroretinograms (PERGs) were studied in 147 normal subjects of different ages (14-79 years) and in 110 eyes of 65 patients with glaucoma or ocular hypertension. The responses showed an increase (P less than 0.001) in peak latency with increasing age and a decrease (P less than 0.001) in amplitude which approximately parallels the loss of ganglion cells estimated by other authors. Many glaucoma eyes showed a loss of the normally present spatial tuning. In the age group above 50 years 50% of the onset responses were significantly diminished and the peak latencies were not significantly different. A negative correlation (P less than 0.001) was found between the size of the PERG and the cup/disc ratio and a positive correlation (P less than 0.001) with the area of the neuroretinal rim of the optic disc. The PERG decreased (P less than 0.01) with increasing visual field losses.
The spatial contrast sensitivity (CS) to static patterns was tested in the central retina of 156 normal subjects. It showed a decrease above 50 years of age at all spatial frequencies tested which was slightly more pronounced in females than in males. The spatial CS was also studied in 32 glaucoma eyes: Small reductions were found only in the group below 50 but not in eyes of patients above 50. The spatiotemporal CS to phase-reversing patterns was tested in four retinal quadrants of 99 normal subjects. It showed no age dependence in males whereas in females it decreased significantly beyond 50 years at all spatial frequencies tested. The spatiotemporal CS was studied also in 21 glaucoma eyes: Strong losses were again noted only in patients below 50. Spatiotemporal CS losses and perimetric losses were also compared in the four quadrants: For both measures the severest losses were found in the lower nasal and the mildest in the upper temporal quadrant. The spatiotemporal CS test of the peripheral retina seems to be a more powerful tool in glaucoma research than the spatial CS test of the central retina; however, effects of age and gender have to be considered.
Previous studies on color vision using the electroretinogram or the evoked potential have concentrated only on brightness and hue but not on the saturation of color. In the present investigation patterns of alternate stripes of a highly saturated color and a totally desaturated color (= white) of equal brightness were presented in the pattern-reversal mode. It can be demonstrated that the reading obtained is in agreement with psychophysical saturation scale data of earlier investigators.
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The effect of carbachol on free intracellular calcium concentration, ([Ca2+]i) and on intracellular hydrogen concentration (pHi) was determined from fluorescence signals obtained from rat ventricular myocytes. Application of carbachol (300 mumol/l) to quin2-loaded myocytes bathed in 2 mmol/l Ca2+-containing solution caused [Ca2+]i to increase within 7-10 minutes from 182 +/- 9 to 212 +/- 11 nmol/l (n = 4). Carbachol acted via stimulation of muscarinic receptors because atropine (1 mumol/l) either prevented or abolished the increase in [Ca2+]i. Carbachol also produced a positive inotropic effect in rat papillary muscles contracting isometrically at a frequency of 0.5 Hz and enhanced contracture in resting preparations in the presence of high extracellular Ca2+ concentration ([Ca2+]o) (20 mmol/l). The effect of carbachol on [Ca2+]i was dependent on [Ca2+]o. In the presence of 10 mmol/l [Ca2+]o, the increase in [Ca2+]i was about two times that elicited by carbachol when bath [Ca2+]o was 2 mmol/l. Reduction of [Ca2+]o to 50 mumol/l abolished the carbachol effect but did not prevent caffeine-induced Ca2+ release. The carbachol-induced rise in [Ca2+]i remained unchanged in the presence of either 10 mmol/l caffeine or 1 mumol/l ryanodine. In the absence of extracellular Na+ concentration [( Na+]o), carbachol no longer produced an increase in [Ca2+]i of cardiomyocytes and failed to enhance Na+-withdrawal contracture of the rat papillary muscle. In contrast to the effect on [Ca2+]i, carbachol did not produce any change in pHi as determined from fluorescence signals obtained from rat ventricular myocytes loaded with 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein.(ABSTRACT TRUNCATED AT 250 WORDS)
Concentration-dependent inotropic effects of (-)-norepinephrine and of (+/-)-isoproterenol were compared in isometrically contracting guinea pig papillary muscles stimulated at a frequency of 0.2 Hz. (-)-Norepinephrine (0.1-100 mumol/l) elicited a positive inotropic effect that was not antagonized by carbachol, failed to produce a positive inotropic staircase after resumption of stimulation and shortened relaxation time in a concentration-dependent fashion.(+/-)-Isoproterenol had a dual action: at low and moderately effective concentrations (1-30 nmol/l), the positive inotropic effect was antagonized by carbachol, a positive inotropic staircase was elicited and time to peak force was shortened. At (+/-)-isoproterenol concentrations exceeding an EC80 for the positive inotropic effect (greater than 30 nmol/l), relaxation time became shorter, staircase and carbachol-induced antagonism became less pronounced until at 300 nmol/l inotropic effects of (+/-)-isoproterenol resembled closely those of (-)-norepinephrine. Cyclic AMP derivatives and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine mimicked (+/-)-isoproterenol in their inotropic actions. Impairment of neuronal uptake caused (-)-norepinephrine 1) to produce (+/-)-isoproterenol-like effects on the isometric contraction, 2) to induce a positive inotropic staircase and 3) to become sensitive to carbachol-induced antagonism. The results are compatible with the concept that neuronal uptake produces a distribution of (-)-norepinephrine within the papillary muscle which allows predominantly high concentrations of (-)-norepinephrine to become effective in the receptor compartment.(ABSTRACT TRUNCATED AT 250 WORDS)
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Pattern electroretinograms to onset-offset stimuli were studied in response to luminance-contrast (e.g. red-black or green-black) and color-contrast (e.g. red-green) stripe patterns of equal luminance. Onset responses to color-contrast patterns show no spatial selectivity and a constant peak latency at all spatial frequencies, a behavior different from that of luminance-contrast evoked responses (spatial selectivity and increasing peak latency with spatial frequency). These results are tentatively related to the physiology of tonic and phasic primate retinal ganglion cells and to the spatially selective and non-selective human contrast sensitivity to respectively luminance-contrast and color-contrast gratings.
The pattern-evoked electroretinogram (PERG) was studied in response to square-wave stripe patterns contrasting either between dark and colored stripes ("red-black" or "green-black" luminance contrast pattern) or between the two colors (red-green chromatic contrast pattern). All lights were matched in photopic luminance. A two-channel Maxwellian view system was used to present the stimuli in the onset-offset mode. When no pattern was present a mixture of both colors was seen. Different spatial frequencies were studied and the amplitudes of the onset response were evaluated. When the two luminance contrast patterns were presented, the responses showed a spatial selectivity. However the combination of the two colors (red-green contrast) resulted in a monotonic decrease of the response with spatial frequency. The spatially selective behavior of the response to luminance contrast patterns could be associated with the on-off center-surround organization of retinal receptive fields. The behavior of the response to chromatic-contrast patterns, on the other hand, could be explained by the action of color-opponent center-surround receptive fields as described in the primate.
The inotropic potencies of 8-substituted cyclic AMP analogues, applied as sodium salts and in form of benzyl esters, were determined in isolated guinea-pig papillary muscles contracting isometrically at a frequency of 0.2 Hz. Half-maximally effective concentrations, EC50, for the positive inotropic effect of 8-substituted cyclic AMP (sodium salt) increased in the order 8-(4-chloro-phenyl)thio-cyclic AMP, 8-tertiary-butyl-thio-cyclic AMP, 8-benzyl-seleno-cyclic AMP, 8-benzyl-thio-cyclic AMP, 8-methyl-thio-cyclic AMP, 8-bromo-cyclic AMP. Neutralization of the phosphate hydroxyl residue of 8-substituted cyclic AMP by a benzyl group yielded cyclic AMP benzyl esters (cAMP-O-Bn) which were 30 to 100 times more potent than the respective cyclic AMP salts. Cyclic AMP derivatives with a 8-(4-chloro-phenyl)thio- or a 8-tertiary butyl-thio substituent showed comparatively high inotropic potencies. The intrinsic activity was uniformely the same for all 8-substituted cyclic AMP derivatives and equalled that of isoprenaline. As measured by octanol/water partitioning (log P), the increase in lipophilicity of 8-substituted cyclic AMP by esterification with a benzyl group was 7000-fold for 8-bromo-cyclic AMP, 5000-fold for 8-methyl-thio-cyclic AMP, and approximately 1000-fold for the other derivatives. Within the series of benzyl esters, differences in lipophilicity were small. The positive inotropic effect of 8-substituted cyclic AMP analogues was accompanied by a shortening of contraction duration, mainly due to an abbreviation of relaxation time.(ABSTRACT TRUNCATED AT 250 WORDS)