Cardiac reflex activity in chemically sympathectomized dogs in response to hypotension or hypertension.
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Biomedical subjects
Publications and source records attributed to J de Champlain.
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Coronary patients exercised on an ergometric bicycle before and after physical training. Plasma catecholamines were sampled simultaneously at the arterial and coronary sinus levels and assayed with a radioenzymatic method. The increase in the level of coronary sinus catecholamines exceeded the increase in the arterial level, indicating a liberation of catecholamines by the myocardium and an activation of the peripheral sympathetic fibers during exercise. With high work loads, these values no longer differed, suggesting that the additional increase in circulating catecholamines originate from extra-myocardial stores, presumably the adrenal medulla. Arterial catecholamine levels were significantly correlated with work loads, heart rate, changes in systolic blood pressure, and rate-pressure product. After physical training, arterial catecholamine increases for various work loads were lower; these lower elevations were associated with diminished responses in heart rate and systolic blood pressure, resulting in a lower rate-pressure product. Physical training results in diminished sympathetic responses for a given level of exercise, which could be associated with the clinical improvement of these patients.
The effect of phenoxybenzamine (PBA), desmethylimipramine (DMI), clonidine (CLND), sotalol (STL), and isoproterenol (ISPR) on the release of endogenous norepinephrine (NE) from the heart on right cardioaccelerator nerve stimulation was studied in anesthetized dogs. Under control conditions, the catecholamine levels in coronary sinus blood increased linearly with increasing frequencies of stimulation up to 10 Hz and did not increase further at 30 Hz. The release of NE was markedly enhanced after PBA (1 mg/kg, iv) and DMI (1 mg/kg, iv). The enhanced release of NE after DMI, but not after PBA, was associated with a prolonged response in heart rate. In contrast, NE release was reduced after CLND (15 microgram/kg, iv) at stimulation frequencies of 1 and 2 Hz and this was associated with reduced responses in heart rate and left ventricular dtp/dt. STL (5 mg/kg, iv) reduced significantly the release of NE at stimulation frequencies of 1-5 Hz, whereas ISPR enhanced NE outflow at frequencies of 1-4 Hz. These results support the existence of both negative and positive feedback mechanisms on the release of norepinephrine by cardiac sympathetic fibers mediated through presynaptic alpha- and beta-adrenoreceptors, respectively. The functional significance of these mechanisms is also suggested by the correlation found between changes in NE release and variations in cardiac responses under the various drug treatements.
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The effect of 6-hydroxydopamine (6-OH-dopamine) and of a cholesterol rich diet on the plasma and aortic cholesterol of female rats were studied. Both the diet and the 6-OH-dopamine produced an important increase in plasmatic and aortic cholesterol. A synergistic effect of these two treatments was observed on the plasma but not on the aortic cholesterol. The mechanism by which 6-OH-dopamine produces hypercholesterolemia and a increase in aortic cholesterol remains to be explained.
The radiometric enzymatic technique of Coyle and Henry (J. Neurochem. 21: 61-67, 1973) was adapted to the measurement of serum catecholamines. This technique requires less time than other enzymatic techniques and is sensitive to quantities as small as 25 pg. In normotensive subjects lying supine for 20 minutes serum catecholamine levels averaged 0.218 ng/ml, with no obvious sex or age difference. Under these standardized conditions, the circulating catecholamine levels for a given individual are highly reproducible on different days over a period of several months. In 22 patients with essential hypertension, circulating levels were significantly higher, with an average of 0.370 ng/ml. More than 50% of the hypertensive patients had values greater than the highest value measured in normotensives. Systolic blood pressure and heart rate were significantly higher in the hypertensive group with elevated levels of circulating catecholamines than in the hypertensive group with normal levels. In one model of experimental hypertension, produced in the rat by administration of deoxycorticosterone acetate (DOCA) and saline for 4-8 weeks, serum catecholamines were significantly elevated. These findings suggest that the sympathetic system may play an important role in maintaining an elevated blood pressure in experimental hypertension and in a significant proportion of patients with essential hypertension.
Correlations between the concentration of endogenous catecholamines in coronary sinus blood and various physiological responses to adrenergic stimulation were studied in anesthetized dogs. Plasma catecholamine levels both in coronary sinus and aortic blood were measured by means of a modification of the radiometric-enzymatic assay for tissue catecholamines, and found to be 0.769 +/- 0.110(S.E.) and 0.972 +/-0.127(S.E.) ng/ml, respectively, under basal conditions. Circulating catecholamine levels increased after the intracoronary injection of 6-hydroxydopamine, which has an indirect sympathomimetic action. Both the increment in catecholamine release from the heart and the intensity of physiological response were dose-related. A frequency-dependent increase in coronary sinus blood catecholamine levels occurred during right cardioaccelerator nerve stimulation. Maximum values were observed with a stimulation frequency of 10 Hz, at which maximum physiological responses were obtained. A highly significant correlation was found between endogenous catecholamine levels in coronary sinus blood and the dp/dt of left ventricular pressure (r = 0.750, p less than 0.001), as well as mean coronary blood flow (r =0.706, p less than 0.001). The present preparation may prove to be a reliable means of studying the role of the sympathetic system in regulating cardiac function.
The effect of catecholamine-depleting pretreatments, reserpine, and 6-hydroxydopamine (6-OH-DA) on left ventricular pressure (LVP) and the inotropic response to graded doses of ouabain (up to 300 mug/0.05 ml) was studied in isolated perfused rat and guinea-pig hearts. In rats, reserpine and 6-OH-DA depleted the cardiac content of catecholamine, but did not increase initial LVP and did not reduce the inotropic response to the highest dose of ouabain. It is concluded that in isolated rat hearts, these catecholamine-depleting pretreatments nearly abolish the inotropic response to ouabain, and this effect appears to be mediated mainly through an increase in initial LVP. The reason why catecholamine depletion failed to increase initial LVP in guinea pigs remains unexplained.
The present study in dogs indicates that the peripheral sympathetic fibers develop mostly after birth and reach a full maturity at about 2 months of life. The norepinephrine content of the heart, spleen, intestine, salivary glands, and adrenal glands increased from birth to 56 days of age. In contrast, the content of the stellate ganglia decreased during this period. In most of the organs studied, the uptake of [3H] norepinephrine developed in parallel with the norepinephrine content, except in the right atrium and salivary glands where it was fully developed soon after birth. During development, the systemic blood pressure increased from 40 to 100 mm Hg. Bilateral adrenal vessel clamping failed to induce a fall in blood pressure in growing dogs which indicates that the adrenal medulla or the baroreceptors did not fully compensate for the lack of peripheral sympathetic fibers and for the lower blood pressure in newborn animals. Although cardiac norepinephrine content was still very low in 10-day-old animals, cardiovascular responses to direct and reflex sympathetic stimulation were similar to those observed in 56-day-old animals. These results indicate that the sympathetic nervous system becomes functional before the fibers reach their full maturity.
The relationship between the increase in catecholamine levels of the coronary sinus blood and the amplitude of various cardiac responses to adrenergic nerve stimulation was studied in anesthetized dogs. Plasma catecholamine levels in both coronary sinus and aortic blood were measured by a modification of the radiometric enzymatic assay for tissue catecholamines and were found to be 0.622 plus or minus 0.104 (SE) ng/ml and 0.933 plus or minus 0.116 ng/ml, respectively, under basal conditions. The catecholamine levels in coronary sinus blood increased linearly during right cardioaccelerator nerve stimulation up to a frequency of 10 Hz. At this frequency, maximum values were observed in both coronary sinus blood catecholamine levels and cardiac responses. The correlation between the response in heart rate, mean coronary blood flow, and dP/dt of left ventricular pressure and the increase in endogenous catecholamine levels of coronary sinus blood was significant, but the relationship was nonlinear. The present experimental design may prove to be a reliable means of studying the role of the sympathetic nervous system in the regulation of cardiovascular function in vivo.
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