Cardiovascular and adrenaline-releasing effects of the 5-HT1A receptor agonist 8-hydroxy-2-(DI-N-propylamino) tetralin in streptozotocin diabetic rats
Laboratoire de Pharmacologie, CNRS, CHU Necker-EM, Paris, France.Life Sciences (Impact Factor: 2.7). 02/1991; 48(26):2543-52. DOI: 10.1016/0024-3205(91)90610-N
The 5-hydroxytryptamine1A (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) has been reported to trigger sympathoinhibition, as evidenced by its cardiovascular effects, and adrenal catecholamine secretion. The purpose of this study was to analyze the cardiovascular and adrenaline-releasing effects of 8-OH-DPAT in 1 week streptozotocin diabetic rats. 8-OH-DPAT-induced changes in mean arterial pressure (MAP) and heart rate (HR) were determined directly in anesthetized rats, whilst changes in plasma adrenaline (and plasma corticosterone and glucose) levels were analyzed in conscious rats. Resting blood pressure and heart rate were diminished in diabetics, when compared with controls. These changes were associated with a decrease in body weight and a marked increase in resting plasma glucose levels. Diabetes did not affect MAP response to 8-OH-DPAT, except for a decrease in the amplitude of MAP maximal fall, which was associated with a diminished bradycardic response to 8-OH-DPAT. Blood pressure response to prazosin (0.5 mg/kg) in 8-OH-DPAT-pretreated rats was also diminished in diabetics. Lastly, diabetes prevented the adrenaline-releasing and hyperglycemic effects of 8-OH-DPAT (250 ug/kg).
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ABSTRACT: The present review tries to delineate some mechanisms through which the sympathetic nervous system (SNS) and the hypothalamo-pituitary-adrenal (HPA) interact with central serotonergic systems. The recent progress in 5-hydroxytryptamine (5-HT) receptor pharmacology has helped to define the means by which central serotonergic activity may alter the respective activities of the SNS (sympathetic nerves and adrenomedulla) and of the HPA axis. These pharmacological findings have also helped to characterize the differential effects of central 5-HT upon different branches of the SNS and the numerous sites at which 5-HT exerts stimulatory influences upon the HPA axis. Although relevant to stress-related neuroendocrinology, the extent to which these interactions are involved in the antidepressant/anxiolytic properties of some serotonergic agents still remains to be clarified. Beside these findings, there is also abundant evidence for a tight control of central serotonergic systems by stress hormones. Activation of the SNS increases, by numerous means, central availability of tryptophan, whereas glucocorticoids exert differential actions upon the intra- and the extraneuronal regulation of 5-HT function. Actually, a significant number of these mechanisms is involved in the maintenance of homeostasis during stressful events, thereby conferring to these mechanisms a key role in adaptation processes.
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ABSTRACT: Cardiac autonomic neuropathy is a common complication in insulin dependent diabetes mellitus. Nevertheless, little is known about when this impairment occurs during the time course of the disease. Analysis of blood pressure (BP) and heart rate (HR) variability could be used to detect early signs of autonomic alteration. To test this proposal, twelve sexually mature male Yucatan miniature pigs were equipped with an arterial catheter for telemetric BP analysis, and with a venous access. BP and HR were recorded together with respiratory movements while the animals were resting in a sling. After the first recording session performed when the pigs were 5 months old, streptozotocin (STZ) was used to induce diabetes in seven pigs, while the five others were controls. BP and HR were measured 3 and 6 months after the onset of diabetes and at a similar age in the controls. BP and HR oscillated at the respiratory range (0.19 Hz). Spectral analysis showed this respiratory component was the main determinant of the short-term variability of BP and HR. Atropine increased HR and BP and markedly diminished the respiratory sinus arrhythmia. Propranolol diminished HR and the respiratory peak of HR. A reduced respiratory oscillation of BP paralleled the diminution of the respiratory peak of HR. Baroreceptor-HR reflex was estimated using injections of phenylephrine and nitroprusside, and by cross-spectral analysis between BP and HR. Atropine shifted the curve to higher HR values, while propranolol reduced the level of the upper plateau. Atropine decreased both the coherence and gain of the cross-spectral analysis. STZ injection resulted in a type 1 diabetes. At 3 months, diabetic pigs exhibited low levels of BP and a reduced overall variability of HR and BP. Spectral analysis indicated the respiratory sinus arrhythmia was markedly reduced. In addition, the sensitivity of the baroreceptor-HR reflex was reduced. At a latter stage of diabetes these alterations were marked and the level of the resting HR was increased. These data demonstrate the dual (vagal and sympathetic) control of HR in pigs and the dominant role of respiration in the genesis of HR and BP fluctuations. The spectral and cross-spectral analysis of BP and HR were altered after 3 months of diabetes and could be proposed as early detectors of cardiac autonomic neuropathy.
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