org-2766 and Body-Weight

Autonomic neuropathy is a common and severe complication of diabetes mellitus that leads to dysfunction of the cardiovascular system. The reduced ability to finely regulate heart rate is attributed to an impairment of cardiac parasympathetic regulation, but it is not known whether this is due to parasympathetic neuropathy and/or direct cardiac impairments. Therefore, we recorded the electrocardiogram of streptozotocin-induced diabetic rats under basal conditions and during electrical stimulation of the vagus nerve. We used the neurotrophic agent Org 2766, an adrenocorticotropic hormone [ACTH]-(4-9) analogue, to investigate the involvement of a neurogenic component in the altered vagal control of heart rate. The R-R interval was increased and atrioventricular transmission time unchanged 1 week after diabetes induction and remained so until 20 weeks. Treatment with Org 2766 could not prevent the bradycardia. After bilateral vagotomy, both diabetic and non-diabetic rats had the same R-R and P-R interval. The response of the R-R interval to electrical stimulation of the right vagus nerve was impaired, and this impairment was not reversed by Org 2766 in diabetic rats. These results suggest that neurogenic factors are of little or no importance in the impaired parasympathetic control of heart rate seen in experimental diabetes.

Topics: Adrenocorticotropic Hormone; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Efferent Pathways; Electric Stimulation; Electrocardiography; Electrophysiology; Heart; Heart Rate; Hemodynamics; Male; Peptide Fragments; Rats; Rats, Wistar; Vagus Nerve

A major side effect of cisplatin treatment is peripheral neuropathy. In the past few years we have provided evidence that the ACTH4-9 analogue ORG 2766 provides protection against this neuropathy in rats and man. In this study we investigated the development of a cisplatin-induced neuropathy and the protective and therapeutic actions of ORG 2766 in mature rats. We also studied the effects of the peptide and of growth impairment caused by food restriction on nerve conduction velocities in healthy young adult rats (not subjected to any other treatment). In the neuropathy experiment, cisplatin induced a significant decrease in sensory nerve conduction velocity (SNCV), which could be prevented by concomitant administration of ORG 2766. The SNCV of the neuropathic animals recovered to control values within 10 weeks of discontinuation of cisplatin treatment. ORG 2766 did not enhance the rate of recovery. In the young adult rats neither ORG 2766 administration nor restricted weight gain significantly influenced either the motor or the sensory nerve conduction velocity. These results validate the animal model of cisplatin-induced neuropathy.

Topics: Adrenocorticotropic Hormone; Analysis of Variance; Animals; Body Weight; Cisplatin; Disease Models, Animal; Electrophysiology; Food Deprivation; Humans; Nervous System Diseases; Neural Conduction; Neurons, Afferent; Peptide Fragments; Rats; Rats, Wistar