In vivo cardiovascular reactivity and baroreflex activity in diabetic rats.
OBJECTIVE
Abnormalities of the cardiovascular system, e.g. impaired vasoreactivity and changes in baroreflex control of heart rate, are known to occur in experimental diabetes. It is not clear whether these cardiovascular dysfunctions are direct consequences of cardiovascular deficits and/or have autonomic neuropathy as a cause.


METHODS
To differentiate between cardiovascular deficits or neuronal impairment as a cause for these cardiovascular dysfunctions, we tested the effects of the ACTH4-9 analogue, Org 2766, a neurotrophic compound without cardiovascular effects, on arterial pressure, heart rate and baroreflex control of heart rate. At 15 weeks, rats were made diabetic by injection of streptozotocin, and from 0-6, 6-12 or 12-18 weeks thereafter 3 groups of rats were treated with Org 2766. These effects were evaluated during phenylephrine-induced increases, and sodium nitroprusside-induced decreases, in blood pressure, in rats that had been diabetic for various periods (2-42 weeks).


RESULTS
Throughout, both depressor response and maximal vasodilator activity in response to sodium nitroprusside were significantly (P < 0.05) reduced as compared to those of the non-diabetic controls. The pressor response of the diabetic rats to phenylephrine was only significantly (P < 0.05) reduced at 4, 6 and 12 weeks, and at 18 weeks, the diabetic rats were either hypo- or normoresponsive; Org 2766 did not restore the disturbed pressor response. From weeks 4 to 42 both maximal decrease in heart rate and sensitivity of baroreflex-mediated bradycardia in the diabetic rats were significantly less (P < 0.05) than those in the non-diabetic controls. Org 2766 restored the diminished baroreflex-mediated bradycardia of diabetic rats to non-diabetic control levels at 6 weeks, had an ameliorating effect at 12 weeks and no effect at 18 weeks.


CONCLUSIONS
Time-dependent decreases in baroreflex sensitivity in diabetic rats was demonstrated and a much less steep decline of baroreflex sensitivity occurred in non-diabetic control rats. The ACTH4-9 analogue, Org 2766, when given immediately upon the induction of diabetes seem to delay the development of autonomic neuropathy, which suggests that cardiovascular factors appear to be of minor importance.
Van Buren
T
T
Department of Medical Pharmacology, Rudolf Magnus Institute for Neurosciences, Medical Faculty, Utrecht University, Netherlands.
Kasbergen
C M
CM
Gispen
W H
WH
De Wildt
D J
DJ
D000324:Adrenocorticotropic Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D017704:Baroreflex / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D000927:Anticonvulsants; D010446:Peptide Fragments; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D010656:Phenylephrine; C013765:Org 2766; D000324:Adrenocorticotropic Hormone