Investigation of the mechanism(s) of 8-OH-DPAT-mediated inhibition of plasma insulin in spontaneously hypertensive rats

Abstract

1 Effects of the prototype selective 5-HT_1A receptor agonist, 8-hydroxy-2-(di-n-dipropylamino)tetralin (8-OH-DPAT), were studied on the glycaemia and insulinaemia in conscious spontaneously hypertensive (SH) rats concurrently with blood pressure (BP) and heart rate (HR); underlying mechanism(s) were investigated in anaesthetized and pithed SH rats and in the perfused rat pancreas. 2 Intravenous (i.v.) injections of 8-OH-DPAT (150 μg kg⁻¹, i.v.) into fasted conscious but not anaesthetized SH rats increased glycaemia; glucose-stimulated (i.v. glucose tolerance test) plasma insulin levels were significantly inhibited in both cases without significant changes in glucose tolerance. Metabolic changes were associated with prominent decreases in BP and HR. 3 No inhibitory effect of 8-OH-DPAT, 150 μg kg⁻¹ i.v., on glucose-stimulated plasma insulin was observed in pithed SH rats; in contrast, clonidine (8 μg kg⁻¹ i.v.), produced marked inhibition of insulin levels in association with glucose intolerance. Neither compound decreased BP; rather, pronounced vasopressor effects were observed. 4 In the isolated perfused pancreas of the rat, 8-OH-DPAT, at 10⁻⁸ and 10⁻⁷m, concentrations known to activate 5-HT_1A receptors in vitro, failed to modify glucose-stimulated insulin release. Inhibition (39 ± 7%) was seen only at a high concentration of 10⁻⁶ m. 5 The present data suggest that like the cardiovascular effects of 8-OH-DPAT, the inhibition of glucose-stimulated insulin release is mediated via the central nervous system. However, it is suggested that different mechanisms are involved in the cardiovascular actions and metabolic effects of 8-OH-DPAT in the SH rat; the latter are likely to reflect a consequence of activation of the hypothalamic-adrenal axis.