iV-Methyl-D-Aspartate Receptor Antagonist MK-801 in Conscious Rats

Evidence from microinjection studies in anesthetized rats suggests that central excitatory amino acid pathways using A'-methyl-D-aspartate receptors are involved in the regulation of the cardiovascular system. To test the hypothesis that these pathways are tonically involved in the maintenance of or the baroreceptor reflex regulation of cardiovascular function, we have examined the effects of intravenous injection of the centrally acting, noncompetitive Nmethyl-o-aspartate receptor antagonist (+)-5-methyl-10,ll-dihydro-5H-dibenzo[a,d]cyclohepten5,10-imine (MK-801), on the mean arterial pressure, heart rate, renal sympathetic nerve activity, and behavior of conscious, freely moving sham-operated and sinoaortic baroreceptordenervated rats. Administration of MK-801 produced, within 5 minutes, dose-dependent elevations in mean arterial pressure, heart rate, and renal sympathetic nerve activity that were sustained for 0.5 to 2.5 hours. For an equivalent dose, MK-801 produced approximately twice the peak changes in mean arterial pressure and heart rate in the sinoaortic baroreceptordenervated rats than in the sham-operated rats. Pretreatment results were as follows: 1) The ganglion blocker chlorisondamine markedly attenuated the hypertension and tachycardia in the sham-operated and sinoaortic baroreceptor-denervated rats, 2) pretreatment with the a,adrenergic receptor antagonist prazosin virtually abolished the hypertension, and 3) the /3,-adrenergic receptor antagonist atenolol markedly reduced the tachycardia. MK-801 also produced stereotypic behaviors and ataxia in the sham-operated and sinoaortic baroreceptordenervated rats; however, qualitatively and quantitatively similar changes in behavior were induced in the latter by doses approximately five times lower than required in the shamoperated rats. We conclude that 1) the MK-801-induced hypertension and tachycardia appear to result largely from centrally mediated sympathoexcitatory actions rather than only by inhibition of the baroreceptor reflex; 2) the cardiovascular changes produced by MK-801 may, in part, result from the behavioral excitation; and 3) tonically active excitatory amino acid pathways using A'-methyl-D-aspartate receptors appear to be involved in the regulation of autonomic function. (Hypertension 1989; 13:759-765)