Hemodynamic responses induced by modulation of the nitric oxide system and mitochondrial permeability in the medullary cardiovascular nuclei of rats

In acute experiments on normotensive rats and those with genetically determined hypertension (urethane anesthesia), we studied hemodynamic effects resulting from modulation of the activities of neuronal NO synthase (NOS-1), arginase II, and superoxide dismutase, and also of the mitochondrial permeability in medullary cardiovascular neurons. Unilateral microinjections of either a nitric oxide (NO) donor, sodium nitroprusside, or a substrate for endogenous NO synthesis, L-arginine, into the medullary cardiovascular nuclei (nucl. tractus solitarius, NTS, nucl. ambiguous, AMB, paramedian nucleus, PMn, and lateral reticular nucleus LRN) were shown to induce hemodynamic responses with rather similar dynamics in both normotensive and spontaneously hypertensive rats, although in the latter the reactions were more intense. Injections of an antagonist of NOS-1, N^G nitro-L-arginine (L-NNA), into the medullary nuclei under study in spontaneously hypertensive rats resulted in shifts of the systemic arterial pressure (SAP), which did not differ dramatically from those observed in normotensive animals. The data obtained serve as the background for the suggestion that the functional activity of NOS-1 is not fundamentally impaired under hypertension conditions, but, probably, the amount of the substrate for adequate synthesis of NO via the NO-synthase pathway of metabolism of L-arginine is insufficient. Considering this, we examined the functional activity of arginase, an enzyme that also, similarly to NOS, uses L-arginine for metabolic transformation. Injections of antagonists of arginase, norvaline or α-difluoromethylornithine hydrochloride (DFMO), into populations of the medullary neurons under study induced similar shifts of the SAP in normotensive and spontaneously hypertensive rats, and those responses did not differ significantly from the effects of inhibition of the NOS-1 activity. Thus, both the above-mentioned enzymes are potentially active in normotensive and spontaneously hypertensive rats; so, a possibility for their competition for L-arginine in certain situations does exist. Modulation of the mitochondrial permeability in medullary cardiovascular neurons in normotensive and spontaneously hypertensive rats induced significant hemodynamic effects. In particular, an increase in the mitochondrial permeability in the medullary cardiovascular nuclei by injections of an inductor of mitochondrial permeability transition pore (mPTP) opening, phenylarsine oxide (PAO), was accompanied by SAP drops in both normotensive and spontaneously hypertensive rats; the effects were dose-dependent and, in some cases, irreversible. A decrease in the mitochondrial permeability in the neurons under study by injections of an inhibitor of mPTP, melatonin, induced mostly hypertensive responses, although in some experiments we observed hypotensive and two-phase responses. Neirofiziologiya/Neurophysiology, Vol. 39, No. 3, pp. 232–244, May–June, 2007.