Intrathecal administration of a substance P receptor antagonist: studies on peripheral and central nervous system hemodynamics and on specificity of action.

Regional central nervous system and peripheral hemodynamic effects of the intrathecal (i.t.) administration of a substance P (SP) receptor antagonist, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-substance P ([D-Arg]-SP), were studied in anesthetized rats. It was found that [D-Arg]-SP (3.3 nmol i.t.) reduced mean arterial pressure and cardiac output due to a reduction in stroke volume. Total peripheral resistance was not altered. Whereas most vascular beds showed no alterations in vascular resistance, a renal vasoconstriction was noted. The hypotensive effect of [D-Arg]-SP was blocked by phentolamine (10 mg/kg i.v.) but not by propranolol (1 mg/kg i.v.). In the absence of changes in vascular arterial resistance due to [D-Arg]-SP, it appears that a change in venous return may contribute to the [D-Arg]-SP-induced reduction in stroke volume. These data provide evidence that a spinal cord SP system may tonically affect sympathetic neurons controlling venous, but not arterial, vasomotor tone. [D-Arg]-SP (i.t.) did not alter brain blood flow but significantly decreased blood flow in the thoracolumbar spinal cord 15 to 20 min after administration. The reduction in spinal cord flow did not appear to be responsible for the [D-Arg]-SP-induced hypotension because kainic acid (i.t.), an agent that interacts with glutamate receptors, produced similar pressor responses in the presence and absence of [D-Arg]-SP. In addition, whereas the pressor effect of low doses of a SP agonist [pGlu5, MePhe8, MeGly9]-substance P (5-11) were blocked by [D-Arg]-SP, a higher dose produced the typical pressor effect.(ABSTRACT TRUNCATED AT 250 WORDS)