Substance P antagonist-induced spinal cord vasoconstriction: effects of thyrotropin-releasing hormone and substance P agonists.
Local spinal cord vasomotor effects of 3 substance P (SP) antagonists were studied in the rat following intrathecal (IT) administration. Each SP antagonist (3.3 nmol) increased spinal cord vascular resistance and reduced blood flow. A LH-RH antagonist analog (10 nmol) of similar molecular weight and which also contained multiple D-Trp residues did not cause spinal cord vasoconstriction. The vasoconstrictor action of the SP antagonist, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-SP [( D-Arg]-SP) was unaffected by pretreatment with a stable SP receptor agonist (5 nmol IT). Given evidence for a cerebral vasodilator action of TRH agonists, the effects of TRH (IV) and a stable TRH analog (MK-771, IT) on [D-Arg]-SP-induced vasoconstriction were also assessed. Neither TRH nor MK-771 prevented the [D-Arg]-SP-induced vasoconstriction. However, TRH (IV) but not MK-771 (IT) partially opposed [D-Arg]-SP-induced reduction in thoracic spinal cord blood flow. Thus, SP antagonists cause spinal cord vasoconstriction by a non-SP receptor mediated phenomenon. In addition, the attenuation of SP-antagonist-induced neuropathological changes previously reported with IV. TRH administration is likely due to less severe consequences of vasoconstriction in the presence of a higher initial baseline blood flow rather than direct prevention of the vasoconstriction.
Helke
C J
CJ
Department of Pharmacology, Uniformed Services University of Health Sciences, Bethesda, MD 20814-4799.
Phillips
E T
ET
D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D008969:Molecular Sequence Data; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects; D013116:Spinal Cord / Q000098:blood supply*; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D013373:Substance P; D013973:Thyrotropin-Releasing Hormone