Effect of calcitonin gene-related peptide receptor antagonism on the systemic blood pressure responses to mechanistically diverse vasomodulators in conscious rats.
The effects of calcitonin gene-related peptide (CGRP) receptor antagonism with CGRP 8-37 on blood pressure changes evoked by the intravenous administration of the vasoactive modulators angiotensin II, phenylephrine, adenosine, nitroglycerine, and sodium nitroprusside were assessed in conscious rats. The effects of sumatriptan and dihydroergotamine on the blood pressure responses evoked by these vasomodulators also were assessed. The intravenous test dose of CGRP 8-37 was validated through block of depressor responses to intravenous CGRP in conscious rats, whereas the intravenous test doses of sumatriptan and dihydroergotamine were validated by reductions in carotid blood flow in anesthetized rats. CGRP 8-37 had no significant effects on blood pressure dose-response profiles and individual dose blood pressure responses to any of the vasomodulators tested. In contrast, sumatriptan altered the blood pressure dose-response profiles to angiotensin II and sodium nitroprusside (P < 0.03) and dihydroergotamine altered the blood pressure dose-response profile to sodium nitroprusside (P < 0.02) and tended to alter that of phenylephrine (P = 0.06). Both sumatriptan and dihydroergotamine displayed frequent alterations of individual dose blood pressure responses to all vasomodulators. These findings are consistent with concerns for sumatriptan and dihydroergotamine to alter systemic hemodynamics, whereas CGRP receptor antagonism did not display the same hemodynamic liability.
Lynch
Joseph J
JJ
Department of Central Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA. joseph_lynch@merck.com
Detwiler
Theodore J
TJ
Kane
Stefanie A
SA
Regan
Christopher P
CP
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D004087:Dihydroergotamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D018170:Sumatriptan / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D010446:Peptide Fragments; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C058636:calcitonin gene-related peptide (8-37); D004087:Dihydroergotamine; D018170:Sumatriptan; D015740:Calcitonin Gene-Related Peptide