adrenomedullin and iberiotoxin

Cerebrovascular dysregulation during hypotension occurs after fluid percussion brain injury (FPI) in the newborn pig owing to impaired K channel function. This study was designed to (1) determine the role of gender and K channel activation in adrenomedullin (ADM) cerebrovasodilation, (2) characterize the role of gender in the loss of hypotensive cerebrovasodilation after FPI, and (3) determine the role of gender in the ability of exogenous ADM to modulate hypotensive dysregulation after FPI. Lateral FPI (2 atm) was induced in newborn male and female newborn pigs (1 to 5 days old) equipped with a closed cranial window, n=6 for each protocol. Adrenomedullin-induced pial artery dilation was significantly greater in female than male piglets and blocked by the K(ATP) channel antagonist glibenclamide, but not by the K(ca) channel antagonist iberiotoxin. Cerebrospinal fluid ADM was increased from 3.8+/-0.7 to 14.6+/-3.0 fmol/mL after FPI in female but was unchanged in male piglets. Hypotensive pial artery dilation was blunted to a significantly greater degree in male versus female piglets after FPI. Topical pretreatment with a subthreshold vascular concentration of ADM (10(-10) mol/L) before FPI reduced the loss of hypotensive pial artery dilation in both genders, but protection was significantly greater in male versus female piglets. These data show that hypotensive pial artery dilation is impaired after FPI in a gender-dependent manner. By unmasking a gender-dependent endogenous protectant, these data suggest novel gender-dependent approaches for clinical intervention in the treatment of perinatal traumatic brain injury.

Topics: Adenosine Triphosphate; Adrenomedullin; Animals; Animals, Newborn; Arteries; Brain Injuries; Female; Glyburide; Hypotension; Male; Peptides; Potassium Channels; Sex Characteristics; Swine; Vasodilation

To examine synergistic interactions among naturally occurring vasodilators, we investigated the effects of i.v. infusion of adrenomedullin (ADM) alone and in combination with low-dose vasoactive intestinal polypeptide (VIP) or calcitonin gene-related peptide (CGRP) on adenosine-induced vasodepression in rats. I.v. infusion of the combination of low-dose ADM (0.1 ng kg(-1) min(-1)) and VIP (3 ng kg(-1) min(-1)), as well as that of ADM (1 ng kg(-1) min(-1)) alone, significantly enhanced the vasodepressor responses to bolus i.v. doses of adenosine (3-100 microg kg(-1)), but not those to acetylcholine (0.1 microg kg(-1)). The observed potentiation did not occur in the presence of glibenclamide (20 mg kg(-1) i.v.), an antagonist of K(ATP) channels. Simultaneous i.v. infusion of low-dose ADM and CGRP (0.1 ng kg(-1) min(-1)) failed to enhance the effects of adenosine as well as acetylcholine. In the whole-cell voltage clamp experiments using single cells of the rat mesenteric artery, ADM (10(-11)-10(-7) M) as well as CGRP (10(-11)-10(-7) M) produced increases of inward current in a concentration-dependent manner. The ADM-induced current was not affected by iberiotoxin, a specific blocker of large conductance Ca2+-activated K+ channels, but suppressed markedly by glibenclamide and CGRP(8-37), a selective antagonist of CGRP1 receptors. From the results, we conclude that several naturally occurring vasodilators involving ADM synergistically interact, probably in link with K(ATP) channels, and furthermore that ADM may act, in part through CGRP1 receptor activation.

Topics: Adenosine; Adenosine Triphosphate; Adrenomedullin; Animals; Blood Pressure; Calcitonin Gene-Related Peptide; Cell Membrane; Dose-Response Relationship, Drug; Evoked Potentials; Glyburide; Heart Rate; Hypoglycemic Agents; Injections, Intravenous; Male; Membrane Potentials; Mesenteric Arteries; Muscle, Smooth, Vascular; Patch-Clamp Techniques; Peptides; Potassium Channels; Rats; Rats, Sprague-Dawley; Vasoactive Intestinal Peptide; Vasodilator Agents