Human coagulation factor XII-related "new pressor protein": role of PACAP in its cardiovascular and sympathoadrenal effects.
OBJECTIVE
To investigate the role of pituitary adenylate cyclase-activating polypeptide (PACAP)-38 and -27 as possible mediators of the actions of "new pressor protein" (NPP), which is related to coagulation factor XIIa, on blood pressure (systolic and diastolic blood pressure) and heart rate, and on the release of adrenal medullary catecholamines.


METHODS
Adult male Wistar bioassay rats (n=8 to 18 per group) were anesthetized with inactin (100 mg/kg intraperitoneally), ganglion-blocked with pentolinium (19.2 mg/kg subcutaneously) and treated with captopril (2.5 mg/kg intravenously). Human NPP was injected at 20 L plasma equivalent per approximately 300 g of rat intravenously, and both PACAPs were injected at 10 g/kg intravenously. The systolic and diastolic blood pressure and heart rate responses to all of these agonists were determined using a MacLab/8 system. Arterial plasma adrenaline and noradrenaline were determined by high performance liquid chromatography with fluorimetric detection. Responses to NPP, the PACAPs and a specific PACAP antagonist were compared to assess the PACAPs as potential mediators of the cardiovascular effects of NPP.


RESULTS
PACAP-38 mimicked the effects of NPP on systolic and diastolic blood pressure and heart rate more closely than did PACAP-27. Generally, NPP raised diastolic blood pressure and heart rate, and especially plasma adrenaline and noradrenaline, more impressively in degree and duration than that achieved by the PACAPs. The antagonism of PACAP receptors (PAC-1) significantly reduced the cardiovascular effects of NPP by 30% to 50%.


CONCLUSIONS
PACAP-38, especially, may qualify as a potential mediator of the cardiovascular and sympathoadrenal effects of NPP but incomplete inhibition of NPP activity by PAC-1 receptor antagonism and the observed differences all suggest that PACAP is not the only peptide involved. Such peptidic mediation of the effects of NPP may explain the potentiation of NPP by captopril and why NPP remains effective after cholinergic blockade. These data suggest that PACAP is involved in a novel axis between NPP, cardiac function and blood pressure that resists angiotensin-converting enzyme inhibition. Any endogenous production of NPP could raise clinically relevant issues pertaining to therapy with ACE inhibitors.
Simos
Demetrios
D
Departments of Physiology and Medicine, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Boomsma
Frans
F
Osmond
Daniel H
DH
D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001795:Blood Pressure Determination; D002319:Cardiovascular System / Q000187:drug effects; D002395:Catecholamines / Q000032:analysis / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005174:Factor XII / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D009479:Neuropeptides / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011336:Probability; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012680:Sensitivity and Specificity
C495401:ADCYAP1 protein, human; C495403:Adcyap1 protein, rat; D002395:Catecholamines; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D005174:Factor XII