Selective blockade of AT1 receptor attenuates impairment of hypotensive autoregulation and improves cerebral blood flow after brain injury in the newborn pig.
BACKGROUND
Fluid percussion injury (FPI) in piglets produces vasoconstriction of pial arteries (PAs), decreases in cerebral blood flow (CBF), and impairment of hypotensive autoregulation. Two types of angiotensin II receptors, AT1 and AT2, have been identified in the brain. This study characterized the effect of pretreatment with AT1- and AT2-selective antagonists on CBF and hypotensive autoregulation after FPI.


METHODS
Fluid percussion injury was induced in chloralose-anesthetized newborn pigs equipped with closed cranial windows. CBF was determined by the radiolabeled microsphere technique.


RESULTS
Moderate and severe hypotension (71 +/- 3, 53 +/- 2, and 40 +/- 1 mmHg for normotension, moderate hypotension, and severe hypotension, respectively) elicited PA dilation without changes in CBF in sham control piglets. The AT1 antagonist ZD 7155 partially restored impaired hypotension-induced PA dilation after FPI (19 +/- 1 and 34 +/- 1 vs. 5 +/- 1 and 7 +/- 1 vs. 12 +/- 1 and 20 +/- 3% for PA dilation during moderate and severe hypotension in sham control, FPI, and FPI + ZD 7155 animals, respectively). ZD 7155 also blunted the reductions in CBF during normotension and hypotension observed in untreated animals (43 +/- 4, 38 +/- 5, and 55 +/- 3 vs. 32 +/- 4, 19 +/- 2, and 27 +/- 5% CBF reductions during normotension, moderate hypotension, and severe hypotension in untreated and pretreated animals, respectively). The AT2 selective antagonist PD 123,319 did not restore hypotension-induced PA dilation and did not prevent decreases in CBF observed during normotension and moderate and severe hypotension after FPI.


CONCLUSIONS
These data indicate that blockade of the AT1 and not the AT2 receptor diminished the reduction in hypotensive PA dilation after FPI. AT1 blockade also blunted the decrease in CBF during normotension as well as the further decrease in CBF observed during hypotension after FPI. These data suggest that AT1 receptor activation by angiotensin II contributes to cerebrovascular dysregulation during hypotension after FPI.
Department of Anesthesia, University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Dimitry
D
Baranov
William M
WM
Armstead
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001774:Blood Chemical Analysis; D001930:Brain Injuries / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D005260:Female; D006706:Homeostasis / Q000187:drug effects*; D007022:Hypotension / Q000188:drug therapy* / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008863:Microspheres; D009287:Naphthyridines / Q000627:therapeutic use; D011453:Prostaglandins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D013552:Swine; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000959:Antihypertensive Agents; D007093:Imidazoles; D009287:Naphthyridines; D011453:Prostaglandins; D011725:Pyridines; C095905:ZD 7155; C073402:PD 123319