Endothelin-A receptor blockade in porcine pulmonary hypertension.
Endothelin-1 can cause pulmonary vasoconstriction via endothelin-A (ET(A)) receptor activation. We hypothesized that ET(A) blockers (EMD 122946 and BQ 610) would reduce hypoxia-induced (HYP) but not group B streptococcal infusion (GBS)-induced pulmonary hypertension in a juvenile whole animal model. Pulmonary hypertension was created by exposing chronically instrumented piglets to HYP (n = 12) or heat-killed GBS (n = 11). ET(A) blockade was produced by increasing bolus doses of EMD122946 or BQ 610. Pulmonary arterial pressure (PAP), systemic arterial pressure (SAP), left atrial pressure, central venous pressure, and cardiac output were continuously measured. Pulmonary and systemic vascular resistance indices (PVRI and SVRI) were calculated. HYP doubled PAP and PVRI. Both ET(A) blockers decreased PAP and PVRI in a dose-dependent manner in HYP, with high doses decreasing PVRI to baseline and reducing PAP by 50%. GBS also doubled both PAP and PVRI. EMD 122946 did not change PAP or PVRI in GBS, although BQ 610 markedly increased PVRI (>100% increase with 0.15 mg/kg) and showed a trend toward increasing PAP. Both models showed minimal (<25%) changes in SAP or SVRI. Neither ETA blocker changed baseline hemodynamics in the absence of HYP or GBS. PaO(2) did not change with GBS but decreased with BQ 610. ET(A) receptor blockade attenuated hypoxic, but not GBS induced pulmonary hypertension. BQ 610 worsened PVRI and oxygenation in the GBS model. Differences in response to ET(A) blockade in pulmonary hypertension may be seen depending on the etiology (hypoxia versus infection-associated), and the specific ET(A) antagonist used.
Ambalavanan
Namasivayam
N
Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA. ambal@sprynet.com
Philips
Joseph B
JB
Bulger
Arlene
A
Oparil
Suzanne
S
Chen
Yiu-Fai
YF
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002245:Carbon Dioxide / Q000097:blood; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications; D007231:Infant, Newborn; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010100:Oxygen / Q000097:blood; D011652:Pulmonary Circulation / Q000187:drug effects; D044022:Receptor, Endothelin A; D013290:Streptococcal Infections / Q000150:complications; D013292:Streptococcus agalactiae; D034421:Sus scrofa; D013844:Thiazoles / Q000494:pharmacology
C116671:EMD 122946; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D044022:Receptor, Endothelin A; D013844:Thiazoles; C087220:BQ 610; D002245:Carbon Dioxide; D010100:Oxygen; D019331:NG-Nitroarginine Methyl Ester