Article Text
PDF
Abstract
Acute Intermittent Porphyria (AIP) is characterized by a deficiency of hepatic porphobilinogen deaminase (PBGD). Symptoms experienced by AIP patients, mostly women of reproductive age, include systemic arterial hypertension and tachycardia. The 21-aa peptide endothelin-1 (ET-1) is one of the more potent vasoconstrictors described and acts on vascular ETA and ETB receptors localized in smooth muscle (ETA and ETB) and in endothelial cells (ETB). In symptomatic AIP patients increased plasma levels of Endothelin-1 (ET-1) have been reported (PMID: 35741113). In arteries of the AIP mouse model (T1/T2-AIP) we aimed to characterize the role of ETA and ETB receptors in mediating ET-1 contractile responses.
Mesenteric arteries were isolated from 8-month-old female C57Bl6 wildtype (WT, n=16) and T1/T2-AIP mice (n=16) and mounted on a Multi Wire Myograph for determination of isometric force (USA-DMT®). The contractile responses to K+75 mM and ET-1 (10-11-10-7M) were measured at basal conditions. Parallel experiments were performed after pre-incubation with the ETA specific blocker BQ123 (10-6M) or the ETB specific blocker BQ788 (10-6M) in intact and endothelium denuded arteries. Maximal responses (ET-1MAX) were expressed as% of contraction to 75mM KCl (%KMAX) and sensitivity as pD2 (-Log[EC50]). Data were analyzed using Prism (GraphPad®).
In intact arteries, a greater ET-1 contraction was observed in AIP arteries (152±7 vs. 125±5 %KMAX, p<0.05); this difference was abolished in arteries without endothelium (141±3 vs. 144±8 %KMAX, p>0.05). In intact and endothelium denuded arteries from both WT and T1/T2-AIP, blockade of ETA or ETB lowered ET-1 sensitivity. In intact arteries with ETA blockade, T1/T2-AIP arteries displayed a greater contraction (145±7 vs. 120±8%KMAX p<0.05) and lower sensitivity (7.47±0.07 vs. 7.8±0.09, p<0.05) with no differences in the presence of ETB blockade. In endothelium denuded arteries with ETA blockade, T1/T2-AIP arteries displayed a greater contraction (138±5 vs. 119±4%KMAX, p<0.05) with no differences in sensitivity. Differences in ET-1MAX and sensitivity were abolished in the presence of ETB blockade in intact and denuded arteries.
We conclude that the increased ET-1-dependent contraction is due to a greater function of the smooth muscle ETB receptor, with a higher function of the endothelial ETB receptor only evident in the presence of ETA blockade. An increased contraction in the presence of greater plasma levels of ET-1 will potentiate the prohypertensive effects of the peptide. Dual ETA/ETB antagonists may offer benefits in the control of hypertensive crisis in AIP patients. Possible effects of ALA, PBG, heme, and givosiran are in need of further study in this model system and are planned.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.