Submitted on November 18, 2005
Accepted on January 4, 2006
Blood Pressure Regulation by ETA and ETB Receptors in Conscious, Telemetry-instrumented Mice and Role of ETA in Hypertension Produced by Selective ETB Blockade
Ryan M Fryer1*, Pamela A Rakestraw1, Patricia N Banfor1, Bryan F Cox1, Terry J Opgenorth2, and Glenn A Reinhart1
1 Integrative Pharmacology, Abbott Laboratories, Abbott Park, IL, USA
2 Metabolic Disease Research, Abbott Laboratories, Abbott Park, IL, USA
* To whom correspondence should be addressed. E-mail: ryan.fryer{at}abbott.com.
The net contribution of ETA and ETB receptors in blood pressure regulation in humans and experimental animals including the conscious mouse remains undefined. Thus, we assessed the role of ETA and ETB receptors in the control of basal blood pressure and also the role of ETA receptors in maintaining the hypertensive effects of systemic ETB blockade in telemetry-instrumented mice. Mean arterial pressure (MAP) and heart rate were recorded continuously from the carotid artery and daily (24-hr) values determined. At baseline, MAP ranged from 99 ± 1 to 101 ± 1 mmHg and heart rate ranged between 547 ± 15 and 567 ± 19 beats/min (n=6). Daily oral administration of the ETB selective antagonist, A-192621 (10 mg/kg; BID), increased MAP to 108 ± 1 and 112 ± 2 mmHg on days 1 and 5, respectively. Subsequent co-administration of the ETA selective antagonist, atrasentan (5 mg/kg BID), in conjunction with A-192621 (10 mg/kg; BID) decreased MAP to baseline values on day 6 (99 ± 2 mmHg) and to below baseline on day 8 (89 ± 3 mmHg). In a separate group of mice (n=6) in which the treatment was reversed systemic blockade of ETB receptors produced no hypertension in animals pretreated with atrasentan underscoring the importance of ETA receptors to maintain the hypertension produced by ETB blockade. In a third group of mice (n=10), ETA blockade alone (atrasentan; 5 mg/kg BID) produced an immediate and sustained decrease in MAP to values below baseline (baseline values = 101 ± 2 to 103 ± 2 mmHg; atrasentan decreased pressure to 95 ± 2 mmHg). Thus, these data suggest that ETA and ETB receptors play a physiologically relevant role in the regulation of basal blood pressure in normal, conscious mice. Furthermore, systemic ETB receptor blockade produces sustained hypertension in conscious telemetry instrumented mice that is absent in mice pre-treated with an ETA antagonist suggesting that ETA receptors maintain the hypertension produced by ETB blockade.
