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Am J Physiol Heart Circ Physiol (June 6, 2002). doi:10.1152/ajpheart.00346.2002
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Articles in PresS, published online ahead of print June 6, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00346.2002
Submitted on April 18, 2002
Accepted on December 31, 1969

Hypertension induced by blockade of ETB receptors in conscious non-human primates: role of ETA receptors

Glenn A. Reinhart1*, Lee C. Preusser1, Sandra E. Burke1, Jerry L. Wessale1, Craig D. Wegner1, Terry J. Opgenorth1, and Bryan F. Cox1

1 Department of Integrative Pharmacology, Global Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, IL, USA

* To whom correspondence should be addressed. E-mail: glenn.reinhart{at}abbott.com.

The role of the endothelin-B (ETB) receptor in circulatory homeostasis is ambiguous, partly due to vasodilator and constrictor effects ascribed to the receptor as well as diuretic and natriuretic responses that seem to oppose the hypertensive effects of ET excess. This study characterized the effects of systemic ETB blockade on long-term arterial pressure homeostasis in conscious cynomolgus monkeys instrumented with telemetry transmitters. We also assessed the role of ETA receptors in mediating the hypertensive effects of ETB blockade. Mean arterial pressure (MAP) and heart rate were measured continuously 24 hr/day for 24 days during a 4-day control period followed by a series of 4 day treatment periods in which the orally active, ETB selective antagonist, A-192621 (0.1, 1, 10 mg/kg; bid) was administered for 4 days at each dose. Subsequently, an ETA selective antagonist (atrasentan; 5 mg/kg; bid) was co-administered with A-192621 (10 mg/kg; bid) for another 4-days, followed by a 4 day recovery period. In response to high dose ETB blockade, 24-hr MAP increased from 79 ± 3 (control) to 87 ± 3 mmHg and 89 ± 3 mmHg on the first and fourth day, respectively; heart rate was unchanged while plasma ET-1 concentration increased from 2.1 ± 0.3 pg/ml (control) to 7.24 ± 0.99 and 11.03 ± 2.37 pg/ml. When atrasentan was co-administered with A-192621 (10 mg/kg), MAP fell from hypertensive levels (89 ± 3) to 75 ± 2 and 71 ± 4 mmHg on the first and fourth day, respectively; plasma ET-1 increased further to 26.64 ± 3.72 and 28.65 ± 2.89 pg/ml; heart rate increased from 113 ± 5 (control) to 132 ± 5 and 133 ± 7 beats/min. Thus, systemic blockade of ETB receptors produces a sustained hypertension in conscious non-human primates that is completely dependent upon functional ETA receptors. These data imply an importance clearance function for the ETB receptor and suggest that ETB receptors indirectly influence arterial pressure homeostasis by reducing plasma ET-1 levels, minimizing endogenous activation of ETA receptors.




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