Alteration in endothelin receptor sub-type responsiveness and in the endothelin-TXA(2) mimetic U46619 interaction, in type-2 hypertensive diabetic Zucker rats.
BACKGROUND
Type-2 diabetes is characterized by endotheliopathy, which increases target organ damage and mortality. There is excessive endothelin-1 and TXA(2) production, and abnormal vascular reactivity to endothelin-1, manifested as a paradoxical hypotensive action in Zucker diabetic, but not lean rats. We examined the hypothesis that there is an alteration in the ET-A/ET-B receptor subtype sensitivity, and/or the interaction or cross-talk between ET-1 and TXA(2) in type-2 diabetes, using Zucker diabetic rats and their lean littermates.


METHODS
Hemodynamic studies were performed in lean and Zucker fatty diabetic rats of both sexes. Laser doppler flowmetry was used to measure renal cortical (RCF) and medullary blood flow (MBF) responses. Dose response curves for mean arterial blood pressure (MAP), MBF and RCF in response to ET-1, U46619, acetylcholine, and L-NAME (25mg/kg) were constructed after pre-treatment of the rats with either BQ610 1mg/kg i.v. or BQ788 0.5mg/kg i.v. The effects of BQ610 and BQ788 on whole blood impedance aggregation were also assessed.


RESULTS
BQ788, but not BQ610 abolished both the paradoxical hypotensive action of ET-1 in Zucker diabetic rats (n=7 each, P<0.001 ANOVA) as well as the dose-dependent rise in MBF (P<0.001 ANOVA). BQ788, but not BQ610 abolished the difference in response to ET-1 between lean and diabetic Zucker rats. U46619 caused a hypotensive action in male Zucker rats which was abolished by L-NAME 25mg/kg or indomethacin 10mg/kg i.v. The U46619 interaction with BQ788 on both MAP and MBF was significantly (P<0.03 ANOVA) different between lean and diabetic Zucker rats. BQ788, but not BQ610 attenuated both the MAP and MBF responses to acetylcholine or L-NAME P<0.02 ANOVA). However, BQ610 dose-dependently attenuated the slope of platelet aggregation in both lean and Zucker diabetic rats (P<0.02 ANOVA).


CONCLUSIONS
ET-B receptor antagonism abolished the abnormal vascular reactivity and MBF responses to ET-1, and also normalized the vasoactive responses to the level seen in healthy lean Zucker rats. ET-1 receptor blockade influences the responses to TXA(2) receptor activation. In the systemic and renal circulation, this interaction appears to be mostly ET-B receptor mediated, whilst in platelets, ET-A receptor role may be predominant. The interaction or cross-talk between ET-1 and TXA(2) is altered in the type-2 diabetic state. Collectively, these pathophysiological changes may contribute to the vicious circle of diabetic endotheliopathy.
Ajayi
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AA
Center for Cardiovascular Diseases, Texas Southern University, 3100 Cleburne Avenue, Houston, TX 77004, USA. adeajayi@aol.com
Ogungbade
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GO
Hercule
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HC
Oyekan
A O
AO
Mutembei
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L
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology*; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology*; D004347:Drug Interactions; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000150:complications / Q000503:physiopathology*; D007672:Kidney Cortex / Q000098:blood supply; D007679:Kidney Medulla / Q000098:blood supply; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D020239:Receptor Cross-Talk; D044022:Receptor, Endothelin A / Q000187:drug effects / Q000502:physiology; D044023:Receptor, Endothelin B / Q000187:drug effects / Q000502:physiology; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology*; D013928:Thromboxane A2 / Q000494:pharmacology*
D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C087220:BQ 610; C086539:BQ 788; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester