Effects of selective endothelin antagonists on the hemodynamic response to cyclosporin A.
Cyclosporin A (CsA) treatment is associated with hypertension and renal dysfunction. Increased circulating endothelin (ET) has been implicated in this renal dysfunction, which is secondary to renal vasoconstriction and decreases in RBF. The effects of the selective blockade of ETA receptors or the combined blockade of ETA and ETB receptors on the acute hemodynamic response to CsA in anesthetized rats were examined. Rats were pretreated with vehicle, BQ-123 (selective ETA receptor antagonist; 0.6 micron/kg per minute), or BQ-123 and PD 142893 (combined ETA/ETB receptor antagonist; 0.6 micron/kg per minute) to achieve both ETA and ETB receptor blockade. After a 10-min pretreatment, CsA (20 mg/kg over 10 min) was administered; mean arterial blood pressure, RBF, and iliac blood flow were monitored continuously. Hemodynamic responses to exogenous endothelin-1 (ET-1, 0.3 and 1 nmol/kg) with and without antagonist pretreatment were measured in separate groups to demonstrate effective receptor blockade. CsA elevated blood pressure 17 to 20% in all three groups; renal resistance maximally increased 23, 20, and 23% in vehicle, BQ-123, and BQ-123 and PD 142893 pretreated groups, respectively. In contrast, the combination of BQ-123 and PD 142893 blocked systemic pressor responses to 0.3 and 1 nmol of ET-1 approximately 50 and 37%, respectively; changes in renal resistance were blocked 81 and 89%, respectively. In conclusion, the elevation in systemic blood pressure and the renal vasoconstrictor activity of CsA do not appear to be mediated through ETA or ETB receptors.
Davis
L S
LS
Parke-Davis Pharmaceutical Research, Division of Warner Lambert Company, Ann Arbor, MI 48105.
Haleen
S J
SJ
Doherty
A M
AM
Cody
W L
WL
Keiser
J A
JA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D016572:Cyclosporine / Q000633:toxicity*; D065128:Endothelin Receptor Antagonists; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000502:physiology; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D009842:Oligopeptides; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; C076213:PD 142893; D016572:Cyclosporine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)