Modulation of renin by thromboxane: studies with thromboxane synthase inhibitor, receptor antagonists, and mimetic.
The regulation of plasma renin activity (PRA) by thromboxane (Tx) A2 was studied in anesthetized rats by measuring PRA before and after administration of drugs that block cyclooxygenase (CO) (indomethacin [INDO], 5 mg/kg), thromboxane synthase (TS) (UK 38485 [UK], 100 mg/kg), or Tx receptors (SQ 29548 [SQ], 8 mg/kg or L 641953 [L], 50 mg/kg) or that activate Tx receptors (U 46619 [U], 10 ng.kg-1.min-1). PRA (ng ANG I.ml-1.h-1) was unaffected by vehicle; it was reduced by INDO (25 +/- 2 to 13 +/- 3, n = 13, P less than 0.001) but was increased by UK (24 +/- 3 to 50 +/- 6, n = 18, P less than 0.005), SQ (27 +/- 4 to 44 +/- 7, n = 6, P less than 0.05), and L (32 +/- 4 to 51 +/- 7, n = 10, P less than 0.05). U reduced PRA in each rat (17 +/- 3 to 10 +/- 3, n = 6, P less than 0.005). UK caused dose-dependent stimulation of PRA (mean effective dose 50 mg/kg) and inhibition of TxB2 excretion (mean inhibitory dose 15 mg/kg). After INDO, SQ no longer changed PRA (-1 +/- 10, n = 7). Prolonged administration of SQ for 4-6 days (20 mg.kg-1.day-1 ip) did not change Na+ or K+ balances, blood pressure, renal hemodynamics, or urine flow. However, SQ stimulated PRA (P less than 0.007) independent of prior salt intake. In conclusion in anesthetized rats 1) PRA is stimulated by products of CO but inhibited by products of TS and by a Tx mimetic; 2) stimulation of PRA by SQ depends on ongoing PG and Tx synthesis; 3) rise in PRA with Tx antagonists is not closely related to changes in salt balance, blood pressure, or renal hemodynamics.
Welch
W J
WJ
Department of Medicine, University of Florida College of Medicine, Gainesville 32610.
Wilcox
C S
CS
Dunbar
K R
KR
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016861:Cyclooxygenase Inhibitors; D003988:Dibenzothiepins / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006834:Hydrazines / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D008297:Male; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012083:Renin / Q000097:blood*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D013931:Thromboxanes / Q000037:antagonists & inhibitors
D019086:Bridged Bicyclo Compounds, Heterocyclic; D016861:Cyclooxygenase Inhibitors; D003988:Dibenzothiepins; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007093:Imidazoles; D011450:Prostaglandin Endoperoxides, Synthetic; D013931:Thromboxanes; C039242:dazmegrel; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; C053051:L 641953; D012083:Renin; D013930:Thromboxane-A Synthase; D007213:Indomethacin