Manipulation of cytochrome P-450 dependent renal thromboxane synthase activity in spontaneously hypertensive rats.
Thromboxane synthase is a cytochrome P-450-like enzyme requiring an iron-centered oxygen attack of the prostaglandin endoperoxide substrate (PGH2) for subsequent thromboxane A2 (TxA2) formation. The activity and levels of P-450 enzymes can be manipulated by decreasing heme availability. Stannous chloride (SnCl2) selectively induces renal heme oxygenase activity, depleting heme and decreasing hemoprotein synthesis. We therefore manipulated the renal cytochrome P-450 system to influence thromboxane synthase activity, as measured by the conversion of 14C-PGH2 to thromboxane B2 (TxB2) in renal cortical microsomes from spontaneously hypertensive rats (SHR). Seven-week-old SHR were treated subcutaneously with SnCl2 (1, 10 and 15 mg/100 g body weight) for 4 consecutive days, and cortical microsomal heme oxygenase activity, heme content, P-450 content, thromboxane synthase activity and systolic blood pressure were measured. Heme oxygenase activity was significantly increased from 1058 +/- 62 nmol/mg protein in controls to 3125 +/- 918, 5057 +/- 690--and 4236 +/- 581 nmol/mg protein in SHR treated with 1, 10 and 15 mg/100 g body weight SnCl2, respectively. The increase in heme oxygenase activity was associated with corresponding decreases in heme content (0.29 mumol/mg protein, for control to 0.12 mumol/mg protein for SHR treated with SnCl2, 10 mg/100 g body weight) and cytochrome P-450 content (0.18 +/- 0.1 nmol/mg protein for control to 0.06 +/- 0.01 nmol/mg protein for SHR treated with SnCl2 10 mg/100 g body weight). The reduction in heme and P-450 content was associated with a reduction in thromboxane synthase activity, i.e., decreases of 38, 35 and 47% from control levels at doses of 1, 10 and 15 mg/100 g body weight.(ABSTRACT TRUNCATED AT 250 WORDS)
Sessa
W C
WC
Department of Pharmacology, New York Medical College, Valhalla 10595.
Abraham
N G
NG
Escalante
B
B
Schwartzman
M L
ML
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D007668:Kidney / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D013930:Thromboxane-A Synthase / Q000378:metabolism*; D014001:Tin / Q000494:pharmacology / Q000627:therapeutic use*; D017971:Tin Compounds
D017971:Tin Compounds; C023599:stannous chloride; D014001:Tin; D013930:Thromboxane-A Synthase