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 15mg/100g 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 ± 62nmol/mg protein in controls to 3125 ± 918, 5057 ± 690 —and 4236 ± 581 nmol/mg protein in SHR treated with 1,10 and 15mg/100g body weight SnCl2, respectively. The increase in heme oxygenase activity was associated with corresponding decreases in heme content (0.29 μmol/mg protein, for control to 0.12 μmol/mg protein for SHR treated with SnCl2, 10mg/100g 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 10mg/100g 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 15mg/100g body weight. Also, blood pressure was reduced dose-dependently with SnCl2 treatment from 151 ± 3 (control) to 135 ± 3, 118 ± 2 and 114 ± 4 in SHR treated with SnCl2 at doses of 1, 10 and 15mg/100g body weight, respectively. We conclude that it is possible to influence thromboxane synthase activity by affecting heme levels and thereby cytochrome P- 450 availability, and that the changes in thromboxane synthase activity may be important in the pathogenesis of hypertension in the SHR
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