Chronic treatment with tin normalizes blood pressure in spontaneously hypertensive rats.

Abstract

We have reported that short-term treatment of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats with stannous chloride (SnCl 2 ), which selectively depletes renal cytochrome P4S0, restores blood pressure to normal in young but not in adult SHR, and is without effect on blood pressure of either young or adult WKY rats. We report in the present study that chronic treatment with SnCl 2 , begun at age 5 weeks, prevented the development of hypertension in SHR over a period of 15 weeks at which time they were killed. Suspension of SnCl 2 treatment after 8 weeks (i.e., at age 13 weeks) did not result in return of blood pressure to hypertensive levels in SHR. Age-matched WKY rats were not affected by tin treatment These findings provide additional evidence that administration of tin, which stimulates heme oxygenase, thereby producing depletion of cytochrome P450, restores blood pressure to normal levels in SHR. {Hypertension 1991;17:776-779) T he kidney, through its endocrine and excretory function, exerts a key role in the regulation of blood pressure. Prostaglandins and other arachidonic acid (AA) metabolites originating within the kidney participate in several mechanisms that can affect blood pressure by contributing to the regulation of extracellular fluid volume and renal hemodynamics. 1 ' 2 Of the variety of AA metabolites generated by the kidney, those arising from cytochrome P450-dependent monooxygenases also demonstrate the requisite biological activity to influence blood pressure. Several of these eicosanoids generated by a cytochrome P450 monooxygenase system operating intrarenally have been shown to affect vascular tone 3 ' 4 and to be capable of modulating Na + ,K + -ATPase activity. 56 To define possible relations between the renal cytochrome P450 system and regulation of blood pressure, we studied spontaneously hypertensive rats (SHR), the animal model most resembling human hypertension. In the SHR, renal Received September 21, 1990; accepted in revised form February 15, 1991. mechanisms are thought to play a decisive role in elevating blood pressure. 78 We have obtained evidence to support the hypothesis that eicosanoids generated by the renal cytochrome P450 system participate in the elevation of blood pressure. These renal metabolites are generated in increased amounts only by the young SHR, when compared with either the mature SHR or with age-matched normotensive Wistar-Kyoto (WKY) rats, during the developmental phase of hypertension from the fifth to the 13th week. 9 We have been able to restore blood pressure to normal levels in young 7-week-old SHR during the developmental stage of hypertension with short-term treatment with stannous chloride (SnCl 2 ). SnCl 2 induces heme oxygenase activity.10 Increased activity of heme oxygenase accelerates heme degradation, including that associated with cytochrome P450, thereby impairing the ability of the renal cytochrome P450 system to form eicosanoids 10 and, presumably, to metabolize other local and circulating hormones t...

Exacerbation of Chronic Renovascular Hypertension and Acute Renal Failure in Heme Oxygenase-1–Deficient Mice

“…Chronically, the 1K1C procedure leads to volume retention by the single clipped kidney and a volume-dependent, low-renin hypertension. 32,33 Because HO-1 expression is regulated by the administration of angiotensin II 19 -21 and that inducers of HO-1 normalize blood pressure in models of hypertension, [7][8][9][10][11] we hypothesized that endogenous HO-1 may attempt to counteract the development of renovascular hypertension. Indeed, in the absence of endogenous HO-1, there was an exacerbation of chronic renovascular hypertension after the 1K1C procedure (Figure 1).…”

“…Sacerdoti et al 7 and Escalante et al 8 have demonstrated that either acute or chronic administration of an inducer of HO-1 (stannous chloride) to spontaneously hypertensive rats led to a normalization of blood pressure. Other inducers of HO-1 or HO substrates have also been shown to decrease blood pressure in hypertensive rats.…”

Elevated production of 20-HETE in the cerebral vasculature contributes to severity of ischemic stroke and oxidative stress in spontaneously hypertensive rats

“…The present studies were performed in these relatively young animals since this is the time that SHR and SHRSP begin to enter the established phase of hypertension, and the previous work on the genetics of ischemic stroke was performed in this age range to minimize the influence of hypertension-induced vascular injury and remodeling on infarct size (19,26). This is also an age at which previous studies have indicated that the renal production of 20-HETE is markedly elevated in SHR and that inhibitors of the formation of 20-HETE blunt the development of hypertension (12,47).…”

CytochromeP-450-dependent metabolism of arachidonic acid in the kidney of rats with diabetes insipidus

“…Inhibition of the synthesis of 20-HETE attenuates the vasoconstrictor response of renal arterioles to elevations in transmural pressure in vitro (16, 18) and autoregulation of renal blood flow and tubuloglomerular feedback responses in vivo (8,48). At the level of the renal tubules, 20-HETE inhibits sodium reabsorption in the proximal tubule and thick ascending limb of the loop of Henle (6,32,34,39).Previous studies indicated that the renal production of EETs and/or 20-HETE is altered in diabetes and in genetic and experimental models of hypertension (1,7,21,24,25,28,41). The release of 20-HETE in renal and peripheral blood vessels is stimulated by ANG II (5), phenylephrine (20a), endothelin (37), and serotonin (3).…”

“…Previous studies indicated that the renal production of EETs and/or 20-HETE is altered in diabetes and in genetic and experimental models of hypertension (1,7,21,24,25,28,41). The release of 20-HETE in renal and peripheral blood vessels is stimulated by ANG II (5), phenylephrine (20a), endothelin (37), and serotonin (3).…”