Renoprotective effects of anti-TGF-ß antibody and antihypertensive therapies in Dahl S rats.

This study examined the effects of anti-TGF-ß antibody (1D11) therapy in Dahl S (S) rats fed a 4% NaCl diet. Baseline renal expression of TGF-ß1 and the degree of injury were lower in female than male S rats maintained on a 0.4% NaCl diet. 4% NaCl diet increased mean arterial pressure (MAP), proteinuria, and renal injury to the same extent in both male and female S rats. Chronic treatment with 1D11 had renoprotective effects in both sexes. The ability of 1D11 to oppose the development of proteinuria when given alone or in combination with antihypertensive agents was further studied in 6-wk-old female S rats, since baseline renal injury was less than that seen in male rats. 1D11, diltiazem, and hydrochlorothiazide (HCT) attenuated the development of hypertension, proteinuria, and glomerular injury. 1D11 had no additional effect when given in combination with these antihypertensive agents. We also explored whether 1D11 could reverse renal injury in 9-wk-old male S rats with preexisting renal injury. MAP increased to 197 ± 4 mmHg and proteinuria rose to >300 mg/day after 3 wk on a 4% NaCl diet. Proteinuria was reduced by 30-40% in rats treated with 1D11, HCT, or captopril + 1D11, but the protective effect was lost in rats fed the 4% NaCl diet for 6 wk. Nevertheless, 1D11, HCT, and captopril + 1D11 still reduced renomedullary and cardiac fibrosis. These results indicate that anti-TGF-ß antibody therapy reduces renal and cardiac fibrosis and affords additional renoprotection when given in combination with various antihypertensive agents in Dahl S rats.

Evidence that 20-HETE contributes to the development of acute and delayed cerebral vasospasm.

Recent studies have indicated that arachidonic acid (AA) is metabolized by the cytochrome P450 4A (CYP4A) enzymes in cerebral arteries to produce 20-hydroxyeicosatetraenoic acid (20-HETE) and that this compound has effects on cerebral vascular tone that mimic those seen following subarachnoid hemorrhage (SAH). In this regard, 20-HETE is a potent constrictor of cerebral arteries that decreases the open state probability of Ca(2+)-activated K(+) channels through activation of protein kinase C (PKC). It increases the sensitivity of the contractile apparatus to Ca(2+) by activating PKC and rho kinase. The formation of 20-HETE is stimulated by angiotensin II (AII), endothelin, adenosine triphosphate (ATP) and serotonin, and inhibited by NO, CO and superoxide radicals. Inhibitors of the formation of 20-HETE block the myogenic response of cerebral arterioles to elevations in transmural pressure in vitro and autoregulation of cerebral blood flow (CBF) in vivo. 20-HETE also plays an important role in modulating the cerebral vascular responses to vasodilators (NO and CO) and vasoconstrictors (AII, endothelin, serotonin). Recent studies have indicated that the levels of 20-HETE in cerebrospinal fluid (CSF) increase in rats, dogs and human patients following SAH and that inhibitors of the synthesis of 20-HETE prevent the acute fall in CBF in rats and reverse delayed vasospasm in both dogs and rats. This review examines the evidence that an elevation in the production of 20-HETE contributes to the initial fall in CBF following SAH and the later development of delayed vasospasm.

Aging increases cytochrome P450 4A modulation of alpha1-adrenergic vasoconstriction in mesenteric arteries.

Aging is associated with peripheral vascular dysfunction. In vascular smooth muscle, cytochrome P450 4A (CYP4A) enzymes form the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE acts as an intracellular messenger to modulate vasoconstriction induced by various agonists, including the alpha1-adrenergic agonist phenylephrine (PE) and endothelin-1 (ET-1). Eicosanoids produced by CYP4A contribute to the elevated vascular tone in hypertension, but the effects of advanced age on CYP4A modulation of vasoconstriction are unknown. Mesenteric arteries were isolated from young (3 to 4 months) and aged (17 to 18 months) Sprague-Dawley rats. Vasoconstriction was induced with PE or ET-1 in the absence or presence of the CYP4A inhibitor DDMS and/or the ETA inhibitor BQ123. CYP4A inhibition with DDMS significantly reduced PE sensitivity in aged rats, but it had no effect in young. Furthermore, in aged rats only, ETA inhibition reduced PE sensitivity while combined inhibition of CYP4A and ETA had no additional effect, suggesting that the pathways work in concert in aging. Exogenous ET-1 constriction was not altered by DDMS in young or aged rats. Overall, our data indicate that aging increases the contribution of CYP4A to alpha1-adrenergic vasoconstriction in systemic arteries. Understanding aging-related changes in vascular function is important for development of novel targets for the prevention of cardiovascular disease.