Angiotensin II, the major effector molecule produced from the renin-angiotensin-aldosterone axis, is a vasoconstrictor contributing to hypertension. Evidence indicates, however, that angiotensin II also is a potent proinflammatory mediator with growth and remodeling effects. In vitro and in vivo studies have shown that angiotensin II blockade significantly reduces concentrations of proinflammatory mediators and oxidative stress products in numerous inflammatory models. Interruption of angiotensin II activity with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers has been beneficial for patients with inflammatory diseases. Much of this benefit occurs independent of the antihypertensive effect of angiotensin II interruption, suggesting a distinctive protective mechanism. Angiotensin II receptor blockers may represent a novel class of antiinflammatory drugs with indications far beyond cardiovascular diseases.
Background and purpose: Inflammation elevates plasma verapamil concentrations but diminishes pharmacological response. Angiotensin II is a pro-inflammatory mediator. We examined the effect of angiotensin II receptor blockade on the pharmacokinetics and pharmacodynamics of verapamil, as well as the binding properties and amounts of its target protein in calcium channels, in a rat model of inflammation. Experimental approach: We used 4 groups of male Sprague-Dawley rats (220-280 g): inflamed-placebo, inflamed-treated, control-placebo and control-treated. Inflammation as pre-adjuvant arthritis was induced by injecting Mycobacterium butyricum on day 0. From day 6 to 12, 30 mg kg À1 oral valsartan or placebo was administered twice daily. On day 12, a single oral dose of 25 mg kg À1 verapamil was administered and prolongation of the PR interval measured and plasma samples collected for verapamil and nor-verapamil analysis. The amounts of the target protein Ca v 1.2 subunit of L-type calcium channels in heart was measured by Western blotting and ligand binding with 3 H-nitrendipine. Key results: Inflammation reduced effects of verapamil, although plasma drug concentrations were increased. This was associated with a reduction in ligand binding capacity and amount of the calcium channel target protein in heart extracts. Valsartan significantly reversed the down-regulating effect of inflammation on verapamil's effects on the PR interval, and the lower level of protein binding and the decreased target protein.
Conclusions and implications:Reduced responses to calcium channel blockers in inflammatory conditions appeared to be due to a reduced amount of target protein that was reversed by the angiotensin II antagonist, valsartan.
Atrial cardiocytes from newborn (2-5 day old) and adult rats were cultured and the secretory patterns of atrial natriuretic factor (ANF) from isolated right and left atrial cells were investigated by radioimmunoassay. Newborn atrial cardiocytes from the left atrium consistently secreted larger amounts of ANF than those from the right with a peak on the 6th day and a decrease up to the 12th day. In contrast, adult atrial cardiocytes secreted much less ANF and this decreased to very low levels from the 3rd day up to the 12th day in culture although ANF was present in measurable amounts in these cells.
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