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John W Funder

Publications and source records attributed to John W Funder.

41 records · Page 3Linked to original sources
PubMed2002

The pathophysiology of aldosterone in the cardiovascular system.

Until relatively recently, the mineralocorticoid hormone aldosterone was thought to be produced uniquely in the adrenal cortex and to act exclusively on epithelia to promote sodium retention and potassium excretion. However, it is now known that aldosterone also acts on nonepithelial tissues, such as brain, heart, and blood vessels, and that enzymes required for aldosterone biosynthesis are expressed in these same tissues, which may be consistent with local aldosterone production acting in a paracrine fashion. A number of studies indicate that aldosterone exerts clearly deleterious effects when levels are inappropriate for salt status. For example, aldosterone in a high-salt environment initiates a vascular inflammation response that leads to cardiac and vascular pathologies. In experimental models of hypertension and heart failure, the nonepithelial effects of aldosterone are mediated via classical mineralocorticoid receptors, and are largely or completely abolished by administration of the selective aldosterone blocker eplerenone or by reduction of circulating aldosterone by adrenalectomy. In the present manuscript, we review some of the most recent discoveries in the field of aldosterone biology, with special emphasis on the mechanisms involved in the deleterious actions of this mineralocorticoid in cardiovascular tissues.

Aldosterone↗
PubMed2002

Mineralocorticoid and angiotensin receptor antagonism during hyperaldosteronemia.

Elevated aldosterone levels induce a spironolactone-inhibitable decrease in cardiac sarcolemmal Na+-K+ pump function. Because pump inhibition has been shown to contribute to myocyte hypertrophy, restoration of Na+-K+ pump function may represent a possible mechanism for the cardioprotective action of mineralocorticoid receptor (MR) blockade. The present study examines whether treatment with the angiotensin type 1 receptor antagonist losartan, with either spironolactone or eplerenone, has additive effects on sarcolemmal Na+-K+ pump activity in hyperaldosteronemia. New Zealand White rabbits were divided into 7 different groups: controls, aldosterone alone, aldosterone plus spironolactone, aldosterone plus eplerenone, aldosterone plus losartan, aldosterone plus losartan and spironolactone, and aldosterone plus losartan and eplerenone. After 7 days, myocytes were isolated by enzymatic digestion. Electrogenic Na+-K+ pump current (I(p)), arising from the 3:2 Na+:K+ exchange ratio, was measured by the whole-cell patch clamp technique. Elevated aldosterone levels lowered I(p); treatment with losartan reversed aldosterone-induced reduced pump function, as did MR blockade. Coadministration of spironolactone or eplerenone with losartan enhanced the losartan effect on pump function to a level similar to that measured in rabbits given losartan alone in the absence of hyperaldosteronemia. In conclusion, hyperaldosteronemia induces a decrease in I(p) at near physiological levels of intracellular Na+ concentration. Treatment with losartan reverses this aldosterone-induced decrease in pump function, and coadministration with MR antagonists produces an additive effect on pump function, consistent with a beneficial effect of MR blockade in patients with hypertension and congestive heart failure treated with angiotensin type 1 receptor antagonists.

Aldosterone↗
PubMed2002

Dehydroepiandrosterone inhibits human vascular smooth muscle cell proliferation independent of ARs and ERs.

Dehyroepiandrosterone (DHEA), an adrenal-derived steroid, has been clinically implicated in protection against coronary artery disease and experimentally in inhibition of atherosclerosis and plaque progression. Because DHEA is enzymatically metabolized to androgens or estrogens, it is not clear whether DHEA exerts effects directly or after conversion to these hormones, both of which are associated with well-characterized pathways of action. We therefore examined the effects of DHEA on proliferation of human vascular smooth muscle cells (VSMCs) in culture in the presence or absence of the ER antagonist ICI 182,780 and the AR antagonist flutamide and compared them with the effects of 17beta-estradiol, androstenedione, and T. We also determined the affinity of DHEA for ERs and ARs in VSMC and its specific binding in intact cells. To explore a possible mechanism for DHEA action in these cells, we measured the phosphorylation of ERK-1, c-jun N-terminal protein kinase, and p38 (three members of the MAPK superfamily). Both DHEA and 17beta-estradiol significantly inhibited platelet derived growth factor (PDGF)-BB-induced increases in VSMC proliferation, whereas androstenedione and T increased proliferation. Although E2-induced inhibition of the PDGF effect was abolished by ICI 182,780 and T-induced stimulation was abolished by flutamide, neither receptor antagonist altered the inhibitory effect of DHEA. Binding studies confirmed the presence of both ERs and ARs; DHEA showed minimal affinity for either receptor but bound specifically and with high affinity to putative receptors in intact cells. Following 4-h incubation with DHEA (1-100 nM), ERK1 phosphorylation was significantly reduced in a dose-dependent manner, whereas neither c-jun N-terminal protein kinase nor p38 kinase activity was altered by either PDGF-BB or DHEA. DHEA inhibits human VSMC proliferation by a mechanism independent of either ARs or ERs, presumably via a DHEA-specific receptor that involves ERK1 signaling pathways.

Androgen Receptor Antagonists↗