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Richard E White

Publications and source records attributed to Richard E White.

9 recordsLinked to original sources
PubMed2003

cAMP activates BKCa channels in pulmonary arterial smooth muscle via cGMP-dependent protein kinase.

The signal transduction mechanisms defining the role of cyclic nucleotides in the regulation of pulmonary vascular tone is currently an area of great interest. Normally, signaling mechanisms that elevate cAMP and guanosine-3',5'-cyclic monophosphate (cGMP) maintain the pulmonary vasculature in a relaxed state. Modulation of the large-conductance, calcium- and voltage-activated potassium (BK(Ca)) channel is important in the regulation of pulmonary arterial pressure, and inhibition (closing) of the BK(Ca) channel has been implicated in the development of pulmonary hypertension. Accordingly, studies were done to determine the effect of cAMP-elevating agents on BK(Ca) channel activity using patch-clamp studies in pulmonary arterial smooth muscle cells (PASMC) of the fawn-hooded rat (FHR), a recognized animal model of pulmonary hypertension. Forskolin (10 micro M), a stimulator of adenylate cyclase and an activator of cAMP-dependent protein kinase (PKA), and 8-4-chlorophenylthio (CPT)-cAMP (100 micro M), a membrane-permeable derivative of cAMP, opened BK(Ca) channels in single FHR PASMC. Treatment of FHR PASMC with 300 nM KT5823, a selective inhibitor of cGMP-dependent protein kinase (PKG) activity inhibited the effect of both forskolin and CPT-cAMP. In contrast, blocking PKA activation with 300 nM KT5720 had no effect on forskolin or CPT-cAMP-stimulated BK(Ca) channel activity. These results indicate that cAMP-dependent vasodilators activate BK(Ca) channels in PASMC of FHR via PKG-dependent and PKA-independent signaling pathways, which suggests cross-activation between cyclic nucleotide-dependent protein kinases in pulmonary arterial smooth muscle and therefore, a unique signaling pathway for cAMP-induced pulmonary vasodilation.

Alkaloids↗
PubMed2003

Indications for lateral retinacular release in total knee replacement.

The rule of no thumb test was compared with the towel clip test in determining the need for lateral retinacular release in 200 consecutive primary total knee replacements. The towel clip test was positive in 13 knees (6.5%) and the rule of no thumb test was positive in 78 knees (39%). Using a positive towel clip test as the indication for lateral retinacular release, there was no radiographic evidence of patellar tilt, subluxation, or dislocation in any knee at 6 months postoperatively. Therefore, the rule of no thumb test falsely predicted the need for lateral release in 65 knees (32.5%). The authors advocate the towel clip test to determine the need for lateral retinacular release.

Adult↗
PubMed2003

Estradiol relaxes rat aorta via endothelium-dependent and -independent mechanisms.

The effects of estrogen on arterial function are heterogeneous with respect to vessel and/or species. We have investigated 17beta-estradiol-induced relaxation in isolated rat aorta with regard to the role of the vascular endothelium and ionic mechanisms. Estrogen induced a concentration-dependent relaxation of 46.5 +/- 7.9% and 70.1 +/- 12.2% (10(-8) and 10(-7)M), which was reduced by endothelial denudation. Furthermore, L-nitroarginine methyl ester completely abrogated this effect; however, estradiol did not relax KCl-contracted rings. Tetraethyl ammonium (1 mmol/l) completely blocked estradiol-induced relaxation. Estradiol increased [cGMP] in isolated aortic rings via NO, but did not significantly affect NOS activity in endothelial cells. Thus, estrogen can relax rat aorta in vitro via both endothelium-dependent and -independent mechanisms involving the NO/cGMP and potassium channel signaling system.

Animals↗
PubMed2002

Endothelium-independent effect of estrogen on Ca(2+)-activated K(+) channels in human coronary artery smooth muscle cells.

OBJECTIVE: Postmenopausal estrogen replacement therapy lowers the incidence of cardiovascular disease, suggesting that estrogens support cardiovascular function. Estrogens dilate coronary arteries; however, little is known about the molecular basis of how estrogen affects the human coronary circulation. The cellular/molecular effects of estrogen action on human coronary smooth muscle were investigated in the present study. METHODS: Patch-clamp and fluorescent microscopy studies were performed on human coronary myocytes in the absence of endothelium. RESULTS: Estrogen increased whole-cell currents over a range of membrane potentials, and further studies indicated that the large-conductance (186.5 +/- 3 pS), calcium- and voltage-activated potassium (BK(Ca)) channel was the target of estrogen action. Channel activity was stimulated approximately 15-fold by nanomolar concentrations of 17 beta-estradiol, and this stimulation was reversed >90% by inhibiting cGMP-dependent protein kinase activity with 300 nM KT5823. 17 beta-Estradiol increased the level of cGMP and nitric oxide in human myocytes, and the stimulatory effect of estrogen on channel activity and NO production was reversed by inhibiting NO synthase with 10 microM N(G)-monomethyl-L-arginine. CONCLUSIONS: Our cellular and molecular studies identify the BK(Ca) channel as a target of estrogen action in human coronary artery smooth muscle. This response to estrogen involves cGMP-dependent phosphorylation of the BK(Ca) channel or a closely associated regulatory molecule, and further evidence suggests involvement of the NO/cGMP signaling system in coronary smooth muscle. These findings are the first to provide direct evidence for a molecular mechanism that can account for endothelium-independent effects of estrogen on human arteries, and may also help explain why estrogens reduce myocardial ischemia and stimulate coronary blood flow in patients with diseased coronary arteries.

Alkaloids↗
PubMed2002

Estrogen and vascular function.

The effects of estrogen on the female reproductive system are well known. In contrast, comparatively recent research has demonstrated that estrogen also exerts specific effects on the cardiovascular system--particularly the vasculature. This review summarizes some of the current ideas of how estrogen regulates and modulates vascular function, and focuses primarily on potential mechanisms of estrogen-induced vasodilation. Although many studies indicate estrogen exerts beneficial effects on the circulatory system, the overall conclusions from clinical studies remain somewhat equivocal. In contrast, it is clear that estrogen reduces atherosclerosis by reducing low-density lipoproteins (LDL) and inflammatory processes in the vasculature, and may also act as an antioxidant; however, these effects account for only a portion of the total cardiovascular benefit of estrogen. Estrogen is also a vasodilator and hypotensive agent, and can induce vascular relaxation by stimulating release of endothelium-derived vasodilatory substances (e.g., nitric oxide [NO]) or by acting directly on the vascular smooth muscle (VSM). Recent evidence indicates that calcium and potassium channels in VSM cells play an important role in mediating estrogen-induced relaxation of many vascular beds, but elucidating the signal transduction mechanisms coupling estrogen receptor (ER alpha and/or ER beta) activation to generation of second messengers and effector mechanisms remains an area of intense study. Not surprisingly, it is becoming apparent that the molecular basis of estrogen's influence on vascular function is multifactorial. A better understanding of these signaling mechanisms should lead to the development of powerful therapeutic agents which can maximize the many beneficial effects of estrogen action, while helping minimize the harmful (and sometimes lethal) side effects.

Animals↗
PubMed2002

Potassium (BK(Ca)) currents are reduced in microvascular smooth muscle cells from insulin-resistant rats.

Insulin resistance (IR) syndrome is associated with impaired vascular relaxation; however, the underlying pathophysiology is unknown. Potassium channel activation causes vascular smooth muscle hyperpolarization and relaxation. The present study determined whether a reduction in large conductance calcium- and voltage-activated potassium (BK(Ca)) channel activity contributes to impaired vascular relaxation in IR rats. BK(Ca) channels were characterized in mesenteric microvessels from IR and control rats. Macroscopic current density was reduced in myocytes from IR animals compared with controls. In addition, inhibition of BK(Ca) channels with tetraethylammonium (1 mM) or iberiotoxin (100 nM) was greater in myocytes from control (70%) compared with IR animals (approximately 20%). Furthermore, activation of BK(Ca) channels with NS-1619 was three times more effective at increasing outward current in cells from control versus IR animals. Single channel and Western blot analysis of BK(Ca) channels revealed similar conductance, amplitude, voltage sensitivity, Ca2+ sensitivity, and expression density between the two groups. These data provide the first direct evidence that microvascular potassium currents are reduced in IR and suggest a molecular mechanism that could account for impaired vascular relaxation in IR.

Animals↗
PubMedDate not supplied

PGE2 action in human coronary artery smooth muscle: role of potassium channels and signaling cross-talk.

Cyclic AMP-stimulating agents are powerful vasodilators, but our knowledge of the signal transduction mechanisms of these agents, particularly in human arteries, is limited. We now report direct molecular effects of prostaglandin E(2) (PGE(2)) on cultured human coronary artery smooth muscle cells (HCASMC). Patch-clamp studies revealed that 10 microM PGE(2) opens a high-conductance (approximately 200 pS), calcium-stimulated potassium (BK(Ca)) channel in intact HCASMC. In contrast, PGE(2) had no direct effect on channels in cell-free patches, indicating involvement of a soluble second messenger. Enzyme immunoassay demonstrated that PGE(2) enhances production of cAMP in HCASMC, but does not increase [cGMP]. Furthermore, forskolin, CPT-cAMP, or CPT-cGMP mimicked the stimulatory effect of PGE(2) on BK(Ca) channel activity. Interestingly, the response to PGE(2) was unaffected by inhibiting the cAMP-dependent protein kinase, but was antagonized by inhibitors of the cGMP-dependent protein kinase (PKG). Furthermore, cAMP-stimulated PKG activity mimicked the effect of PGE(2). These studies suggest a novel PGE(2) action in human arteries: opening of BK(Ca) channels via cAMP cross-activation of PKG in HCASMC. It is proposed that this signaling mechanism may mediate the vasodilatory response to cAMP-dependent agents in the human coronary and other vascular beds.

Cells, Cultured↗