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M T Nelson

Publications and source records attributed to M T Nelson.

At least 55 records · Page 3Linked to original sources
PubMed1998

Ryanodine receptors regulate arterial diameter and wall [Ca2+] in cerebral arteries of rat via Ca2+-dependent K+ channels.

1. The effects of inhibitors of ryanodine-sensitive calcium release (RyR) channels in the sarcoplasmic reticulum (SR) and Ca2+-dependent potassium (KCa) channels on the membrane potential, intracellular [Ca2+], and diameters of small pressurized (60 mmHg) cerebral arteries (100-200 micron) were studied using digital fluorescence video imaging of arterial diameter and wall [Ca2+], combined with microelectrode measurements of arterial membrane potential. 2. Ryanodine (10 microM), an inhibitor of RyR channels, depolarized by 9 mV, increased intracellular [Ca2+] by 46 nM and constricted pressurized (to 60 mmHg) arteries with myogenic tone by 44 micron (approximately 22 %). Iberiotoxin (100 nM), a blocker of KCa channels, under the same conditions, depolarized the arteries by 10 mV, increased arterial wall calcium by 51 nM, and constricted by 37 micron (approximately 19 %). The effects of ryanodine and iberiotoxin were not additive and were blocked by inhibitors of voltage-dependent Ca2+ channels. 3. Caffeine (10 mM), an activator of RyR channels, transiently increased arterial wall [Ca2+] by 136 +/- 9 nM in control arteries and by 158 +/- 12 nM in the presence of iberiotoxin. Caffeine was relatively ineffective in the presence of ryanodine, increasing [calcium] by 18 +/- 5 nM. 4. In the presence of blockers of voltage-dependent Ca2+ channels (nimodipine, diltiazem), ryanodine and inhibitors of the SR calcium ATPase (thapsigargin, cyclopiazonic acid) were without effect on arterial wall [Ca2+] and diameter. 5. These results suggest that local Ca2+ release originating from RyR channels (Ca2+ sparks) in the SR of arterial smooth muscle regulates myogenic tone in cerebral arteries solely through activation of KCa channels, which regulate membrane potential through tonic hyperpolarization, thus limiting Ca2+ entry through L-type voltage-dependent Ca2+ channels. KCa channels therefore act as a negative feedback control element regulating arterial diameter through a reduction in global intracellular free [Ca2+].

Animals↗
PubMed1998

Laparoscopic intraperitoneal onlay inguinal herniorrhaphy.

BACKGROUND: This study presents intermediate follow-up data on a randomized prospective series of patients undergoing either a modified laparoscopic intraperitoneal onlay mesh herniorrhaphy (IPOM) or conventional anterior inguinal herniorrhaphy (CH). METHODS: All patients from two university affiliated hospitals with primary or recurrent inguinal hernias were recruited for randomization to either the IPOM technique utilizing a meshed expanded polytetrafluorethylene (ePTFE) soft tissue patch or CH. Follow-up data were gathered from postoperative clinic visits and telephone and mail surveys. RESULTS: Previously reported early recurrence and complication rates at a mean follow-up of 8 months were 1 of 30 (3%) and 5 of 30 (17%) for IPOM, and 2 of 28 (7%) and 5 of 28 (18%) for CH. Intermediate follow-up with 50 (23 IPOM and 27 CH) of the original 58 patients (86%) at a mean of 41 months reveals a recurrence rate of 10 of 23 (43%) for the IPOM group and 4 of 27 (15%) for the CH group (P = 0.053). Five delayed complications occurred in 4 IPOM patients (port site hernia 4, painful neuroma 1), while 2 delayed complications (unilateral testicular atrophy 2) occurred in 2 patients in the CH group. One IPOM versus 5 CH patients subsequently developed previously unrecognized contralateral hernias. There was 1 death unrelated to previous herniorrhaphy in each group. CONCLUSIONS: IPOM recurrence rates (43%) at a mean follow-up of 41 months are excessively high when compared with CH (15%) or with preliminary results of IPOM at 8 months of follow-up (3%). Despite reduced perioperative pain and disability and promising preliminary results in the IPOM group, these intermediate follow-up data strongly suggest that the IPOM technique should not be used for repair of inguinal hernias.

Female↗
PubMed1998

Ca2+ channels, ryanodine receptors and Ca(2+)-activated K+ channels: a functional unit for regulating arterial tone.

Local calcium transients ('Ca2+ sparks') are thought to be elementary Ca2+ signals in heart, skeletal and smooth muscle cells. Ca2+ sparks result from the opening of a single, or the coordinated opening of many, tightly clustered ryanodine receptor (RyR) channels in the sarcoplasmic reticulum (SR). In arterial smooth muscle, Ca2+ sparks appear to be involved in opposing the tonic contraction of the blood vessel. Intravascular pressure causes a graded membrane potential depolarization to approximately -40 mV, an elevation of arterial wall [Ca2+]i and contraction ('myogenic tone') of arteries. Ca2+ sparks activate calcium-sensitive K+ (KCa) channels in the sarcolemmal membrane to cause membrane hyperpolarization, which opposes the pressure induced depolarization. Thus, inhibition of Ca2+ sparks by ryanodine, or of KCa channels by iberiotoxin, leads to membrane depolarization, activation of L-type voltage-gated Ca2+ channels, and vasoconstriction. Conversely, activation of Ca2+ sparks can lead to vasodilation through activation of KCa channels. Our recent work is aimed at studying the properties and roles of Ca2+ sparks in the regulation of arterial smooth muscle function. The modulation of Ca2+ spark frequency and amplitude by membrane potential, cyclic nucleotides and protein kinase C will be explored. The role of local Ca2+ entry through voltage-dependent Ca2+ channels in the regulation of Ca2+ spark properties will also be examined. Finally, using functional evidence from cardiac myocytes, and histological evidence from smooth muscle, we shall explore whether Ca2+ channels, RyR channels, and KCa channels function as a coupled unit, through Ca2+ and voltage, to regulate arterial smooth muscle membrane potential and vascular tone.

Animals↗
PubMed1998

Frequency modulation of Ca2+ sparks is involved in regulation of arterial diameter by cyclic nucleotides.

Forskolin, which elevates cAMP levels, and sodium nitroprusside (SNP) and nicorandil, which elevate cGMP levels, increased, by two- to threefold, the frequency of subcellular Ca2+ release ("Ca2+ sparks") through ryanodine-sensitive Ca2+ release (RyR) channels in the sarcoplasmic reticulum (SR) of myocytes isolated from cerebral and coronary arteries of rats. Forskolin, SNP, nicorandil, dibutyryl-cAMP, and adenosine increased the frequency of Ca(2+)-sensitive K+ (KCa) currents ["spontaneous transient outward currents" (STOCs)] by two- to threefold, consistent with Ca2+ sparks activating STOCs. These agents also increased the mean amplitude of STOCs by 1.3-fold, an effect that could be explained by activation of KCa channels, independent of effects on Ca2+ sparks. To test the hypothesis that cAMP could act to dilate arteries through activation of the Ca2+ spark-->KCa channel pathway, the effects of blockers of KCa channels (iberiotoxin) and of Ca2+ sparks (ryanodine) on forskolin-induced dilations of pressurized cerebral arteries were examined. Forskolin-induced dilations were partially inhibited by iberiotoxin and ryanodine (with no additive effects) and were entirely prevented by elevating external K+. Forskolin lowered average Ca2+ in pressurized arteries while increasing ryanodine-sensitive, caffeine-induced Ca2+ transients. These experiments suggest a new mechanism for cyclic nucleotide-mediated dilations through an increase in Ca2+ spark frequency, caused by effects on SR Ca2+ load and possibly on the RyR channel, which leads to increased STOC frequency, membrane potential hyperpolarization, closure of voltage-dependent Ca2+ channels, decrease in arterial wall Ca2+, and, ultimately, vasodilation.

Animals↗
PubMed1998

Voltage dependence of Ca2+ sparks in intact cerebral arteries.

Ca2+ sparks have been previously described in isolated smooth muscle cells. Here we present the first measurements of local Ca2+ transients ("Ca2+ sparks") in an intact smooth muscle preparation. Ca2+ sparks appear to result from the opening of ryanodine-sensitive Ca2+ release (RyR) channels in the sarcoplasmic reticulum (SR). Intracellular Ca2+ concentration ([Ca2+]i) was measured in intact cerebral arteries (40-150 micron in diameter) from rats, using the fluorescent Ca2+ indicator fluo 3 and a laser scanning confocal microscope. Membrane potential depolarization by elevation of external K+ from 6 to 30 mM increased Ca2+ spark frequency (4. 3-fold) and amplitude (approximately 2-fold) as well as global arterial wall [Ca2+]i (approximately 1.7-fold). The half time of decay ( approximately 50 ms) was not affected by membrane potential depolarization. Ryanodine (10 microM), which inhibits RyR channels and Ca2+ sparks in isolated cells, and thapsigargin (100 nM), which indirectly inhibits RyR channels by blocking the SR Ca2+-ATPase, completely inhibited Ca2+ sparks in intact cerebral arteries. Diltiazem, an inhibitor of voltage-dependent Ca2+ channels, lowered global [Ca2+]i and Ca2+ spark frequency and amplitude in intact cerebral arteries in a concentration-dependent manner. The frequency of Ca2+ sparks (<1 s-1 . cell-1), even under conditions of steady depolarization, was too low to contribute significant amounts of Ca2+ to global Ca2+ in intact arteries. These results provide direct evidence that Ca2+ sparks exist in quiescent smooth muscle cells in intact arteries and that changes of membrane potential that would simulate physiological changes modulate both Ca2+ spark frequency and amplitude in arterial smooth muscle.

Animals↗
PubMed1998

Voltage-dependent K+ currents in smooth muscle cells from mouse gallbladder.

The ionic mechanisms associated with the control of gallbladder contractility are incompletely understood. One type of K+ current, the voltage-dependent K+ (KV) current, is relatively uncharacterized in gallbladder cells and may contribute to muscular excitability. The main focus of this study was therefore to determine the voltage dependence and pharmacological nature of this K+ current in isolated myocytes from mouse gallbladder, using the patch-clamp technique. Currents through Ca(2+)-activated K+ channels were minimized by buffering of intracellular Ca2+ (20 nM free Ca2+) and by inclusion of 1 mM tetraethylammonium (TEA+) in the bathing solution. With 140 mM symmetrical K+, membrane depolarization increased K+ currents, independent of driving force, as assessed by tail current analysis. Half-maximal activation of K+ currents occurred at approximately 1 mV and increased e-fold per 9 mV. Inactivation also increased on depolarization, with a midpoint of -24 mV. Single KV channels were recorded in the cell-attached configuration, exhibiting a single-channel conductance of 4.9 pS. TEA+ at 10 mM reduced KV currents by 36%. At +50 mV, 1 mM and 10 mM 4-aminopyridine inhibited currents by 18% and 35%, respectively, whereas 1 and 10 mM 3,4-diaminopyridine inhibited currents by 11% and 21%, respectively. Quinine inhibited KV currents (at +50 mV, 100 microM and 1 mM quinine inhibited current by 24% and 70%, respectively). In summary, we describe voltage-activated K+ currents from the mouse gallbladder that are likely to contribute to the control of muscular excitability.

Aminopyridines↗
PubMed1997

Chloride channel blockers inhibit myogenic tone in rat cerebral arteries.

1. We have investigated the role of chloride channels in pressure-induced depolarization and contraction of cerebral artery smooth muscle cells. 2. Two chloride channel blockers, indanyloxyacetic acid (IAA-94) and 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS), caused hyperpolarizations (10-15 mV) and dilatations (up to 90%) of pressurized (80 mmHg), rat posterior cerebral arteries. Niflumic acid, a blocker of calcium-activated chloride channels, did not affect arterial tone. 3. Dilatations to IAA-94 and DIDS were unaffected by potassium channel blockers, but were prevented by elevated potassium. IAA-94 and DIDS had no effect on membrane potential or diameter of arteries at low intravascular pressure, where myogenic tone is absent. Reduction of extracellular chloride (60 mM Cl-) increased the pressure-induced contractions. Removal of extracellular sodium did not affect the pressure-induced responses. 4. Our results suggest that intravascular pressure activates DIDS- and IAA-94-sensitive chloride channels to depolarize arterial smooth muscle, thereby contributing to the myogenic constriction.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1997

Ca(2+)-activated K+ channels regulate action potential repolarization in urinary bladder smooth muscle.

The goal of this study was to examine the role of large conductance Ca(2+)-activated K+ channels in the regulation of cell excitability in urinary bladder smooth muscle from the guinea pig. Ca(2+)-activated K+ channels were studied with single-channel recording techniques and found to be intracellular Ca2+ and voltage dependent and sensitive to external tetraethylammonium and blocked by nanomolar concentrations of iberiotoxin (apparent dissociation constant of 4 nM). Spontaneous action potentials recorded from intact tissue strips depended on external Ca2+ and were inhibited by Ca2+ channel blockers. Iberiotoxin (100 nM) significantly altered the configuration of the action potential by increasing the duration and peak amplitude of the action potential and decreasing the rate of decay. Iberiotoxin also increased the action potential frequency from 0.11 to 0.29 Hz. This study suggests that Ca(2+)-activated K+ channels play a significant role in the repolarization of the action potential and in the maintenance of the resting membrane potential of the urinary bladder smooth muscle.

Action Potentials↗
PubMed1997

Activators of protein kinase C decrease Ca2+ spark frequency in smooth muscle cells from cerebral arteries.

Local Ca2+ transients ("Ca2+ sparks") caused by the opening of one or the coordinated opening of a number of tightly clustered ryanodine-sensitive Ca(2+)-release (RyR) channels in the sarcoplasmic reticulum (SR) activate nearby Ca(2+)-dependent K+ (KCa) channels to cause an outward current [referred to as a "spontaneous transient outward current" (STOC)]. These KCa currents cause membrane potential hyperpolarization of arterial myocytes, which would lead to vasodilation through decreasing Ca2+ entry through voltage-dependent Ca2+ channels. Therefore, modulation of Ca2+ spark frequency should be a means to regulation of KCa channel currents and hence membrane potential. We examined the frequency modulation of Ca2+ sparks and STOCs by activation of protein kinase C (PKC). The PKC activators, phorbol 12-myristate 13-acetate (PMA; 10 nM) and 1,2-dioctanoyl-sn-glycerol (1 microM), decreased Ca2+ spark frequency by 72% and 60%, respectively, and PMA reduced STOC frequency by 83%. PMA also decreased STOC amplitude by 22%, which could be explained by an observed reduction (29%) in KCa channel open probability in the absence of Ca2+ sparks. The reduction in STOC frequency occurred in the presence of an inorganic blocker (Cd2+) of voltage-dependent Ca2+ channels. The reduction in Ca2+ spark frequency did not result from SR Ca2+ depletion, since caffeine-induced Ca2+ transients did not decrease in the presence of PMA. These results suggest that activators of PKC can modulate the frequency of Ca2+ sparks, through an effect on the RyR channel, which would decrease STOC frequency (i.e., KCa channel activity).

Animals↗
PubMed1997

ATP-sensitive and inwardly rectifying potassium channels in smooth muscle.

The properties and roles of ATP-sensitive (KATP) and inwardly rectifying (KIR) potassium channels are reviewed. Potassium channels regulate the membrane potential of smooth muscle, which controls calcium entry through voltage-dependent calcium channels, and thereby contractility through changes in intracellular calcium. The KATP channel is likely to be composed of members of the inward rectifier channel gene family (Kir6) and sulfonylurea receptor proteins. The KIR channels do not appear to be as widely distributed as KATP channels in smooth muscle and may provide a mechanism by which changes in extracellular K+ can alter smooth muscle membrane potential, and thereby arterial diameter. The KATP channels contribute to the resting membrane conductance of some types of smooth muscle and can open under situations of metabolic compromise. The KATP channels are targets of a wide variety of vasodilators and constrictors, which act, respectively, through adenosine 3',5'-cyclic monophosphate/protein kinase A and protein kinase C. The KATP channels are also activated by a number of synthetic vasodilators (e.g., diazoxide and pinacidil) and are inhibited by the oral hypoglycemic sulfonylurea drugs (e.g., glibenclamide). Together, KATP and KIR channels are important regulators of smooth muscle function and represent important therapeutic targets.

Adenosine Triphosphate↗
PubMed1997

Voltage-dependent Ca2+ channels in arterial smooth muscle cells.

The past years have seen some significant advances in our understanding of the functional and molecular properties of voltage-dependent Ca2+ channels in arterial smooth muscle. Molecular cloning and expression studies together with experiments on native voltage-dependent Ca2+ channels revealed that these channels are built upon a molecular structure with properties appropriate to function as the main source for Ca2+ entry into arterial smooth muscle cells. This Ca2+ entry regulates intracellular free Ca2+, and thereby arterial tone. We summarize several avenues of recent research that should provide significant insights into the functioning of voltage-dependent Ca2+ channels under conditions that occur in arterial smooth muscle. These experiments have identified important features of voltage-dependent Ca2+ channels, including the steep steady-state voltage-dependence of the channel open probability at steady physiological membrane potentials between -60 and -30 mV, and a relatively high permeation rate at physiological Ca2+ concentrations, being about one million Ca2+ ions/s at -50 mV. This calcium permeation rate seems to be a feature of the pore-forming Ca2+ channel alpha1 subunit, since it was identical for native channels and the expressed alpha1 subunit alone. The channel activity is regulated by dihydropyridines, vasoactive hormones and intracellular signaling pathways. While the membrane potential of smooth muscle cells primarily regulates arterial muscle tone through alterations in Ca2+ influx through dihydropyridine-sensitive voltage-dependent ('L-type') Ca2+ channels, the role of these channels in the differentiation and proliferation of vascular smooth muscle cells is less clear. We discuss recent findings suggesting that other Ca2+ permeable ion channels might be important for the control of Ca2+ influx in dedifferentiated vascular smooth muscle cells.

Animals↗
PubMed1997

Increased myogenic tone and diminished responsiveness to ATP-sensitive K+ channel openers in cerebral arteries from diabetic rats.

Diabetes mellitus has profound adverse effects on vascular and, in particular, endothelial function. Although pressure-induced constriction ("myogenic tone") is a major contributor to the regulation of blood flow, little is known about the effects of diabetes on this response. Diabetes has been shown to diminish the dilation of cerebral arteries to synthetic ATP-sensitive K+ (KATP) channel openers. In this study, we explored the effects of diabetes induced in rats by streptozotocin on cerebral artery (250 to 300 microns) myogenic tone and on vasodilations to the synthetic KATP channel openers pinacidil and levcromakalim. Elevation of intravascular pressure caused a graded membrane potential depolarization and constriction, which was greater in arteries from diabetic rats compared with normal rats (at 60 mm Hg, 5 mV more depolarized and 22 microns more constricted). Pressurized arteries (at 60 mm Hg) from diabetic rats were 5- to 15-fold less sensitive to pinacidil and levcromakalim than were control arteries (EC50 values for pinacidil and levcromakalim were 1.4 and 0.6 mumol/L, respectively, in diabetic animals and 0.3 and 0.04, respectively, in control animals; P < .05). Removal of the endothelium or addition of a NO synthase inhibitor, NG-nitro-L-arginine (LNNA), in control arteries decreased the sensitivity to KATP channel openers and depolarized and constricted control arteries to levels similar to those observed in arteries from diabetic animals. Sodium nitroprusside caused a membrane potential hyperpolarization and enhanced the response to pinacidil in arteries from diabetic animals. Removal of the endothelium or LNNA had little effect on the apparent KATP channel opener sensitivity, the membrane potential, and pressure-induced constrictions of arteries from diabetic animals. The results are consistent with the hypothesis that this type of diabetes leads to a decrease in tonic NO release from the endothelium, which in turn causes membrane potential depolarization and vasoconstriction, resulting in a diminished response to KATP channel openers.

Acetylcholine↗
PubMed1996

Extracellular K(+)-induced hyperpolarizations and dilatations of rat coronary and cerebral arteries involve inward rectifier K(+) channels.

1. The hypothesis that inward rectifier K(+) channels are involved in the vasodilatation of small coronary and cerebral arteries (100-200 microm diameter) in response to elevated [K+]o was tested. The diameters and membrane potentials of pressurized arteries from rat were measured using a video-imaging system and conventional microelectrodes, respectively. 2. Elevation of [K+]o from 6 to 16 mM caused the membrane potential of pressurized (60 mmHg) arteries to hyperpolarize by 12-14 mV. Extracellular Ba(2+) (Ba2+(o)) blocked K(+)-induced membrane potential hyperpolarizations at concentrations (IC(50), 6 microM) that block inward rectifier K(+) currents in smooth muscle cells isolated from these arteries. 3. Elevation of [K+]o from 6 to 16 mM caused sustained dilatations of pressurized coronary and cerebral arteries with diameters increasing from 125 to 192 microm and 110 to 180 microm in coronary and cerebral arteries, respectively. Ba2+(o) blocked K(+)-induced dilatations of pressurized coronary and cerebral arteries (IC50, 3-8 microM). 4. Elevated [K+]o-induced vasodilatation was not prevented by blockers of other types of K(+) channels (1 mM 4-aminopyridine, 1 mM TEA+, and 10 mu M glibenclamide), and blockers of Na(+)-K(+)-ATPase. Elevated [K+]o-induced vasodilatation was unaffected by removal of the endothelium. 5. These findings suggest that K+(o) dilates small rat coronary and cerebral arteries through activation of inward rectifier K(+) channels. Furthermore, these results support the hypothesis that inward rectifier K(+) channels may be involved in metabolic regulation of coronary and cerebral blood flow in response to changes in [K+]o.

Animals↗
PubMed1996

Ca2+ currents in cerebral artery smooth muscle cells of rat at physiological Ca2+ concentrations.

Single Ca2+ channel and whole cell currents were measured in smooth muscle cells dissociated from resistance-sized (100-microns diameter) rat cerebral arteries. We sought to quantify the magnitude of Ca2+ channel currents and activity under the putative physiological conditions of these cells: 2 mM [Ca2+]o, steady depolarizations to potentials between -50 and -20 mV, and (where possible) without extrinsic channel agonists. Single Ca2+ channel conductance was measured over a broad range of Ca2+ concentrations (0.5-80 mM). The saturating conductance ranged from 1.5 pS at 0.5 mM to 7.8 pS at 80 mM, with a value of 3.5 pS at 2 mM Ca (unitary currents of 0.18 pA at -40 mV). Both single channel and whole cell Ca2+ currents were measured during pulses and at steady holding potentials. Ca2+ channel open probability and the lower limit for the total number of channels per cell were estimated by dividing the whole-cell Ca2+ currents by the single channel current. We estimate that an average cell has at least 5,000 functional channels with open probabilities of 3.4 x 10(-4) and 2 x 10(-3) at -40 and -20 mV, respectively. An average of 1-10 (-40 mV and -20 mV, respectively) Ca2+ channels are thus open at physiological potentials, carrying approximately 0.5 pA steady Ca2+ current at -30 mV. We also observed a very slow reduction in open probability during steady test potentials when compared with peak pulse responses. This 4-10-fold reduction in activity could not be accounted for by the channel's normal inactivation at our recording potentials between -50 and -20 mV, implying that an additional slow inactivation process may be important in regulating Ca2+ channel activity during steady depolarization.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1996

Vasoconstrictors inhibit ATP-sensitive K+ channels in arterial smooth muscle through protein kinase C.

The effects of vasoconstrictor-receptor (neuropeptide Y, alpha-adrenergic, serotonergic, histaminergic) stimulation on currents through ATP-sensitive potassium (KATP) channels in arterial smooth muscle cells were examined. Whole-cell KATP currents, activated by the synthetic KATP channel opener pinacidil or by the endogenous vasodilator, calcitonin gene-related peptide, which acts through protein kinase A, were measured in smooth muscle cells isolated from mesenteric arteries of rabbit. Stimulation of NPY-, alpha 1-, serotonin (5-HT2)-, and histamine (H1)-receptors inhibited KATP currents by 40-56%. The signal transduction pathway that links these receptors to KATP channels was investigated. An inhibitor of phospholipase C (D609) and of protein kinase C (GF 109203X) reduced the inhibitory effect of these vasoconstrictors on KATP currents from 40-56% to 11-23%. Activators of protein kinase C, a diacylglycerol analogue and phorbol 12-myristate 13-acetate (PMA), inhibited KATP currents by 87.3 and 84.2%, respectively. KATP currents, activated by calcitonin gene-related peptide, were also inhibited (47-87%) by serotonin, phenylephrine, and PMA. We propose that KATP channels in these arterial myocytes are subject to dual modulation by protein kinase C (inhibition) and protein kinase A (activation).

Adenosine Triphosphate↗
PubMed1996

A proposed mechanism for the cardioprotective effect of oestrogen in women: enhanced endothelial nitric oxide release decreases coronary artery reactivity.

1. During their reproductive years women have a much lower incidence of coronary heart disease than men of similar age. A cardioprotective effect of circulating oestrogen appears to be responsible for this decrease in cardiovascular mortality in women. 2. Oestrogen can enhance nitric oxide (NO) production by the vascular endothelium, possibly through enhanced production of the enzyme NO synthase. 3. Pressure-induced constrictions in isolated coronary arteries from rats with physiological circulating levels of oestrogen are reduced compared to oestrogen-deficient animals. This difference is abolished by endothelial removal or inhibition of NO synthase. 4. NO through stimulation of guanylyl cyclase increases levels of the cytosolic second messenger cyclic GMP (cGMP) which activates a cGMP-dependent protein kinase in vascular smooth muscle cells. 5. Potassium currents through calcium-activated channels in vascular smooth muscle cells are increased in response to NO or upon exposure to cGMP-dependent protein kinase. 6. In rat coronary arteries dilations to NO are reduced by agents which inhibit calcium-activated potassium channels. NO can also hyperpolarize this tissue, suggesting membrane potential changes are involved in the response to NO. 7. We propose that oestrogen increases NO production leading to more negative membrane potentials and decreased calcium entry in coronary vascular smooth muscle cells.

Animals↗