Biomedical subjects

Timothy R Nurkiewicz

Publications and source records attributed to Timothy R Nurkiewicz.

6 recordsLinked to original sources

PubMed2006

High salt intake reduces endothelium-dependent dilation of mouse arterioles via superoxide anion generated from nitric oxide synthase.

In skeletal muscle arterioles of normotensive rats fed a high salt diet, the bioavailability of endothelium-derived nitric oxide (NO) is reduced by superoxide anion. Because the impact of dietary salt on resistance vessels in other species is largely unknown, we investigated endothelium-dependent dilation and oxidant activity in spinotrapezius muscle arterioles of C57BL/6J mice fed normal (0.45%, NS) or high salt (7%, HS) diets for 4 wk. Mean arterial pressure in HS mice was not different from that in NS mice, but the magnitude of arteriolar dilation in response to different levels of ACh was 42-57% smaller in HS mice than in NS mice. Inhibition of nitric oxide synthase (NOS) with N(G) monomethyl L-arginine (L-NMMA) significantly reduced resting diameters and reduced responses to ACh (by 45-63%) in NS mice but not in HS mice. Arteriolar wall oxidant activity, as assessed by tetranitroblue tetrazolium reduction or hydroethidine oxidation, was greater in HS mice than in NS mice. Exposure to the superoxide scavenger 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) + catalase reduced this oxidant activity to normal and restored normal arteriolar responsiveness to ACh in HS mice but had no effect in NS mice. L-NMMA also restored arteriolar oxidant activity to normal in HS mice. ACh further increased arteriolar oxidant activity in HS mice but not in NS mice, and this effect was prevented with L-NMMA. These data suggest that a high salt diet promotes increased generation of superoxide anion from NOS in the murine skeletal muscle microcirculation, thus impairing endothelium-dependent dilation through reduced NO bioavailability.

Acetylcholine↗

PubMed2006

Systemic microvascular dysfunction and inflammation after pulmonary particulate matter exposure.

The epidemiologic association between pulmonary exposure to ambient particulate matter (PM) and cardiovascular dysfunction is well known, but the systemic mechanisms that drive this effect remain unclear. We have previously shown that acute pulmonary exposure to PM impairs or abolishes endothelium-dependent arteriolar dilation in the rat spinotrapezius muscle. The purpose of this study was to further characterize the effect of pulmonary PM exposure on systemic microvascular function and to identify local inflammatory events that may contribute to these effects. Rats were intratracheally instilled with residual oil fly ash (ROFA) or titanium dioxide at 0.1 or 0.25 mg/rat 24 hr before measurement of pulmonary and systemic microvascular responses. In vivo microscopy of the spinotrapezius muscle was used to study systemic arteriolar responses to intraluminal infusion of the Ca2+ ionophore A23187 or iontophoretic abluminal application of the adrenergic agonist phenylephrine (PHE). Leukocyte rolling and adhesion were quantified in venules paired with the studied arterioles. Histologic techniques were used to assess pulmonary inflammation, characterize the adherence of leukocytes to systemic venules, verify the presence of myeloperoxidase (MPO) in the systemic microvascular wall, and quantify systemic microvascular oxidative stress. In the lungs of rats exposed to ROFA or TiO2, changes in some bronchoalveolar lavage markers of inflammation were noted, but an indication of cellular damage was not found. In rats exposed to 0.1 mg ROFA, focal alveolitis was evident, particularly at sites of particle deposition. Exposure to either ROFA or TiO2 caused a dose-dependent impairment of endothelium-dependent arteriolar dilation. However, exposure to these particles did not affect microvascular constriction in response to PHE. ROFA and TiO2 exposure significantly increased leukocyte rolling and adhesion in paired venules, and these cells were positively identified as polymorphonuclear leukocytes (PMNLs). In ROFA- and TiO2-exposed rats, MPO was found in PMNLs adhering to the systemic microvascular wall. Evidence suggests that some of this MPO had been deposited in the microvascular wall. There was also evidence for oxidative stress in the microvascular wall. These results indicate that after PM exposure, the impairment of endothelium-dependent dilation in the systemic microcirculation coincides with PMNL adhesion, MPO deposition, and local oxidative stress. Collectively, these microvascular observations are consistent with events that contribute to the disruption of the control of peripheral resistance and/or cardiac dysfunction associated with PM exposure.

Air Pollutants↗

PubMed2005

Reduced arteriolar responses to skeletal muscle contraction after ingestion of a high salt diet.

We previously reported that in skeletal muscle arterioles of rats fed a very high salt (HS; 7%) diet, the bioavailability of endothelium-derived nitric oxide (NO) is reduced through scavenging by reactive oxygen species. Because arteriolar NO can play an important role in local blood flow control, we investigated whether arteriolar responses to increased tissue metabolism become compromised in skeletal muscle of salt-fed rats. Consumption of a HS (4%) diet for 4 weeks had no effect on arteriolar diameters, volume flow or shear stress in resting spinotrapezius muscle. Arteriolar responses to a modest elevation in metabolic demand (0.5 Hz contraction) were not different from those in rats fed a normal diet, but diameter responses to a greater elevation in metabolic demand (4 Hz contraction) were significantly less in HS rats than in rats fed a normal diet. In both groups, the NO synthase inhibitor N(G)-monomethyl-L-arginine reduced resting arteriolar diameters and flow by a similar amount and had little or no effect on arteriolar diameter or flow responses to muscle contraction. Arterioles in HS rats exhibited an increase in overall oxidant activity (tetranitroblue tetrazolium reduction) but not in superoxide activity (dihydroethidine oxidation). Reactive oxygen species scavengers (2,2,6,6-tetramethylpiperidine-N-oxyl and catalase) did not normalize the reduced arteriolar responses to muscle contraction in HS rats. These findings suggest that increased oxidant activity in the arteriolar network of salt-fed rats is not due to accumulation of superoxide anion and that neither this oxidant activity nor reduced NO availability can account for the blunted active arteriolar dilation in rats fed a 4% salt diet.

Animals↗

PubMed2004

Calcium-independent release of endothelial nitric oxide in the arteriolar network: onset during rapid juvenile growth.

OBJECTIVE: In young rats, skeletal muscle arterioles respond to acetylcholine, which elicits Ca2+-dependent endothelial nitric oxide (NO) release, but not to shear stress, which does not require increased intracellular Ca2+ for endothelial NO release. The aim of this study was to determine if, in general, signaling pathways for endothelial NO release that differ in their reliance on Ca2+ may be developing at different times during normal arteriolar network growth in skeletal muscle. METHODS: Arteriolar responses to intraluminal infusion of the Ca2+ ionophore A23187, and the Ca2+-independent agonists vascular endothelial growth factor (VEGF) and simvastatin, were studied before and during NO synthase (NOS) inhibition with NG-monomethyl-L-arginine (L-NMMA) in the exteriorized spinotrapezius muscle of weanling (age 4-5 wks) and juvenile (7-8 wks) rats. RESULTS: There were no age-dependent differences in arteriolar responses to A23187 applied over a concentration range that dilated arterioles from 9 +/- 2 to 74 +/- 8% of maximum, and L-NMMA attenuated these responses by the same amount in both age groups. In juveniles, arterioles dilated up to 39+/-5% of maximum in response to VEGF, and up to 83 +/- 6% of maximum in response to simvastatin, with L-NMMA greatly reducing the responses to both agonists. In contrast, arterioles in weanlings did not dilate in response to either agonist. CONCLUSIONS: These findings suggest that some Ca2+-independent signaling pathways for endothelial NO release may not initially be operational in the arteriolar network, but quickly become established during juvenile growth. This is consistent with the idea that microvascular control mechanisms are not fixed at birth, but rather undergo progressive changes in concert with microvascular network growth and changes in tissue metabolic requirements.

Animals↗

PubMed2004

Particulate matter exposure impairs systemic microvascular endothelium-dependent dilation.

Acute exposure to airborne pollutants, such as solid particulate matter (PM), increases the risk of cardiovascular dysfunction, but the mechanisms by which PM evokes systemic effects remain to be identified. The purpose of this study was to determine if pulmonary exposure to a PM surrogate, such as residual oil fly ash (ROFA), affects endothelium-dependent dilation in the systemic microcirculation. Rats were intratracheally instilled with ROFA at 0.1, 0.25, 1 or 2 mg/rat 24 hr before experimental measurements. Rats intratracheally instilled with saline or titanium dioxide (0.25 mg/rat) served as vehicle or particle control groups, respectively. In vivo microscopy of the spinotrapezius muscle was used to study systemic arteriolar dilator responses to the Ca2+ ionophore A23187, administered by ejection via pressurized micropipette into the arteriolar lumen. We used analysis of bronchoalveolar lavage (BAL) samples to monitor identified pulmonary inflammation and damage. To determine if ROFA exposure affected arteriolar nitric oxide sensitivity, sodium nitroprusside was iontophoretically applied to arterioles of rats exposed to ROFA. In saline-treated rats, A23187 dilated arterioles up to 72 +/- 7% of maximum. In ROFA- and TiO2-exposed rats, A23187-induced dilation was significantly attenuated. BAL fluid analysis revealed measurable pulmonary inflammation and damage after exposure to 1 and 2 mg ROFA (but not TiO2 or < 1 mg ROFA), as evidenced by significantly higher polymorphonuclear leukocyte cell counts, enhanced BAL albumin levels, and increased lactate dehydrogenase activity in BAL fluid. The sensitivity of arteriolar smooth muscle to NO was similar in saline-treated and ROFA-exposed rats, suggesting that pulmonary exposure to ROFA affected endothelial rather than smooth muscle function. A significant increase in venular leukocyte adhesion and rolling was observed in ROFA-exposed rats, suggesting local inflammation at the systemic microvascular level. These results indicate that pulmonary PM exposure impairs systemic endothelium-dependent arteriolar dilation. Moreover, because rats exposed to < 1 mg ROFA or TiO2 did not exhibit BAL signs of pulmonary damage or inflammation, it appears that PM exposure can impair systemic microvascular function independently of detectable pulmonary inflammation.

Air Pollutants↗

PubMed2002

Regulation of ion channels by integrins.

Ion channels are regulated by protein phosphorylation and dephosphorylation of serine, threonine, and tyrosine residues. Evidence for regulation of channels by tyrosine phosphorylation comes primarily from investigations of the effects of growth factors, which act through receptor tyrosine kinases. The purpose of the present work is to summarize evidence for the regulation of ion channels by integrins, through their downstream, nonreceptor tyrosine kinases. We review both direct and indirect evidence for this regulation, with particular emphasis on Ca2+-activated K+ and voltage-gated Ca2+ channels. We then discuss the critical roles that cytoskeletal, focal-adhesion, and channel-associated scaffolding proteins may play in localizing nonreceptor tyrosine kinases to the vicinity of ion channels. We conclude by speculating on the physiological significance of these regulatory pathways.

Animals↗