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Biomedical subjects

Gregory P Victorino

Publications and source records attributed to Gregory P Victorino.

At least 19 recordsLinked to original sources
PubMed2006

Angiotensin II effect on hydraulic permeability: interaction with endothelin-1, nitric oxide, and platelet activating factor.

BACKGROUND: The purposes of this study were: 1) to examine the influence of endothelin (ET-1) release on the ability of angiotensin (Ang) II to modulate permeability, 2) to determine if the action of Ang II on microvascular permeability is dependent on nitric oxide (NO) release, and 3) to explore the effect of Ang II in microvessels activated with platelet activating factor (PAF). METHODS: Hydraulic permeability (L(p)) was measured using the modified Landis in vivo micro occlusion technique during perfusion with: 1) the ET-1 receptor antagonist PD145065 (50 microM), then PD145065 + Ang II, 2) Ang II (20 nm), a NO synthase inhibitor L-NAME (100 microM), then L-NAME + Ang II, and 3) after endothelial activation with 10 nM of PAF, then PAF + Ang II. RESULTS: 1) The ET-1 antagonist increased L(p) 2.5-fold, Ang II alone increased L(p) five-fold, while Ang II perfusion during ET-1 antagonism increased L(p) over 6-fold (P < 0.04); 2) L-NAME increased L(p) over 3-fold. Ang II perfusion during NO synthase inhibition had no effect compared to NO synthase inhibition alone (P = 0.9) while Ang II alone increased L(p) 5-fold (P < or = 0.01); 3) PAF + Ang II (L(p) = 2.74 +/- 0.12) was decreased versus PAF alone (L(p) = 4.66 +/- 0.25) (P < 0.02). CONCLUSIONS: Ang II does not increase hydraulic permeability via ET-1 release. Ang II may act via NO release to increase hydraulic permeability in the basal state. Finally, Ang II attenuates the increase in hydraulic permeability because of endothelial activation with platelet activating factor.

Angiotensin II↗
PubMed2006

Role of endothelin-1 and cyclic nucleotides in ischemia/reperfusion-mediated microvascular leak.

BACKGROUND: A consequence of ischemia/reperfusion (IR) is endothelial barrier dysfunction and intravascular volume loss. The purposes of our study are to explore the impact of: 1) cyclic guanosine monophosphate (cGMP) synthesis inhibition, 2) cyclic adenosine monophosphate (cAMP) synthesis inhibition, 3) treatment with endothelin-1, and 4) endothelin-1 (ET-1)-mediated cAMP changes on IR-induced fluid leak. We hypothesize that IR-mediated microvascular fluid leak results from increased cGMP activity and ET-1 decreases IR-induced fluid leak via cAMP. METHODS: A micro-cannulation technique was used to determine fluid leak or hydraulic permeability (Lp) in rat mesenteric venules. Lp was measured during IR and after treatment with 1) cGMP synthesis inhibitor (LY83583,10 micromol/L) 2) cAMP synthesis inhibitor (2',5'dideoxyadenosine,10 micromol/L), 3) ET-1 (80 pM), and 4) cAMP synthesis inhibitor plus ET-1 (n=6 in each group; Lp represented as mean+/-standard error of the mean; units 10-cm/sec/cmH2O). RESULTS: IR resulted in an increase in Lp (Lp=7.07+/-0.20) sevenfold above baseline (1.05+/-0.31) (p<or=0.001). Compared with IR alone, 1) pretreatment with cGMP synthesis inhibitor completely blocked IR-induced fluid leak (Lp=1.08+/-0.18) (p<or=0.001), 2) pretreatment with cAMP synthesis inhibitor attenuated fluid leak (Lp=3.92+/-0.20) (p<or=0.005), 3) treatment with ET-1 decreased fluid leak (Lp=5.38+/-0.28) (p<or=0.005), and 4) pretreatment with a cAMP inhibitor plus treatment with ET-1 reduced fluid leak nearly 50% compared with ET-1 alone (Lp=2.95+/-0.12) (p<or=0.005). CONCLUSION: cGMP inhibition completely blocks fluid leak, pointing toward a central role as a mediator of IR-induced postcapillary venular leak. ET-1 mildly decreased leak. Furthermore, ET-1 may not exert its effects on microvascular fluid leak during IR via cAMP.

Animals↗
PubMed2006

Admission serum lactate levels do not predict mortality in the acutely injured patient.

INTRODUCTION: The conventional view that admission lactate levels predict outcome in trauma patients stems from simple comparisons of mean blood levels between groups and small sample sizes. To better address this question, we performed more rigorous statistical analyses of lactate in a larger patient sample. METHODS: We prospectively collected data on admission lactate and outcomes in 5,995 patients admitted to an urban, university-based trauma center. The ability of admission lactate to predict mortality was assessed by logistic regression, calculation of positive predictive values (PPV), and measurement of areas under receiver operating characteristic (ROC) curves. RESULTS: Differences between survivors and nonsurvivors in means of most proposed prognosticators was again demonstrated. However, the large overlap in these variables between survivors and nonsurvivors prevented clinically useful predictions. The overall PPV of elevated lactate was only 5.4%. Even in severely injured patients (Injury Severity Score >20; mortality 23%), elevated admission lactate level was a poor predictor of outcome. ROC analyses found no useful sensitivity threshold overall or after stratification by age, sex, Glasgow Coma Scale score, revised trauma score, or mechanism of injury. CONCLUSIONS: This large retrospective examination of admission lactate levels failed to show useful predictive accuracy for hospital death. Serum lactate levels need not be obtained routinely but can be reserved for patients who will be admitted to the intensive care unit and/or require an emergency operation.

Adult↗
PubMed2005

Hydrolysis of phosphatidylserine-exposing red blood cells by secretory phospholipase A2 generates lysophosphatidic acid and results in vascular dysfunction.

Secretory phospholipase A(2) (sPLA(2)) type IIa, elevated in inflammation, breaks down membrane phospholipids and generates arachidonic acid. We hypothesized that sPLA(2) will hydrolyze red blood cells that expose phosphatidylserine (PS) and generate lysophosphatidic acid (LPA) from phosphatidic acid that is elevated in PS-exposing red blood cells. In turn, LPA, a powerful lipid mediator, could affect vascular endothelial cell function. Although normal red blood cells were not affected by sPLA(2), at levels of sPLA(2) observed under inflammatory conditions (100 ng/ml) PS-exposing red blood cells hemolyzed and generated LPA (1.2 nM/10(8) RBC). When endothelial cell monolayers were incubated in vitro with LPA, a loss of confluence was noted. Moreover, a dose-dependent increase in hydraulic conductivity was identified in rat mesenteric venules in vivo with 5 microM LPA, and the combination of PS-exposing red blood cells with PLA(2) caused a similar increase in permeability. In the presence of N-palmitoyl L-serine phosphoric acid, a competitive inhibitor for the endothelial LPA receptor, loss of confluence in vitro and the hydraulic permeability caused by 5 microM LPA in vivo were abolished. The present study demonstrates that increased sPLA(2) activity in inflammation in the presence of cells that have lost their membrane phospholipid asymmetry can lead to LPA-mediated endothelial dysfunction and loss of vascular integrity.

Animals↗
PubMed2005

Angiotensin II subtype AT1 and AT2 receptors regulate microvascular hydraulic permeability via cAMP and cGMP.

INTRODUCTION: Angiotensin II receptor subtypes (AT1 and AT2) have been shown to modulate microvascular fluid leak. However, their intracellular signal transduction pathways have not been elucidated. We hypothesized that AT1 activation exerts its permeability-increasing effect by provoking cGMP synthesis and inducing cAMP degradation and that AT2 activation decreases fluid leak by stimulating cAMP synthesis and enhancing cGMP degradation. METHODS: Using a microcannulation technique, hydraulic permeability (Lp) was measured in rat mesenteric venules. The messenger signal transduction of ATI was studied during continuous perfusion with the AT1 agonist, Sar1 plus either 1) a cGMP synthesis inhibitor, LY83583, or 2) an inhibitor of cAMP degradation, Rolipram. Likewise, AT2 signal transduction was studied with the AT2 agonist, CGP42112A, plus either 1) a cAMP synthesis inhibitor, dideoxyadenosine, or 2) an inhibitor of cGMP degradation, Zaprinast. Lp values are represented as mean +/- SEM x 10(-7) cm/s/cm H2O. For each group n = 6. RESULTS: Inhibition of cGMP synthesis blunted the permeability-increasing effect of AT1 agonism and decreased the peak Lp from 4.91 +/- 0.25 to 2.30 +/- 0.10 (P < 0.001). Inhibition of cAMP degradation also reduced the effect of AT1 agonism on peak L(p) from 2.25 +/- 0.22 to 1.30 +/- 0.13 (P < 0.001). Meanwhile, cAMP synthesis inhibition completely blocked the permeability-decreasing effect of AT2 agonism during which Lp increased from a baseline of 0.92 +/- 0.08 to a peak of 4.38 +/- 0.20 (P < 0.001). During inhibition of cGMP degradation, AT2 activation was able to decrease peak Lp from 2.26 +/- 0.15 to 1.46 +/- 0.05 (P < 0.001). CONCLUSIONS: When cGMP synthesis and cAMP degradation were inhibited, the effect on fluid leak by AT1 activation was blunted. Inhibition of cAMP synthesis completely blocked the effect of AT2 activation on fluid leak, while AT2 activation continued to decrease fluid leak despite inhibition of cGMP degradation. The AT1 receptor appears to increase fluid leak by stimulating both cGMP synthesis and cAMP degradation, while the AT2 receptor decreases fluid leak by stimulating cAMP synthesis, but not cGMP degradation.

Animals↗
PubMed2005

Head computed tomography scans in trauma patients with seizure disorder: justifying routine use.

HYPOTHESES: A majority of trauma patients with known seizure disorder with seizure activity were noncompliant with their medications, normal neurologic examination findings would predict negative results of head computed tomography (CT) scans, and the yield of CT scans would be insufficient to justify their routine use. DESIGN: Retrospective consecutive case series. MAIN OUTCOME MEASURES: Blood levels of antiepileptic drugs, predictive values and receiver operating characteristic curves of Glasgow Coma Scale scores, and findings on head CT. SETTING: Urban trauma center. PATIENTS: All trauma patients treated between September 1995 and June 2002 with seizure-related illness. RESULTS: The diagnosis of seizure identified 356 patients. Most (62%) had preexisting seizure disorder. Of the 101 who had antiepileptic drug levels drawn, 75% of these patients were noncompliant. The negative predictive value of a Glasgow Coma Scale score of 15 for intracranial abnormalities on CT scans was 90%. Receiver operating characteristic curve analyses of Glasgow Coma Scale score vs head CT abnormalities for all patients with seizure activity showed the area under the curve was 0.53, indicating poor discriminating ability. Intracranial abnormality was identified in 27% if the seizure resulted from injury and in 11% if the seizure preceded injury (P = .001). CONCLUSIONS: Neurologic examination is an unreliable predictor of intracranial injury in patients with seizure disorder. In trauma patients with seizure activity, the yield of CT scans in finding unsuspected intracranial abnormalities justifies its routine use regardless of prior history.

Adolescent↗
PubMed2005

Quantification of surgical resident stress "on call".

BACKGROUND: We hypothesized that surgical resident stress involves both psychologic and physiologic components that manifest as changes in heart rate (HR) and circulating white blood cell (WBC) count. The purposes of this series of experiments were to monitor HR as a measure of stress "on call"; to monitor WBC count (1,000 cells/microL) during "on call" periods as a measure of stress; and to relate maximum HR and WBC count "on call" to surgical resident training level. STUDY DESIGN: HR was continuously documented by Holter monitor for 24hours "on call" in interns (n = 6), junior residents (n = 5), and senior residents (n = 5). Interns (n = 4), junior residents (n = 4), and senior residents (n = 4) during periods devoid of clinical responsibilities served as controls. WBC counts were obtained from residents "off" and "on call" for interns (n = 5) and junior residents (n = 5). RESULTS: Mean HR "on call" increased in all resident groups as compared with controls: intern mean HR increased from 71 +/- 3 to 87 +/- 2 beats per minute (bpm) (p = 0.003), junior resident mean HR increased from 74 +/- 3 to 88 +/- 4 bpm (p = 0.03), and senior resident mean HR increased from 69 +/- 2 to 80 +/- 2 bpm (p = 0.004). Intern maximum control HR was 119 +/- 3 and increased to 149 +/- 6 bpm (p = 0.005). The increase in maximum HR (control versus "on call") did not reach significance in junior residents (123 +/- 5 to 136 +/- 6 bpm, p = 0.14) and senior residents (115 +/- 6 to 116 +/- 3 bpm, p = 0.9). WBC count in interns increased from control values of 5.2 +/- 0.6 x 1,000 cells/microL to 7.5 +/- 0.9 x 1,000 cells/microL"on call" (p = 0.005). The WBC change in juniors was not significant (control: 6.8 +/- 0.7 x 1,000 cells/microL, "on call": 7.1 +/- 0.7 x 1,000 cells/microL; p = 0.37). CONCLUSIONS: When heart rate is used as an indicator of combined physiologic and psychologic stress, surgical residents achieve stress levels of tachycardia "on call." Surgical residents also exhibit an increase in circulating WBC count "on call." Both the degree of tachycardia and the increase in WBC count are inversely related to the level of training. Senior residents cope better with stress "on call" than junior residents and interns.

Adult↗
PubMed2005

Angiotensin II type 1 receptor activation increases microvascular permeability via a calcium dependent process.

BACKGROUND: Elevated serum angiotensin II (Ang II) has been implicated in the endothelial barrier dysfunction associated with shock. We hypothesized that the increase in microvascular permeability seen with activation of the type 1 (AT1) receptor is a calcium dependent process. MATERIALS AND METHODS: Microvascular hydraulic permeability (Lp) was measured in rat mesenteric venules using the Landis micro-occlusion model. A 100 mm KCl (HK) solution was used to negate the electrochemical potential of calcium influx, and measures of Lp were obtained before and after 20 ng/ml Ang II plus HK solution (n = 5). Intracellular calcium dependence on AT1 activation was evaluated two ways: 1) Lp changes were measured in response to 10 microm of the type 1 receptor agonist [SAR] [1]-angiotensin II in HK solution (n = 6), and 2) Lp changes were measured in response to 25 microg/ml of the type 2 (AT2) receptor blocker PD-123319 (PD) plus 20 ng/ml Ang II in HK solution (n = 6). RESULTS: As expected, HK perfusion (P < 0.08) and Ang II plus HK solution (P < 0.42) did not affect Lp. Although perfusion of [SAR] [1]-angiotensin II in HK solution (P < 0.001) and PD plus Ang II in HK solution (P < 0.003) both significantly increased Lp, the magnitude of this response was less than that observed with Ang II alone. CONCLUSIONS: Abrogation of intracellular calcium influx during AT1 activation blunted the known Ang II induced increase in microvascular permeability. Although the effect observed during AT1 activation was blunted by the HK solution, a significant elevation of Lp was still observed. This suggests that Ang II activation of the AT1 receptor increases microvascular permeability primarily, but not exclusively, via modulation of endothelial intracellular calcium ion levels.

Angiotensin II↗
PubMed2005

Cyclic nucleotide second messengers (cAMP and cGMP) play a central role in signal transduction and regulation of mesenteric postcapillary fluid leak.

BACKGROUND: Endothelial cell receptors involved in post-injury/sepsis fluid extravasation are coupled to G-proteins that stimulate production of cGMP and cAMP. We hypothesize that cGMP and cAMP are endothelial second messengers that control microvascular permeability. The purposes of this series of experiments are to determine microvascular permeability under the following conditions: 1) reduced cGMP levels, 2) elevated cGMP levels, 3) reduced cAMP levels, and 4) elevated cAMP levels. METHODS: Rat mesenteric venules were cannulated and hydraulic permeability (Lp) was measured at 3 to 5 minute intervals during 1) cGMP synthesis inhibition, 2) inhibition of cGMP degradation, 3) cAMP synthesis inhibition, and 4) inhibition of cAMP degradation (n = 6 in each study group). Lp units are x10 cm(-7)/sec/cmH2O and represented as mean +/- SEM. RESULTS: Compared with baseline Lp (1.10 +/- 0.06), reduced cGMP levels by inhibiting its synthesis decreased Lp by over 50% (0.50 +/- 0.02, p < 0.001), while elevated cGMP levels by preventing its degradation increased Lp by more than 2-fold (0.91 +/- 0.10 to 2.26 +/- 0.15, p < 0.001). The reduction of cAMP levels by synthesis inhibition elevated Lp over 400% from 0.92 +/- 0.04 to 4.11 +/- 0.54 (p < 0.001), and elevation of cAMP level by blocking its degradation reduced Lp almost 50% from 1.11 +/- 0.04 to 0.59 +/- 0.06 (p < 0.001). CONCLUSIONS: The second messengers, cGMP and cAMP, contribute to the control mechanisms that govern fluid leak across the endothelial barrier: cGMP increases microvascular permeability, while cAMP decreases microvascular permeability. Endothelial cell cyclic nucleotide second messengers are pharmacologically accessible and may be targeted during post-injury/sepsis-associated microvascular fluid leak.

Aminoquinolines↗
PubMed2004

Angiotensin II type 2 receptor effect on microvascular hydraulic permeability.

BACKGROUND: Angiotensin II (Ang II) is a potent vasoconstrictor that modulates microvascular permeability. Angiotensin II type 1 (AT1) and type 2 (AT2) receptors have been described with subsequent development of their respective antagonists. We hypothesized that the AT2 receptor modulates microvascular permeability. MATERIALS AND METHODS: Hydraulic permeability (L(p)) was measured in rat mesenteric venules using the Landis micro-occlusion technique. Following baseline L(p) measurements, paired measures of microvessel L(p) were obtained after perfusion with a test solution. The test solutions consisted of the AT2 receptor agonist CGP42112A at 10 microm (n = 6), 100 microm (n = 6), and 200 microm (n = 6), as well as the AT2 receptor antagonist PD-123319 at 3 microm (n = 6), 30 microm (n = 6), 300 microm (n = 6), and 600 microm (n = 6). RESULTS: From mean baseline L(p) of 0.99 +/- 0.03, 100 microm CGP42112A decreased L(p) to 0.76 +/- 0.02 (P = 0.005), and 200 microm CGP42112A decreased L(p) to 0.61 +/- 0.02 (P < 0.001). From mean baseline L(p) of 0.90 +/- 0.05, PD-123319 increased L(p) at 30 microm to 1.60 +/- 0.2 (P = 0.003), at 300 microm to 2.28 +/- 0.3 (P = 0.008), and at 600 microm to 4.30 +/- 0.9 (P = 0.03). Units for L(p) are mean +/- SEM x 10(-7) cm s(-1) cmH(2)O(-1). CONCLUSION: AT2 activation decreased L(p), while AT2 blockade increased L(p). These changes in L(p) may be explained by (1). a permeability-decreasing effect of the AT2 receptor that is induced by AT2 activation and inhibited by AT2 blockade; and/or (2). a permeability-increasing effect of the AT1 receptor observed during AT2 blockade and selective AT1 activation by endogenous locally released Ang II. These mechanisms would support the theories that the AT1 receptor increases microvascular permeability, while the AT2 receptor decreases microvascular permeability.

Angiotensin II Type 2 Receptor Blockers↗
PubMed2004

Albumin impacts the effects of tonicity on microvascular hydraulic permeability.

BACKGROUND: An increase in tonicity shrinks endothelial cells. This cell shrinkage may open inter-endothelial gaps and allow more fluid to escape from the microvasculature. This increase in microvascular permeability is not supported by clinical studies suggesting that water is pulled into the vascular space, not lost into the interstitium. We hypothesized that albumin influences the change in trans-endothelial water movement caused by alterations in tonicity by a mechanism other than oncotic pressure. MATERIALS AND METHODS: Hydraulic permeability (L(p)) was measured in rat mesenteric venules using the Landis micro-occlusion model. Measures of L(p) were obtained after successive perfusions with 1% albumin solution (BSA) of varying sodium chloride (NaCl) concentrations (85, 135, 185, and 235 mm) (n = 6). Additional venules were perfused with 7% NaCl followed by 7% NaCl + BSA and L(p) measured (n = 6). Units for L(p) are x10(-7) cm/sec(-1) cm/H(2)O(-1). RESULTS: As the NaCl concentration in BSA increased from 85 mm to 235 mm, L(p) decreased from 1.93 +/- 0.41 to 0.97 +/- 0.11. Compared to results without albumin, BSA with 185 mm NaCl decreased L(p) from 3.93 +/- 0.08 to 1.25 +/- 0.18 (P = 0.04), and BSA with 235 mm NaCl decreased L(p) from 6.14 +/- 0.05 to 0.96 +/- 0.11 (P = 0.002). There was a three-fold decrease in L(p) when BSA was added to the 7% NaCl solution (P = 0.02). CONCLUSIONS: Albumin attenuated the increase in L(p) that is associated with higher NaCl concentrations. Because this model controls for oncotic pressure, albumin may impact L(p) by a mechanism other than oncotic force. Albumin appears to stabilize the endothelial barrier during HS perfusion and prevents the loss of intravascular fluid. Appropriate albumin levels may play an important clinical role in modulating trans-endothelial fluid efflux during HS administration.

Animals↗
PubMed2004

Angiotensin II type 1 receptor activation increases microvascular hydraulic permeability.

BACKGROUND: In addition to its vasoconstricting effects, angiotensin II (Ang II) has also demonstrated the ability to modulate microvessel permeability. We hypothesized that activation of the angiotensin II type 1 receptor (AT1) would increase hydraulic permeability. METHODS: Hydraulic permeability (L(p)) was measured in rat mesenteric venules using the Landis micro-occlusion technique. Paired measures of L(p) were obtained at baseline and after perfusion with the AT1 agonist, [Sar(1)]-angiotensin II, at 10 micromol/L (n=6) and 100 micromol/L (n=6). Activation of the AT1 receptor was also achieved by perfusion with 20 nmol/L Ang II plus the angiotensin II type 2 receptor (AT2) antagonist, PD123319. In these studies, 30 micromol/L (n=6) and 300 micromol/L (n=6) of PD123319 were used. RESULTS: [Sar(1)]-angiotensin II increased L(p) 2-fold with the 10 micromol/L dose (P=.04) and 4-fold with the 100 micromol/L dose (P < .001). The L(p) peak due to [Sar(1)]-angiotensin II occurred sooner than the peak observed with Ang II. PD123319 (30 micromol/L) plus 20 nmol/L Ang II increased L(p) 5-fold (P=.003), while PD123319 (300 micromol/L) plus 20 nmol/L Ang II increased L(p) 20-fold (P < .0001). The magnitude of the effect due to PD123319 (300 micromol/L) plus Ang II (20 nmol/L) was approximately twice the summation of effects due to PD123319 (300 micromol/L) alone and Ang II (20 nmol/L) alone. CONCLUSIONS: We conclude that endothelial cell Ang II receptors play an important role in modulating transendothelial fluid flux. Activating the AT1 receptor increases L(p); the AT2 receptor may operate to oppose this action. Pharmacologic manipulation of Ang II receptors may be beneficial during shock states to limit intravascular fluid loss.

Analysis of Variance↗
PubMed2004

Endothelin-1 decreases postcapillary fluid efflux via prostacyclin release.

BACKGROUND: Endothelin-1 (ET-1) decreases water efflux across the endothelial barrier (Lp). ET-1 may exert this permeability-decreasing effect by stimulating prostacyclin (PGI2) release. The purposes of this study were to (1) examine the effect of PGI2 on Lp, (2) measure Lp after inhibition of PGI(2) synthesis, and (3) determine the effect of ET-1 on Lp during inhibition of PGI2 production. METHODS: After microscopic cannulation of mesenteric venules, Lp was measured during PGI2 infusion (0.1 micromol/L, 1 micromol/L, and 10 micromol/L; n = 6 in each group). Lp was also measured after 100 micromol/L of the PGI2 synthase inhibitor, tranylcypromine (TCPN) (n = 6). Finally, the influence of ET-1 on Lp during PGI2 synthase inhibition was assessed (n = 6). RESULTS: Compared to baseline Lp of 1.05 +/- 0.06, PGI2 decreased Lp at 1 micromol/L (Lp = 0.63 +/- 0.03, P < .003) and 10 micromol/L (Lp = 0.52 +/- 0.04, P < .0001). TCPN increased Lp compared to baseline (P < .0001). Compared to ET-1 alone, venules perfused with TCPN + ET-1 increased Lp (P < .005). Units for Lp ) are 10(-7) cm x sec(-1) x cmH2O(-1). CONCLUSIONS: We found that (1) PGI2 decreases Lp, (2) inhibition of PGI2 synthesis increases Lp, and (3) permeability-decreasing effects of ET-1 can be blocked by inhibiting PGI2 synthesis. These data suggest that constitutive production of PGI2 modulates basal microvessel permeability and that ET-1 may exert its permeability-decreasing effect via the stimulation of PGI2 release.

Animals↗
PubMed2004

Modulation of microvascular hydraulic permeability by platelet-activating factor.

BACKGROUND: Platelet-activating factor (PAF) is a modulator of the inflammatory response to shock. Edema formation and intravascular fluid loss have been associated with PAF. The increase in microvessel permeability caused by PAF may be related to direct endothelial cell activation and leukocyte activation. We hypothesized that PAF increases hydraulic permeability by means of the direct activation of endothelial cells. METHODS: Hydraulic permeability (Lp) was measured in rat mesenteric venules using the modified Landis micro-occlusion technique. After baseline Lp measurements, paired measures of Lp were obtained during PAF perfusion at doses of 0.1 nmol/L (n = 6), 1.0 nmol/L (n = 6), 10 nmol/L (n = 6), and 50 nmol/L (n = 6). The temporal effects of pulse administration of PAF and repeated exposures to PAF were also assessed. RESULTS: Compared with baseline values (Lp = 1.16 +/- 0.11), the Lp of the microvessels significantly increased at PAF doses of 0.1 nmol/L (Lp = 1.46 +/- 0.1) (p < 0.002), 1 nmol/L (Lp = 2.0 +/- 0.11) (p < 0.004), 10 nmol/L (Lp = 4.09 +/- 0.09) (p < 0.005), and 50 nmol/L (Lp = 5.13 +/- 0.07) (p < 0.0001). All units for Lp are given as +/- SE x 10 -7 cm s-1. cm H2O-1. CONCLUSION: PAF increased microvessel permeability in a dose-dependent manner. The permeability-increasing effect of PAF was transient even with continuous endothelial exposure to PAF. This study emphasizes the ability of PAF to directly modulate microvascular permeability and increase venular permeability.

Animals↗
PubMed2004

Endothelin-1 decreases microvessel permeability after endothelial activation.

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor that is released during shock and sepsis. We hypothesized that ET-1 plays a role in the modulation of the elevated microvascular permeability state of the activated endothelium. METHODS: Hydraulic permeability (Lp) was measured using the modified Landis micro-occlusion technique. The effect of different ET-1 doses on Lp was determined by obtaining paired measures of Lp at baseline and after the vessels were perfused with ET-1 at doses of 2.0 pg/mL (n = 6), 20 pg/mL (n = 6), 200 pg/mL (n = 6), or 2,000 pg/mL (n = 6). To evaluate the effects of ET-1 in the activated endothelium, additional vessels were perfused with either 10 micromol/L adenosine triphosphate (ATP) (n = 6) or 1 nmol/L bradykinin (n = 6). The vessels were then perfused with 200 pg/mL ET-1 followed by the final L determination. RESULTS: ET-1 significantly decreased Lp at doses of 20 pg/mL (p = 0.03), 200 pg/mL (p = 0.03), and 2,000 pg/mL (p = 0.01). Endothelial activation with ATP and bradykinin increased Lp to 4.21 +/- 0.39 (p < 0.0001) and 2.72 +/- 0.24 (p = 0.001), respectively. ET-1 significantly decreased the Lp to 1.99 +/- 0.48 after activation with ATP (p = 0.004). ET-1 also decreased the Lp to 1.10 +/- 0.19 after activation with bradykinin (p = 0.001). Units for Lp are x10(-7) cm x s(-1) x cm H2O(-1). CONCLUSION: In this model, ET-1 attenuated the increase in microvascular permeability that can be seen in inflamed vessels. In addition to its vasopressor function, ET-1 may be of benefit in pathophysiologic states by decreasing third-space fluid loss. This receptor-mediated function of ET-1 may be amenable to pharmacologic manipulation.

Adenosine Diphosphate↗
PubMed2003

Effect of hypertonic saline on microvascular permeability in the activated endothelium.

INTRODUCTION: The effect of hypertonic saline (HTS) on microvascular permeability in microvessels with activated endothelial cells is unclear. We hypothesized that HTS and HTS with dextran would decrease hydraulic permeability after activation of the endothelium. METHODS: Hydraulic permeability (L(p)) was measured in rat mesenteric venules using the modified Landis micro-occlusion technique. The effects of 185 mM HTS and HTS plus 2% dextran (HSD) were tested in the activated endothelium by measuring L(p) at baseline, after perfusion with ATP, and again after HTS (n = 6) or HSD (n = 6). ATP (10 microM) activated endothelial cells and increased L(p) 4-fold. Additional venules were used to test the effects of 135 mM NaCl (n = 6) and 235 mM (n = 6) NaCl after endothelial activation with ATP. RESULTS: After endothelial activation with ATP, L(p) values were 6.05 +/- 1.63. Subsequent perfusion with HTS decreased L(p) to 2.05 +/- 0.52 (P = 0.01). In the HSD trails, L(p) values after ATP were 6.17 +/- 1.38. Perfusion with HSD decreased L(p) to 1.65 +/- 0.30 (P = 0.001). After endothelial activation, 135 mM NaCl had no effect on L(p); however, 185 mM NaCl decreased L(p) 3-fold and 235 mM NaCl decreased L(p) 6-fold. Units for L(p) are x10(-7) cm - s(-1). cmH(2)O(-1). CONCLUSIONS: Both HTS and HSD decreased hydraulic permeability after endothelial activation. These findings suggest that HTS may decrease microvascular fluid loss during states of elevated microvascular leak. In addition to the ability of hypertonic solutions to withdraw intracellular water to increase plasma volume, these findings propose an endothelial barrier mechanism whereby HTS and HSD act to maintain intravascular volume.

Animals↗