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We investigated the influence of aging on cardiac baroreflex function during dynamic exercise in seven young (22 [+ or -] 1 yr) and eight older middle-aged (59 [+ or 1] 2 yr) healthy subjects. Carotid-cardiac baroreflex function was assessed at rest and during moderate-intensity steady-state cycling performed at 50% heart rate reserve (HRR). Five-second pulses of neck pressure and neck suction from +40 to -80 Torr were applied to determine the operating point gain ([G.sub.OP]) and maximal gain ([G.sub.MAX]) of the full carotid-cardiac baroreflex function curve and examine baroreflex resetting during exercise. At rest, mean arterial pressure (MAP) and heart rate were similar between the younger and older subjects. In contrast, the resting [G.sub.OP] and [G.sub.MAX] were significantly lower in the older subjects. The increase in MAP from rest to exercise was greater in the older subjects ([DELTA] +20 [+ or 1] 2 older vs. [DELTA] +6 [+ or 1] 3 younger mmHg; P < 0.001). However, the [G.sub.OP] was similar in both groups during exercise because of a reduction in the younger subjects. In contrast, [G.sub.MAX] was unchanged from rest and therefore remained lower in older subjects (-0.19 [+ or 1] 0.05 older vs. -0.42 [+ or 1] 0.05 younger beats x [min.sup.-l] x [mmHg.sup.-1]; 50% HRR; P < 0.001). Furthermore, exercise resulted in an upward and rightward resetting of the cardiac baroreflex function curve in both groups. Collectively, these findings suggest that the cardiac baroreflex function curve appropriately resets during exercise in older subjects but operates at a reduced [G.sub.MAX] primarily because of age-related reductions in carotid-cardiac control manifest at rest. arterial baroreceptors; aging; heart rate doi:10.1152/ajpregu.00199.2007

Intravital microscopic methods were used to investigate the dose-dependent effects of bradykinin on leukocyte-endothelial cell interactions, formation of platelet-leukocyte aggregates and venular hemodynamics in rat mesentery. Results showed that the effects of bradykinin on leukocyte rolling and adhesion is highly concentration dependent. The mechanism of these effects was found to be dependent on the activation of bradykinin B2 receptors and was mediated by the formation of platelet-activating factor (PAF) and PAF-like lipids. The effects of bradykinin on venular erythrocyte velocity and blood flow were also concentration dependent.

The effect of ischemic preconditioning (IPC) on the modulation of ischemia-reperfusion injury (I/R) was investigated in murine cremaster muscle. Muscles showed increased leukocyte adhesion and migration after I/R compared to nonischemic muscles. Exposure of the muscles to adenosine deaminase attenuated the inhibitory effect of IPC on leukocytes. However, topical application of adenosine to the cremaster before ischemia increased leukocyte adhesion and migration, suggesting that postischemic leukocyte adhesion and migration may be mediated by adenosine.

Fructose-1,6-diphosphate (FDP) and adenosine were found to minimize the harmful effects of ischemia and reperfusion in microvessels by participating in ATP metabolism. In ischemia and reperfusion, an inflammation occurs in the blood vessels that is characterized by permeability of the vascular membrane and leukocytes adhering to the vessel wall. These lead to a destruction of the vessel through a glycolytic pathway that is inhibited by the FDP and adenosine.

Long-term ethanol consumption at low to moderate levels exerts cardioprotective effects in the setting of ischemia and reperfusion (I/R). The aims of this study were to determine whether 1) a single orally administered dose of ethanol [ethanol preconditioning (EtOH-PC)] would induce a biphasic temporal pattern of protection (early and late phases) against the inflammatory responses to I/R and 2) adenosine and nitric oxide (NO) act as initiators of the late phase of protection. Ethanol was administered as a bolus to C57BL/6 mice at a dose that achieved a peak plasma concentration of ~45 mg/dl 30 min after gavage and returned to control levels within 60 min of alcohol ingestion. The superior mesenteric artery was occluded for 45 min followed by 60 min of reperfusion beginning 10 min or 1, 2, 3, 4, or 24 h after ethanol ingestion, and the numbers of fluorescently labeled rolling and firmly adherent (stationary) leukocytes in single postcapillary venules of the small intestine were quantified using intravital microscopic approaches. I/R induced marked increases in leukocyte rolling and adhesion, effects that were attenuated by EtOH-PC 2-3 h before I/R (early phase), absent when assessed after 10 min, 1 h, and 4 h of ethanol ingestion, with an even more powerful late phase of protection reemerging when I/R was induced 24 h later. The anti-inflammatory effects of late EtOH-PC were abolished by treatment with adenosine deaminase, an adenosine [A.sub.2] (but not [A.sub.1]) receptor antagonist, or a NO synthase (NOS) inhibitor during the period of EtOH-PC. Preconditioning with an adenosine [A.sub.2] (but not an [A.sub.1]) receptor agonist in lieu of ethanol 24 h before I/R mimicked the protective actions of late phase EtOH-PC. Like EtOH-PC, the effect of preconditioning with an adenosine [A.sub.2] receptor agonist was abrogated by coincident NOS inhibition. These findings suggest that EtOH-PC induces a biphasic temporal pattern of protection against the proinflammatory effects of I/R. In addition, our observations are consistent with the hypothesis that the late phase of EtOH-PC is triggered by NO formed secondary to adenosine [A.sub.2] receptor-dependent activation of NOS during the period of ethanol exposure. ischemia; reperfusion; adenosine; inflammation; postcapillary venules; endothelium; adenosine [A.sub.2] receptors; small intestine; mice; endothelial nitric oxide synthase

Postischemic anti-inflammatory effects of bradykinin preconditioning. Am J Physiol Heart Circ Physiol 280: H441-H454, 2001.--We sought to determine the mechanisms whereby brief administration of bradykinin (bradykinin preconditioning, BK-PC) before prolonged ischemia followed by reperfusion (I/R) prevents postischemic, microvascular dysfunction. Intravital videomicroscopic approaches were used to quantify I/R-induced leukocyte/endothelial cell adhesive interactions and microvascular barrier disruption in single postcapillary venules of the rat mesentery. I/R increased the number of rolling, adherent, and emigrated leukocytes and enhanced venular albumin leakage, effects that were prevented by BK-PC. The anti-inflammatory effects of BK-PC were largely prevented by concomitant administration of a [B.sub.2]-receptor antagonist but not by coincident [B.sub.1] receptor blockade, nitric oxide (NO) synthase inhibition, or cyclooxygenase blockade. However, NO synthase blockade during reperfusion after prolonged ischemia was effective in attenuating the anti-inflammatory effects of BK-PC. Pan protein kinase C (PKC) inhibition antagonized the beneficial effects of BK-PC but only when administered during prolonged ischemia. In contrast, specific inhibition of the conventional PKC isotypes failed to alter the effectiveness of BK-PC. These results indicate that bradykinin can be used to pharmacologically precondition single mesenteric postcapillary venules to resist I/R-induced leukocyte recruitment and microvascular barrier dysfunction by a mechanism that involves [B.sub.2] receptor-dependent activation of nonconventional PKC isotypes and subsequent formation of NO. ischemic preconditioning; leukocyte adhesion; leukocyte emigration; venular albumin leakage; protein kinase C; bradykinin [B.sub.2] receptors

Davis, Jon M., Dean C. Gute, Steven Jones, Aleksandra Krsmanovic, and Ronald J. Korthuis. Ischemic preconditioning prevents postischemic P-selectin expression in the rat small intestine. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H2476-H2481, 1999.--Ischemic preconditioning (IPC) prevents the deleterious effects of prolonged ischemia and reperfusion (I/R). Because leukocyte infiltration is required to produce the microvascular dysfunction induced by I/R in the small intestine, and P-selectin-dependent leukocyte rolling is a requisite step in this process, we hypothesized that IPC would attenuate postischemic P-selectin expression. To address this postulate, P-selectin expression was evaluated in nonischemic (control) rat jejunum and in rat jejunum subjected to I/R alone (20 min ischemia/60 min reperfusion), or IPC (5 min ischemia/10 min reperfusion) + I/R using a dual radiolabeled monoclonal antibody approach. I/R was associated with a sevenfold increase in jejunal P-selectin expression, an effect that was completely abolished by IPC. Exposing the bowel to adenosine deaminase or an adenosine [A.sub.1], but not an [A.sub.2], receptor antagonist during the period of preconditioning ischemia or to selective PKC antagonists during prolonged ischemia prevented the beneficial effect of IPC to limit I/R-induced P-selectin expression. Our data indicate that P-selectin expression is a novel downstream effector target of the adenosine-initiated, PKC-dependent, anti-inflammatory signaling pathway in IPC. ischemia; reperfusion; adenosine; protein kinase C; leukocyte rolling

Korthuis, Ronald J., Dean C. Gute, Frank Blecha, and Chris R. Ross. PR-39, a proline/arginine-rich antimicrobial peptide, prevents postischemic microvascular dysfunction. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H1007-H1013, 1999.--We and others have previously demonstrated that intestinal ischemia-reperfusion (I/R) is associated with a large increase in oxidant production that contributes to microvascular barrier disruption in the small bowel. It has been suggested that the bulk of tissue damage during reperfusion can be attributed to adherent, activated neutrophils. From these observations, we hypothesized that pretreatment with PR-39, an endogenous neutrophil antibacterial peptide that is also a potent inhibitor of the neutrophil NADPH oxidase, would prevent postischemic oxidant production and the development of oxidant-dependent sequelae to I/R such as increased venular protein leakage. To test this postulate, oxidant production, venular protein leakage, leukocyte adhesion, and leukocyte emigration were monitored during reperfusion in control (no ischemia) rat mesenteric venules and in mesenteric venules subjected to I/R alone or PR-39 + I/R. Treatment with a single intravenous bolus injection of PR-39 (administered at a dose to achieve an initial blood concentration of 5 [micro]M) abolished I/R-induced leukocyte adhesion and emigration in vivo. In vitro studies indicated that PR-39 prevents platelet-activating factor-induced neutrophil chemotaxis as well as phorbol myristate acetate (PMA)-stimulated intercellular adhesion molecule-1 expression by cultured endothelial cells. PR-39 pretreatment of rat neutrophils also blocked PMA-stimulated neutrophil adhesion to activated endothelial monolayers. In vivo, I/R was associated with a marked and progressive increase in oxidant production and venular protein leakage during reperfusion, effects that were abolished by PR-39 treatment. The results of this study indicate that PR-39 completely abolishes postischemic leukocyte adhesion and emigration. The time course for inhibition of oxidant production by PR-39 suggests that its antiadhesive properties account for this effect of the peptide. PR-39 may thus be therapeutically useful for prevention of neutrophil adhesion and activation during the postischemic inflammatory response. leukocyte adhesion; leukocyte emigration; venular protein leakage; oxidant production; intravital microscopy; intercellular adhesion molecule-1

A study was conducted to test the hypothesis that bradykinin act to reduce ischemia-reperfusion (I/R)-induced tissue injury by preventing leukocyte recruitment and preserving microvascular barrier function. The leukocyte-endothelial cell interactions and microvascular barrier function in rat mesentery was measured using intravital video microscopic techniques. Results indicated that bradykinin reduces I/R-induced leukocyte recruitment and microvascular dysfunction through a mechanism involving bradykinin B2-receptor-dependent nitric oxide production.

Intravital microscopic techniques were used to examine the mechanisms underlying bradykinin-induced leukocyte/endothelial cell adhesive interactions (LECA) and venular protein leakage (VPL) in single postcapillary venules of the rat mesentery. The effects of bradykinin superfusion to increase LECA and VPL were prevented by coincident topical application of either a bradykinin-B(2) receptor antagonist, a cell-permeant superoxide dismutase (SOD) mimetic or antioxidant, or inhibitors of cytochrome P-450 epoxygenase (CYPE) or protein kinase C (PKC) but not by concomitant treatment with either SOD, a mast cell stabilizer, or inhibitors of nitric oxide synthase, cyclooxygenase, xanthine oxidase, NADPH oxidase, or platelet-activating factor. Immunoneutralizing P-selectin or intercellular adhesion molecule-1 (ICAM-1) completely prevented bradykinin-induced leukocyte adhesion and emigration but did not affect VPL. On the other hand, stabilization of F-actin with phalloidin prevented bradykinin-induced leukocyte emigration and VPL but did not alter leukocyte adhesion. These data indicate that bradykinin induces LECA in rat mesenteric venules via a B(2)-receptor-initiated, CYPE-, oxidant- and PKC-mediated, P-selectin- and ICAM-1-dependent mechanism. Bradykinin also produced VPL, an effect that was initiated by stimulation of B(2) receptors and involved CYPE and PKC activation, oxidant generation, and cytoskeletal reorganization but was independent of leukocyte adherence and emigration.

It is now recognized that reperfusion after a prolonged period of reduced or absent blood flow, although necessary to salvage ischemic tissue, initiates a complex series of deleterious reactions which ultimately induce the same effects as ischemia per se, i.e., cell injury and necrosis. Work conducted over the past 15 years has uncovered the fact that post-ischemic leukocyte infiltration plays a major role in the reperfusion component of ischemia/reperfusion (I/R) injury. This discovery has led to a concerted research effort directed at identifying interventions that prevent post-ischemic leukocyte adhesion and emigration. Recent work indicates that flavonoids are particularly effective anti-inflammatory agents in the setting of I/R. While the mechanisms underlying the powerful protective effects of these compounds is uncertain, a growing body of evidence indicates that flavonoids are potent anti-oxidants that also act to inhibit the activity of key regulatory enzymes involved in the activation of pro-inflammatory signaling cascades. In addition, it appears that these compounds prevent the expression of specific adhesion molecules involved in leukocyte recruitment, observations which provide the molecular basis for the anti-adhesive properties of these compounds.