Microvascular Vasoconstriction Research Articles

Lazaroid and pentoxifylline suppress sepsis-induced increases in renal vascular resistance via altered arachidonic acid metabolism.

Early sepsis leads to renal hypoperfusion, despite a hyperdynamic systemic circulation. It is thought that failure of local control of the renal microcirculation leads to hypoperfusion and organ dysfunction. Of the many mediators implicated in the pathogenesis of microvascular vasoconstriction, arachidonic acid metabolites are thought to be important. Vasoconstriction may be due to excess production of vasoconstrictors or loss of vasodilators. Using the isolated perfused kidney model, we describe a sepsis-induced rise in renal vascular resistance and increased production of key arachidonic acid metabolites, both vasoconstrictors and vasodilators, suggesting excessive production of vasoconstrictors as a cause for microcirculatory hypoperfusion. There is evidence of increased enzymatic production of arachidonic acid metabolites as well as nonenzymatic, free radical, catalyzed conversion of arachidonic acid. Pentoxifylline (a phosphodiesterase inhibitor) and U74389G (an antioxidant) both have a protective effect on the renal microcirculation during sepsis. Both drugs appear to alter the renal microvascular response to sepsis by altering renal arachidonic acid metabolism. This study demonstrates that sepsis leads to increased renal vascular resistance. This response is in part mediated by metabolites produced by metabolism of arachidonic acid within the kidney. The ability of drugs to modulate arachidonic acid metabolism and so alter the renal response to sepsis suggests a possible role for these agents in protecting the renal microcirculation during sepsis.

Increased microvascular reactivity and improved mortality in septic mice lacking inducible nitric oxide synthase.

Persistent vasodilation characteristic of septic shock may result from overproduction of nitric oxide and can lead to pressor-refractory hypotension and death. To evaluate the significance of cytokine-inducible nitric oxide synthase (iNOS) in the pathogenesis of sepsis, we used a clinically relevant mouse model of sepsis and compared mortality and microvascular reactivity in wild-type (WT) mice and transgenic mice deficient in iNOS. WT C57BL/6 and iNOS-deficient mice were made septic by cecal ligation and puncture. Treated mice were given fluids and antibiotics every 6 hours. Microvascular vasoconstriction in response to topical norepinephrine was measured in cremasteric arterioles (15 to 30 microm) by videomicroscopy. Mortality at 48 hours was significantly lower in treated septic iNOS-deficient mice (45%) than in treated septic WT mice (76%), untreated septic iNOS-deficient mice (87%), or untreated WT mice (100%) (P<0.01). Norepinephrine-induced vasoconstriction was decreased in WT septic mice (EC(50) 200+/-56 nmol/L) compared with WT and iNOS-deficient shams (16+/-4 and 13+/-6 nmol/L), and vasoconstriction was significantly improved in septic iNOS-deficient mice (35+/-13 nmol/L, P<0.01). Microvascular catecholamine responsiveness and survival were improved in iNOS-deficient mice in a clinically relevant model of sepsis, suggesting that iNOS plays an important, but not exclusive, role in refractory vasodilation in patients with septic shock.

Small Intestinal Production of Nitric Oxide Is Decreased Following Resuscitated Hemorrhage

Background.Small intestine microvascular vasoconstriction and hypoperfusion develop after resuscitation (RES) from hemorrhage (HEM), despite restoration of central hemodynamics. The responsible mechanisms are unclear. We hypothesized that the microvascular impairment following HEM/RES was due to decreased intestinal microvascular nitric oxide (NO) production.Methods.Male Sprague–Dawley rats (195–230 g) were utilized and three experimental groups were studied: (1) SHAM (cannulated but no HEM), (2) HEM only, and (3) HEM/RES. HEM was to 50% of baseline mean arterial pressure for 60 min, and RES was with shed blood and an equivalent volume of saline.Ex vivoisolated intestinal perfusion and a fluorometric modification of the Greiss reaction were used to quantify production of NO metabolites (NOx). Perfusate von Willebrand factor (vWF) was used as an indirect marker of endothelial cell activation or injury. To assess the degree of NO scavenging by oxygen-derived free radicals, immunohistochemistry was used to detect nitrotyrosine formation in the intestine.Results.Intestinal NOxdecreased following HEM/RES (SHAM 1.35 ± 0.2 mM vs HEM/RES 0.60 ± 0.1 mM,P< 0.05), but not with HEM alone (1.09 ± 0.3 mM). There were no differences in serum NOxlevels between the three groups. Release of vWF was increased during the HEM period (SHAM 0.18 ± 0.1 g/dl vs HEM 1.66 ± 0.6 g/dl,P< 0.05). There was no detectable nitrotyrosine formation in any group.Conclusions.Intestinal NO metabolites decrease following HEM/RES. Elevated vWF levels during HEM and the lack of detectable nitrotyrosine suggest that this is due to decreased endothelial cell production of NO. HEM/RES-induced endothelial cell dysfunction may contribute to persistent small intestine post-RES hypoperfusion and vasoconstriction.

Coronary vasoconstriction during myocardial ischemia induced by rises in metabolic demand in patients with coronary artery disease.

In patients with coronary artery disease, a maximal vasodilation of the coronary microcirculation is generally assumed to occur during myocardial ischemia induced by rises in metabolic demand. However, vasoconstriction has been documented during severe prolonged ischemia in animals. The aim of this study was to investigate coronary vasomotor tone during pacing-induced ischemia in humans. The study included 11 patients with exercise-induced ischemia and single-vessel disease of the left anterior descending artery and 7 control subjects with normal coronary arteries. Blood flow velocity was monitored with a Doppler catheter in the left anterior descending artery. Coronary resistance index was calculated as the ratio between mean arterial pressure and flow velocity. Measurements were obtained at baseline, after intracoronary adenosine (2 mg), and during maximal atrial pacing in the absence and presence of adenosine. After adenosine administration at rest, coronary resistance decreased more in control subjects than in patients (25 +/- 7% of baseline versus 61 +/- 19%; P < .01). Coronary resistance decreased in all control subjects (P < .01) both at maximal pacing (60 +/- 17% of baseline) and after administration of adenosine during tachycardia (31 +/- 13% of baseline). By contrast, all 10 ischemic patients displayed increased coronary resistance at maximal heart rate (221 +/- 131% of baseline; P < .01 versus baseline, P < .01 versus control subjects). At this stage, adenosine decreased coronary resistance to 44 +/- 20% of values observed before injection. Additionally, it reduced ST-segment depression in 5 of 8 patients. In patients with coronary artery disease, transient myocardial ischemia induced by increased metabolic demand is not associated with maximal vasodilation. Rather, an inappropriate severe microvascular vasoconstriction is present that can be abolished by intracoronary adenosine.

Lazaroids prevent acute cyclosporine-induced renal vasoconstriction.

Cyclosporine (CsA)-induced nephrotoxicity may be due to intrarenal vasoconstriction and glomerular hypoperfusion. Several factors, including endothelin and prostanoids, are suggested mediators of this response. Recent evidence suggests that CsA leads to increased oxygen-derived free radical (ODFR) production and lipid peroxidation in renal tissue. Whether this leads to alterations in renal vessel reactivity is unclear. Lazaroids, such as U74389G, are radical-quenching antioxidants that inhibit ODFR-induced lipid peroxidation and may improve renal function after ischemia and reperfusion. We hypothesized that ODFRs contribute to CsA-induced alterations of the renal microcirculation. Rat hydronephrotic kidneys were studied by video microscopy. Interlobular arteriolar diameter and flow, afferent and efferent arteriolar diameters, and cardiac output were measured at 15-min intervals for 120 min. U74389G or its vehicle was infused 15 min before topical application of CsA to the kidney. The results were compared with U74389G alone and normal saline. CsA administration caused renal microvascular vasoconstriction (10-25% below baseline) and hypoperfusion (35% below baseline). Both vasoconstriction and hypoperfusion were significantly attenuated by U74389G (5-8% and 20% below baseline, respectively). Inhibition of lipid peroxidation by U74389G maintained renal blood flow during acute CsA administration. These data suggest that ODFRs are involved in the renal microvascular response to CsA. Inhibition of ODFR-induced lipid peroxidation may help prevent CsA-induced glomerular hypoperfusion. Lazaroids may prove an effective adjunct in reducing CsA-induced nephrotoxicity.

Characterization of microvascular vasoconstriction following ischemia/reperfusion in skeletal muscle using videomicroscopy.

This study investigated the possible contribution of microvascular vasoconstriction to no-reflow following ischemia/reperfusion in a mouse skeletal muscle model. Using paired cremaster muscles, arterioles of diameter 10-100 microns were directly viewed and measured by the use of an in vivo videomicroscopy before and after a 6-hr period of complete ischemia at 27 degrees C. Following ischemia/reperfusion, feeder and arcading arterioles constricted significantly to 54.5 and 62% of pre-ischemic baseline diameters respectively (P < .05). While the calcium antagonist diltiazem and nitroprusside were both able to reverse arteriolar constriction, endothelium-dependent acetylcholine-induced dilatation was markedly impaired following reperfusion (P < 0.05). Superoxide dismutase did not attenuate the microvascular response, suggesting that the mechanism is likely to be at least partly free radical-independent.

Thromboxane contributes to submaximal coronary dilation during myocardial ischemia.

Thromboxane has been shown to contribute to coronary constriction in conduit coronary arteries during platelet aggregation at the site of a critical stenosis. Previous studies from our laboratory suggest that following a critical coronary stenosis, persistent vasomotor tone occurs. We tested the hypothesis that thromboxane is responsible for that increased tone. To test this hypothesis, 14 mongrel dogs of either sex were anesthetized and subjected to a critical coronary stenosis where distal coronary perfusion pressure was reduced to 36 +/- 2 mm Hg. During the coronary stenosis, SQ 29,548 (thromboxane/endoperoxide receptor antagonist) was administered intravenously (0.2 mg/kg and 2.0 mg/kg). Coronary microvascular responses were observed by directly visualizing the epicardial microcirculation. Diameters were measured using intravital microscopy coupled to stroboscopic epi-illumination and jet ventilation to compensate for cardiac and respiratory-induced motion. Coronary microvessels were divided into small (< 150 microns) and large (> 150 microns) arterioles. During SQ 29,548 administration, small coronary arterioles demonstrated no additional dilation during a critical coronary stenosis. In contrast, coronary microvessels > 150 microns demonstrated a dose-dependent vasodilation to SQ 29,548 (0.2 mg/kg: 6 +/- 2%; 2.0 mg/kg: 11 +/- 4%; P < 0.05 vs. no change). A time control study in six additional animals demonstrated no significant microvascular diameter changes following a critical stenosis over the time course of SQ 29,548 administration. Endoperoxides contribute to poststenotic microvascular vasoconstriction in vessels 150-300 microns.

928-81 Importance of Holter Monitoring, as Compared to Exercise Testing, in Revealing ST-segment Changes in Patients with Syndrome X

Despite growing interest and a large body of studies on syndrome X (anginal chest pain and angiographically normal coronary arteries), there are no data concerning the respective diagnostic value of exercise testing (ExT) and ambulatory Holter monitoring (HM) in revealing ischemic ST-segment changes in these patients. To address this problem, we performed ExT and 24-hour HM, off therapy, in 38 syndrome X patients (27 women, age 54 ± 8 years). ExT showed ST-segment depression (STd) in 28 patients (74% Group 1), whereas it was normal in 10 patients (26%, Group 2). Anginal chest pain during ExT was reported by 10 patients (36%) of Group 1 and 9 patients (90%) of Group 2 (p &lt; 0.01). On the other hand, STd episodes were detected on HM in 22 patients (59%), 17 (61%) of whom belonging to Group 1 and 5 (50%) to Group 2 (p = NS). On the whole, 129 STd episodes, 14 (11%) of which associated to anginal pain, were found in the 22 patients (mean 5.8 ± 4.6 episodes/patient). A total of 21 STd episodes (5 associated to anginal pain) were detected on HM in the 5 patients with negative ExT (mean 4.3 ± 3.5 episodes/patient, range 1–10). In these 5 patients, heart rate at 1 mm STd during HM was significantly lower than that achieved at peak exercise during ExT (111 ± 19 vs. 136 ± 22 bpm, p = 0.01). The prevalence of positive HM in patients with negative ExT in our syndrome X patients was significantly higher than that observed in an unselected group of 76 patients with stable angina, significant coronary artery disease and negative ExT (50% vs 8%, p &lt; 0.01). Thus, our data show that HM, with respect to ExT, has a significant additional diagnostic value in revealing the occurrence of ischemic ST-segment changes in patients with syndrome X. These findings also support the hypothesis that a microvascular vasoconstriction, rather than an impaired vasodilation, plays a major role in the pathophysiologic mechanisms leading to transient ischemia in these patients.

Angina Pectoris Associated with ST Segment Elevation in the Absence of Epicardial Coronary Arterial Obstruction

Two cases are presented in which angina pectoris associated with ST segment elevation occurred during either an ergonovine provocation test or coronary angioplasty, despite the absence of epicardial coronary artery obstruction. In both cases, no epicardial coronary spasm, thromboembolic occlusion, coronary air embolus, vessel dissection, or side-branch occlusion was observed. These findings suggest that transmural myocardial ischemia without epicardial coronary artery obstruction can occur owing to abnormalities of the coronary microcirculation. Microvascular vasoconstriction leading to transmural myocardial ischemia may be induced by ergonovine or by the release of potent vasoconstrictors from disrupted coronary lesions during angioplasty.

In Vivo Effects of Endothelin on the Renal Microcirculation

Endothelin-1 (ET) is a recently discovered vasoconstrictor peptide which is released by renal vascular endothelial cells in response to a number of pathologic insults including ischemia, endotoxemia, bacteremia, and cyclosporine nephrotoxicity. Because microvascular vasoconstriction is an integral component of the acute renal dysfunction associated with these conditions, this study was undertaken to determine the in vivo effects of ET on the renal microcirculation. We used the split hydronephrotic kidney model in decerebrate Sprague-Dawley rats to study vessel diameter and red cell velocity responses to ET using intravital videomicroscopy and doppler velocimetry. Topical administration of increasing concentrations of ET caused a dose-dependent constriction of interlobular arteries which reached a maximum of 27 ± 5% at an ET concentration of 10 -8 M. A corresponding decrease of 64 ± 8% in interlobular arterial blood flow was observed. Afferent and efferent arteriole diameters were reduced by 39 ± 2% and 27 ± 5%, respectively. These vascular effects were completely prevented by the systemic preinfusion of anti-endothelin antiserum. Infusion of antiserum alone had no effect on systemic hemodynamics or renal microvascular variables, suggesting that ET has little or no role in maintaining basal vascular tone in the kidney. We conclude that ET is a potent in vivo constrictor of the renal microcirculation and may be involved in mediating pathologic vasoconstriction.

Digital Cutaneous Vascular Responses to Histamine and Neuropeptides in Raynaud's Phenomenon

The pathophysiology of Raynaud's phenomenon is not well defined, but active cutaneous microvascular vasoconstriction and emptying must occur to account for the pallor and are reasons for studying the microvasculature. It has been proposed that there may be a defect in a local histamine vasodilator mechanism. The role of the peptidergic nervous system in Raynaud's phenomenon has not been previously investigated. To study the histaminergic and peptidergic axes in Raynaud's phenomenon, we measured the cutaneous microvascular responses of patients with Raynaud's phenomenon to digital intradermal injections of saline, histamine, the histamine-releasing agent, compound 48/80, substance P, and calcitonin gene-related peptide. We compared these results with those obtained in normal subjects. Intradermal cutaneous microvascular blood flow responses were quantified by planimetry and laser Doppler flowmetry. The results show: a) that in primary Raynaud's phenomenon there is no evidence of local deficiency in histamine release or insensitivity to histamine in the cutaneous microvasculature; and b) that patients with Raynaud's phenomenon react normally to the neuropeptides calcitonin gene-related peptide and substance P, providing a rationale for treating Raynaud's phenomenon with vasoactive peptides.

Resolution of Experimental Microvascular Vasoconstriction in Rats by Topical Application of Lidocaine Hydrochloride in Varying Concentrations

Various lidocaine hydrocholoride concentrations were used to measure the degree of resolution of ergotamine-induced vasospasm of the rat tail artery. Also further studies are indicated; 12% lidocaine seems to be as effective as 20% lidocaine. The widely used 2% lidocaine had little effect on the experimentally induced vasospasm.

Segmental vascular resistances and compliances in dog lung.

The segmental distribution of vascular resistances and compliances were evaluated in isolated blood perfused lung lobes using arterial, venous, and double-occlusion pressures and were compared with filtration midpoint capillary pressures (Pc,f). We separated total vascular resistance (RT) and compliance (CT) into large artery (Ra, Ca), large vein (Rv, Cv), and microvascular compartments (Rmc, Cmc) at base-line and increased vascular pressures and during infusions of histamine, serotonin, and norepinephrine. In control lobes, double-occlusion pressure (Pdo) closely approximated Pc,f at all vascular pressures. Pre- and postcapillary resistance were approximately equal when referenced to either Pc,f or Pdo. Although Rmc comprised 42% of RT and Cmc constituted 76% of CT, a twofold increase in base-line Pc,f caused RT to decrease to 67% and Rmc/RT to 29% of control values, whereas CT decreased to 87% and Cmc/CT decreased to 88% of control values over the same Pc,f range. Mean static CT was 2.25 +/- 0.09 ml X cmH2O-1. 100 g-1, whereas dynamic CT was 1.54 +/- 0.08 ml X cmH2O-1. 100 g-1, or only 68% of static vascular compliance. Drug infusions increased mean RT from 4.2- to 5.3-fold and significantly decreased both static and dynamic CT. Although all vascular segments were constricted, histamine affected primarily large veins, serotonin increased Ra greater than Rv, and norepinephrine constricted upstream and downstream vessels about equally. Increased Pc,f in the presence of these drugs decreased RT significantly in every case primarily through attenuation of the drug vasoconstrictor effect on Rmc and decreased CT primarily due to a decrease in Cmc, but increased Cmc/(Ca + Cv). Thus the microvascular compartment appears to be the major site of both fluid filtration and vascular compliance and contributes significantly to total vascular resistance. Drug infusions constricted large and small vessel compartments as defined here, but increased Pc,f attenuated microvascular vasoconstriction and to a lesser extent large vessel vasoconstriction resulting in a reduced microvascular resistance in both drug-treated and control lobes. This effect can be attributed to recruitment and/or distension of microvessels and distension of larger vessels.