Kininogens are antithrombotic proteins In vivo. (41/1413)

Kininogens have recently been shown to possess antiadhesive, anticoagulant, and profibrinolytic properties and can inhibit platelet activation at low thrombin concentrations. To test whether kininogens have antithrombotic properties in vivo, we devised a model of limited arterial injury confined to removal of the endothelium. Brown-Norway Katholiek strain rats with an absence of low- and high-molecular-weight kininogen due to a single point mutation, A163T, were compared in the thrombosis model to the wild-type animals, which were otherwise genetically identical. Despite an equivalent vascular injury, the mean time (+/-SEM) for a 90% decrease in flow measured by laser Doppler was 38.4+/-17 minutes in the kininogen-deficient rats compared with 194+/-29 minutes in the wild-type animals (P<0.002). The degree of vascular injury was the same. No evidence for disseminated intravascular coagulation (decrease in factor V, antithrombin, or fibrinogen) or excessive fibrinolysis (elevation of fibrinogen degradation products) was found in either group of animals. The results suggest that kininogens have antithrombotic properties at low concentrations of thrombin and that inhibitory peptides derived from kininogen may constitute a new antithrombotic strategy.  (+info)

Human bronchial artery blood flow after lung Tx with direct bronchial artery revascularization. (42/1413)

The inaccuracy of measuring human bronchial artery blood flow has previously been considerable. En bloc double-lung transplantation with bronchial artery revascularization (BAR) using a single conduit offers the unique opportunity of direct measurement of the total bronchial artery blood flow. In eight en bloc double-lung-transplanted patients with complete BAR, the basal blood flow was measured by using a 0.014-in. Doppler guide wire and arteriography. The average peak velocity in the conduit was 12-73 cm/s [+/-2.1 (SD) cm/s], and the conduit diameter was 1.7-3.1 mm [+/-0.10 (SD) mm], giving individual basal flow values between 19 and 67 ml/min [+/-5 (SD) ml/min], or 0.2-1.9% of estimated cardiac output. In three patients basal measurements were followed by injection of nitroglycerin and verapamil into the conduit. This increased the bronchial artery flow to 121-262% of basal values (31-89 ml/min). The measured values appear more physiologically plausible than previous bronchial artery blood flow measurements in humans.  (+info)

Modification of activity-dependent increases in cerebellar blood flow by extracellular potassium in anaesthetized rats. (43/1413)

1. The hypothesis that potassium ions mediate activity-dependent increases of cerebral blood flow was examined in rat cerebellar cortex using ion-selective microelectrodes and laser-Doppler flowmetry. Increases of cerebellar blood flow (CeBF) and extracellular potassium concentration ([K+]o) were evoked by stimulation of parallel fibres and climbing fibres, and by microinjection of KCl into the cortex. 2. For parallel fibre stimulation, there was a maximal increase in [K+]o to 6.3 +/- 0.5 mM and in CeBF of 122 +/- 11 %. Climbing fibre stimulation gave a maximal increase in [K+]o to 4.4 +/- 0.2 mM and in CeBF of 157 +/- 20 %. This indicates different maxima for [K+]o and CeBF, dependent on the afferent system activated. 3. [K+]o and CeBF responses evoked by parallel or climbing fibre stimulation increased rapidly at the onset of stimulation, but exhibited different time courses during the remainder of the stimulation period and during return to baseline. 4. Microinjections of KCl into the cortex increased [K+]o to levels comparable to those evoked by parallel fibre stimulation. The corresponding CeBF increases were the same as, or smaller than, for parallel fibre stimulation, and much smaller than for climbing fibre stimulation. This suggests that mediators other than [K+]o are important for activity-dependent cerebral blood flow increases. 5. The present study showed that increased [K+]o is involved in CeBF regulation in the parallel fibre system, but is of limited importance for CeBF regulation in the climbing fibre system. The hypothesis that K+ is a major mediator of activity-dependent blood flow increases is probably not generally applicable to all brain regions and all types of neuronal stimulation.  (+info)

Responses to acute changes in arterial pressure on renal medullary nitric oxide activity in dogs. (44/1413)

A direct relationship between renal arterial pressure (RAP) and cortical tissue nitric oxide (NO) activity in the canine kidney was reported earlier. We have conducted further experiments to evaluate medullary NO responses to alterations in RAP with the use of a NO-selective microelectrode inserted into the renal medulla of 6 anesthetized, sodium-replete dogs. Graded reductions in RAP (from 140 to 80 mm Hg) elicited decreases in medullary tissue NO concentration, with a slope of 10.2+/-4.5 nmol x L(-1) x mm Hg(-1). These changes in NO levels were associated with decreases in urinary excretion rate of nitrate and nitrite (U(NOx)V; control value, 1.7+/-0.03 nmol x min(-1) x g(-1); slope, 0.02+/-0.004 nmol x min(-1) x g(-1) x mm Hg(-1)) and sodium excretion (U(Na)V; control, 3.2+/-0.7 micromol x min(-1) x g(-1); slope, 0.06+/-0.02 micromol x min(-1) x g(-1) x mm Hg(-1)) without changes in glomerular filtration rate control (0.84+/-0.06 mL x min(-1) x g(-1)). Intra-arterial administration of the NO synthase inhibitor N(omega)-nitro-L-arginine (NLA; 50 microg x kg(-1) x min(-1)) decreased medullary NO concentration by 218+/-55 nmol x L(-1) (n=5) and attenuated the relationship between RAP and NO concentration (slope, 2.7+/-2.2 nmol x L(-1) x mm Hg(-1)). NLA infusion decreased U(NOx)V (0.8+/-0.06 nmol x min(-1) x g(-1)) and U(Na)V (1.1+/-0.2 micromol x min(-1) x g(-1)) without changes in glomerular filtration rate and attenuated RAP versus U(Nox)V and U(Na)V relationships. Total and regional blood flows, as measured by electromagnetic and laser Doppler needle flow probes, respectively, remained autoregulated both before and during NLA infusion. These data support the hypothesis that acute changes in RAP elicit changes in intrarenal NO production, which may participate in the mediation of pressure natriuresis.  (+info)

In vivo evaluation of platelet-endothelial interactions in retinal microcirculation of rats. (45/1413)

PURPOSE: This study was designed to develop a new method to evaluate the dynamics of platelets in the retinal microcirculation in vivo and to investigate quantitatively the platelet-endothelial interactions in rat retina with the use of this system. METHODS: Isolated platelet samples were labeled with carboxyfluorescein diacetate succinimidyl ester. After intravenous administration, platelet behavior in the retinal microcirculation was evaluated with a scanning laser ophthalmoscope. The images were recorded on S-VHS videotape and analyzed with a computer-assisted image analysis system. The platelet- endothelial interactions in the retinal microcirculation were also investigated with the use of lipopolysaccharide-stimulated endothelium or platelets activated with thrombin. RESULTS: Fluorescent platelets were recognized as distinct dots in the retinal microcirculation and could be traced frame by frame. The velocity of platelets in the retinal arteries, capillaries, and veins was 26.1+/-6.4, 1.6+/-0.4, and 19.9+/-8.2 mm/sec, respectively. In control rats, even the activated platelets showed minimal interaction with retinal endothelial cells. In contrast, stimulated retinal endothelium showed active platelet- endothelial interactions; many platelets were observed rolling and adhering along the major retinal veins. The interactions between platelets and stimulated endothelial cells were substantially inhibited with the injection of P-selectin monoclonal antibody. CONCLUSIONS: The present study demonstrated a new method to visualize platelet behavior in the retinal microcirculation in vivo. This method will allow quantitative evaluation of platelet dynamics and platelet- endothelial interactions in retinal pathologic conditions.  (+info)

Dorsal root reflexes and cutaneous neurogenic inflammation after intradermal injection of capsaicin in rats. (46/1413)

The role of dorsal root reflexes (DRRs) in acute cutaneous neurogenic inflammation induced by intradermal injection of capsaicin (CAP) was examined in anesthetized rats. Changes in cutaneous blood flow (flare) on the plantar surface of the foot were measured using a laser Doppler flowmeter, and neurogenic edema was examined by measurements of paw thickness. To implicate DRRs in neurogenic inflammation after CAP injection, the ipsilateral sciatic and femoral nerves were sectioned, dorsal rhizotomies were performed at L(3-)-S(1), and antagonists of GABA or excitatory amino acid receptors were administered intrathecally. Intradermal injection of CAP evoked a flare response that was largest at 15-20 mm from the injection site and that spread >30 mm. Acute transection of the sciatic and femoral nerves or dorsal rhizotomies nearly completely abolished the blood flow changes 15-20 mm from the CAP injection site, although there was only a minimal effect on blood flow near the injection site. These procedures also significantly reduced neurogenic edema. Intrathecal bicuculline, 6-cyano-7-nitroquinoxaline-2,3-dione, (CNQX) or D(-)-2-amino-7-phosphonoheptanoic acid (AP7), but not phaclofen, also reduced dramatically the increases in blood flow 15-20 mm from the CAP injection site, but had only a minimal effect on blood flow near the injection site. Neurogenic edema was reduced by the same agents that reduced blood flow. Multiunit DRRs recorded from the central stumps of cut dorsal rootlets in the lumbar spinal cord were enhanced after CAP injection. This enhanced DRR activity could be reduced significantly by posttreatment of the spinal cord with bicuculline, CNQX or AP7, but not phaclofen. It is concluded that peripheral cutaneous inflammation induced by intradermal injection of CAP involves central nervous mechanisms. DRRs play a major role in the development of neurogenic cutaneous inflammation, although a direct action of CAP on peripheral nerve terminals or the generation of axon reflexes also may contribute to changes in the skin near the injection site.  (+info)

Influence of female reproductive hormones on local thermal control of skin blood flow. (47/1413)

Progesterone and estrogen modify thermoregulatory control such that, when both steroids are elevated, body temperature increases and the reflex thermoregulatory control of cutaneous vasodilation is shifted to higher internal temperatures. We hypothesized that the influence of these hormones would also include effects on local thermal control of skin blood flow. Experiments were conducted in women in high-hormone (HH) and low-hormone (LH) phases of oral contraceptive use. Skin blood flow was measured by laser-Doppler flowmetry, and local temperature (T(loc)) was controlled over 12 cm(2) around the sites of blood flow measurement. T(loc) was held at 32 degrees C for 10-15 min and was then decreased at one site from 32 to 20 degrees C in a ramp over 20 min. Next, T(loc) was increased from 32 to 42 degrees C in a ramp over 15 min at a separate site. Finally, T(loc) at both sites was held at 42 degrees C for 30 min to elicit maximum vasodilation; data for cutaneous vascular conductance (CVC) are expressed relative to that maximum. Whole body skin temperature (T(sk)) was held at 34 degrees C throughout each study to minimize reflex effects from differences in T(sk) between experiments. Baseline CVC did not differ between phases [8.18 +/- 1.38 (LH) vs. 8. 41 +/- 1.31% of maximum (HH); P > 0.05]. The vasodilator response to local warming was augmented in HH (P < 0.05, ANOVA). For example, at T(loc) of 40-42 degrees C, CVC averaged 76.41 +/- 3.08% of maximum in HH and 67.71 +/- 4.43% of maximum in LH (P < 0.01 LH vs. HH). The vasoconstrictor response to local cooling was unaffected by phase (P > 0.05). These findings indicate that modifications in cutaneous vascular control by female steroid hormones include enhancement of the vasodilator response to local warming and are consistent with reports of the influence of estrogen to enhance nitric oxide-dependent vasodilator responses.  (+info)

Substance P may attenuate gastric hyperemia by a mast cell-dependent mechanism in the damaged gastric mucosa. (48/1413)

Calcitonin gene-related peptide (CGRP) released from sensory neurons, which are closely apposed to mast cells and blood vessels, mediates gastric hyperemia in response to acid challenge of the damaged mucosa. Substance P (SP) is coreleased with CGRP from sensory neurons, but the role of this peptide in gastric blood flow regulation is largely unknown. Chambered rat stomachs were exposed to 1.5 M NaCl and acidic saline after treatment with SP, aprotinin (serine protease inhibitor), and the mast cell stabilizers ketotifen and sodium cromoglycate (SCG). Gastric hyperemia (measured with a laser Doppler flow velocimeter) after hypertonic injury and acid challenge was nearly abolished by SP. Aprotinin infused together with SP and pretreatment with ketotifen and SCG before SP restored the gastric hyperemia. Ketotifen and SCG inhibited mast cell degranulation in SP-treated rats. Preservation of gastric hyperemia was correlated with improved mucosal repair. These data suggest that impaired hyperemia by SP during acid challenge of the gastric mucosa may be mediated by a mast cell-dependent mechanism involving the release of proteases from mast cells.  (+info)