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Evidence for the conversion of angiotensin I to angiotensin II by the coronary microcirculation.

Cardiac tissue from hamster neonates was transplanted into the hamster cheek pouch. After vascularization of the transplanted tissue the vessels were tested for their ability to convert angiotensin I (AI) to angiotensin II (AII). AI caused vasoconstriction of the coronary vessels which was reduced significantly by converting enzyme inhibitor and the AII antagonist (Sar1-Ala8) angiotensin II. It was concluded that the vessels of transplanted cardiac allografts convert AI to AII in a manner similar to that observed in the whole heart indicating that this procedure provides a good model for studying the microcirculation of the heart.

Angiotensin I↗

Angiotensin I conversion by the microcirculation of the nonhuman primate.

Previous studies have shown that angiotensin I (AI) is converted to angiotensin II (AII) by converting enzyme (CE) or by tonin. Since all work on tonin has been done in the rodent, its relevance to the primate is yet to be shown. This study examines the conversion of AI to AII by the cheek pouch microcirculation of the monkey (macaca fascicularis). In 9 of the 11 monkeys studied, the conversion of AI to AII was blocked by converting enzyme inhibitor (CEI). However, in 2 older monkeys, AI conversion was not altered by CEI although the vascular response to AI was attenuated by both the AII antagonist (saralasin) and the antibody to AII (Ab-AII). In these 2 older animals, renin substrate caused vasoconstriction that was not altered by CEI, but was reduced by saralasin and Ab-AII. It is concluded that the tonin-angiotensin system is not active in the young macaque, but may be present in the older animals.

Aging↗

The effect of norepinephrine on the coronary microcirculation.

The role of the sympathetic nervous system in the regulation of large coronary artery tone has been well defined. Studies of adrenergic regulation of coronary-resistance vessels have largely been limited to indirect inferences based on flow measurement obtained in vivo. The purpose of the present study was to determine the effects of norepinephrine (NE) on the coronary microcirculation using direct in vitro approaches. Porcine coronary microvessels (80-200 microns in diameter) were pressurized in isolated organ chambers. Diameters were measured using a Halpern microvessel imaging apparatus. After preconstriction with leukotriene D4, NE caused complete relaxation. Relaxations to NE were inhibited by propranolol. Relaxations to NE were also inhibited by LY83583 (which depletes cGMP) and hemoglobin (which binds endothelium-derived relaxing factor, EDRF). NE caused minimal or no constriction in both preconstricted and nonpreconstricted microvessels even in the presence of hemoglobin and propranolol. In conclusion, NE predominantly dilates porcine coronary microvessels, both by beta-adrenoceptor activation and by stimulating release of EDRF. There is minimal alpha-adrenoceptor-mediated constriction of coronary microvessels.

Aminoquinolines↗

Mediator role of prostaglandins in acetylcholine-induced vasodilation and control of resting vascular diameter in the hamster cremaster microcirculation in vivo.

Acetylcholine (ACh) is widely used as a standard test substance for nitric oxide (NO)-mediated vasodilation. However, it also augments the release of prostaglandins, a group of other endothelium-derived smooth muscle relaxants. Using intravital microscopy in the cremaster muscle of anesthetized hamsters, we studied the relative roles of NO and prostaglandins in mediating ACh-induced dilation and in the control of basal vessel tone (253 arterioles in 31 experiments) N omega-nitro-L-arginine (L-NNA), a competitive inhibitor of NO synthase, significantly reduced ACh-induced vasodilation (by 42-73%), irrespective of whether it was applied intravenously (30 mg/kg) or topically (30 microM). Additional indomethacin (3 microM, topical) nearly abolished the dilator response. In contrast, the vascular responses to the endothelium-independent dilator sodium nitroprusside were not affected. The resting diameters (range: 6-114 microns) were significantly (p < 0.05) reduced after L-NNA or indomethacin by 10.2 and 16.6% of control diameter, respectively. The constriction induced by L-NNA was stronger in larger (> 50 microns) than in smaller (< 50 microns) vessels, whereas indomethacin was equipotent in both groups. Thus, in addition to NO, dilating prostaglandins are important mediators of the ACh-induced dilation and contribute to the control of resting arteriolar diameter in the hamster cremaster microcirculation in vivo.

Abdominal Muscles↗

Long-term effects of recombinant human erythropoietin on macro- and microcirculation in chronic hemodialysis patients.

Recombinant human erythropoietin therapy (ReHuEpo) at short term leads to an increase in systemic vascular resistance and to a decrease in cardiac index and skin microcirculatory flow. Long-term adaptive changes might occur. We studied the effects of ReHuEpo therapy on macrocirculation and skin microcirculation in 8 normotensive and normovolemic hemodialysis patients before and after, respectively, 4 and 14 months of treatment. The reported macrocirculatory changes at short term were at long term not significantly different as compared with the initial values. The mean arterial pressure remained unaltered, as might be explained by the slow correction of the hematocrit and the decrease in cardiac output in all initially long-lasting normotensive patients who were maintained normovolemic. Left ventricular end-diastolic dimensions decreased, and also the left ventricular muscle mass decreased, depending on the initial left ventricular muscle mass. The skin oxygenation improved, whereas the maximal capillary flow decreased both at short- and long-term ReHuEpo treatment. The number of capillaries in the nail fold remained unchanged. However, the percentage of tortuosity decreased significantly during ReHuEpo therapy.

Adult↗

Effects of endothelin on the renal microcirculation of the split hydronephrotic rat kidney.

We have examined the effects of endothelin (ET) on the renal microcirculation by in vivo microscopy using the model of the split hydronephrotic rat kidney. ET, a potent vasoconstrictor peptide synthesized by vascular endothelial cells, showed marked and long-lasting effects on glomerular blood flow and vessel diameters in various segments of the renal vascular bed. Intravenously applied ET (100 ng/min/kg) increased systemic blood pressure from 123 +/- 7 to 156 +/- 4 mm Hg, decreased glomerular blood flow by 70%, and preferentially constricted larger preglomerular vessels, e.g. the arcuate artery. The competitive leukotriene antagonist FPL55712 significantly attenuated the vasoconstrictor response of the larger vessels. Local ET administration decreased glomerular blood flow in a dose-dependent manner (50% reduction at a concentration of 2.6 +/- 0.7 x 10(-9) M) and constricted smaller vessel segments, e.g. the afferent and efferent arterioles near the glomerulus. The constriction induced by ET was not significantly affected by the Ca2+ channel blocker nitrendipine (2.8 x 10(-6) to 1.1 x 10(-5) M). We conclude that intravenous ET effects are probably mediated by leukotrienes, inducing constriction of larger renal vessels. Locally administered ET acts directly on the renal vasculature, especially on smaller vessels.

Acetylcholine↗

Development and evaluation of an in vivo mouse model for studying myocutaneous flap microcirculation and viability before and after suturing or stapling.

A model was developed in albino hairless mice to study microcirculation and viability of dorsal distally based myocutaneous flaps. The efficacy of this model was tested in 120 mice by evaluating the effects of excessive crimping and tension attributed to Proximate or Signet staples or to simple or mattress nylon sutures. Microhemodynamics were assessed using computer-assisted intravital videomicroscopic and electro-optical methods. Volumetric rates of blood flow were calculated within terminal arterioles from measurements of internal diameter and mean centerline cellular velocity. The viability was determined on day 5 by measuring the areas of necrosis (mm2) along the cut edges of these flaps. In 80 mice, flaps were elevated and examined at 0 h and then again at 24 or 48 h. There were 40 mice in each of these disturbed groups. In a third group of 40 mice, flaps were raised at 0 h without videomicroscopic examination at 0, 24, or 48 h (undisturbed group). All flaps were stapled or sutured to the original donor site with one of the four methods of closure. The results of this study indicate that sutures produce the highest incidence of necrosis at 5 days when compared to staples in the undisturbed groups of mice. However, no significant differences in necrosis were observed when flaps were disturbed at 48 h despite videomicroscopic evidence of depressed blood flow along their cut edges. In contrast, results at 24 h were equivocal and statistically not significant. These data suggest that the phenomenon of delay and/or flap recirculation following removal and reapproximation of sutures or staples drastically improves perfusion and viability of disturbed flaps.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Characterization of the microcirculation during ischemia and reperfusion in the penumbra of a rat model of temporary middle cerebral artery occlusion: a laser Doppler flowmetry study.

The dynamic changes in microcirculation were investigated with laser Doppler flowmetry in two selected regions of interest (ROI) of a stroke lesion during ischemia and early reperfusion using a rat model of temporary middle cerebral artery (MCA) occlusion. In each ROI measurements were made either during 30 min or 2 h of MCA occlusion followed by 1 h of reperfusion. On the periphery of the MCA territory, an area of mild ischemia with a mean reduction of flow to 38% (39.9% in the group with 30 min MCA occlusion and 35.9% in the group with 2 h MCA occlusion) of preischemic values was demonstrated. Closer to the center of the MCA territory, more severe ischemia with a mean reduction of flow to 21% (19.9% in the 30-min group and 22.9% in the 2-hour group) was seen. In the two groups with laser Doppler flowmetry in the ROI of mild ischemia, a compensatory increase in flow during the first 3-6 min after MCA occlusion could be seen. All rats displayed a peak hyperperfusion immediately after re-establishing of flow which then stabilized above, below, or equal to the preischemic level. This peak hyperemia was most abundant in the group in which flow was measured in the ROI of more severe ischemia after the 30-min MCA occlusion. In the same area a short hyperemic peak was followed by a significant hypoperfusion of 60% of preischemic flow after 2 h of MCA occlusion. In the groups with flow measurements in the ROI of mild ischemia, there was a return to preischemic flow after the 30-min ischemia and a tendency of preserved hyperemia after 2 h of MCA occlusion.

Animals↗

Exogenous adenosine induces flowmotion in skeletal muscle microcirculation of the anesthetized rat.

The aim of this study was to investigate the characteristics of the microcirculatory blood flow with laser-Doppler flowmetry (LDF) in skeletal muscle during both regional and systemic infusions of adenosine. A laser-Doppler flowmeter probe was placed on the left gastrocnemius muscle in anesthetized rats. Adenosine was given either systemically in the jugular vein (group A) or administered regionally in the iliac artery (group B). The infusion of adenosine was increased stepwise by 50 micrograms/kg/min, every 10 min, up to 400 micrograms/kg/min. In group A there was a dose-dependent decrease in mean arterial pressure as well as in LDF flow; flowmotion of the LDF signal with a frequency of 1.6 cycles/min was seen at a mean adenosine dose of 240 micrograms/kg/min at a blood pressure of 60 mm Hg. In group B there was a dose-dependent decrease of mean arterial blood pressure but not as marked compared to group A, meanwhile the LDF flow was unchanged; flowmotion was seen at a mean adenosine dose of 220 microgram/kg/min at a blood pressure of 72 mm Hg, with a frequency of 1.5 cycles/min. This study demonstrates that adenosine, given either regionally intraarterially with maintained blood flow, or intravenously with reduced blood flow, induces flowmotion in skeletal muscle microcirculation with a frequency of approximately 1.5 cycles/min.

Adenosine↗

Skin microcirculation in patients with sequelae from local cold injuries.

The microcirculation in the skin was assessed in 31 patients with sequelae from local cold injuries (LCI) in the extremities. All patients reported cold intolerance 3-4 years after the primary cold injury, which they sustained during military service. The used methods were laser Doppler fluxmetry, transcutaneous oxygen tension (TCpO2) and vital capillaroscopy. Neurovascular reflexes were stimulated by deep inspiration, digital cuff occlusion of venous and arterial circulation, neck cooling with an ice bag and water immersion at 5 and 15 degrees C. Unaffected lower or upper extremities were also investigated as part of a search for generalized effects of LCI. During immersion in ice water the cold-induced vasodilation (CIVD or Lewis' 'hunting' reaction) was profoundly delayed or abolished in the affected limbs. These also showed the lowest skin temperatures after 15-20 min of immersion. Additionally, a delayed CIVD was found in the unaffected feet of patients with a previous hand injury. TCpO2 resting values were decreased in the patients, but oxygen reappearance time, oxygen recovery index, postocclusive reactive hyperemia and the venoarterial reflex were normal. No capillary abnormalities were found. In conclusion, LCI induces disturbances in the CIVD, impairs cold tolerance and increases the risk of future cold injuries. These data demonstrate disturbances of reflex mechanisms mediated by the central nervous system. Neurophysiologic factors seem to be more important than ischemic mechanisms in the pathophysiology of late sequelae from LCI.

Adult↗

Abnormal peripheral microcirculation in seemingly normal subjects living in blackfoot-disease-hyperendemic villages in Taiwan.

Blackfoot disease (BFD) is an endemic peripheral arterial disease confined to the southwestern coast of Taiwan. The cause of the disease has been ascribed to the high-arsenic artesian well water. The purpose of this study was to examine the possible association between the long-term exposure to artesian well water and the change in microvascular circulation in the absence of peripheral arterial insufficiency. A total of 45 men living in the BFD-hyperendemic villages and another 51 age- sex- body-mass index-matched men who lived in nonendemic villages nearby were recruited into this study. All subjects were free from peripheral vascular disease (resting ankle-brachial index > 1.00), clinical claudication, cigarette smoking, diabetes mellitus, hypertension, ischemic heart disease, cerebral infarction and obesity. Laser Doppler flowmetry was used to measure the peripheral microcirculation on the big toes both at 36 degrees C (basal perfusion, Pb) and after a hyperthermic test at 42 degrees C (Ph). The time required to reach Ph (T), and the average rate (R) of increase from Pb to Ph measured by (Ph-Pb)/T were also calculated. Results showed that those living in the BFD-hyperendemic area had a lower Pb [32.8 +/- 6.0 perfusion units (PU) vs. 67.0 +/- 4.3 PU, p < 0.001], a lower Ph (193.2 +/- 13.6 vs. 231.1 +/- 6.3 PU, p < 0.005), a longer T (3.04 +/- 0.19 vs. 1.31 +/- 0.08 min, p < 0.001) and a slower rate of increase from Pb to Ph (48.0 +/- 4.8 vs. 76.2 +/- 5.4 PU/min, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

Effects of iloprost, a stable prostacyclin analog, and its combination with NW-nitro-L-arginine on early events following lipopolysaccharide injection: observations in the hamster cheek pouch microcirculation.

The effects of iloprost, a stable prostacyclin analog, and of its combination with NW-nitro-L-arginine (L-NAG) on the microcirculatory changes observed in early stages of endotoxemia were investigated in male hamsters treated with Escherichia coli lipopolysaccharide (LPS). The cheek pouch was studied in vivo by means of intravital microscopy and mean arterial and venous pressures, mean arteriolar internal diameter, spontaneous arteriolar vasomotion, microvascular blood flow, macromolecular permeability, leukocyte adhesion and mean survival time were evaluated in animals treated with LPS alone or with the combination of LPS+iloprost and LPS+iloprost+L-NAG. Intravenous injection of LPS (100 mg/kg) per se elicited a significant reduction in mean arterial blood pressure (MABP) and arteriolar blood flow. The observed arterioles dilated and spontaneous vasomotion ceased. Iloprost (40 ng/kg/min) prevented LPS-induced reduction of MABP, ameliorated the decrease in arteriolar blood flow and reduced the vasodilation. Arteriolar vasomotion was reduced but it did not cease. The combination of L-NAG (0.5 mg/kg) + iloprost (40 ng/kg/min) with LPS (100 mg/kg) did not improve the results obtained with iloprost alone, except that it prevented the vasodilation and the vasomotion ceased 1 h after the bolus injection of LPS+L-NAG. The mean survival time compared to LPS alone (57 +/- 7 h) was significantly increased by the combination of LPS+iloprost (102 +/- 6 h) and it did not change significantly with the combination L-NAG+iloprost (64 +/- 9 h). Topical addition of iloprost (10 ng/kg/min) evoked an early increase in macromolecular permeability and a significant decrease in leukocyte adhesion compared with animals treated with topical LPS (0.7 microgram/ml/min) alone. The combination of L-NAG+iloprost (1.3 + 10 ng/ml/min) enhanced the early increase in macromolecular permeability even further, tended to increase the macromolecular permeability and evoked a smaller decrease in leukocyte adhesion than the one observed with iloprost combined with LPS. Our results, in the hamster cheek pouch microcirculation, suggest that the use of prostacyclin could be beneficial in the treatment of early changes in endotoxic shock, but L-NAG showed no benefit in this preparation.

Animals↗

Rhythmical fluctuations of the intracerebral microcirculation studied in pigs.

Rhythmic variations in blood flow have been observed in various vascular beds, including brain. We have characterized fluctuations of the microcirculation in different locations in the brain, and studied the response to changes in arterial carbon dioxide tension, arterial pressure, and cerebrospinal fluid pressure. Laser Doppler flowmetry was performed in 20 pentobarbital-anesthetized pigs. Flow probes were positioned on the brain surface and 3, 10, and 20 mm into the cerebral tissue. The protocol included carbon dioxide breath- ing, hemorrhagic hypotension, and infusion into the cisterna magna. Twenty-five periods of low-frequency oscillations (4.5/min) were found in 10 pigs with superimposed spindle-shaped rhythmic variations (0.5/min) of the amplitude in 7. There were no rhythmic changes in arterial pressure or intracranial pressure. Rhythmic activity was most often seen in the probe positioned 20 mm into the brain and was often seen in several probes at the same time. Animals with rhythmic oscillations before interventions had lower cerebral perfusion pressure and arterial pressure, lower heart rate, and higher laser Doppler signal than the others. Blood loss often initiatied oscillations. High intracranial pressure tended to abolish preexisting oscillations. Hypercapnia always abolished preexisting oscillations. Oscillations were more frequent if the cerebral perfusion pressure was in the low range of cerebral autoregulation, occurred more often in the cerebral locations with relatively high local flow, were most likely to be localized, and therefore probably caused by local metabolic or myogenic variations.

Animals↗

Microcirculation in venous disorders: the role of the white blood cells.

The haemodynamic hallmark of chronic venous disease in the legs is raised ambulatory venous pressure. This is probably the principal cause of both the symptoms of long-standing varicose veins and the trophic changes round the ankle characteristics of chronic venous insufficiency, presumably by an effect on the microcirculation. The microcirculatory consequences of raised venous pressure include morphological changes, as well as functional abnormalities ranging from haemorheological changes, increased capillary permeability and abnormalities of fibrinogen metabolism to trapping of white blood cells in the dependent legs. This last is now known to be accompanied by sequestration of platelets, which is irreversible. It is postulated that leucocyte activation releases cytokines, leucocyte-derived oxygen free radicals, proteolytic enzymes and platelet activating factor. It has been shown that external compression not only relieves stasis but also decreases white cell trapping. A strategy for management of the complications of venous disease should therefore be aimed at treatment of both the macrocirculatory haemodynamic defect and the microcirculatory abnormalities. The latter is an ideal target for systemic pharmacotherapy.

Humans↗

Impaired microcirculation in heart failure.

The aim of the present study was to examine the nailfold capillary morphology and dynamics in treated chronic heart failure (CHF) in relation to parameters of left ventricular structure and function. Twenty patients with CHF class II according to the New York Heart Association underwent a capillaroscopic examination at the finger nailfold using a computerized videophotometric system (Capiflow) at rest and after 1 min arterial occlusion. Study parameters ere number, length and diameter of the capillaries as well as capillary blood velocity (CBV). Further experiments included echocardiography and determination of left ventricular ejection fraction by Tc scintigraphy. Nailfold capillaries in established CHF are enlarged and the CBV is dramatically decreased. The reactive hyperemic response to 1 min arterial occlusion is attenuated. CBV correlates positively with left ventricular ejection fraction (r = 0.61, p = 0.01) and inversely with left ventricular end-diastolic (r = -0.56, p = 0.04) and end-systolic (r = -0.69, p = 0.01) diameters. The time-to-peak flow after 1 min arterial occlusion is positively related (r = 0.68, p < 0.05) to the duration of CHF. Our data indicate that finger microcirculation in CHF deteriorates as a function of the severity and duration of heart failure.

Aged↗

Correlation between laser Doppler perfusion monitoring and hematocrit in hamster cheek pouch microcirculation.

The aim of this study was to investigate the relationships between laser Doppler perfusion monitoring (LDPM) measurements and different systemic hematocrits in microcirculation in terms of changes in oscillatory flow patterns. The hamster cheek pouch microvasculature was visualized by a fluorescent microscopy technique, and LDPM signals were derived from arterioles and venules under control conditions and after isovolemic hemodilution with saline and 6% dextran, MW 70,000 to 26.1 +/- 2.1%. Vasomotion, oscillations of microvascular blood flow (flow motion) and red blood cell (RBC) velocity were analyzed with Fourier transform and autoregressive modeling. LDPM recordings presented a significant increase in perfusion units (PU) during hemodilution-184 +/- 15 versus baseline 137 +/- 11 PU in arterioles and 40.2 +/- 3.5 versus 28.6 +/- 4.3 PU in venules-that was correlated with a significant increment in arteriolar and venular RBC velocity. There was a rise in the frequency [2.9 +/- 0.5 cycles per min (cpm) vs. 1.8 +/- 0.5 cpm] and spectral power of flow motion in arterioles whereas the increase in spectral power was related to a decrease in frequency (12.6 +/- 2.1 vs. 3.6 +/- 0.7 cpm) in venules. Oscillations in arteriolar and venular RBC velocity revealed coincident frequency components with flow motion patterns. The present data suggest that the LDPM measurements are more sensitive to velocity than hematocrit. Furthermore, hemodilution appears to affect differently arteriolar and venular flow motion patterns.

Animals↗

Skin microcirculation responses to severe local cooling.

When skin is exposed to cold, cutaneous blood flow is initially restricted due to sympathetic vasoconstriction. Prolonged exposure to cold has a secondary protective vasodilator effect. In the present study, the effects of severe and prolonged local cold on the cutaneous microcirculation were assessed. In 10 young healthy subjects, laser Doppler skin flux and flux motion were measured at the calf during 20 min of local ice cooling and 15 min subsequent recovery. In the 6th minute of cooling, mean skin flux decreased to 58 +/- 6% of the resting value (p < 0.05), then increased and reached 129 +/- 10% of the resting value at the end of the cooling period, followed by a phase of reactive hyperemia with a maximum of 225 +/- 24% (p < 0.05). Mean flux motion frequency, spontaneously present at rest with a frequency of 2.6 +/- 0.2 cycles/ min decreased rapidly during the first minutes of cold exposure, was absent during the 6th to the 10th minute, reappeared and started to increase from the 11th minute and reached 4.4 +/- 0.3 cycles/min during the recovery period (p < 0.05). This study seems to indicate that the phenomenon of protective increase of cutaneous microcirculatory blood flow consists of an initial phase of vasodilation, followed by a phase of active and enhanced microvessel vasomotor activity.

Adult↗

Long-term registration of cutaneous microcirculation during general anesthesia.

The temporal dynamics of the systemic arterial pressure can be monitored noninvasively from the skin of the earlobe or forehead by photoplethysmography under the provision that the active control of the microcirculatory perfusion is eliminated. Using this approach, we have been able to detect a highly stable blood pressure rhythm in the range of 0.15 Hz during psychophysical relaxation or sleep. The aim of the present study was to investigate the occurrence and behavior of blood pressure rhythms below 0.2 Hz during general anesthesia. In 30 patients (ASA groups I-II) undergoing basic surgical procedures, photoplethysmographic recordings from the earlobe were made during the whole time of anesthesia. The recorded signals were divided into segments of 200 s of duration, the temporal structure of which was analyzed by fast Fourier transform. Different characteristic patterns of rhythmical behavior were detected: (1) absence of activity below 0.2 Hz ('low-frequency range'); (2) slow sinusoidal rhythmicity below 0.05 Hz; (3) 'chaotic' behavior, i.e. multiple incoherent fluctuations without stationary periods or amplitudes; (4) short-term rhythmical activity at about 0.15 Hz, and (5) long-term rhythmical activity at about 0.15 Hz. In patients sufficiently sedated to eliminate low-frequency activity, rhythmicity could sometimes be triggered by certain surgical stimuli, the response to which was suppressed by injection of opioids. The data presented strongly suggest that rhythmical perfusion patterns of the cutaneous microcirculation could serve as an indicator for the depth of anesthesia.

Adolescent↗