Photodynamic therapy reduces intimal hyperplasia in prosthetic vascular bypass grafts in a pig model.

BACKGROUND: Bypass surgery has a failing frequency of 30% during the first year, mainly due to intimal hyperplasia (IH). This negative effect is most pronounced in artificial grafts. Photodynamic therapy (PDT) is a technique in which light activates photosensitizer dyes to produce free-radicals resulting in an eradication of cells in the vascular wall. The aim of this study was to determine the effectiveness of PDT to reduce IH in a preclinical porcine PTFE bypass model. MATERIAL AND METHODS: Ten pigs were used. After a pilot PDT dosimetry study (n=3) PTFE grafts were bilaterally placed into the circulation as bypasses from the common to the external iliac arteries (n=7). The right sides served as controls (C). Before implantation of the left grafts, the arterial connecting sites of the left distal anastomoses were PDT-treated. The arteries were pressurized at 180 mmHg for 5 minutes with the photosensitizer Methylene Blue (330 microg/ml), and thereafter endoluminally irradiated with laser light (lambda = 660 nm, 100 mW/cm(2), 150 J/cm(2)). After 4 weeks the specimens were retrieved and formalin fixed. Cross sections through the midportions of the distal anastomoses and the grafts were used for histology, immunohistochemistry to identify inflammatory cells and morphometric evaluation (n=7). RESULTS: No systemic side effects and no graft occlusions were noted. PDT-treated anastomoses showed reduced IH in the mid-portions of the anastomoses (Area of IH: microm(2)/microm graft: C: 6970+/-1536, PDT: 2734+/-2560; P<0.005) as well as in the grafts (C: 5391+/-4031, PDT: 777+/-1331; P<0.02). The number of inflammatory cells per microscopic field was increased after PDT (C: 24+/-16, PDT: 37+/-15; P<0.009). CONCLUSIONS: Adjuvant PDT, performed in an endovascular fashion, was a safe method to reduce prosthetic graftstenosis in a preclinical setting. This study underscores the clinical potential of PDT to inhibit the development of clinical bypass graftstenosis.

Healing of PTFE grafts in a pig model recruit neointimal cells from different sources and do not endothelialize.

OBJECTIVES: The aim of this study was to analyze the cellular sources for the neointima and the cell type that is lining the lumen in artificial grafts implanted in pigs. MATERIALS AND METHODS: We used polytetrafluoroethylene grafts as bypasses from the common to the external iliac arteries. The animals were sacrificed after 1, 4, 7, 14, 21, 30, 60 and 90 days. Morphological, immunohistochemical and electron microscope assessments were made. RESULTS: After 7 days a circumferential neoadventitia was formed. At day 14 isolated cellular islets of proliferating cells were observed on the luminal side of the graft without connection to the neoadventitia or the adjacent arteries. In the anastomotic regions at day 14 we observed an isolated neointima in contact with the adjacent artery. The cells lining the lumen had characteristics of both smooth muscle cells and endothelial cells. CONCLUSIONS: Our study suggests that in artificial porcine grafts, the perivascular tissue, the blood and the adjacent artery contribute to the formation of the neointima. The luminal surface is covered by a hybrid cell with both smooth muscle cell and endothelial cell properties.

Treatment of descending thoracic aneurysms by endovascular stent grafting.

PURPOSE: Endovascular stent-graft treatment for true aneurysms of the descending thoracic aorta is a valid and effective alternative to conventional surgery. A review of our experience with 21 consecutive patients is reported and technical considerations are discussed. METHODS: Twenty-one patients (mean age 73 years) with true aneurysms of the descending thoracic aorta (n = 14) or contained rupture (n = 7) were treated between October 1999 and July 2001. Seven patients (33%) underwent emergency endovascular procedure. Postoperatively, the patients were followed with CT scans at 1, 3, 6, and 12 months. Follow-up, which averaged 17 months, was 100% complete. THIRTY-DAY RESULTS: No conversions to open repair were necessary. Two patients died (10%), one of acute intestinal ischemia and the other because of multiorgan failure. Four patients showed endoleaks immediately after stenting. Two patients required new endovascular stentgrafts, while the remaining two were treated conservatively. Besides endoleaks, eight major complications occurred in six patients (two stroke, two paraplegia, two respiratory insufficiency, and one renal failure). MID-TERM RESULTS: Three more patients died during the follow-up period. One patient died of heart failure after a complicated postoperative course, 91 days after stenting. The second patient died because of aortic rupture, 139 days after stenting. The third patient died of heart failure, 15 months after the endovascular procedure. The remaining 16 patients are alive and have been regularly controlled by CT scans. No late migration or endoleaks have been detected. In all the survivors, the size of the aneurysm was unchanged or diminished. CONCLUSIONS: Treatment of descending thoracic aortic aneurysms by endovascular stentgraft devices has good early and mid-term results. More accurate selection of patients may further reduce mortality and morbidity.

A prognostic index of unsuccessful laparoscopic cholecystectomy for acute calculous cholecystitis.

The aim of this retrospective study was to investigate the accuracy of using preoperative data for the prediction of conversion from laparoscopic to open cholecystectomy in patients operated on for acute calculous cholecystitis. Laparoscopic cholecystectomy was scheduled in eighty-nine of 184 consecutive patients with acute calculous cholecystitis who underwent urgent or early cholecystectomy without bile duct exploration in our department between 1991 and 1998. The correlation between 11 preoperative clinical, laboratory and ultrasonographic variables, and the rate of conversion to open cholecystectomy was studied. Among the 11 variables tested, age and leukocyte count were independent factors of predictive significance. These two factors were used for constructing an additive prognostic index for conversion to open cholecystectomy. Thus, three groups of patients could be identified having a 10%, 30-70% or over 88% risk of conversion. Logistic regression analysis permits accurate preoperative identification of unsuccessful laparoscopic cholecystectomy in patients with acute calculous cholecystitis.

Alpha 2-adrenoceptor activation may trigger the increased production of endothelium-derived nitric oxide in skeletal muscle during acute haemorrhage.

Our previous studies indicated that acute haemorrhage leads to a pronounced increase in the release of endothelium-derived nitric oxide (EDNO) graded in relation to the magnitude of the blood loss. The EDNO-induced vasodilatation, confined selectively to the arterial 'feeder' vessels, attenuates the concomitant reflex adrenergic constriction and thereby prevents deleterious reduction of blood flow. The present study aimed at investigating whether the reflex release of blood-borne catecholamines might trigger this EDNO release via activation of endothelial alpha 2-adrenoceptors. The study was performed on the sympathectomized vascular bed of cat skeletal muscle with a technique permitting quantitative recordings of resistance (tone) in consecutive vascular sections. Selection alpha 2-adrenoceptor blockade with idazoxan applied at steady state vasoconstriction after a 35% blood loss evoked an initial generalized dilator response (attributable to inhibition of post-synaptic smooth muscle alpha 2-adrenoceptors), followed by a constrictor response selectively in the arterial feeder vessels, the latter compatible with the hypothesis of reduced EDNO release by alpha 2-adrenoceptor blockade. More direct evidence for the hypothesis was obtained from studies of the vascular response to EDNO blockade (L-NAME) after haemorrhage in the presence and absence of alpha 2-adrenoceptor blockade. The constrictor response to EDNO blockade, which is a measure of the pre-existing EDNO dilator influence (EDNO production), was significantly smaller (P < 0.01) in the presence than absence of alpha 2-adrenoceptor blockade. The results indicate that blood-borne catecholamines, via activation of endothelial alpha 2-adrenoceptors, trigger the increase in the EDNO release in acute haemorrhage, implying a functionally important negative feedback in the integrated control of vascular tone in bleeding.

Cardiovascular regulation by endogenous nitric oxide is essential for survival after acute haemorrhage.

Our previous studies have indicated that endogenous nitric oxide serves as a physiologically important inhibitor of vascular tone during acute haemorrhage. This vasodilator action attenuates the concomitant reflex adrenergic constriction and thereby prevents critical reduction of tissue blood flow. The present study aimed to evaluate the overall importance of this nitric oxide regulation for survival after acute haemorrhage. This was done by comparative observations of survival time and circulatory, metabolic and histopathological changes after an acute standardized lethal blood loss (45%) in cats exposed to nitric oxide synthase (NOS) inhibition and in matched control animals with intact nitric oxide regulation. NOS inhibition was instituted by intravenously administered N omega-nitro-L-arginine methyl ester. The survival time averaged 2 h 49 min in the NOS-blocked animals and 10 h 14 min in the control animals (P < 0.001). NOS inhibition thus reduced the posthaemorrhagic survival time to < 30% of that in the control cats. Haemorrhage in the NOS-blocked animals led to rapidly developing arterial hypotension, increased anaerobic metabolism, metabolic lactacidosis, hyperkalaemia, and morphological tissue damage especially in heart and liver, in spite of maintained arterial normoxia, which signifies tissue hypoxia caused by seriously impaired nutritional blood supply. At the time of death of the NOS-blocked cats, the control animals still exhibited a virtually normal circulatory/metabolic state. A much later, and more slowly developing circulatory/metabolic deterioration was observed in the control animals. These differences between the two groups of animals indicate that nitric oxide release, by its vasodilator action, to a significant extent helps to maintain an adequate nutritional blood supply to the tissues in acute haemorrhage.

Endogenous nitric oxide as a physiological regulator of vascular tone in cat skeletal muscle during haemorrhage.

The problem whether endogenous nitric oxide (NO) may serve as a true physiological regulator of vascular tone in vivo was approached by testing its role during graded acute haemorrhage with the aid of the nitric oxide synthase (NOS) inhibitor L-NAME. The study was performed on the vascular bed of cat skeletal muscle with a technique permitting quantitative recordings of vascular resistance in the whole vascular bed (RT) and in its consecutive sections, the proximal arterial resistance ('feeder') vessels (> 25 microns; Ra,prox), the small arterioles (< 25 microns) and the veins. NO blockade by close-arterial L-NAME infusion in the control situation increased RT from 16.3 to 33.0 PRU (+102%), because of a selective increase in Ra,prox by 16.7 PRU. A 35% blood loss per se raised RT from 13.6 to 21.7 PRU. Superimposed NO blockade in this state caused a much stronger vasoconstriction than in the control situation, increasing RT to 60.9 PRU (+181%) and Ra,prox by 40.5 PRU, which indicated an approximately 2.4-fold increase (P < 0.001) in the NO dilator influence in the Ra,prox section above control. The effect was independent of autonomic nerves. The increased NO dilator influence during haemorrhage most likely was caused by an increased production of endothelium-derived nitric oxide (EDNO), The constrictor response to L-NAME was graded in relation to the blood loss (17.5 vs. 35%). The results indicate that EDNO functions as a physiological regulator of vascular tone in the arterial 'feeder' vessels during haemorrhage, serving to counterbalance to a significant extent the concomitant adrenergic constriction, and thereby preventing critical reduction of blood flow and untoward heterogeneous flow distribution within the tissue.

Muscle blood flow in cats: comparison of microdialysis ethanol technique with direct measurement.

A quantitative validation of the microdialysis ethanol technique was performed in cat gastrocnemius muscle. Six to eight microdialysis probes were inserted into the isolated muscle preparation and perfused (0.5-10.0 microliters/min) with Krebs-Henseleit buffer containing between 5 and 1,000 mmol/l ethanol. Skeletal muscle blood flow was held constant in the range of 4-99 ml.100 g-1.min-1 by a servo-controlled roller pump and was determined with the microdialysis ethanol technique as well as by timed collection of venous outflow. The ethanol concentration outflow-to-inflow ratio ([ethanol]collected dialysate/[ethanol]infused perfusion medium) decreased in a nonlinear fashion when microdialysis perfusion flow rates of 0.5 and 1.0 microliter/min were employed. However, a linear decrease was found between 4 and approximately 45 ml.100 g-1.min-1 (r = -0.92 to -0.99). The lower outflow-to-inflow ratio was at 4 ml.100 g-1.min-1 (i.e., due to a low probe perfusion flow rate or a large dialysis membrane), the greater the sensitivity of the method was. It is concluded that this nonradioactive technique provides a simple and valid method for determining nutritive blood flow in skeletal muscle.

Effects of the combined ETA and ETB receptor antagonist PD145065 on arteries, arterioles, and veins in the cat hindlimb.

The aim of this study was to describe in quantitative terms the effects of ETA and ETB receptor blockade on vascular tone (resistance) in large-bore arterial resistance vessels (> 25 microns), small arterioles (< 25 microns), and veins in the cat gastrocnemius muscle in vivo. In the muscle vascular bed, the combined ETA and ETB receptor antagonist PD145065 (1 mg/kg/min, intra-arterially) abolished the biphasic vascular responses (dilatation followed by constriction) to both ET-1 (0.4 microgram/kg/min, intra-arterially) and to the selective ETB receptor agonist IRL1620 (3.2 micrograms/kg/min, intra-arterially). In the cat femoral artery and vein in vitro, PD145065 competitively inhibited the contractile responses to both ET-1 and IRL1620. The contractile response to the latter agonist could be evoked only after long-term incubation of the vessels (37 degrees C for 5 days). These results indicate that PD145065 is a potent antagonist at both ETA and ETB receptors in vivo and in vitro. Therefore, this antagonist may prove useful for elucidating the possible physiologic and/or pathophysiologic roles of the endothelins. For example, it was shown that PD145065 had no effect on vascular tone in the resting state, indicating no role for the endothelins in the regulation of basal vascular tone in cat skeletal muscle.

Effects of increased and decreased tissue pressure on haemodynamic and capillary events in cat skeletal muscle.

1. The controversial problem concerning the unusual haemodynamics of the deranged circulation during increased hydrostatic tissue pressure (PT) was elucidated by detailed studies of arterial, capillary and venous functions in cat skeletal muscle exposed to graded experimental changes of PT over a wide range. 2. The results indicated that the impaired circulatory state in skeletal muscle during raised tissue pressure is characterized by the following train of events: (a) a primary partial passive compression of the most distal part of the venous system due to negative vascular transmural pressure selectively at this site, in turn leading to the prompt development of a distinct 'venous outflow orifice resistance' graded in relation to the PT rise; (b) a consequent reduction of blood flow graded in relation to this resistance increase; (c) a rise in intramuscular venous pressure proximal of the 'venous outflow orifice' by the same extent as the PT increase; (d) transmission of the raised venous pressure to more proximal vessels in relation to the prevailing segmental resistance ratios; (e) a consequent maintenance of clearly positive transmural pressures in all vascular sections proximal to the 'venous outflow orifice', preventing collapse of these vessels; (f) maintenance of a largely normal capillary filtration coefficient and functional capillary surface area; and (g) an increase in capillary pressure by approximately 85% of the PT rise which reduces the rate of net transcapillary fluid absorption to about one-seventh of that expected from the PT rise per se. 3. Previous concepts of a 'vascular waterfall phenomenon', a capillary collapse, or an arteriolar 'critical closure phenomenon' did not seem to be valid for the skeletal muscle circulation during increased PT. 4. The rate of net transcapillary fluid flux per unit PT change was much smaller during positive than negative PT, since capillary pressure rose considerably when PT was increased above control, but was largely unchanged when PT was decreased below control. 5. Possible ways to improve the circulatory state in conditions with an oedema-induced tissue pressure rise are discussed.

Effects of selective ETB-receptor stimulation on arterial, venous and capillary functions in cat skeletal muscle.

1. This paper describes, in quantitative terms, the in vivo effects of two selective ETB-receptor agonists (IRL 1620 and BQ 3020) on vascular resistance (tone) in the following consecutive sections of the vascular bed of sympathectomized cat skeletal muscle: large-bore arterial resistance vessels (> 25 microns), small arterioles (< 25 microns) and the veins. The effects on capillary pressure transcapillary fluid exchange were also recorded. 2. Both IRL 1620 and BQ 3020, infused i.a. to the muscle preparation, evoked an initial transient dilator response followed by a moderate dose-dependent constrictor response, both being preferentially confined to the small arterioles. The dilator response was associated with a transient increase, and the constrictor response with a sustained decrease, in capillary pressure, the latter causing net transcapillary fluid absorption. The capillary filtration coefficient decreased during the constrictor response, indicating constriction of terminal arterioles/precapillary sphincters. 3. The vascular responses to the ETB-receptor agonists were unaffected by blockade of endothelium-derived nitric oxide (NG-nitro-L-arginine methyl ester) and by selective ETA-receptor blockade (FR139317). However, blockade of prostacyclin production with indomethacin decreased the amplitude of the dilator response, and decreased the time required to reach a steady-state vasoconstrictor response to the ETB-receptor agonists. 4. The effect of ETB-receptor stimulation on vascular tone was also evaluated in vitro on the cat femoral artery and vein. IRL 1620 had no effect on the femoral artery but caused a weak dose-dependent relaxation in the femoral vein. This large vein relaxation response seemed to be mediated by endothelium-derived nitric oxide and not by prostacyclin. 5. It may be concluded that ETB-receptor stimulation is responsible for the dilator response, and can contribute to the constrictor response, elicited by endothelins in cat skeletal muscle in vivo.

In-vivo effects of endothelin-1 and ETA receptor blockade on arterial, venous and capillary functions in skeletal muscle.

Results from in vitro studies have indicated that endothelin-1 is a main candidate for endothelium-derived contracting factors. The aim of this in vivo study was to describe in quantitative terms the effects of endothelin-1 (ET-1), and of ETA receptor blockade, on vascular tone (resistance) in large-bore arterial resistance vessels (> 25 microns), small arterioles (< 25 microns) and the veins, as well as on capillary pressure and fluid exchange in cat gastrocnemius muscle. Endothelin-1 (100-1600 ng kg-1 min-1, i.a.) elicited, after an initial transient dilation, a strong dose-dependent constrictor response in all three consecutive vascular sections, yet with a preferential action on the small arterioles and the veins. The vasoconstriction developed very slowly over about 1 h and was also long-lasting after cessation of the infusion. Our main quantitative analysis refers to effects elicited by 20 min long i.a. infusions of ET-1 at a dose of 400 ng kg-1 min-1. At the end of this period, the peptide caused, on average, a three-fold increase in total regional vascular resistance, in turn explained by a 70% increase in large-bore arterial resistance, a 280% increase in arteriolar resistance and a 220% increase in venous resistance. The latter effect was also manifested as a pronounced capacitance response, and as a decrease in the pre- to post-capillary resistance ratio leading regularly to a rise in capillary pressure, net transcapillary fluid filtration and oedema formation which is unusual for a vasoconstrictor. The new specific competitive ETA receptor antagonist FR 139317 was found to be fully effective in vivo, insofar as it abolished the constrictor response to endothelin-1. ETA receptor blockade, or administration of phosphoramidon, an inhibitor of ET-1 production, did not influence the level of basal vascular tone, indicating no significant endogenous release of ET-1 under resting conditions. This contrasts to the established pronounced endogenous release of endothelium-derived nitric oxide. Finally, vascular myogenic regulation was found not to be mediated by ET-1. The results, taken together, suggest a possible role of ET-1 in long-term, rather than short-term, regulation of vascular tone in vivo, perhaps especially during pathophysiological conditions.

Myogenic vascular regulation in skeletal muscle in vivo is not dependent of endothelium-derived nitric oxide.

The hypothesis, based on in vitro experiments on large conduit arteries, that endothelium-derived nitric oxide is a mediator of vascular myogenic reactivity was tested in cat gastrocnemius muscle in vivo. This was done by comparing, in the absence and presence of effective endothelium-derived nitric oxide blockade by the specific inhibitors NG-monomethyl-L-arginine or NG-nitro-L-arginine methyl ester, myogenic responses in defined consecutive vascular sections to dynamic vascular transmural pressure stimuli, to arterial occlusion (reactive hyperaemia), and to arterial pressure changes (autoregulation of blood flow and capillary pressure). The results demonstrated that the myogenic vascular reactivity to quick ramp transmural pressure stimuli was not attenuated by endothelium-derived nitric oxide blockade, but rather reinforced. The amplitude of the reactive hyperaemia response was unaffected by endothelium-derived nitric oxide blockade, but its duration was shortened because of faster myogenic constriction, especially of large-bore arterial resistance vessels greater than 25 microns, in the recovery phase. Both the improved myogenic responsiveness to transmural pressure stimuli and the shortening of the reactive hyperaemia by endothelium-derived nitric oxide blockade suggested that endothelium-derived nitric oxide released in vivo acts as a 'metabolic' factor which certainly does not improve, but rather depresses myogenic vascular reactivity. Autoregulation of blood flow and capillary pressure were well preserved in the presence of endothelium-derived nitric oxide blockade. It was concluded from the results of these multifaceted tests that myogenic vascular regulation in skeletal muscle in vivo seems independent of endothelium-derived nitric oxide.(ABSTRACT TRUNCATED AT 250 WORDS)

Protective role of sympathetic nerve activity to exercising skeletal muscle in the regulation of capillary pressure and fluid filtration.

This study describes the integrated sympathetic/metabolic control of capillary pressure (Pc) and filtration in cat skeletal muscle as studied during graded exercise and superimposed graded (2, 6 and 16 Hz) vasoconstrictor nerve excitation. The applied technique permitted simultaneous analysis of the underlying changes of resistance in the whole vascular bed (RT) and in its large-bore arterial resistance vessels (greater than 25 microns), small arterioles (less than 25 microns) and veins. Graded exercise per se caused graded increases in capillary pressure, which at heavy work exceeded the resting control value by 12.2 mmHg, in turn leading to marked loss of plasma fluid by filtration. Sympathetic nerve stimulation was much more efficient in lowering capillary pressure during exercise than at rest, in spite of an exercise-induced marked attenuation of the vasoconstrictor response (RT). The sympathetically evoked capillary pressure fall per unit resistance increase was larger the greater the degree of exercise vasodilation, implying a highly nonlinear relation between capillary pressure and RT and also between the more direct determinant of capillary pressure the post- to precapillary resistance ratio, and RT. Strenuous exercise in vivo is known to be associated with a markedly increased reflex sympathetic discharge to exercising muscle which has been a puzzling feature in view of its untoward restriction of the exercise hyperaemia response. To the extent the present results are representative for this in vivo situation, they suggest that sympathetic discharge to exercising muscle, in spite of some flow restricting effect, might serve a highly beneficial function, causing effective protection against excessive work-induced rise of capillary pressure and harmful plasma fluid loss into the extravascular space of working muscle.

Role of endothelium-derived nitric oxide in the regulation of tonus in large-bore arterial resistance vessels, arterioles and veins in cat skeletal muscle.

The role of endothelium-derived nitric oxide in the regulation of vascular resistance (tonus) in cat skeletal muscle was studied with the use of NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide formation from L-arginine. The study was performed with a whole-organ technique which permits simultaneous, continuous and quantitative recordings of resistance reactions in the whole vascular bed (RT) and in its three consecutive sections: large-bore arterial resistance vessels (greater than 25 microns; Ra,prox), small arterioles (less than 25 microns; Ra,micro) and veins (Rv). NG-monomethyl-L-arginine (3-100 mg kg-1 tissue, i.a.) induced a dose-dependent increase in resistance that was preferentially, but not selectively, confined to the large-bore arterial resistance vessels. At a maximally effective dose (100 mg kg-1), the nitric oxide inhibitor caused a marked constriction, within 5 min, on average increasing RT by 99%, Ra,prox by 138%, Ra,micro by 18% and Rv by 23%. The constrictor response to NG-monomethyl-L-arginine was long-lasting but disappeared gradually over a period of about 1 h. However, it could be abruptly abolished by excess L-arginine (300 mg kg-1, i.a.). The vasodilator response (RT) to acetylcholine was significantly attenuated in the presence of NG-monomethyl-L-arginine compared with the control response. The results suggested that nitric oxide formation from L-arginine by the vascular endothelium plays a fundamental role in the regulation of vascular resistance (tone) in vivo, with its main site of action located in the large-bore arterial resistance vessels.

Relation between capillary pressure and vascular tone over the range from maximum dilatation to maximum constriction in cat skeletal muscle.

An attempt was made to assess, from a large sample (n = 567), the normal level of hydrostatic capillary pressure (Pc) in resting skeletal muscle and the extent of Pc regulation as effected by strictly graded activation of metabolic and adrenergic control mechanisms over the entire physiological range of vascular tone. With the use of a new whole-organ technique, Pc towards the venous end of the capillary was continuously recorded at constant arterial pressure (100 mmHg) and under simultaneous observations of total regional vascular resistance (RT), precapillary resistance (Ra) and post-capillary resistance (RV). In the control state with a Starling fluid equilibrium, a venous pressure of 7 mmHg and normal vascular tone (RT = 19.1 +/- 0.3 PRU), Pc averaged 16.7 +/- 0.3 mmHg. Graded metabolic dilatation (muscle exercise), decreasing RT to a minimum value of 1.7 PRU, caused progressive increase in Pc up to 32 mmHg and consequent fluid filtration. Conversely, graded adrenergic constriction, increasing RT to a maximum of 100 PRU, caused a progressive decrease in Pc down to 10 mmHg and consequent fluid absorption. The relation between Pc and RT was highly non-linear, Pc increasing more steeply the more RT approached low values, and was described by the power function: Pc = 36.43 x RT-0.27 (r = -0.79, P less than 0.001). The resistance ratio, Rv/Ra (the main determinant of Pc), and vascular tone (RT) showed a similar non-linear relation. Regulatory change of Rv/Ra was mainly accomplished by active change of Ra, but a pronounced Rv decrease (venodilatation) occurred in the lowest RT range, exerting a protective function against excessive increase in Pc and detrimental plasma fluid loss.

Effects of hypertonic NaCl solution on microvascular haemodynamics in normo- and hypovolaemia.

The aims of this study were to investigate possible resuscitation effects of a single, 10-min, 350-microliters intravenous infusion of 7.5% NaCl in hamsters in hemorrhagic shock and to compare the effects of such infusion with an identical one of 0.9% NaCl on the hamster cheek pouch microcirculation during normovolaemia and after acute bleeding to a hypotension level of about 40 mmHg. No significant differences could be detected between the effects of either infusion given to normovolaemic normotensive hamsters. In the animals subjected to haemorrhage, upon bleeding, arterioles larger than 40 microns constricted, arterioles smaller than 40 microns dilated and venular diameter did not change, while blood flow decreased in all vessels. The main differences between the infusions after haemorrhage were a significant increase in mean arterial pressure and arteriolar blood flow, venoconstriction and a tendency for the smaller arterioles to remain more dilated and the larger ones more constricted after the hypertonic infusion. Central nervous and/or reflex excitation of the sympathetic nervous system could account for the constriction of venules and larger arterioles, while a direct effect of hyperosmolarity could explain the dilatation of the smaller arterioles. The study can therefore help to explain some of the mechanisms underlying the reported resuscitation effect of 7.5% NaCl infusion in animals during severe haemorrhagic hypovolaemia.

Resistance responses in proximal arterial vessels, arterioles and veins during reactive hyperaemia in skeletal muscle and their underlying regulatory mechanisms.

The reactive hyperaemia response cat skeletal muscle to 2-120 s arterial occlusions was analysed with regard to amplitude, duration, 'excess blood flow' and site of dilator action along the vascular bed. The last-mentioned was assessed with a new whole-organ technique permitting continuous segmental resistance recordings in arterial vessels greater than 25 microns, arterioles less than 25 microns and veins. Peak amplitude, duration and excess flow all increased with increasing occlusion length, of which excess flow was linearly related to occlusion length. The site of active dilatation was preferentially confined to arterioles less than 25 microns in which complete relaxation was observed after only 20 s occlusion, although the duration of the response continued to increase with more prolonged occlusions. A graded, but less pronounced, dilatation occurred in the arterial vessels greater than 25 microns and in the veins, the former exhibiting a 63% inhibition of tone as a maximum response at 120 s occlusion. The recovery phase was characterized by a vivid active constrictor component apparently protecting the capillaries from excessive pressure load upon arterial occlusion release, but this constriction became attenuated at long occlusions, thereby prolonging the hyperaemia response. The role of myogenic regulatory mechanisms in the responses was assessed from observed segmental resistance reactions to selectively applied transmural pressure stimuli similar to those elicited by arterial occlusion/release. It was concluded that myogenic mechanisms alone could explain the amplitude of the reactive hyperaemia response at short (up to 30 s) occlusions. Metabolic mechanisms seemed to be responsible for further relaxation of the proximal arterial vessels at longer occlusions, and also for the increased duration of the hyperaemia response at occlusions exceeding 10 s. Blockade of nitric oxide formation (endothelium-derived relaxing factor) did not seem to affect the reactive hyperaemia response.