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Biomedical subjects

R Cirillo

Publications and source records attributed to R Cirillo.

At least 37 records · Page 2Linked to original sources
PubMed1997

Sardinia: a battlefield approach to type I diabetes epidemiology. Sardinia-IDDM Study Groups.

Sardinia and Finland have the highest incidence of insulin-dependent diabetes mellitus (IDDM) in the world. Therefore, both regions represent ideal observatories for investigating the environmental, genetic and immunological factors which have led to this dramatic increase. We have concentrated our efforts on Sardinia. Among several projects, there is the mapping of the island for hot and cold spots for overt IDDM. In order to map the island for pre-IDDM, we have collected and bled around 10,000 school children (age 6-14 years) and we are now in the process of enrolling around 30,000 new-born babies. We report here our initial results, which show that progression to IDDM is accompanied in both cohorts by the presence of a combination of islet-cell antibodies with either glutamic acid decarboxylase or IA-2 antibodies or both. This approach should lead to the design of reliable models of IDDM prediction in the general population, which will benefit an early insulin treatment and, hopefully, an effective prevention of the disease.

Adolescent↗
PubMed1997

Effect of tibolone on glucose and lipid metabolism in postmenopausal women.

The effect of tibolone, a new therapeutic agent for menopause, on glucose and lipid metabolism was investigated in 11 healthy postmenopausal women. At baseline and after 3 months of tibolone administration (2.5 mg/day), glucose metabolism was evaluated in each subject using both an oral glucose tolerance test (75 g) and the minimal model method of a frequently sampled intravenous glucose tolerance test. Frequently sampled intravenous glucose tolerance test allows the calculation of insulin sensitivity and peripheral glucose use independent of insulin. High-density lipoprotein-cholesterol, total cholesterol, apoprotein-A, and apoprotein-B measured in fasting conditions were not modified by tibolone, whereas triglycerides were reduced significantly (P < 0.01). Fasting levels of glucose were reduced significantly (P < 0.025), whereas those of insulin, C-peptide, and the C-peptide/insulin ratio were not modified. Glucose, insulin, C-peptide, and the C-peptide/insulin ratio responses to oral or iv glucose were not modified. Insulin sensitivity was inversely correlated to body mass index, and independent on that body mass index was significantly enhanced (P < 0.01). Glucose utilization independent of insulin was not modified. The present data indicate that tibolone does not negatively influence glucose metabolism and may indeed improve both the peripheral tissue sensitivity to insulin and the lipid profile.

Anabolic Agents↗
PubMed1997

The "Sardinia-IDDM study": an attempt to unravel the cause of insulin-dependent diabetes mellitus in one of the countries with the highest incidence of the disease in the world.

Sardinia and Finland have the highest incidence of IDDM in the world. Thus, both regions represent ideal observatories for investigating the environmental, genetic and immunological factors, which have led to this dramatic increase. We have concentrated our efforts in Sardinia. Among several projects, there is the mapping of the Island for hot and cold spots for overt IDDM. In order to map the Island for pre-IDDM, we have collected and bled around 10,000 school children (age 6-14 years) and we are now in the process to enroll around 30,000 newborn. We report here our initial results, which show that progression to IDDM is accompanied in both cohorts by the presence of a combination of ICA with either GAD and IA-2 antibodies or both. This approach should lead to design reliable models of IDDM prediction in the general population, which will benefit an early insulin treatment and, hopefully, an effective prevention of the disease.

Adolescent↗
PubMed1996

Characterization of tachykinin NK2 receptor on dog proximal colon. Antagonism by MEN 10,627 and SR 48,968.

The nature of the tachykinin receptors involved in the contraction of the circular muscle of dog colon has been investigated. The following rank order of potency for agonists was obtained: [Sar9,Met(O2)11]substance P > or = neurokinin A > [beta-Ala8]neurokinin A-(4-10) >> [MePhe7]neurokinin B. The efficacy of the tachykinin NK2 receptor agonists was significantly greater than that of the tachykinin NK1 receptor agonists and of carbachol. A concentration-dependent rightward shift of the motor response to neurokinin A (obtained in the presence of (+/-)-CP 96,345) was induced by peptide and non-peptide tachykinin NK2 receptor antagonists with this rank order: MEN 10,627 = SR 48,968 >> L 659,877 > MEN 10,376 > MDL 28,564. MEN 10,627 and SR 48,968 affinities were similar to those measured in human tissues. In conclusion, the tachykinin NK2 receptor plays a predominant role in tachykinin-induced contraction of the canine colonic circular muscle and this tissue could be useful to predict the pharmacological actions of MEN 10,627 and SR 48,968 in human colon.

Animals↗
PubMed1996

Functional evidence for the ability of angiotensin AT1 receptor antagonists to cross the blood-brain barrier in rats.

The angiotensin AT1 receptor antagonists, losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'(1H-tetrazol-5-yl)biphen yl-4- yl)methyl]imidazole potassium salt), EXP3174 (2-n-butyl-4-chloro-1-[(2'(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid), GR117289 (1-[[3-bromo-2-[2-(1 H-tetrazol-5-yl)phenyl]-5-benzofuranyl]methyl]-2-butyl-4-chloro-1 H-imidazole-5-carboxylic acid) and LR-B/081 (methyl-2-[[4-butyl-2-methyl-6-oxo-5-[[2'-(1 H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1(6H)-pyrimidinyl]met hyl]-3- thiophenecarboxylate), given by intraperitoneal (i.p.) injection 15 min before intracerebroventricular administration of angiotensin II, inhibited drinking with the following order of potency: EXP3174 > GR117289 > losartan > LR-B/081. When 20 mumol/kg of each antagonist was i.p. injected 15 min, 4, 12 or 24 h before angiotensin II, EXP3174 and GR117289 inhibited water intake at each observation time, losartan at 4, 12 and 24 h, LR-B/081 only at 4 and 12 h. After per os administration of the same dose 4 or 12 h before angiotensin II, losartan reduced drinking at 4, but not at 12 h; LR-B/081 did not inhibit drinking either at 4 or 12 h. The present results suggest that EXP3174 and GR117289 cross the barrier readily. The effect of i.p. losartan on central angiotensin mechanisms is not prompt, suggesting that it may require conversion to EXP3174. LR-B/081 apparently crosses the barrier less readily than the other antagonists following both i.p. and per os administration.

Administration, Oral↗
PubMed1996

Cyclosporin H is a potent and selective competitive antagonist of human basophil activation by N-formyl-methionyl-leucyl-phenylalanine.

BACKGROUND: Cyclosporin A (CsA) binds with high affinity to cyclophilin, a critical step in the molecular mechanism of action of cyclosporins, where cyclosporin H (CsH) has extremely low affinity for cyclophilin. CsH differs from CsA by the substitution of the L-methyl valine at position 11 with it D-isomer. METHODS: We compared the effects of CsA and CsH on the release of performed (histamine) and de novo synthesized inflammatory mediators (peptide leukotriene C4) from peripheral blood basophils activated by N-formyl-methionyl-leucyl-phenylalanine (FMLP). RESULTS: CsH (8 to 800 nmol/L) concentration-dependently inhibited histamine and leukotriene C4 release from purified and unpurified basophils activated by FMLP, whereas CsA (8 to 800 nmol/L) had little inhibitory effect on histamine release from basophils challenged with FMLP. Inhibition of histamine release from basophils challenged with FMLP was extremely rapid and was abolished by washing the cells (three times) before challenge. CsH (8 to 800 nmol/L) had no effect on the release of histamine caused by C5a, platelet activating factor, monocyte chemotactic activating factor, RANTES, IL-8, bryostatin 1, and phorbol myristate. Preincubation of basophils with granulocyte-macrophage colony-stimulating factor (30 and 100 pmol/L), but not IL-1 beta (30 and 100 ng/ml), concentration-dependently reversed the inhibitory effect of CsH on FMLP-induced histamine release. CsH competitively inhibited the effect of FMLP on histamine release from basophils. The dissociation constant (Kd) for the CsH-FMLP receptor complex was approximately 9 x 10(-8) mol/L, more than 10-fold lower than that (approximately equal to 1.3 x 10(-6) mol/L) of N-t-BOC-methionyl-L-leucyl-phenylalanine (BocMLP), a known formyl peptide receptor antagonist. CsH inhibited tritiated FMLP binding to human polymorphonuclear leukocytes with a concentration required to inhibit binding by 50% of approximately 5.4 x 10(-7) mol/L, whereas BocMLP was less potent with a concentration required to inhibit binding by 50% of approximately 9.1 x 10(-5) mol/L. Scatchard analysis revealed that the decreased tritiated FMLP binding caused by CsH was due to a decrease in the Bmax (0.22 +/- 0.04 nmol/L/5 x 10(6) cells vs 0.09 +/- 0.01 nmol/L/5 x 10(6) cells; p < 0.05), without a significant difference in the Kd (5.16 +/- 1.22 nmol/L vs 6.32 +/- 2.42 nmol/L; p = NS). CONCLUSION: CsH is a potent and selective inhibitor of mediator release from basophils induced by activation of the formyl peptide receptor; it acts by interfering with agonist binding to FMLP receptors.

Basophils↗
PubMed1996

Experimental pharmacology of hirunorm: a novel synthetic peptide thrombin inhibitor.

Enhanced thrombin activity has been associated with coronary thrombosis and with acute and long-term complications following coronary balloon angioplasty. Blocking thrombin activity with specific inhibitors is proposed as a promising antithrombotic therapy. We describe the anticoagulant and antithrombotic properties of hirunorm, a novel synthetic 26-aminoacid peptide thrombin inhibitor, in comparison with r-hirudin and hirulog-1. Hirunorm was equipotent to hirulog-1 and 1/30 as potent as r-hirudin in blocking alpha-thrombin amidolytic activity (IC50 = 10 +/- 2, 15 +/- 1 and 0.3 +/- 0.1 nM, respectively), but it did not affect trypsin, plasmin and t-PA activities at 10 microM. All the compounds inhibited clot-bound thrombin to clots prepared by thrombin hydrolysis of purified fibrinogen in buffer. Hirunorm and hirulog-1 showed similar species-dependent potency in doubling basal in vitro clotting times of human, rat and rabbit plasma (EC200 varied 70 to 200 nM for TT, 0.7 to 16 microM for aPTT and 0.8 to 17 microM for PT), while r-hirudin was always at least three times more active. When assayed by HPLC or by bioassay of the intact peptide, hirunorm was stable against alpha-thrombin and plasma hydrolases, but it was catabolized by rat liver and kidney enzymes. Venous thrombosis was produced in anaesthetized rats by vena cava ligation following a procoagulant serum injection. Intravenous and subcutaneous hirunorm inhibited venous thrombosis at doses (< or = 0.3 mg/kg) two-three times higher than those of r-hirudin. Hirulog-1 was as active as hirunorm only after i.v. infusion. Arterial thrombosis was obtained in the anaesthetized rat by chemical (FeCl2) stimulation of a common carotid and i.v. infused hirunorm (1-3 mg/kg/30 min) inhibited it dose-dependently; r-hirudin was partly active only at 3 mg/kg, but hirulog-1 was inactive at either dose. Full antithrombotic doses of hirunorm did not affect the bleeding time as measured from punctured mesenteric vessels, in anaesthetized rats. In conclusion, hirunorm is a potent peptide thrombin inhibitor endowed with antithrombotic activity in models of venous and arterial thrombosis.

Animals↗
PubMed1995

N-3-substituted pyrimidinones as potent, orally active, AT1 selective angiotensin II receptor antagonists.

A novel series of nonpeptide angiotensin II (A II) antagonists containing a pyrimidinone ring which carries a C-linked biphenyltetrazole moiety and a carboxyheteroaryl group on the 3-position have been prepared. Their affinity for the AT1 receptor was determined in a binding assay on rat adrenal cortical membranes. The in vivo antihypertensive properties were tested by evaluating the inhibition of the pressor response to A II followed by iv and id administration. Extensive molecular modeling studies, including comparison of molecular electrostatic potential distributions, conformational analysis, and overlays on a computational pharmacophore model of A II, were used to evaluate structural parameters of the new compounds, in comparison to other known A II antagonists (e.g., DUP-753 and SK&F 108566). According to the modeling studies, the introduction of a (carboxyheteroaryl)methyl moiety at the 3-position of the pyrimidinone ring led to derivatives with increased potency. Methyl 2-[[4-butyl-2-methyl-6-oxo-5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl ]- 4-yl]methyl]-1-(6H)-pyrimidinyl]methyl]-3-thiophenecarboxylate (3k, LR-B/081), one of the most potent compounds in the series (Ki = 1.4 nM), exhibited a marked antihypertensive activity on oral administration to conscious renal hypertensive rats, with long duration of action. It was selected for clinical evaluation in the treatment of hypertension in man.

Administration, Oral↗
PubMed1995

4-Diazinyl- and 4-pyridinylimidazoles: potent angiotensin II antagonists. A study of their activity and computational characterization.

A series of N-[biphenylyl(tetrazolyl)methyl]-2-butylimidazoles containing variously substituted diazine or pyridine moieties either as their free bases or N-oxide derivatives attached to the 4-position of the imidazole ring was synthesized and tested for interaction with the AT1 receptors of rat adrenal cortex membranes (receptor binding assay). Some compounds were then chosen for further evaluation in vivo in the A II-induced pressor response in conscious normotensive rats. The most potent in the AT1 binding assay were found to be compounds in which the diazine or pyridine ring nitrogen is adjacent to the point of attachment between the two heteroaromatic rings such as 2-butyl-4-(3,6-dimethylpyrazin-2-yl)-1-[[2'-(1H-tetrazol-5-y l)-biphenyl-4- yl]methyl]-1H-imidazole (3b) or 2-butyl-4-[5-(methoxycarbonyl)pyrid-2-yl]-1-[[2'-(1H-tetrazol++ +-5- yl)biphenyl-4-yl]methyl]-1H-imidazole (6c). The binding affinities and oral activities of the pyridine N-oxide imidazoles in which a stabilizing group ortho to the pyridine ring nitrogen is present were markedly improved as in 2-butyl-4-[(3-methoxycarbonyl)-6-methyl-N-oxopyridin-2-yl]-1-[[2'- (1H- tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-imidazole 31b. Molecular modeling studies were carried out to determine the molecular electrostatic potential values of related model systems and to correlate their receptor interaction energies with the observed activities of our compounds.

Administration, Oral↗
PubMed1995

The selective angiotensin AT1 receptor antagonist LR-B/081 potently inhibits drinking induced by central injection of angiotensin II in rats.

LR-B/081, methyl-2-[[4-butyl-2-methyl-6-oxo-5-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl] methyl]-1(6H)-pyrimidinyl] methyl]-3-thiophenecarboxylate, is a recently developed nonpeptide antagonist selective for angiotensin AT1 receptors. The drug has been reported to be an insurmountable angiotensin AT1 receptor antagonist endowed with long-lasting antihypertensive activity. A large body of evidence indicates that angiotensin AT1 receptors mediate the dipsogenic action of angiotensin II in the central nervous system. The present study evaluated the ability of LR-B/081, in comparison with losartan and with its active metabolite EXP3174, to inhibit drinking induced by central injection of angiotensin II in water-sated rats. LR-B/081, in the dose range of 10-1000 pmol/rat, dose dependently inhibited the drinking response to angiotensin II, 10 pmol/rat. The ID50 of LR-B/081 was 25.9 pmol/rat, while that of losartan and EXP3174 was 357 and 3.9 pmol/rat, respectively. Therefore LR-B/081 was about 7 times less potent than EXP3174, but about 14 times more potent than the parent molecule losartan. LR-B/081 altered neither carbachol-induced water intake, nor 15% fat milk intake in rats, suggesting that its effect on angiotensin II-induced drinking is a behaviourally selective effect. These findings show that LR-B/081 potently inhibits central angiotensin AT1 receptors involved in behaviourally selective effect. These findings show that LR-B/081 potently inhibits central angiotensin AT1 receptors involved in the control of body fluid homeostasis and suggest that this drug might be an interesting pharmacological tool to further investigate the role of the central renin-angiotensin system in physiological or pathological conditions.

Analysis of Variance↗
PubMed1995

Pharmacology of LR-B/057, a novel orally active AT1 receptor antagonist.

We studied the pharmacologic properties of LR-B/057, a novel nonpeptide angiotensin II (AII) receptor antagonist. The compound potently displaced [3H]AII from AT1 but not from AT2 receptors in rat adrenal cortex (Ki 3 nM), but did not modify the dissociation rate of the radioligand from the receptors. Both its affinity and the nature of its interaction with AT1 receptors (saturation studies) were markedly affected by the presence of bovine serum albumin (BSA) in the binding assay. In rabbit aorta, LR-B/057 caused nonparallel shifts to the right of the dose-response curve to AII and decreased the maximal response (pKB 9.6). Oral (p.o.) administration of LR-B/057 to conscious rats dose-dependently antagonized the pressor response to AII. LR-B/057 administered either intravenously (i.v.) or p.o. to conscious renal hypertensive rats produced a powerful dose-dependent antihypertensive effect. These results show that LR-B/057 is a potent and selective antagonist at AT1 receptors and has p.o. bioavailability.

Adrenal Cortex↗
PubMed1995

Pharmacology of LR-B/081, a new highly potent, selective and orally active, nonpeptide angiotensin II AT1 receptor antagonist.

1. The pharmacological profile of LR-B/081, (methyl 2-[[4-butyl-2-methyl- 6-oxo-5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1(6H)- pyrimidinyl]methyl]-3-thiophenecarboxylate), a novel antagonist at the angiotensin II (AII) AT1-receptor, was studied in vitro and in vivo. 2. In rabbit aortic strips incubated with LR-B/081 (1-1,000 nM), the concentration-response curve to AII was displaced to the right in a nonparallel fashion and the maximal contraction was progressively reduced, indicating that the compound is an insurmountable antagonist in this preparation (apparent pKB = 9.50 +/- 0.23). However, the interaction of LR-B/081 with AII receptors was found to be reversible, since the maximal response to AII was restored by coincubation with losartan, a surmountable AII AT1-antagonist. Contractions elicited by KCl or phenylephrine were not affected by 10 microM LR-B/081. 3. In rat isolated perfused kidney, LR-B/081 and losartan antagonized the AII-induced vasoconstriction [IC50 (95% confidence limits) = 17(13-24) and 39(32-54) nM, respectively]. The LR-B/081 antagonism was incompletely reversed by excess AII, while losartan was fully displaced. The IC50 values of LR-B/081 and losartan obtained against vasoconstriction induced by endothelin-1 and noradrenaline were two orders of magnitude higher. 4. In pithed rats, the intravenous administration of LR-B/081 (0.2-2 mumol kg-1) dose-dependently shifted to the right in a nonparallel fashion the dose-pressor response curve to AII. The maximal pressor response to AII was reduced by LR-B/081 in a dose-dependent fashion. The coadministration of losartan induced a progressive recovery of the maximal pressor response to All, indicating that in vivo the interaction of LR-B/081 with All receptors is reversible. LR-B/081 at 6 micromol kg-1, i.v. also did not affect the vasopressor response induced by noradrenaline in the pithed rat.5. In conscious normotensive rats, single oral administration of LR-B/081 at 6 micromol kg-1 markedly inhibited the All-induced pressor response; the inhibition lasted more than 24 h.6. In conscious renal hypertensive rats, intravenous LR-B/081 appeared as potent as losartan (ED40mmHg(95% confidence limits) = 0.50(0.36-0.70) and 0.86(0.57-1.3) micromol kg-1, respectively). A single intravenous(2 micromol kg-1) or oral (6 micromol kg-1) administration of LR-B/081 induced a marked fall in blood pressure which lasted for at least 12 h.7. In conscious spontaneously hypertensive rats, LR-B/081 at 20 micromol kg-1 , p.o., induced a marked and sustained fall in blood pressure. The duration of the antihypertensive effect was longer than 12 h.Heart rate was not modified by LR-B/081 treatment. Repeated oral administration of 17 micromol kg-1LR-B/081 for 16 days did not result in the development of tolerance.8 These results demonstrate that LR-B/081 is a potent, selective and orally active antagonist of All at the AT1-receptor subtype, which markedly lowers the blood-pressure in conscious renal and spontaneously hypertensive rats.

Administration, Oral↗
PubMed1994

Beneficial effects of cloricromene in ischemic reperfused myocardium.

Cloricromene (Clo) has been used to prevent myocardial damage after transient occlusion of the circumflex coronary artery (Cx). Twenty rabbits were injected for 4 days with a single dose of Clo (0.25 mg/kg i.v.) or placebo. On the 5th day, the Cx was occluded, and Clo (6.4 micrograms/kg/min) or placebo was continuously infused. After 50 min, the occlusion was removed and after 20 min of reperfusion, the rabbits were sacrificed. In the placebo group, all rabbits showed marked ST segment changes and severe ischemic arrhythmias (6/10 animals). In 5 of them, ventricular fibrillation was followed by death. In the Clo group smaller ST segment elevations were observed, and in 2 rabbits ventricular fibrillation spontaneously reversed as did ST segment elevations. A significant reduction of the necrotic area was also observed in the Clo group by postmortem examination.

Animals↗
PubMed1994

[Low levels of dehydroepiandrosterone sulfate in adult males with insulin-dependent diabetes mellitus].

UNLABELLED: Studies on animals and humans have suggested that dehydroepiandrosterone sulphate (DHEAS) has antiatherogenic effects. It has been hypothesized that insulin may have an atherogenic role and it has been reported recently that, surprisingly, DHEAS levels decreased in normal men and women during the hyperinsulinemic-euglycemic technique. Since a hyperinsulinemia frequently occurs during insulin therapy in patients with insulin dependent diabetes mellitus (IDDM), the present work was undertaken to determine whether DHEAS serum concentrations were decreased in IDDM patients as compared to controls and if so, to discover the possible causes. To this, purpose, out of 805 outpatients afferent to our Diabetes Centre from 1989 to 1992, three groups were selected on the basis of the criteria described below. Known interferences with the DHEAS serum concentrations such as gender (all males), age (aged 20-40 years) and Body Mass Index (BMI < 30) were excluded. Group A (cross-sectional study) was made up of 15 IDDM patients on insulin treatment with good metabolic control (HbA1C < 8%); group B (control study) was made of 18 healthy subjects (these patients were selected also on the basis of their normal oral glucose tolerance test) and group C (longitudinal study) was made up of 7 IDDM patients who had been examined previously and who were on insulin treatment. METHODS: In all three groups serum concentrations of DHEAS, 17 OH progesterone (17 OHP), delta 4 androstenedione (A4) and cortisol (F) were measured. In 10 patients from group A and in 9 patients from group B the ACTH test (9.25 mg IM Synacthen) was administered and the same hormonal pattern was measured after 60 min. In group C the same hormonal evaluation was performed 5 +/- 2.8 months after commencement of insulin therapy. RESULTS: DHEAS serum concentrations were significantly decreased in group A (median 2.9; range 1.1-5.2 mumol/l) with respect to group B (median 5.7; range 3.0-9.5 mumol/l) (p < 0.0012). However, the serum concentrations of 17 OHP (median 3.9 nm/l; range 2.9-6.9 nm/l and A4 (median 5.2 nm/l; range 1.8-10.2 nm/l) were also significantly reduced, while cortisol levels and the 17 OHP/A4 ratio were comparable to group B. After administration of ACTH, the delta increment in cortisol percentage showed a frank increase (55.1%) in group A with respect to group B (33.1%) (p < 0.01). The rise in DHEAS showed a lower increase in group A (10.2%) with respect to group B (65.5%) even though not statistically significant, while the other hormones showed an overlap between the two groups. In group C the serum concentrations of hormones before insulin therapy did not show any statistical differences with respect to the values in group B. A second evaluation, which was performed during insulin therapy, showed that only the 17 OHP/A4 ratio tended towards higher values with respect to pretherapy values (1.1 and 0.6 respectively; p = 0.07). In conclusion our data confirm low DHEAS levels during chronic insulin administration therapy. The underlying mechanism could be a general aspecific reduction in the activity of P 450 C 21 SCC enzymes in contrast with the specific inhibition of 17.20-lyase obtained during insulin bolus. Whether the low serum concentrations of DHEAS can determine an atherogenic effect of insulin needs further investigation, but the hormone could constitute a new parameter for the follow-up of patients affected by diabetes mellitus.

Adrenocorticotropic Hormone↗
PubMed1993

Changes in vessel ultrastructure during ischemia and reperfusion of rabbit hindlimb: implications for therapeutic intervention.

Peripheral ischemia was induced in the rabbit by occlusion of the left iliac artery for 6 hr, followed by 24 hr of reperfusion. Biochemical and morphological investigations were performed to evaluate the extent of vascular and tissue injury. Blood samples for plasma enzyme determinations (creatine kinase (CK) and lactate dehydrogenase (LDH) activities) were obtained at times t = 0, t = 6, t = 30 hr. Plasma CK and LDH activities in ischemic animals were approximately twice as high as those in sham-operated animals at the end of reperfusion, although no difference was observed at the end of the period of ischemia. Morphological and morphometric analysis of extensor digitorum longus muscle from ischemic animals showed a reduction in the number of patent capillary vessels per muscle fiber (1.54 +/- 0.1 and 1.04 +/- 0.09, P < 0.05, in sham and ischemic groups, respectively; mean +/- SEM). In addition, the number of microvilli on endothelial surfaces were considerably increased in the ischemic group (0.14 +/- 0.02 and 0.41 +/- 0.01 microns -2, P < 0.001, in sham and ischemic groups, respectively). A great number of adhered leucocytes were found on the vessel surface with some leucocytes having migrated through the vessel wall. Microcirculatory damage was accompanied by the formation of microthrombi which sometimes occluded the entire vessel lumen. The infusion of 1 mg/kg/hr of cloricromene for 6 hr prevented ischemic injury in microvessels and also prevented swelling of muscle mitochondria. In the treated group the number of patent capillaries per muscle fiber was very similar to that found in sham-operated animals (1.49 +/- 0.08; P < 0.01 vs. ischemic control). In conclusion, several different cell types are involved in the pathophysiological changes which occur in microvessels during ischemia/reperfusion injury. Pharmacological interventions, which inhibit the interactions of blood cells with endothelium, may be of value in the treatment of peripheral ischemia/reperfusion injury.

Animals↗