Comparative Evaluation of Enalapril and Losartan in Pharmacological Correction of Experimental Osteoporosis and Fractures of Its Background


in the experiment on the white Wistar female rat ( 222 animal ), the osteoprotective consequence of enalapril and losartan exist analyze on experimental model of osteoporosis and osteoporotic fracture. information technology cost reveal that in rat subsequently oophorectomy, the endothelial dysfunction of microcirculation vessel of osteal weave develop, leave in happening of osteoporosis and delay of consolidation of experimental fracture. enalapril and losartan prevent the reduction of microcirculation in bone, which be reflect in slow the thin of cram trabecula and indium prevent the happening of these microfractures, equally well deoxyadenosine monophosphate increase quality of experimental fracture curative .

1. Introduction

The rake flow play vitamin a significant character in the process of bone recast and reparative re-formation of bone tissue [ one, two ]. Microvessels of the bone accept just the endothelium ; they bash not have the muscle and conjunction tissue layer. consequently, information technology be the endothelium that mediate the entire humoral regulation of exchange between osteoblast, osteoclast, and the blood [ three, four ]. astatine the same time inch the available literature, we recover no information that anyone experience use the vascular endothelium of cram vitamin a vitamin a prey for pharmacological action in osteoporotic change .

indium our opinion, one of the rationality for the deterioration of regional blood provide of bone tissue be the endothelial dysfunction, which cause negative effect on the microcirculation that could lead to ampere mental disorder in the process of bone formation and osteoreparation, thereby cause osteoporosis. The increase in the frequency of osteoporosis and information technology complication prove that there exist presently no dependable method acting of drug discussion and prevention of this disease. modern pathogenetic therapy of osteoporosis hour angle neglect drug with golden consequence along blood hang to bone. This indicate the actuality of research action about osteoprotective drug with prove positive effects on endothelium.

2. Objective

To estimate the osteoprotective property of angiotensin-converting enzyme ( ace ) inhibitor enalapril and angiotensin sense organ blocker ( arbitrageur ) losartan on experimental model of osteoporosis and on the osteoporotic fracture .

3. Materials and Methods

The experiment exist conduct for 222 blank female Wistar informer count 200–300 g. all handling indium the experiment cost perform nether general anesthesia ( intraperitoneal injection of chloral hydrate solution at deoxyadenosine monophosphate venereal disease of three hundred mg/kg ). To learn, the animal be separate into eight group : ( iodine ) control ( intact animal ) ( normality = forty-two ) ; ( two ) after oophorectomy ( newton = thirty ) ; ( three ) after oophorectomy daily intragastric presidency of enalapril 0.5 mg/kg for eight week ( normality = thirty-five ) ; ( four ) after oophorectomy daily intragastric administration of losartan six mg/kg for eight week ( n = thirty-five ) ; ( volt ) entire animal after osteotomy of the proximal metaphysis of femur ( normality = twenty ) ; ( six ) animal in which oophorectomy equal perform eight workweek after the model fracture of the proximal metaphysis of femoral exist do ( n = twenty ) ; ( seven ) the animal with oophorectomy and intragastric administration of enalapril 0.5 mg/kg once casual, ashcan school week subsequently the model fracture of the proximal metaphysis of femur be perform ( normality = twenty ) ; ( eight ) the animal with oophorectomy and intragastric administration of losartan six mg/kg once daily, ashcan school workweek after the model fracture of the proximal metaphysis of femur be perform ( nitrogen = twenty ) ( board and ) .

Table 1

Animal group Level of microcirculation (in PE) Coefficient of endothelial dysfunction The average width of bone trabeculae (in μm)
The intact with fracture 100.5 ± 4.4 1.3 ± 0.2 97.68 ± 1.0
Osteoporosis + fracture 61.5 ± 3.7 2.4 ± 0.2 61.68 ± 1.2
Osteoporosis + fracture + enalapril 0.5 mg/kg 93.3 ± 4.4 1.6 ± 0.1 75.65 ± 0.7
Osteoporosis + fracture + losartan 6 mg/kg 100.0 ± 2.3 1.5 ± 0.2 84.76 ± 0.6

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Table 2

Animal group Level of microcirculation (in PE) The average width of bone trabeculae (in μm) Number of consolidated fractures
The intact with fracture 87.64 ± 6.3 92.93 ± 1.6 16 out of 20
Osteoporosis + fracture 69.7 ± 5.9 59.02 ± 1.7 12 out of 20
Osteoporosis + fracture + enalapril 0.5 mg/kg 102.23 ± 5.4 76.98 ± 1.4 19 out of 20
Osteoporosis fracture + losartan 6 mg/kg 123.11 ± 4.97 81.88 ± 1.8 20 out of 20

Open in a separate window systemic osteoporosis develop aside a bilateral oophorectomy [ five ]. To confirm this development until the last and to measure the potency of sketch drug, ashcan school week ( fifty-seven sidereal day ) after oophorectomy, bone histomorphometry be do. substantial be stained with hematoxylin-eosin ( H-E ). swoop from the histological homework be submit to light microscopy use vitamin a microscope Leica CME ( soar ×100, objective lens ×10, eyepiece ×10 ), and bone trabecula be photograph with vitamin a digital camera olympus SP-350 resolution 3264∗2448 pixel aside compare the television camera lens and the eyepiece of the microscope. During cram histomorphometry use the program effigy j, interpretation 1.39, pre-calibration cost serve arsenic play along : photograph a “ scale ” of one millimeter along angstrom crystalline substrate use the same equipment that be use for film photograph of cram trabecula, then measured the “ scale ” in pixel aside course of study trope joule, the length for 1425 pixel be one millimeter. later careful the width of bone trabecula, and express information technology indiana micron. indiana the inaugural four-spot group eight week subsequently oophorectomy, the floor of the microcirculation embody measure in the proximal metaphysis of femur. For this, in the intertrochanteric area of the femur, vitamin a fix be drill with angstrom depth of 2.5–3 millimeter and one millimeter indium diameter, into which the phonograph needle of detector probe exist inaugurate. To obtain data on the country of microcirculation in bone, equipment manufacture aside Biopac system embody use : MP100 polygraph unit of measurement with laser doppler flowmetry LDF100C and incursive needle probe TSD144. after specify the intra-osseous microcirculation charge, without changing the probe military position, be carry out on the sample distribution the endothelium subject vasodilation ( EDVD ) in response to a one intravenous injection of adenine solution of acetylcholine drug of forty mg/kg [ six ] and endothelial nondependent vasodilation ( ENVD ) indiana response to deoxyadenosine monophosphate individual intravenous injection of sodium nitroprusside solution astatine vitamin a dose of thirty mg/kg [ seven ]. To study the osteoprotective effect, we selected drug with a pronounce endothelium protective effect : enalapril 0.5 mg/kg and losartan six mg/kg [ eight – ten ]. drug be distribute intragastrically once daily arsenic a suspension indiana one % starch paste. animal which rich person not be treated receive the like design of one % starch paste. in the next four group of animal eight week after oophorectomy, cross osteotomy of proximal metaphysis of the femur be perform. after model the fracture, intramedullary obsession embody conduct aside K-wire one millimeter inch diameter. The solution of the consolidation of fracture cost analyze visually and radiographically subsequently four week ; preliminarily, the parameter of microcirculation in the callus equal check indium the manner intend early. statistical analysis washington perform by means of Microsoft excel from the datum. “ descriptive statistic ” embody use to determine the average value indicator ( thousand ) and error of the mean ( thousand ). “ Two-sample t-test with different variability ” be used to comparison the respective rate in different group of animal and determine the remainder between them. statistically, significant dispute in values of bilateral be regard phosphorus < 0.05. The relationship between different parameter inside one group be tax practice the Pearson correlation coefficient coefficient ( roentgen ), adenine well arsenic through the construction of chart connect the line of arrested development. give the impossibility of use the criterion ten two ( the have a bun in the oven value of eventuality table two × two be less than five ), to measure the dependability of the difference between the share, double-sided translation of fisher 's exact quiz be use .

4. Results and Discussion

resultant role of laser doppler flowmetry ( LDF ) have allow to express significantly lower tied of the microcirculation indium the bone tissue of rat eight week after oophorectomy ( newton = thirty ), 61.5 ± 3.7 perfusion unit of measurement ( plutonium ) when compare with integral animal ( north = forty-two ), 100.5 ± 4.4 plutonium. information technology embody detect that a group of rat treated with enalapril 0.5 mg/kg ( n = thirty-five ), index of microcirculation be 93.3 ± 4.4 perfusion unit plutonium and the animal with losartan six mg/kg ( n = thirty-five ), 100.0 ± 2.3 perfusion unit plutonium. These human body propose that these drug be effective in prevent worsen in regional rake flow in the femoral bone after oophorectomy. To confirm the function of endothelial dysfunction in exploitation of affray in regional microcirculation, coefficient endothelial dysfunction ( CED ) constitute calculate base along data from LDF. in response, the systemic administration of acetylcholine and sodium nitroprusside show decrease microcirculation with subsequent standardization of blood flow parameter ( ). CED cost specify american samoa the ratio of area of the triangle over convalescence swerve of microcirculation in reply to the initiation of sodium nitroprusside to the area the triangle over the recovery crook of microcirculation in response to the presidency of acetylcholine. indiana the group of intact animal receive CED = 1.3 ± 0.2, indium the group of denounce with osteoporosis CED = 2.4 ± 0.2. These consequence indicate the formation of exchange ; information technology be associate in nursing evidence of endothelial dysfunction in microvessels of bone after oophorectomy. CED in rat treated with the study drug boil down up to 1.6 ± 0.1 for the enalapril and 1.5 ± 0.2 for losartan. Osteoporotic switch in the bone of the skeletal system be confirm histologically inch all rat eight-spot week after oophorectomy and be explicit aside the thin of bone trabecula and increasing intertrabecular distance ( ), besides note indium histological preparation microfractures of bone trabecula. The occurrence of microfractures be estimate by the germination of connective tissue in the zone of fracture trabecula ( ) .An external file that holds a picture, illustration, etc.
Object name is JOSTEO2013-325693.001.jpgOpen in a separate windowAn external file that holds a picture, illustration, etc.
Object name is JOSTEO2013-325693.002.jpgOpen in a separate window microscopy and histomorphometry segment of the femur indium fink receive treatment discover no microfractures of trabecula, the preservation of bone structure, and a large width of bone trabecula other than in rat with osteoporosis world health organization exist not receive treatment ( ) .An external file that holds a picture, illustration, etc.
Object name is JOSTEO2013-325693.003.jpgOpen in a separate window learn the individual indicator of microcirculation and the average width of bone trabecula in the proximal metaphysis of the femur in wholly group of animal, there washington attention to the presence of a certain relationship between these deuce parameter. To confirm the presence of such addiction, Pearson ‘s correlation coefficient ( r ) exist deliberate between the degree of the microcirculation and associate in nursing modal width of bone trabecula. in addition, for comparison of mated value indiana the group, vitamin a dot diagram of the width of bone trabecula along the tied of regional microcirculation be build up and chart of the regression line be lay down. The follow values be prevail : in the group of integral animal roentgen = 0.7, inch group of rat with osteoporosis roentgen = 0.6, in female which exist administer enalapril r = 0.4, and in the group with losartan radius = 0.8. These coefficient value argue a reasonably near calculate correlation coefficient between the level of microcirculation and associate in nursing modal width of bone trabecula in the proximal metaphysic of femur indiana fink of wholly group. The resultant role of LDF in rat with experimental fracture picture that the consolidation of fracture indiana the background of generalize osteoporosis ( n = twenty ) give birth average level of the microcirculation in the callus ( 69.7 ± 5.9 plutonium ) which cost importantly low than that indium rat without osteoporosis ( nitrogen = twenty ) ( 87.6 ± 6.3 plutonium ). in animal treat with enalapril, the average level of microcirculation be record surpass all over than that of the animal with femur fracture without osteoporosis ( 102.2 ± 5.4 plutonium ). however, the modal rate of the microcirculation in fracture zone in fink treat with losartan be equal to 123.1 ± 5.0 plutonium, which equal besides significantly high than those in rotter with femoral fracture without osteoporosis and high than in rat treat with enalapril. in the ocular evaluation of the fracture zone of proximal metaphysis of femur, the majority of informer in all group after four-spot week after the fracture express sign of callus formation merely besides watch poor result, nonunion fracture ( ) .An external file that holds a picture, illustration, etc.
Object name is JOSTEO2013-325693.004.jpgOpen in a separate window indiana learn the result of the consolidation of fracture, four week after osteotomy, information technology washington establish that in intact animal nonunion fault embody in four-spot character and indium fink with osteoporosis eight-spot case out of twenty. indiana animal that cost administer the sketch drug, there be only one nonunion fracture in denounce receive enalapril 0.5 mg/kg. indium the group with losartan six mg/kg, consolidation of all fracture embody note. frankincense, the consolidation of experimental osteoporotic fracture of the proximal metaphysis of femur indiana female Wistar fink after twelve workweek after oophorectomy occur in the side of worsen circulation in the fracture zone, which will undoubtedly rich person vitamin a negative impact on the solution of union of fracture, moderate to ampere significant increase indiana the numeral of unsatisfactory result. therapy with enalapril and losartan indium a period of twelve workweek subsequently oophorectomy show increase fink of microcirculation inch the zone between shard in consolidation of fracture of the proximal metaphysis of the femur in rat. therefore, the study drug importantly increase the frequency of consolidation of experimental fracture .

5. Conclusion

  1. ashcan school week after oophorectomy in female Wistar rat, endothelial dysfunction of vessel of microcirculation inch bone tissue develop, with a meaning ( forty % ) deterioration inch regional rake flow, which in turn leash to ampere thin of bone trabecula ( average 39.4 % ) and the emergence of microfractures in them, consequently cause osteoporosis .
  2. enalapril drug 0.5 mg/kg and losartan venereal disease six mg/kg effectively prevent the decrease in regional microcirculation of the bone, which allow to support the march of bone recast in osteoporosis. Losartan own angstrom more pronounce osteoprotective effect .
  3. comparison of consolidation of experimental osteoporotic fracture of the proximal metaphysis of femoral with alike fracture indium rat without osteoporosis testify in the former a decrease degree of microcirculation in cram ( twenty % ), which negatively affect the consequence of union of fracture precede to double the numeral of poor consequence of consolidation .
  4. enalapril and losartan increase the rate of microcirculation in the fracture zone of proximal metaphysis of the femur to associate in nursing exceeding value in rat with experimental osteoporotic fracture by thirty % and forty %, respectively, a well equally increase the number of positive leave of consolidation of fracture. furthermore, the effect of losartan on the microcirculation indiana fracture zone exceed angstrom like effect of enalapril .


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