犬・猫の腎性高血圧に関する基礎的研究

高血圧には本態性高血圧と二次性高血圧があり、本態性高血圧の原因は未だ不明であるが、二次性高血圧の原因として最も頻度が高いのは、腎疾患に起因する腎性高血圧である。　腎性高血圧の成因には、腎機能の低下に伴う体液貯留、心拍出量および末梢血管抵抗の増加、ならびにレニン-アンジオテンシン-アルドステロン系などの昇圧因子の亢進、カリクレイン-キニン-プロスタグランジン系などの降圧因子の抑制などが関与していると考えられている。　獣医学領域、特に小動物臨床においては、近年、医学臨床と同様に慢性腎不全の症例が増加し、その診断・治療が検討されているが、腎性高血圧に関する詳細な報告はない。　その理由として、高血圧は明確な臨床症状を伴わないため、その診断には正確な血圧測定が必要であるが、血圧は生体に加わる様々な要因で変化するため、犬・猫では測定された血圧値を正しく評価し、高血圧を診断することが困難であることが挙げられる。　本研究では小動物、特に犬および猫における腎性高血圧の発現の有無ならびにその成因について検討することを目的とし、無麻酔、無拘束下で24時間連続的な観血的血圧を数カ月間にわたり測定が可能なテレメトリーシステムを用いて、正常な犬・猫の血圧を測定し、その日内変動ならびに正常値について検討を行った。　ついで、実験的に犬・猫の腎不全モデルを作成し、血圧およびレニン-アンジオテンシン-アルドステロン系の観点から、腎障害による腎性高血圧の発現について検討を行った。さらにアンジオテンシン変換酵素阻害薬が、腎不全モデルにより発現した腎性高血圧に及ぼす影響について検討を行った。　あわせて、犬・猫の慢性腎不全の症例で、オシロメトリック法を用いた血圧の測定ならびにレニン-アンジオテンシン-アルドステロン系の測定を行い、臨床例における腎性高血圧の発現についても検討を行った。1. 無麻酔・無拘束下における犬・猫の正常血圧の検討　実験には、臨床検査によって異常が認められない雑種成犬5頭(雄2頭・雌3頭、体重7.0～13.0kg)および雑種成猫6頭(雌6頭、体重2.3～2.8kg)を使用し、血圧変動ならびに正常血圧について検討を行った。　テレメトリーシステムの血圧測定用送信器のカテーテルは、大腿動脈内に留置し、血圧測定用送信器本体は皮下に埋没固定した。血圧測定用送信器設置後、血圧は約1～2週間で安定した。　血圧測定用送信器設置後、血圧が安定した時点から24時間にわたり10日間連続して血圧を測定し、正常な犬・猫における血圧の日内変動について検討を行った。その結果、テレメトリーシステムによって測定された収縮期血圧、平均血圧ならびに拡張期血圧を1時間毎の平均値でみると、8時と19時の時点でピークを示す日内変動が観察された。この日内変動は、ピークを示す約3～4時間前から徐々に上昇し、ピークを示した後は、1時間以内に下降して、安定する傾向を示した。　テレメトリーシステムによる24時間血圧については、日差変動は比較的小さく、正常犬5頭における平均値は、収縮期血圧125.4±7.4mmHg、平均血圧93.4±3.7mmHg、拡張期血圧76.2±3.4mmHgであった。また、正常猫6頭における平均値は収縮期血圧115.7±14.6mmHg、平均血圧94.3±13.2mmHg、拡張期血圧79.2±12.7mmHgであった。　これらのことから、テレメトリーシステムによって測定された犬・猫の血圧測定値の解釈には、日内変動を考慮して、24時間の血圧を平均した24時間血圧を用いて評価することが適当であると考えられた。2. 腎不全モデルによる腎性高血圧の発現　実験には、臨床検査によって異常が認められない雑種成犬5頭(雄2頭・雌3頭、体重7.0～13.0kg)および雑種成猫4頭(雌4頭、体重2.3～2.8kg)を使用した。血圧の測定方法は前実験と同一とし、24時間血圧を用いて検討を行った。　腎不全モデルは、外科的に右腎を摘出した後、左腎に供給される血流量が1/4になるように、腎動脈背側枝および腹側枝の一部を結紮し、血流を遮断して作成した。腎不全作成前後における血圧およびBUN、Cr、CCrの変動を検討した結果、犬の腎不全モデルでは作成前のコントロールに比較して、BUN、Crの上昇およびCCrの低下と同時に血圧値が有意(p<0.05)に上昇した。また、猫の腎不全モデルではCrの上昇、CCrの低下と同時に血圧値が有意(p<0.05)に上昇した。　犬および猫の正常例と腎不全モデルにおいて血漿レニン活性、アンジオテンシンI濃度、アンジオテンシンII濃度、アルドステロン濃度を比較した結果、すべてにおいて、腎不全モデルでは正常例に比較して有意(p<0.05)に高値を示した。　このことから、犬および猫において腎障害によって腎性高血圧を発現することが明らかにされ、この発現機序にはレニン-アンジオテンシン-アルドステロン系が関与しているものと考えられた。3. 腎不全モデルに対するアンジオテンシン変換酵素阻害薬の投与　この実験には、腎性高血圧を発現した腎不全モデルの犬4頭(雄1頭・雌3頭、体重7.5～13.0㎏)および猫3頭(雌3頭、体重2.3～2.8kg)を使用した。血圧測定方法は前実験と同一とし、24時間血圧を用いて検討を行った。　腎不全モデルに対し、アンジオテンシン変換酵素阻害薬を投与し、血圧値および血漿レニン活性、アンジオテンシンI濃度、アンジオテンシンII濃度ならびにアルドステロン濃度を比較した。　その結果、腎不全モデルの犬・猫におけるすべての例で、アンジオテンシン変換酵素阻害薬の投薬時における血圧値は有意(p<0.05)に低下した。　また、アンジオテンシン変換酵素阻害薬を投与した場合、血漿レニン活性ならびにアンジオテンシンI濃度の変化は認められなかったが、アンジオテンシンII濃度ならびにアルドステロン濃度は有意(p<0.05)に低下した。　これらのことから、犬・猫における腎性高血圧の発現機序にレニン-アンジオテンシン-アルドステロン系の亢進が関与しているものと考えられた。4. 臨床例における慢性腎不全の高血圧に関する検討　対象とした症例は、麻布大学獣医学部附属動物病院に来院した犬115例(雄59例、雌65例)、猫97例(雄56例、雌41例)である。　これらを一般臨床検査、血液・血清生化学検査で異常が認められなかった犬102例(雄42例、雌60例)、猫61例(雄26例、雌35例)を正常群、Cr 2.0mg/dl以上ならびに臨床症状より慢性腎不全と診断された犬13例(雄8例、雌5例)、猫36例(雄30例、雌6例)を腎疾患群とした。　収縮期血圧、平均血圧、拡張期血圧ならびに心拍数の測定にはオシロメトリック法を用い、測定部位は前腕部または尾根部とした。測定に際しては症例に可能なかぎり、ストレスを与えないように注意して行った。　オシロメトリック法における正常群の犬における血圧測定値の平均値は、収縮期血圧118.6±18.7mmHg、平均血圧93.8±15.8mmHg、拡張期血圧67.4±14.4mmHgであった。また、猫における平均値は、収縮期血圧115.4±18.8㎜Hg、平均血圧98.6±19.2mmHg、拡張期血圧74.1±18.8mmHgであった。　犬・猫の正常群および腎疾患群の血圧を比較した結果、収縮期血圧、平均血圧ならびに拡張期血圧のすべてにおいて、正常群に比較して腎疾患群では有意な(p<0.05)な高値を示した。　さらに、正常群に比較して腎疾患群においては血漿レニン活性、アンジオテンシンI濃度、アンジオテンシンII濃度ならびにアルドステロン濃度が有意(p<0.05)に高値を示した。　これらのことから、オシロメトリック法による血圧測定においても、腎疾患の症例では、レニン-アンジオテンシン-アルドステロン系の亢進と同時に血圧の上昇が確認され、臨床例においても慢性腎不全の症例では腎性高血圧が存在することを確認した。以上の実験成績より次のような結論が得られた。　1)　テレメトリーシステムによって測定した犬・猫の血圧には、8時と9時をピークとする日内変動が認められた。また、24時間血圧の正常犬における平均値は収縮期血圧125.4±7.4mmHg、平均血圧93.4±3.7mmHg、拡張期血圧76.2±3.4mmHgで、正常猫における平均値は収縮期血圧115.7±14.6mmHg、平均血圧94.3±13.2mmHg、拡張期血圧79.2±12.7mmHgであり、日差変動は比較的小さいことから、テレメトリーシステムによる血圧を評価する際には、24時間血圧をもって個体の絶対値として評価すべきであると考えられた。　2)　犬・猫の実験的腎不全モデルでは、BUN、Crの上昇およびCCrの低下とともに、有意(p<0.05)に血圧が上昇し、腎性高血圧の発現が認められた。また、レニン-アンジオテンシン-アルドステロン系の亢進が観察された。　3)　腎性高血圧を発症した腎不全モデルに対して、アンジオテンシン変換酵素阻害薬を投与すると、アンジオテンシンII濃度、アルドステロン濃度および血圧の低下が認められたことから、犬・猫の腎性高血圧の発現機序にレニン-アンジオテンシン-アルドステロン系の亢進が関与しているものと考えられた。　4)　オシロメトリック法による臨床例の血圧測定では、正常犬における平均値は、収縮期血圧118.6±18.7mmHg、平均血圧93.8±15.8mmHg、拡張期血圧67.4±14.4mmHgで、正常猫における平均値は、収縮期血圧115.4±18.8mmHg、平均血圧98.6±19.2㎜Hg、拡張期血圧74.1±18.8mmHgであった。また、犬・猫における正常例に比較して、腎疾患例では血圧が有意(p<0.05)に高値を示し、さらにレニン-アンジオテンシン-アルドステロン系の亢進も認められたことから、臨床例における慢性腎不全の症例においても、腎性高血圧の存在が確認された。There are two types of hypertension, essential hypertension and secondary hypertension, and whereas the causes of essential hypertension remain unclear, the most frequent cause of secondary hypertension is kidney failure. The origins of renal hypertension are thought to lie in an accumulation of bodily fluids due to a reduction in renal function, an increase in the heart rate and resistance in the peripheral blood vessels, and also accentuation of pressure-raising factors such as the renin-angiotensin-aldosterone system, and the suppression of pressure-reducing factors such as the kallikrein-kinin-prostaglandin system. In the field of veterinary medicine, in particular in small animal clinical cases, in recent years, there has been an increase in chronic renal failure in the same way as for human cases, and the diagnoses and treatments are being examined, but there are no detailed reports concerning renal hypertension. As a reason for this, it is necessary to measure the blood pressure accurately in an examination because hypertension does not manifest any attendant clinical symptoms, but because blood pressure changes within the body due to various causes, the accurate evaluation of blood pressure which have been obtained from dogs and cats, and the diagnosis of hypertension remain problematic. The object of this research was to investigate the manifestation of renal hypertension in small animals, in particular in dogs and cats, and their causes, and to begin with, the blood pressure of normal dogs and cats was measured using a telemetry system which made possible 24-hour continuous invasive blood pressure measurements across a period of several months without being anesthetized or restrained and the daily fluctuations and normal values were examined. Five mature mongrel dogs (two male, three female, weight 7.0 to 13.0 kg) and six mature mongrel cats (six females, weight 2.3 to 2.8 kg) in whom no abnormalities could be identified through clinical examination were used in this experiment, and blood pressure fluctuations and normal blood pressure were examined. The telemetry system blood pressure measuring transmitter catheter was inserted into the femoral artery, and the blood pressure measuring transmitter per se was implanted subcutaneously. Blood pressure settled approximately one to two weeks after the blood pressure measuring transmitter was installed. After installation of the blood pressure measuring transmitter, the blood pressure was measured continuously for 24 hours over a 10-day period from the point in time when the blood pressure settled, and the daily blood pressure fluctuations in normal dogs and cats was examined. As a result, when the average hourly values of the systolic blood pressure, mean blood pressure and diastolic blood pressure which were measured using the telemetry system were observed, it was discovered that the daily fluctuations showed a peak at 08:00 and 19:00. These daily fluctuations gradually rose approximately three to four hours before the peak was revealed, and then showed a tendency towards stabilization, lowering within the hour after the peak was reached. The daily variance in fluctuations of the blood pressure over a 24-hour period according to the telemetry system were relatively small, and the mean values in the five normal dogs were: systolic blood pressure 125.4±7.4 mmHG, mean blood pressure 93.4±3.7 mmHg, diastolic blood pressure 76.2±3.4 mmHg. Further, the mean values in the six normal cats were: systolic blood pressure 115.7±14.6 mmHG, mean blood pressure 94.3±13.2 mmHg, diastolic blood pressure 79.2±12.7 mmHg. From these facts, it is considered that for the purposes of interpretation of blood pressure values in dogs and cats which have been measured using the telemetry system, it is appropriate to make evaluations using a 24-hour period for which the mean values of the blood pressure over the 24 hours are taken, while taking the daily fluctuations into consideration. Next, an experimental model of dogs and cats suffering from renal failure was established, and the manifestation of renal hypertension due to renal damage from the point of view of both blood pressure and the renin-angiotensin-aldosterone system was examined. Five mature mongrel dogs (two male, three female, weight 7.0 to 13.0 kg) and six mature mongrel cats (six females, weight 2.3 to 2.8 kg) in whom no abnormalities could be identified through clinical examination were used in the experiment. The methods of measuring blood pressure were the same as for the first experiment, and the blood pressure was examined over a 24-hour period. The renal failure model was established with the blood flow blocked through partial ligation of the dorsal and ventral branch of the renal artery, in order to reduce to 1/4 the amount of blood flow supplied to the left kidney following surgical removal of the right kidney. As a result of examining the fluctuations in blood pressure, BUN, Cr and CCR both before and after construction of the renal failure, in the dog renal failure model, compared with the control prior to construction, there was a significant increase in blood pressure values (p<0.05) at the same time as an increase in BUN and Cr, and a decrease in CCr. Further, in the cat renal failure model, there was a significant increase in blood pressure values (p<0.05) at the same time as an increase in Cr and a reduction in CCr. As a result of comparing plasma renin activity, angiotensin I and II concentrations, and aldosterone concentration in normal cases of dogs and cats and in the renal failure models, in all cases, the renal failure models showed significantly higher values (p<0.05) compared with the normal cases. From this fact, it is clear that renal hypertension manifests in dogs and cats due to renal damage, and it is considered that the renin-angiotensin-aldosterone system is involved with the manifestation mechanism. Moreover, the effects of an angiotensin converting enzyme inhibitor on renal hypertension as manifested according to the renal failure model were examined.Four dogs (one male, three females, weight 7.5 to 13.0 kg), and three cats (three females, weight 2.3 to 2.8 kg) in the renal hypertension model who manifested renal hypertension were used in the experiment. The methods of measuring blood pressure were the same as for the first experiment, and the blood pressure was examined over a 24-hour period. An angiotensin converting enzyme inhibitor was given to the renal failure model and the blood pressure values, plasma renin activity, angiotensin I and II concentrations, and aldosterone concentration were compared. As a result, in all cases of dogs and cats in the renal failure model, blood pressure values when the angiotensin converting enzyme inhibitor was given were significantly decreased (p<0.05). Further, when the angiotensin converting enzyme inhibitor was given, although no change in the plasma renin activity or the angiotensin I concentration was identified, there was a significant decrease (p<0.05) in angiotensin II concentration and aldosterone concentration. From these facts, it is thought that the renin-angiotensin-aldosterone system plays a large role in the manifestation mechanism of renal hypertension in dogs and cats. Based upon these results, in cases of chronic renal failure in dogs and cats, blood pressure measurements using the oscillometric method, and measurements of the renin-angiotensin-aldosterone system were taken, and the manifestation of renal hypertension in clinical cases was examined. The target cases were 115 dogs (50 male, 65 female), and 97 cats (56 male, 41 female) which were brought into Azabu University Animal Teaching Hospital. These were divided into the control group of 102 dogs (42 male, 60 female), and 61 cats (26 male, 35 female) in whom no abnormalities were identified following general clinical examinations, and blood and sero-biochemistry examinations, and the kidney disease group of 13 dogs (8 male, 5 female), and 36 cats (30 male, 6 female), in whom chronic renal failure was diagnosed as a result of clinical symptoms and a minimum Cr 2.0 mg/dl. The oscillometric method was used to measure diastolic blood pressure, mean blood pressure, and systolic blood pressure, as well as the number of heart rates, with the area of measurement being either the forelimbs or the tail head. During the measurements, care was taken not to apply stress to the patient as far as possible. The mean values of the measured blood pressure values in the dogs in the control group according to the oscillometric method were: diastolic blood pressure 118.6±18.7 mmHg, mean blood pressure 93.8±15.8 mmHg, and systolic blood pressure 67.4±14.4 mmHg. Further, the mean values in cats were diastolic blood pressure 115.4±18.8 mmHg, mean blood pressure 98.6±19.2 mmHg, and systolic blood pressure 74.1±18.8 mmHg. As a result of comparing blood pressures in both cats and dogs in both the control group and the kidney disease group, for all cases of diastolic blood pressure, mean blood pressure, and systolic blood pressure, the kidney disease group showed a significantly higher value (p<0.05) compared with the control group. Moreover, the kidney disease group showed significantly higher values (p<0.05) compared with the control group in plasma renin activity, angiotensin I and II concentrations and aldosterone concentration. From these facts, an increase in blood pressure at the same time as accentuation of the renin-angiotensin-aldosterone system was identified in the cases of kidney disease, even with blood pressure measurements taken using the oscillometric method, and the existence of renal hypertension was further identified in the cases of chronic renal failure in the clinical cases as well.博士(獣医学)麻布大

Chondroitin sulfate N-acetylgalactosaminyltransferase-1 is required for normal cartilage development

CS (chondroitin sulfate) is a glycosaminoglycan species that is widely distributed in the extracellular matrix. To understand the physiological roles of enzymes involved in CS synthesis, we produced CSGalNAcT1 (CS N-acetylgalactosaminyltransferase 1)-null mice. CS production was reduced by approximately half in CSGalNAcT1-null mice, and the amount of short-chain CS was also reduced. Moreover, the cartilage of the null mice was significantly smaller than that of wild-type mice. Additionally, type-II collagen fibres in developing cartilage were abnormally aggregated and disarranged in the homozygous mutant mice. These results suggest that CSGalNAcT1 is required for normal CS production in developing cartilage

腎生検を行った蛋白漏出性腎疾患の犬2例，猫1例における比較検討

高度蛋白尿を呈す犬2例，猫1例について腎生検を行い，病理学的変化，治療経過および予後を比較した。　病理学的変化は，病変なし（糸球体微小変化型病変の疑い），膜性増殖性糸球体腎炎（MPGN），巣状分節性硬化（FSGS）の疑いであった。MPGNの症例は急性経過をとり死亡し，他の2例は長期生存した。　生存した2症例にはACEI （アンギオテンシン変換酵素阻害剤）およびシクロスポリンによる治療を行った。UPCの推移や治療反応は一様ではなかった。　獣医療域において蛋白漏出性腎疾患には多様な病態が含まれていることが示唆され，糸球体障害の種類や障害の程度の把握などに腎生検が有益であった。　一方で臨床症状と生検結果に沿った適切な薬剤の選択には更なる検討が必要であり，今後は症例数を重ねて更なる検討が必要であると考えられた。A cat and two dogs with severe proteinuria underwent renal biopsy for pathological diagnosis, and their clinical outcome and prognosis were compared. Their pathological findings were all different: no abnormality (suspected of minimal change glomerular disease); membranoproliferative glomerulonephritis (MPGN) and suspected focal segmental glomerulosclerosis. The dog with MPGN died in an acute course. They were treated with angiotensin-converting enzyme inhibitor and cyclosporine. The urine protein-to-creatinine ratio and response to treatment were not consistent in these cases. These results suggest that protein-losing nephropathy may present various pathological forms in small animalsand thus renal biopsy is essential for understanding the pathological process of the disease. Further research is needed to determine the best drug of choice based on the clinical symptoms and biopsy results

膀胱反転による尿路変更術を実施した尿道腫瘍のイヌ1症例

排尿困難を主訴として来院した8歳齢，雌のミニチュアダックスフントに対し各種検査を行った結果，近位尿道部に発生した腫瘍に起因する尿道閉塞と診断した。排尿困難の改善と腫瘍摘出を目的とし，尿道膣吻合術を計画した。しかし，開腹下での所見において腫瘍が膀胱尿道移行部にまで浸潤していたため，計画していた術式を断念し，膀胱を反転させ膀胱尖部と遠位尿道部を吻合する新たな尿路変更術を試みた。術後，生存期間中は蓄尿機能の温存および自力排尿が可能となり，良好な排尿状態が得られた。An 8-year-old female Miniature Dachshund was presented for evaluation of dysuria, and urethral obstruction due to a proximal urethral tumor was diagnosed after a series of examinations. To relieve dysuria and to remove the tumor, urethral-vaginal anastomosis was the initial option but it was not possible, because tumor invasion into the vesicoureteral junction was found during the surgery. A new urinary diversion technique was attempted instead, and the bladder apex was flipped caudally and anastomosed to the distal urethra. After the surgery, good urinary patency was restored, and the bladder’s pooling function and voluntary urination were maintained throughout the duration of survival

Simplified Quantification of Adenosine A1 Receptor with [11C]MPDX and Graphical Analysis

Objectives: [11C]MPDX is a clinically available radioligand for quantification of the adenosine A1 receptor (A1R) [1], and its kinetic analysis was reported in [2]. The purpose of this study was to investigate an applicability of simplified graphical algorithms for human studies based on ROI analysis.\nMethods: Six normal subjects were included in this study. The dose was 610+/-126 MBq, and the specific activity was 53+/-37 MBq/nmol. Dynamic PET scans were performed for 1 hour using SET-2400W (Shimadzu, Kyoto, Japan) in two-dimensional mode with arterial blood sampling. A total of 24 ROIs was placed manually on the summed images: cerebellum (reference), pons, midbrain, caudate, putamen, thalamus, posterior cingulate, and frontal, temporal, occipital, and parietal lobes. The ROI-averaged tissue time activity curves (tTACs) were analyzed using five algorithms: one- and two-tissue compartment models (1T and 2T), Logan graphical analysis (LGA), and a reference LGA with or without a clearance rate of a reference region (k2) (LGAR-k2 and LGARNok2)[3]. For LGAR-k2, the k2 in a reference region was derived from the cerebellum using 1T. All graphical analyses were applied after 20-minute post-injection.\nResults: The metabolism of [11C]MPDX was slow; the parent fraction was 0.74+-0.07 at 60 min after injection. The tTACs were well described using 2T with a constraint of VND that was estimated from the reference region using 1T. The values of VT and K1 ranged from 0.52+-0.11 (cerebellum) to 0.72+-0.13 mL/cm3 (posterior putamen) and from 0.10+-0.03 (cerebellum) to 0.13+-0.04 mL/min/cm3 (posterior putamen), respectively. The k2 in reference regions were (0.45+-0.11 min-1). The kinetics in reference regions was described using 1T model, and 2T fitting could not give us reasonable VND, VND(1T)=0.98*VND(LGA)-0.06 (r2=0.96). In the graphical analyses, BPND using the simplified algorithms of LGAR-k2 and LGAR-Nok2 matched well with those using LGA: BPND(LGAR-k2)= 0.99*BPND(LGA)+0.01 (r2=0.95) and BPND(LGAR-Nok2)= 0.96*BPND(LGA)-0.01(r2=0.94).\nConclusions: Both the simplified algorithms based on Logan graphical analysis without an arterial input function provided corresponding BPND with those of LGA using an input function in ROI-based analysis. These results implied that LGAR-Nok2 was applicable for the quantification of A1Rs using [11C]MPDX.\nReferences:[1] Ishiwata, et al., Ann Nucl Med, 16, 377-382, 2002.[2] Y Kimura, et al., Nucl Med Biol, 31, 975-981, 2004.[3] J Logan, et al., J Cereb Blood Flow Metabo, 16, 834-840, 1996.Acknowledgement: This work was supported by Grants-in-Aid for Scientific Research (B) No. 20390333,(B) 20390334 and (B) No. 16390348.Brain\u2709 & BrainPET\u270

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