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Biomedical subjects

K Kanno

Publications and source records attributed to K Kanno.

At least 37 records · Page 2Linked to original sources

[All-trans retinoic acid was effective for marked skin infiltration in a relapsed acute myelogenous leukemia (AML-M2) patient with t(12; 17)].

A 64-year-old man who had taken acute myelogenous leukemia (AML-M2) in 1989 have relapsed with t(12; 17) (p13; q11.2-21) chromosomal abnormality and presenting marked infiltration to the skin in 1994. Blasts were seen on his peripheral blood smear (15%) and bone marrow examination showed increased leukemic cells (56%), with maturation. Leukemic cells expressed CD13 and CD33 antigen but not HLA-DR. Although leukemic cells had not promyelocytic feature morphologically, detection of PML/RAR alpha infusion signal of peripheral leukemic cells were positive for 8% (1% for control) by fluorescence in situ hybridization method. Because he did not response to standard combination chemotherapy and because we considered the possibility that t(12; 17) (p13; q11.2-21) observed in this case are t(15; 17) variant, we tried all trans retinoic acid (ATRA) to him. Interestingly, ATRA was very effective for skin lesion but hematologically it had no effect at all, and he died because of bacterial pneumonia.

Antineoplastic Agents↗

[Lipid peroxide and antioxidants in the elderly].

Aging is associated with changes in physical characteristics and decline of many physiological functions. The aging process have been described by various theories, in particular the free radical theory of aging has received widespread attention. It has been accepted that the oxidative stress or damage induced by free radicals is related to aging. In this study, we determined the serum concentration of lipid peroxide and antioxidant as biomarker for aging. Healthy subjects were classified into 3 groups, elderly (65-), middle-aged (40-64) and young group (20-39). Findings in the elderly were as follows: 1. Lipid peroxides in the elderly group were significantly higher than those in the young group. 2. Preventive antioxidant concentrations of superoxide dismutase, glutathione peroxidase and albumin were lower than those in the young group, but ceruloplasmin values increased and catalase activity was unchanged. 3. The total antioxidant capacity of serum was slightly decreased. 4. Superoxide generation by neutrophils while resting was significantly higher in the young group.

Adult↗

Cell display library for gene cloning of variable regions of human antibodies to hepatitis B surface antigen.

A novel cell display system was developed for cloning the variable region (V) genes of antigen-specific human antibodies. The system is based on an antibody library displayed on the surface of COS cells, using a plasmid vector designed to direct expression of membrane-bound antibodies. COS cells expressing antigen-specific antibodies were separated using a flow cytometer for their binding to a fluorescent dye-labeled antigen. To test the performance of this system. We cloned V genes of 4 antibodies directed against hepatitis B surface antigen (HBsAg) from a library prepared from peripheral blood lymphocytes of a vaccinated donor. These membrane-bound anti-HBsAg antibodies were easily converted to soluble forms, all of which showed a size similar to human serum IgG in SDS-PAGE and the same specific binding to HBsAg as membrane-bound forms in ELISA. All VH and VK gene segments of the 4 clones isolated in this study belonged to VHIII and VKI subgroups, respectively. These findings demonstrate the potential and selection capabilities of our cell display system for cloning the V genes of antigen-specific human antibodies.

Amino Acid Sequence↗

Treatment of esophageal cancer in patients over 80 years old.

A total of 828 patients with esophageal cancer were treated at the Second Department of Surgery of Tokai University in the 20-year period from 1975 to June 1994, including 45 patients over 80 years old. We reviewed these elderly patients to assess the optimum therapeutic approach for such individuals. In recent years, the number of elderly patients with esophageal cancer has steadily been increasing. Advanced cancer is more common among this group, but early cancer has also been detected more frequently in recent years. Of the 45 elderly patients (80%) in our series, 36 were encountered in the last 10 years. As 28.9% of the patients had multiple cancers, a careful workup was necessary preoperatively. Since most patients (88.9%) had complications and were also in a poor general condition, limited surgery was recommended in consideration of the postoperative quality of life. The indications for endoscopic mucosal resection (EMR) may be able to be extended to submucosal1 (sm1) cancer without lymph node swelling. Postoperative complications occurred in 60% of those undergoing surgical resection or esophageal bypass, although death only resulted in 1 case. The 5-year survival rate after surgical resection was 30.8%. These results therefore support the use of surgical treatment for selected elderly patients with esophageal cancer.

Adult↗

Urinary excretion of aquaporin-2 water channel protein in human and rat.

Previous studies by the authors demonstrated that the response of urinary aquaporin-2 (AQP2) excretion to dDAVP (deamino-8-D-arginine vasopressin) infusion is an index of vasopressin action on the kidney (N Engl J Med 332: 1540-1545, 1995). In the study presented here, the characteristics of urinary excretion of AQP2 were examined further. An RIA suitable for AQP2 in the urine was established. Relatively high concentrations of detergent and bovine serum albumin in the RIA buffer allowed analysis of urine samples with a wide range of concentrations and increased the sensitivity of the assay. AQP2 in the urine existed as a high molecular weight form of approximately 190 kD by HPLC analysis. The mean urinary AQP2 concentration corrected for creatinine in spot urine samples of healthy subjects who voided in the morning was 1081 +/- 699 fmol/mg creatinine (mean +/- SD, n = 208). The amount of daily excretion of AQP2 in the urine was the same in men and women. Urinary AQP2 content was not affected by age of the subjects and showed a positive correlation with urine osmolality. Finally, the fraction of AQP2 excreted in the urine compared with whole kidney content was determined in the rat. Approximately 3% of AQP2 in the kidney was excreted daily, and this fraction did not change when rats were dehydrated for 3 d. These data demonstrate the necessity of establishing well-designed protocols to use urinary AQP2 as a marker of AVP action.

Adult↗

[Characteristics of bedridden elderly people living at home and in a hospital].

We compared bedridden elderly people living at home to others who were hospital inpatients. Questionnaires regarding medical status and care were returned by 85 of 116 people caring for a bedridden elderly person at home in Obu city, Aichi prefecture and by 62 of 64 nurses and family members caring for bedridden inpatients at Chubu National hospital. All subjects were at least 65 years old. The median age in both groups was 81 years, neither age distribution nor female sex predominance differed between both groups. The percentage of subjects with only one underlying disease was 62.5% among those living at home and 64.4% among inpatients. In both groups the most common disease was cerebrovascular disease (42.5% among those at home and 39.0% among inpatients), followed by dementia (31.3%), infirmity of old age (17.5%) and bone fracture (13.8%) among those at home, and by bone fracture (27.1%), dementia (20.3%) and infirmity of old age (16.9%) among inpatients. The median durations of bedridden status were 2 years and 3 months among those at home and 3 months among inpatients. The proportion of subjects bedridden for less than 6 months was greater among inpatients (p < 0.0001). The percentage who needed medical treatment was 60.0% among those at home and 67.7% among inpatients. The most common conditions for which drugs were taken were hypertension, dementia, chronic cerebrovascular dysfunction, and osteoporosis. Among inpatients, 54.8% were ambulatory before admission, 24.2% were almost completely bedridden, and 17.7% were completely bedridden. The most common cause rending the patients bedridden was infection (usually pneumonia). The degree of disability did not differ between groups. Decubitus ulcers were present in 25.9% of those at home and 17.7% of inpatients.

Activities of Daily Living↗

[A case of moyamoya disease in the aged associated with cerebral embolism].

We reported a rare case of Moyamoya disease in the aged associated with cerebral embolism. A 76-year-old female was brought into our hospital by ambulance 30 min after an attack of fainting. She had no past history of cerebrovascular disease. On admission her consciousness level was JCS 3-IA and she showed Rt. hemiparesis ECG exhibited Af tachycardia. No abnormal region was recognized on brain CT. Emergency cerebral angiograms (AG) disclosed that unexpectedly she had Moyamoya disease. Stenotic or occluded lesions were seen from bilateral IC terminal portions to MCA and ACA, and basal moyamoya vessels were visualized. Transdural anastomosis was poor and posterior circulation was the main source of collateral flow. Mode of onset and neurological signs suggested that the cause of the attack was Lt. MCA occlusion at its sphenoidal portion by cardiogenic embolism. Superselective endovascular fibrinolysis was carried out by the use of urokinase and low molecular weight Dextran and Lt. MCA was able to be recanalized. She was recovered without neurological deficit. Lt. STA-MCA anastomosis and encephalo-myosynangiosis was performed in the chronic stage because stenosis had remained in Lt. MCA and hypo-perfusion in bilateral frontal lobes was presented on SPECT. Post-operative AG demonstrated that Lt. MCA was occluded but Lt. frontal lobe was supplied with plenty of blood flow from Lt. STA. During the next day morning, she had another attack of fainting and showed moderate consciousness disturbance and motor aphasia. No abnormal change was noticed on brain CT. Emergency AG revealed that Lt. STA had become stuffed up with embolic and bypass flow had disappeared. Superselective endovascular fibrinolysis was able to recanalize the blood flow imperfectly, but mild motor apasia remained due to Lt. frontal infarction.

Aged↗

Urinary excretion of aquaporin-2 in patients with diabetes insipidus.

BACKGROUND: Urine-concentrating ability is regulated by vasopressin. Recently, the specific water-channel protein of the renal collecting duct, known as aquaporin-2, was cloned. However, it is not certain whether this molecule is responsive to vasopressin. METHODS: We measured the urinary excretion of aquaporin-2 and its response to vasopressin in 11 normal subjects and 9 patients with central or nephrogenic diabetes insipidus. The urine samples were collected during periods of dehydration and hydration and after the administration of vasopressin. Urine samples were analyzed for aquaporin-2 by the Western blot assay and immunogold labeling, and the amount of aquaporin-2 was determined by radioimmunoassay. RESULTS: Aquaporin-2 was detectable in the urine in both soluble and membrane-bound forms. In the five normal subjects tested, the mean (+/- SE) urinary excretion of aquaporin-2 was 11.2 +/- 2.2 pmol per milligram of creatinine after a period of dehydration, and it decreased to 3.9 +/- 1.9 pmol per milligram of creatinine (P = 0.03) during the second hour after a period of hydration. In the six other normal subjects, an infusion of desmopressin (1-desamino-8-D-arginine vasopressin) increased the urinary excretion of aquaporin-2 from 0.8 +/- 0.3 to 11.2 +/- 1.6 pmol per milligram of creatinine (P < 0.001). The five patients with central diabetes insipidus also had increases in urinary excretion of aquaporin-2 in response to the administration of vasopressin, but the four patients with X-linked or non-X-linked nephrogenic diabetes insipidus did not. CONCLUSIONS: Aquaporin-2 is detectable in the urine, and changes in the urinary excretion of this protein can be used as an index of the action of vasopressin on the kidney.

Adult↗

Food restriction inhibits an autoimmune disease resembling systemic lupus erythematosus in (NZB x NZW) F1 mice.

To investigate the beneficial effects of food restriction on systemic lupus erythematosus in NZB x NZW F1 mice, we separated the mice into three groups. One was fed a diet in which total food intake was reduced to 60% of normal from age 2 mo onward, while the animals were still healthy (group 2R). A second group was selected at age 7 mo based on a positive lupus nephritis (proteinuria) and fed the 40% restricted diet thereafter (group 7R); a third group was allowed to consume food ad libitum (control). All control mice died of renal disease by age 14 mo, whereas all mice in group 2R and 80% of those in group 7R were living at that age. Measurements of anti-double stranded DNA antibody concentrations in sera and in supernatants of in vitro spleen cell cultures revealed that the production of the immunoglobulin G, but not immunoglobulin M, class of antibodies was markedly and significantly reduced in food-restricted mice. Age-associated changes in lymphocyte subsets seen in control mice, i.e., increases in B:T and CD4:CD8 T cell ratios, decreases in NTA260+ T cell subsets, and increases in aberrant activated NTA204+CD4+ T cells and cycling cells, were all significantly lessened in underfed mice. Food restriction did not suppress the secondary acquired antibody responses to a foreign antigen. Thus, the beneficial effects of food restriction in these mice may be related to the lessening of the age-related onset of T cell subset abnormalities, including activation of autoreactive T cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides.

In this study, we have identified the source of nitric oxide (NO) produced in the human inflammatory joints by analyzing expression of inducible NO synthase. In ex vivo organ cultures, both inflammatory synovium and cartilage from patients with rheumatoid arthritis produced NO. The NO production was suppressed by NG-monomethyl-L-arginine, an inhibitor of NO synthase. The amount of NO produced by the synovium correlated with the proportion of CD14+ cells in the corresponding tissue (r = 0.8, P < 0.05). Immunohistochemical analysis as well as in situ hybridization showed that inducible NO synthase was predominantly expressed in synovial lining cells, endothelial cells, chondrocytes, and to a lesser extent, in infiltrating mononuclear cells and synovial fibroblasts. The synovial lining cells and the infiltrating cells expressing inducible NO synthase were identified where CD14+ cells were located. Together with morphological features, this suggests that they are type A synoviocytes. NO production from freshly isolated synoviocytes and chondrocytes was up-regulated by in vitro stimulation with a combination of IL-TNF-beta, TNF-alpha, and LPS. In summary, the present results suggest that NO is produced primarily by CD14+ synoviocytes, chondrocytes, and endothelial cells in inflammatory joints of arthritides. NO production can be upregulated by cytokines present in inflamed joints. The increased NO production may thus contribute to the pathological features in inflammatory arthritides.

Arthritis, Rheumatoid↗

[A case of growing up aneurysms with occlusion of basilar artery].

This is a report of unruptured aneurysms with occlusion of the basilar artery. A 61-year-old female was admitted to our hospital because of dysarthria and numbness of her left face. Angiography revealed occlusion of the basilar artery and severe arteriosclerosis of the bilateral cerebral carotid arteries. Pcom was not visualized on bilateral carotid angiogram. These neurological signs were considered to be derived from vertebrobasilar insufficiency by occlusion of the basilar artery. Right STA-SCA anatomosis was performed to prevent brain stem infarction. Postoperative angiography showed a good filling of both PCA and SCA by collateral circulation via a right STA and an unruptured basilar top aneurysm. Seven months after the bypass surgery, angiography disclosed that the basilar top aneurysm was visualized clearly, and its size was unchanged. The fact that there was no thrombus formation in the aneurysm was considered to be due to ticlopidine, and the hemodynamic changes after the bypass surgery were suspected to have increased the intraaneurysmal pressure. Therefore we performed neck clipping of the basilar top aneurysm by using a right pterional approach. Two years after the second operation, the patient complained of severe headache and vomiting. CT scan showed subarachnoid hemorrhage, and angiography demonstrated a newly developed aneurysm which might have ruptured on left internal carotid anterior choroidal artery bifurcation. Emergency neck clipping of the second aneurysm was performed, and the patient showed a good postoperative course. The newly developed second aneurysm might have been caused by severe arteriosclerosis and hypertension in addition to hemodynamic stress.

Arterial Occlusive Diseases↗

[Marked dilatation of the bilateral common carotid artery: a case report].

We reported a rare case of marked dilatation of the bilateral common carotid artery (CCA) associated with stenosis of the left middle cerebral artery (MCA). A 64-year-old female was admitted with right hemiparesis and dysarthria. She was hospitalized 2 years ago for cholecystitis. For 5 years, she has been under medical treatment for hypertension, diabetes mellitus, hyperlipidemia, cardiac failure associated with hypertrophic cardiomyopathy, and atrial fibrillation. Brain CT scan showed infarction of the left corona radiata. Angiography revealed marked dilatation of the bilateral CCA and the internal carotid artery (ICA), moderate dilatation of the innominate artery and the right subclavian artery, kinking of the right CCA, diverticular outpouching of the left ICA, and stenosis of the right external carotid artery and the left MCA. Breast CT scan revealed moderate dilatation and marked calcification of the ascending aorta and the aortic arch. Laboratory examination did not show any sign of inflammation, rheumatoid factor (RA), antistreptolysis-O (ASLO) and antinucleotic antibody. Based on the clinical course, radiological findings and laboratory data, possible diagnosis of the dilatation of the bilateral CCA was discussed with particular emphasis on arteriosclerotic aneurysm and aortitis syndrome.

Aortic Arch Syndromes↗

[Clinical usefulness of FUT-187 (sepimostat mesilate) on reflux esophagitis and gastritis after gastrectomy].

The efficacy and safety of the proteolytic enzyme inhibitor FUT-187 were evaluated in postgastrectomy reflux esophagitis and gastric remnant inflammation. FUT-187 was administered orally in a dose of 50 mg four times daily, after meals and bedtime, for periods of 4 to 8 weeks. The subjects consisted of 4 patients with postgastrectomy reflux esophagitis and 9 patients with gastric remnant inflammation. In the endoscopic classification of lesions, postgastrectomy reflux esophagitis was classified as erosive or ulcerative and gastric remnant inflammation as superficial. The general improvement rating, general improvement rating of endoscopic findings, and final global improvement rating were 85% (11/13), 82% (9/11), and 85% (11/13), respectively. Neither adverse reactions nor abnormal laboratory findings due to the test drug were noted. Based on the results of this study, it may be concluded that FUT-187 is an effective drug with a wide margin of safety for postgastrectomy reflux esophagitis and gastric remnant inflammation.

Administration, Oral↗

Usefulness of narrow pedicled intercostal cutaneous perforator flap for coverage of the burned hand.

A narrow pedicled intercostal cutaneous perforator (np-ICP) flap is used for reconstruction of hand scar contractures after burns. This flap is designed with a narrow pedicle which includes some intercostal cutaneous perforators of 4-7th intercostal spaces, and with a wide distal area which lies over the costal cage and upper abdomen. Additionally the flap is thinned until only the subdermal vascular network is preserved in most of the wide distal area. It seems that this flap is more useful, not only functionally but also aesthetically, than conventional methods. This report describes the technique and concept, with a demonstration of some clinical examples.

Adult↗

Effects of TNF-alpha on hemodynamic changes and circulating endothelium-derived vasoactive factors in dogs.

To elucidate the relation of tumor necrosis factor-alpha (TNF-alpha)-induced hemodynamic change to endothelium-derived vasoactive factors, we simultaneously measured hemodynamic parameters and circulating endothelin (ET)-1, ET-3, nitrite/nitrate (NOx), and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) in anesthetized dogs following administration of TNF-alpha with or without NG-nitro-L-arginine (L-NNA), a nitric oxide (NO) synthase inhibitor, and indomethacin, a cyclooxygenase inhibitor. Natural human TNF-alpha (10 micrograms/kg, n = 5) with or without L-NNA (1 mg/kg, n = 5) or indomethacin (2 mg/kg, n = 5) was administered intravenously as a bolus, while administration of vehicle served as control (n = 5). After administration of TNF-alpha, mean arterial pressure and cardiac index significantly decreased, whereas systemic (SVRI) and pulmonary (PVRI) vascular resistance index increased. Plasma levels of ET-1, ET-3, NOx, and 6-keto-PGF1 alpha significantly (P < 0.01) increased at 1 h. L-NNA or indomethacin blocked TNF-alpha-induced hypotension and remarkably increased SVRI but did not affect decreased cardiac index. Our data suggest that endogenous ET-1 may partly contribute to TNF-alpha-induced increases in SVRI and PVRI, against which ET-3, NO, and prostacyclin may function as compensatory vasodilators.

6-Ketoprostaglandin F1 alpha↗

Regulation of inducible nitric oxide synthase gene by interleukin-1 beta in rat vascular endothelial cells.

To elucidate the regulation of endothelial inducible nitric oxide synthase (iNOS), we studied the effects of interleukin (IL)-1 beta on production of nitric oxide (NO) and expression of iNOS mRNA and iNOS protein in cultured rat aortic endothelial cells (ECs) by measurement of NO2-/NO3- (NOx) and Northern blot and Western blot analyses. Among several cytokines and bacterial lipopolysaccharide tested, IL-1 beta most effectively stimulated NOx production. IL-1 beta dose and time dependently stimulated NOx production. Northern blot analysis using cDNA for mouse liver iNOS as a probe showed that IL-1 beta induced expression of iNOS mRNA and stimulated NOx production in a dose- and time-dependent manner. Transforming growth factor (TGF)-beta and dexamethasone blocked the IL-1 beta-induced NOx production as well as expression of iNOS mRNA and protein. TGF-beta dose dependently inhibited the IL-1 beta-induced NOx production and iNOS mRNA expression. Northern blot analysis for the decay of the IL-1 beta-induced iNOS mRNA revealed the approximate half-life of 4 h. These data indicate that IL-1 beta induces iNOS gene expression and de novo synthesis of iNOS and subsequent NO generation in vascular endothelium and that TGF-beta and glucocorticoid block iNOS gene expression at the transcriptional level.

Amino Acid Oxidoreductases↗

Induction of nitric oxide synthase gene by interleukin-1 beta in cultured rat cardiocytes.

BACKGROUND: Impaired myocardial contractility in septic shock is protracting, which may be caused by cytokine-induced nitric oxide (NO) synthesis in the heart. However, the cellular mechanism by which cytokines induce nitric oxide synthase (NOS) in cardiocytes remains obscure. METHODS AND RESULTS: We studied the effect of human recombinant interleukin-1 beta (IL-1 beta) on synthesis of NO2-/NO3- (NOx) and the expression of NOS mRNA and protein in cultured neonatal rat cardiocytes. IL-1 beta dose-dependently (0.1 to 10 ng/mL) stimulated NOx production as a function of time (6 to 48 hours). Northern blot analysis using complementary DNAs for rat brain-type constitutive (c) NOS and mouse macrophage-type inducible (i) NOS as probes showed that IL-1 beta induced expression of mRNA for iNOS but not for cNOS, starting after 6 hours and reaching a maximum after 48 hours in cardiocytes. IL-1 beta similarly induced iNOS mRNA expression in cultured adult rat cardiocytes in a time-dependent manner. Western blot analysis using specific antibody against the N-terminal fragment of mouse iNOS revealed the expression of 130-kD iNOS-like protein in IL-1 beta-treated cardiocytes. Northern blotting and immunocytochemical study revealed that IL-1 beta-induced iNOS mRNA and iNOS-like immunoreactivity were exclusively localized to cardiac myocytes but also to nonmyocytes, to a lesser extent. NG-mono-methyl-L-arginine, an NOS inhibitor, completely blocked the IL-1 beta-induced NOx production, whose effect was reversed by L-arginine but not by D-arginine. Dexamethasone inhibited the IL-1 beta-induced NOx production as well as iNOS mRNA expression. Cycloheximide and actinomycin D completely inhibited the IL-1 beta-induced NOx production and iNOS mRNA expression. Neither a calmodulin inhibitor (W-7), a protein kinase C inhibitor (calphostin C), nor a Ca2+ channel antagonist (nicardipine) showed any effect on the IL-1 beta-induced NOx production. CONCLUSIONS: These data demonstrate that IL-1 beta induces macrophage-type iNOS mRNA expression mainly by cardiac myocytes but also by nonmyocytes to a lesser extent, and subsequent de novo protein synthesis of iNOS leads to excessive local production of NO by cardiocytes.

Amino Acid Oxidoreductases↗

Induction of nitric oxide synthase by cyclic AMP in rat vascular smooth muscle cells.

By measurements of NO2-/NO3- (NOx) production and Northern blot analysis, we studied the effects of a membrane-permeable cAMP derivative, 8-bromo-cAMP, on the expression of inducible nitric oxide synthase (iNOS) gene and the synthesis of NOx in cultured rat vascular smooth muscle cells (VSMCs). 8-bromo-cAMP stimulated NOx production and increased steady-state levels of iNOS mRNA in rat VSMC in a time- and dose-dependent manner. NG-monomethyl-L-arginine, a NOS inhibitor, completely blocked the 8-bromo-cAMP-induced NOx production, whose effect was partially, but significantly reversed by an excess L-arginine, but not by D-arginine. Compounds that increase intracellular cAMP levels (cholera toxin, forskolin, and 3-isobutyl-1-methylxanthine), all stimulated NOx production. Dexamethasone inhibited the stimulated NOx production, as well as the induction of iNOS mRNA by cAMP. Both actinomycin D and cycloheximide completely blocked the stimulated NOx production by cAMP. Actinomycin D abolished the cAMP-induced iNOS mRNA, whereas cycloheximide remarkably increased iNOS mRNA levels in the presence and absence of 8-bromo-cAMP (superinduction). Actinomycin D, but not dexamethasone, completely abolished the cycloheximide-induced iNOS mRNA. The half-life of cAMP-induced iNOS mRNA was approximately 2 h, whereas no decay in the cycloheximide-induced iNOS mRNA was observed during 12 h. These results demonstrate that iNOS gene is upregulated by cAMP and the superinduction of iNOS mRNA is attributable to increased mRNA stability in rat VSMC.

1-Methyl-3-isobutylxanthine↗