Both hypo- and hyperglycaemia are associated with increased fracture risk in Japanese people with type 2 diabetes: the Fukuoka Diabetes Registry.

AIM: The impact of glycaemic control on fracture risk is controversial, which may be due to the possible presence of hypoglycaemia. The aim of this study was to separately investigate the impacts of severe hypoglycaemia and poor glycaemic control on fracture risk in people with type 2 diabetes. METHODS: Overall, 4706 Japanese participants (2755 men and 1951 postmenopausal women) with type 2 diabetes (mean age 66 years) were followed prospectively (a median of 5.3 years; follow-up rate, 97.6%), and were stratified by severe hypoglycaemia status and glycaemic control. The primary outcome was fractures at any anatomic site. RESULTS: Fractures occurred in 662 participants (249 men and 413 women). The age- and sex-adjusted incidence rates (expressed per 1000 person-years) were: 71.2 (multiple episodes of severe hypoglycaemia), 43.1 (one episode), 25.2 [HbA1c < 53 mmol/mol (< 7%) without severe hypoglycaemia], 28.7 [HbA1c 53 to < 64 mmol/mol (7% to < 8%) without severe hypoglycaemia], 27.7 [HbA1c 64 to < 75 mmol/mol (8% to < 9%) without severe hypoglycaemia] and 40.5 [HbA1c ≥ 75 mmol/mol (≥ 9%) without severe hypoglycaemia]. Multivariate-adjusted hazard ratios (95% confidence intervals) for fractures were 2.24 (1.56, 3.21) in those with multiple episodes of severe hypoglycaemia, and 1.42 (1.04, 1.95) in those with HbA1c ≥ 75 mmol/mol (≥ 9%) without severe hypoglycaemia, compared with those with HbA1c < 53 mmol/mol (< 7%) without severe hypoglycaemia. CONCLUSIONS: Both severe hypoglycaemia and poor glycaemic control were significantly related to an increased risk of fracture in people with type 2 diabetes, although severe hypoglycaemia conferred a stronger risk.

Association between eating rate and obesity: a systematic review and meta-analysis.

BACKGROUND: The association between eating rate and obesity has recently been reported. However, the findings remain inconclusive. OBJECTIVES: We undertook a systematic review with a meta-analysis of published epidemiological studies to provide a reliable close estimate of the association between eating rate and obesity. METHODS: A comprehensive search of MEDLINE, EMBASE and CINAHL was conducted to identify studies that reported quantitative estimates for indices of obesity based on the category of eating rate. Interventional studies or studies conducted using children as subjects were excluded. Two independent researchers extracted the data. A summary estimate was calculated using a random-effects model, and subgroup analyses were conducted to identify sources of heterogeneity. RESULTS: Data from 23 published studies were eligible for inclusion. The mean difference in body mass indices (BMIs) between individuals who ate quickly and those who ate slowly was 1.78 kg m(-2) (95% confidence interval (CI), 1.53-2.04 kg m(-2)). The pooled odds ratio of eating quickly on the presence of obesity was 2.15 (95% CI, 1.84-2.51). There was evidence of significant quantitative heterogeneity in the magnitudes of the association across studies (I2=78.4%, P-value for heterogeneity <0.001 for BMI, I2=71.9%, P-value for heterogeneity <0.001 for obesity), which may be partially explained by differences in the type of study population (a weaker association was observed for BMI in diabetic patients). CONCLUSIONS: Eating quickly is positively associated with excess body weight. Further studies are warranted to determine whether interventions to slow the speed of eating are effective for weight control.

Phosphate binders prevent phosphate-induced cellular senescence of vascular smooth muscle cells and vascular calcification in a modified, adenine-based uremic rat model.

Clinical and experimental studies have reported that phosphate overload plays a central role in the pathogenesis of vascular calcification in chronic kidney disease. However, it remains undetermined whether phosphate induces cellular senescence during vascular calcification. We established a modified uremic rat model induced by a diet containing 0.3% adenine that showed more slowly progressive kidney failure, more robust vascular calcification, and longer survival than the conventional model (0.75% adenine). To determine the effect of phosphate on senescence of vascular smooth muscle cells (VSMCs) and the protective effect of phosphate binders, rats were divided into four groups: (1) normal control rats; (2) rats fed with the modified adenine-based diet (CKD); (3) CKD rats treated with 6% lanthanum carbonate (CKD-LaC); and (4) CKD rats treated with 6% calcium carbonate (CKD-CaC). After 8 weeks, CKD rats showed circumferential arterial medial calcification, which was inhibited in CKD-LaC and CKD-CaC rats. CKD rats showed increased protein expression of senescence-associated ß-galactosidase, bone-related proteins, p16 and p21, and increased oxidative stress levels in the calcified area, which were inhibited by both phosphate binders. However, serum levels of oxidative stress and inflammatory markers, serum fibroblast growth factor 23, and aortic calcium content in CKD-CaC rats were higher than those in CKD-LaC rats. In conclusion, phosphate induces cellular senescence of VSMCs in the modified uremic rat model, and phosphate binders can prevent both cellular senescence and calcification of VSMCs via phosphate unloading. Our modified adenine-based uremic rat model is useful for evaluating uremia-related complications, including vascular calcification.

Impact of eating rate on obesity and cardiovascular risk factors according to glucose tolerance status: the Fukuoka Diabetes Registry and the Hisayama Study.

AIMS/HYPOTHESIS: Medical nutrition therapy plays a critical role in the prevention and treatment of type 2 diabetes. However, appropriate measures of eating behaviours, such as eating rate, have not yet been clearly established. The aim of the present study was to examine the associations among eating rate, obesity and cardiovascular risk factors. METHODS: A total of 7,275 Japanese individuals aged ≥40 years who had normal fasting glucose levels, impaired fasting glucose or diabetes were divided into four groups according to self-reported eating rate: slow, medium, relatively fast and very fast. The associations between eating rate and various cardiovascular risk factors were investigated cross-sectionally. RESULTS: The proportions of participants who were obese or who had elevated waist circumference levels increased progressively with increases in eating rate (p for trend <0.001), regardless of glucose tolerance status. These associations remained significant after adjustment for potential confounders, namely, age, sex, total energy intake, dietary fibre intake, current smoking, current drinking and regular exercise (p for trend <0.001). Blood pressure and lipid levels also tended to increase in association with eating rate. HbA(1c) rose significantly as eating rate increased, even after multivariate adjustment, including BMI, in diabetic patients on insulin therapy (p = 0.02), whereas fasting plasma glucose did not increase significantly. CONCLUSIONS/INTERPRETATION: Our findings suggest that eating rate is associated with obesity and other cardiovascular risk factors and therefore may be a modifiable risk factor in the management of cardiovascular risk factors and diabetes.

Magnesium intake decreases Type 2 diabetes risk through the improvement of insulin resistance and inflammation: the Hisayama Study.

AIMS: Early studies have shown that magnesium intake decreases the risk of Type 2 diabetes, but the results are still inconsistent. We prospectively examined the association between magnesium intake and incidence of Type 2 diabetes in a general Japanese population. METHODS: A total of 1999 subjects without diabetes aged 40-79 years who underwent a 75-g oral glucose tolerance test were followed up prospectively for a mean of 15.6 years. RESULTS: During the follow-up, 417 subjects developed Type 2 diabetes. The age- and sex-adjusted incidence of Type 2 diabetes significantly decreased with increasing magnesium intake quartile levels (≤ 148.5, 148.6-171.5, 171.6-195.5 and ≥ 195.6 mg/day, P for trend = 0.01). In multivariate analyses, after adjusting for comprehensive risk factors and other dietary factors, the hazard ratio of Type 2 diabetes was 0.67 (95% CI 0.49-0.92; P = 0.01) in the third quartile and 0.63 (95% CI 0.44-0.90; P = 0.01) in the highest quartile compared with the first quartile. In addition, the risk of Type 2 diabetes was 14% lower (P = 0.04) for a 1-sd increment of log-transformed magnesium intake in the multivariate-adjusted model. In stratified analysis, there were statistically significant interactions between magnesium intake and levels of homeostasis model assessment of insulin resistance, high-sensitivity C-reactive protein or alcohol intake on the risk of Type 2 diabetes (all P < 0.05). CONCLUSIONS: Our findings suggest that increased magnesium intake was a significant protective factor for the incidence of Type 2 diabetes in the general Japanese population, especially among subjects with insulin resistance, low-grade inflammation and a drinking habit.

The impact of predisposing factors on long-term outcome after stroke in diabetic patients: the Fukuoka Stroke Registry.

BACKGROUND AND PURPOSE: Although stroke patients with diabetes mellitus have a poor prognosis, the prognostic factors of patients with diabetes mellitus have not been adequately studied. The aim of this study was to determine the predisposing factors for outcome 1 year after stroke in diabetic patients. METHODS: Patients' characteristics, findings on admission and outcome 1 year after first ischaemic stroke were prospectively investigated in 452 consecutive patients with diabetes mellitus (305 males, 147 females; 69 ±â€…10 years old). A poor outcome was defined as a modified Rankin Scale (mRS) score ≥ 2, 1 year after stroke onset. RESULTS: There were 286 patients with a good outcome (mRS score ≤ 1) and 166 with a poor outcome (mRS score ≥ 2). On multivariate logistic regression analysis, age [odds ratio (OR) 1.06, 95% confidence interval (CI) 1.03-1.10, P < 0.001, per 1-year increase], National Institutes of Health Stroke Scale (NIHSS) score on admission (OR 1.21, 95% CI 1.11-1.32, P < 0.001, per 1-point increase), diabetic nephropathy (OR 1.93, 95% CI 1.02-3.65, P = 0.044) and hemoglobin A1c (HbA1c; OR 1.27, 95% CI 1.07-1.51, P = 0.007, per 1% increase) were independently related to poor outcome (mRS score ≥ 2) 1 year after the onset of the first stroke in diabetic patients. CONCLUSIONS: In stroke patients with diabetes mellitus, age, NIHSS score on admission, diabetic nephropathy and HbA1c were independently associated with a poor outcome 1 year after the first ischaemic stroke.

Polymorphism in the sorbin and SH3-domain-containing-1 (SORBS1) gene and the risk of brain infarction in the Japanese population: the Fukuoka Stroke Registry and the Hisayama study.

BACKGROUND AND PURPOSE: Sorbin and SH3-domain-containing-1 (SORBS1) is an important adaptor protein in insulin-signalling pathway, and its genetic polymorphism may regulate the activity of insulin resistance. We investigated the association between the SORBS1 T228A polymorphism and ischaemic stroke. METHODS: Genotyping was achieved by a rapid-cycle PCR and melting curve analysis using fluorescent probes in 1049 incident cases of ischaemic stroke and 1049 age- and sex-matched control subjects recruited from the Hisayama study. RESULTS: The allele distributions of the SORBS1 T228A polymorphism were similar amongst cases and controls. The multivariate-adjusted odds ratio (OR) of the AA genotype for ischaemic stroke was 2.897 (95% CI, 0.907-8.018) compared with the TT genotype. In terms of stroke subtype, there was a trend toward a difference in the AA genotypes for lacunar infarction, compared with the TT genotype (OR = 8.740, P = 0.0510), and combined TT and TA genotypes (OR = 8.768, P = 0.0505). The other polymorphisms genotyped were not associated with any subtypes of ischaemic stroke. T228A polymorphism of SORBS1 was not associated with the prevalence of diabetes. CONCLUSIONS: The AA genotype of SORBS1 T228A polymorphism may play a role in lacunar infarction in the Japanese population.

NAD(P)H oxidase p22phox C242T polymorphism and ischemic stroke in Japan: the Fukuoka Stroke Registry and the Hisayama study.

The C242T polymorphism of p22phox, a component of NAD(P)H oxidase, may have an impact on cardiovascular diseases; however, the association between this polymorphism and brain infarction is not fully understood. Here, we investigate the relationship between the C242T polymorphism and brain infarction in Japan. We recruited 1055 patients with brain infarction and 1055 control subjects. A chi-squared test revealed that the T-allele frequency was lower in patients with cardioembolic infarction (5.6%) than in control subjects (11.0%, P < 0.001); however, allele frequencies in patients with lacunar and atherothrombotic infarction (11.2%) were not significantly different from those in control subjects (11.0%). A multivariate-adjusted conditional logistic regression analysis also revealed no association between CT + TT genotype, and lacunar and atherothrombotic infarction (odds ratio = 0.97, 95% confidence interval: 0.72-1.32). To investigate the functional effects of the C242T polymorphism, we examined superoxide production in COS-7 cells cotransfected with Nox4 and p22phox of each genotype. The superoxide-producing activity in those cells expressing p22phox with the T allele was not significantly different from that in cells expressing p22phox with the C allele. The present results suggest that the p22phox C242T polymorphism may have a protective effect against cardioembolic infarction, but is not related to lacunar and atherothrombotic infarction in Japan.

The influence of CYP2C19 polymorphisms on exacerbating effect of rabeprazole in celecoxib-induced small bowel injury.

BACKGROUND: Simultaneous use of proton pump inhibitors (PPIs) has been shown to increase the risk of nonsteroidal anti-inflammatory drug (NSAID)-induced small bowel injury. AIM: To investigate whether polymorphisms of the cytochrome P450 2C19 gene (CYP2C19), encoding a key metabolising enzyme for PPIs, are associated with small bowel injury induced by celecoxib in combination with the PPI rabeprazole. METHODS: Study participants included 55 healthy Japanese volunteers, who participated in the PPI-NSAID Kyushu University Study using video capsule endoscopy. For 2 weeks, 26 subjects were treated with celecoxib plus rabeprazole (rabeprazole group), and 29 subjects received celecoxib plus placebo (placebo group). All subjects were genotyped for CYP2C19 using real-time fluorescent polymerase chain reaction. Subjects were sub-classified as poor metabolizers or extensive metabolizers. The incidence and number of small bowel injuries were compared between poor metabolizers and extensive metabolizers in each group. RESULTS: In the rabeprazole group, the incidence of small bowel injuries was significantly higher in poor metabolizers than in extensive metabolizers (85.7% vs 31.6%, P=.026). The number of mucosal injuries in the rabeprazole group was also significantly higher in poor metabolizers compared with extensive metabolizers (median [range] 3 [0-31] vs 0 [0-7], P=.01). In addition, we found a significant interaction between CYP2C19 genotype and concomitant use of rabeprazole in subjects at risk for celecoxib-induced small bowel injury. CONCLUSIONS: The CYP2C19 genotype might be associated with the risk of small bowel injury when celecoxib is combined with rabeprazole.

Selective induction of DeltaFosB in the brain after transient forebrain ischemia accompanied by an increased expression of galectin-1, and the implication of DeltaFosB and galectin-1 in neuroprotection and neurogenesis.

Transient forebrain ischemia causes selective induction of DeltaFosB, an AP-1 (activator protein-1) subunit, in cells within the ventricle wall or those in the dentate gyrus in the rat brain prior to neurogenesis, followed by induction of nestin, a marker for neuronal precursor cells, or galectin-1, a beta-galactoside sugar-binding lectin. The adenovirus-mediated expression of FosB or DeltaFosB induced expression of nestin, glial fibrillary acidic protein and galectin-1 in rat embryonic cortical cells. DeltaFosB-expressing cells exhibited a significantly higher survival and proliferation after the withdrawal of B27 supplement than the control or FosB-expressing cells. The decline in the DeltaFosB expression in the survivors enhanced the MAP2 expression. The expression of DeltaFosB in cells within the ventricle wall of the rat brain also resulted in an elevated expression of nestin. We therefore conclude that DeltaFosB can promote the proliferation of quiescent neuronal precursor cells, thus enhancing neurogenesis after transient forebrain ischemia.

Sodium-coupled glucose transporter as a functional glucose sensor of retinal microvascular circulation.

To clarify the function of the Na(+)-coupled glucose transporter in the regulation of cellular tone of cultured retinal pericytes, we investigated the effects of extracellular glucose concentration on cell size. The surface area and diameter of cultured bovine retinal pericytes under different glucose concentrations were measured by using a light microscope with a digital camera. We also examined the effects of extracellular Na(+) and Ca(2+), inhibitors of the Na(+)-coupled glucose transporter and Na(+)-Ca(2+) exchanger, a Ca(2+) channel blocker, and nonmetabolizable sugars on cell size. The surface area and diameter of the cells changed according to extracellular glucose concentrations. alpha-Methyl glucoside, which enters the cell through the Na(+)-coupled glucose transporter, induced cellular contraction. However, the cells did not contract in response to 2-deoxyglucose, which enters the cell through a facilitated glucose transporter. Glucose-induced cellular contraction was abolished in the absence of extracellular Na(+) and Ca(2+). Moreover, phlorizin, an inhibitor of the Na(+)-coupled glucose transporter, and 2',4'-dichlorobenzamil-HCl, an inhibitor of the Na(+)-Ca(2+) exchanger, also abolished glucose-induced cellular contraction, whereas nicardipine, a Ca(2+) channel blocker, did not. Our results indicate that high extracellular glucose concentrations induce contraction of bovine retinal pericytes via Na(+) entry through a Na(+)-coupled glucose transporter, suggesting that the Na(+)-coupled glucose transporter may act as a functional glucose sensor of retinal microvascular circulation.>

Involvement of calcium and protein kinase C in the activation of the Na+/H+ exchanger in cultured bovine aortic endothelial cells stimulated by extracellular ATP.

We have studied the activation of the Na+/H+ exchanger which leads to the intracellular alkalinization in cultured bovine aortic endothelial cells stimulated by extracellular ATP. The alkalinization induced by ATP was largely dependent on extracellular Ca2+ and the rate of alkalinization was decreased by about 60% in the absence of extracellular Ca2+. ATP caused a rapid and transient increase and a subsequent sustained increase of the intracellular Ca2+ concentration ([Ca2+]i) in the Ca2+ buffer, while only the rapid and transient increase of [Ca2+]i was observed in the absence of extracellular Ca2+. The Ca2+-depleted cells prepared by incubation in Ca2+-free buffer containing 0.1 mM EGTA showed only a slight increase of [Ca2+]i with no alkalinization on stimulation by ATP. The alkalinization was inhibited by 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7), an inhibitor of protein kinase C, but not by another isoquinoline analogue (HA 1004), which has a less inhibitory effect on the kinase. Phorbol 12-myristate 13-acetate also induced the alkalinization by the activation of the Na+/H+ exchanger. Neither dibutyryl cyclic AMP nor dibutyryl cyclic GMP affected the alkalinization induced by ATP. Treatment of the cells by pertussis and cholera toxins had no effect on the alkalinization. The results suggest that the increase in [Ca2+]i is essential for the ATP-induced activation of the Na+/H+ exchanger in cultured bovine aortic endothelial cells and a protein kinase C-dependent pathway is involved in the activation.

Role of phosphatidylinositol 3-kinase in acetylcholine-induced dilatation of rat basilar artery.

BACKGROUND AND PURPOSE: We tested the hypothesis that activation of phosphatidylinositol (PI) 3-kinase is involved in dilator responses of the basilar artery to acetylcholine in vivo. METHODS: Responses of the basilar artery were measured by the cranial window technique in anesthetized rats. To examine the role of PI 3-kinase in acetylcholine-induced calcium signaling, we measured intracellular free calcium concentration ([Ca(2+)](i)) of cultured rat basilar arterial endothelial cells using a fluorescent calcium indicator, indo 1. RESULTS: -Topical application of acetylcholine (10(-6), 10(-5.5), and 10(-5) mol/L) increased the diameter of the basilar artery by 8+/-1%, 14+/-2%, and 24+/-3%, respectively. An inhibitor of PI 3-kinase, wortmannin (10(-8) mol/L), did not change the baseline diameter of the artery. In the presence of wortmannin, acetylcholine (10(-6), 10(-5.5), and 10(-5) mol/L) dilated the artery only by 3+/-2%, 6+/-2%, and 12+/-2%, respectively. Thus, wortmannin attenuated acetylcholine-induced dilatation of the basilar artery (P<0.05 versus control). Wortmannin had no effect on dilatation of the artery in response to a nitric oxide donor, sodium nitroprusside. LY294002, another inhibitor of PI 3-kinase, also inhibited dilator response of the basilar artery to acetylcholine. Acetylcholine produced an increase in [Ca(2+)](i) of the endothelial cells. Genistein, an inhibitor of tyrosine kinase, markedly attenuated acetylcholine-induced calcium influx to the cells; however, wortmannin had no effect on acetylcholine-induced calcium changes. CONCLUSIONS: These results suggest that acetylcholine-induced dilatation of the basilar artery is mediated, at least in part, by activation of PI 3-kinase in vivo. Acetylcholine-induced [Ca(2+)](i) changes of the endothelial cells may not be mediated by activation of the kinase. PI 3-kinase as well as [Ca(2+)](i) may play an important role in the acetylcholine-induced nitric oxide production of the basilar arterial endothelial cells.

Bradykinin mediates the acute effect of an angiotensin-converting enzyme inhibitor on cerebral autoregulation in rats.

BACKGROUND AND PURPOSE: In patients with stroke and long-standing hypertension, the autoregulation curve of cerebral blood flow (CBF) shifts toward higher blood pressure levels. Angiotensin-converting enzyme (ACE) inhibitors reduce blood pressure and shift the autoregulation curve back to normal in hypertensive patients. ACE inhibitors have 2 major pharmacological properties: they inhibit both the production of angiotensin II and the breakdown of kinins. Hence, we investigated whether the effect of an ACE inhibitor on the lower limit of CBF autoregulation is mediated by the potentiation of bradykinin-mediated vasodilatation. METHODS: In 28 male Sprague-Dawley rats, CBF was measured by laser-Doppler flowmetry during stepwise controlled hypotension. The lower limit of CBF autoregulation was defined as the mean arterial pressure at which CBF decreased by 20% of the baseline value. The rats were treated with an ACE inhibitor, captopril, in the captopril group; a bradykinin BK2-receptor antagonist, Hoe140, in the Hoe140 group; and both agents in the captopril+Hoe140 group. Other rats served as a control group. The lower limits of CBF autoregulation were compared among the 4 groups. RESULTS: In the captopril group, the lower limit of CBF autoregulation was 43+/-8 mm Hg (mean+/-SD), which was significantly lower than that in the control group (57+/-14 mm Hg). Inhibition of bradykinin abolished the effect of captopril on the lower limit of CBF autoregulation. Hoe140 alone had no significant effect on the lower limit of CBF autoregulation. CONCLUSIONS: These results suggest that the shift of the lower limit of CBF autoregulation by captopril is mediated, at least in part, by bradykinin.

Adenovirus-mediated gene transfer to ischemic brain: ischemic flow threshold for transgene expression.

BACKGROUND AND PURPOSE: Gene therapy may be a promising approach for treatment of brain ischemia, although protein synthesis is generally inhibited in ischemic conditions. Our goal in this study was to examine effects of brain ischemia on transgene expression of adenovirus-mediated gene transfer to ischemic brain. METHODS: Brain ischemia was produced by photochemical occlusion of the distal middle cerebral artery of spontaneously hypertensive rats (n=15). Ninety minutes after ischemia, adenoviral vectors encoding bacterial beta-galactosidase were injected into ipsilateral (nonischemic [I-n], peri-ischemic [I-p], and ischemic core [I-c] areas) and contralateral parietal (C) cortices. Cerebral blood flow before and during ischemia at each injected area was measured by laser-Doppler flowmetry. Expression of transgene was detected by histochemistry for semiquantitative scoring or by biochemical assay for quantitative analysis. RESULTS: Blood flow to the cortex decreased to 72+/-10% (mean+/-SEM) at I-n, 41+/-6% at I-p, and 23+/-3% at I-c after 10 minutes of ischemia. Expression of the reporter gene was consistently detected at C and I-n at each survival period. The semiquantitative score for transgene expression decreased according to severity of ischemia (C, 2.3; I-n, 2.6; I-p, 1.1; I-c, 0.3; mean values). beta-Galactosidase activity detected by chemiluminescent assay revealed that the values (mean+/-SEM) in the ischemic area (I-p, 15.9+/-9.2 mU/mg protein; I-c, 1.3+/-0.5) were significantly smaller than that of the nonischemic area (C, 45.4+/-6.9). Analysis of cerebral blood flow at I-p revealed that cerebral blood flow threshold for transgene expression was approximately 40% of the resting value. CONCLUSIONS: Adenovirus-mediated gene transfer into the ischemic brain provided effective expression of transgene at the nonischemic and peri-ischemic areas. Gene transfer to the ischemic brain may be a promising approach for treatment of ischemic penumbra.

ATP-sensitive potassium channels in the basilar artery during chronic hypertension.

We examined the hypothesis that dilatation of the basilar artery in response to activation of ATP-sensitive potassium channels is impaired in stroke-prone spontaneously hypertensive rats (SHRSP). Changes in basilar artery diameter in response to aprikalim, a direct activator of ATP-sensitive potassium channels, were measured in anesthetized SHRSP and normotensive Wistar-Kyoto (WKY) rats through a cranial window. Topical application of aprikalim increased basilar artery diameter in WKY rats. Glibenclamide, a selective inhibitor of ATP-sensitive potassium channels, abolished aprikalim-induced vasodilatation. Thus, ATP-sensitive potassium channels are functional in the basilar artery of WKY rats in vivo. Aprikalim (10(-6) mol/L) dilated the basilar artery by 31 +/- 5% (mean +/- SEM) in WKY rats but only 5 +/- 1% in SHRSP. The concentration-response curve to aprikalim in SHRSP was significantly shifted to the right, but the response to the highest concentration of aprikalim (10(-5.5) mol/L) was similar in SHRSP and WKY rats. Vasodilatation in response to norepinephrine was also impaired in SHRSP. Dilator responses of the basilar artery to forskolin, a direct activator of adenylate cyclase, and nitroprusside, a direct activator of guanylate cyclase, were normal in SHRSP. The findings suggest that dilatation of the basilar artery in response to direct activation of ATP-sensitive potassium channels is impaired in SHRSP compared with WKY rats in vivo.

Enhanced responses of the basilar artery to activation of endothelin-B receptors in stroke-prone spontaneously hypertensive rats.

We tested the hypothesis that responses of the basilar artery to selective activation of endothelin-B receptors are altered during chronic hypertension. Using a cranial window in anesthetized rats, we examined responses of the basilar artery to a selective endothelin-B receptor agonist, IRL 1620, in stroke-prone spontaneously hypertensive rats (SHRSP). Under control conditions, baseline basilar artery diameter was smaller in SHRSP (196 +/- 8 microns [mean +/- SEM]) than in normotensive Wistar-Kyoto rats (WKY) (245 +/- 9 microns, P < .05). Topical application of IRL 1620 (10(-8) mol/L) dilated the basilar artery by 27 +/- 5% in WKY and 56 +/- 4% in SHRSP (P < .05). Dilatation of the basilar artery in response to sodium nitroprusside was similar in WKY and SHRSP. In contrast, acetylcholine-induced vasodilatation in SHRSP was markedly impaired. NG-Nitro-L-arginine methyl ester and NG-nitro-L-arginine, inhibitors of nitric oxide synthase, inhibited IRL 1620-induced vasodilatation in WKY. Neither NG-nitro-L-arginine methyl ester nor indomethacin attenuated vasodilatation produced by IRL 1620 in SHRSP. The major finding is that dilator responses of the basilar artery to selective activation of endothelin-B receptors are paradoxically enhanced in SHRSP compared with WKY. Dilator responses of the basilar artery to endothelin-B receptor activation are mediated by endothelium-derived relaxing factor in WKY. In contrast, responses to activation of endothelin receptors in SHRSP do not depend on the production of nitric oxide or prostanoids.