The changes in beta-adrenoceptor-mediated cardiac function in experimental hypothyroidism: the possible contribution of cardiac beta3-adrenoceptors.

Thyroid hormone deficiency has been reported to decrease expression and function of both beta(1)- and beta(2)-adrenoceptor in different tissues including heart. The purpose of this study was to examine the possible contribution of beta(3)-adrenoceptors to cardiac dysfunction in hypothyroidism. In addition, effect of this pathology on beta(1)- and beta(2)-adrenoceptor was investigated. Hypothyroidism was induced by adding methimazole (300 mg/l) to drinking water of rats for 8 weeks. Cardiac hemodynamic parameters were measured in anesthetised rats in vivo. Responses to beta-adrenoceptor agonists were examined in rat papillary muscle in vitro. We also studied the effect of hypotyroidism on mRNA expression of beta-adrenoceptors, Gialpha, GRK, and eNOS in rat heart. All of the hemodynamic parameters (systolic, diastolic and mean arterial pressure, left ventricular pressure, heart rate, +dp/dt, and -dp/dt) were significantly reduced by the methimazole treatment. The negative inotropic effect elicited by BRL 37344 (a beta(3)-adrenoceptor preferential agonist) and positive inotropic effects produced by isoprenaline and noradrenaline, respectively, were significantly decreased in papillary muscle of hypothyroid rats as compared to those of controls. On the other hand, hypothyroidism resulted in increased cardiac beta(2)- and beta(3)-adrenoceptor, Gialpha(2), Gialpha(3), GRK3, and eNOS mRNA expressions. However, beta(1)-adrenoceptor and GRK2 mRNA expressions were not changed significantly in this pathology. These results show that mRNA expression of beta(3)-adrenoceptors as well as the signalling pathway components mediated through beta(3)-adrenoceptors are significantly increased in hypothyroid rat heart. Since we could not correlate these alternates with the decreased negative inotropic response mediated by this receptor subtype, it is not clear whether these changes are important for hypothyroid induced reduction in cardiac function.

The effect of diabetes on expression of beta1-, beta2-, and beta3-adrenoreceptors in rat hearts.

Diabetic hearts exhibit decreased responsiveness to stimulation by beta-adrenoreceptor (beta-AR) agonists. This decrease in activity may be due to changes in expression and/or signaling of beta-AR. Recently we showed that right atrial strips from 14-week streptozotocin (STZ)-induced diabetic rat hearts exhibit decreased responsiveness to beta1-AR agonist stimulation, but not to beta2-AR agonist. In the present study, we investigated the effects of long-term diabetes on the expression of cardiac beta1-, beta2-, and beta3-ARs and looked at whether these changes could be restored with insulin treatment. Using reverse transcription-polymerase chain reaction (RT-PCR), PAGE, and Western blot analysis, we found that beta1-AR mRNA and protein levels decreased by 34.9 +/- 5.8 and 44.4 +/- 5.8%, respectively, in 14 week-STZ-treated diabetic rat hearts when compared with age-matched controls. On the other hand, mRNA levels encoding beta2- and beta3-ARs increased by 72.5 +/- 16.6 and 97.3 +/- 26.1%, respectively. Although the latter translated into a proportional increase in beta3-AR protein levels (100.0 +/- 17.0%), beta2-AR protein levels decreased to 82.6 +/- 1.1% of control. Insulin treatment for 2 weeks, after 12 weeks of untreated diabetes, partially restored beta1-AR mRNA and protein levels to 60.1 +/- 8.4 and 83.2 +/- 5.0%, respectively, of control. Although insulin treatment minimally attenuated the rise in mRNA levels encoding beta2- and beta3-ARs, the steady-state levels of these proteins returned to near control values. These data suggest that the decreased responsiveness of diabetic hearts to stimulation of beta-AR agonists may be due to a decrease in beta1-AR and an increase beta3-AR expression.

The effects of chronic L-name and L-arginine administration on beta-adrenergic responsiveness of STZ-diabetic rat atria.

Recent studies have shown that NO acts as a negative inotrope and chronotrop in cardiac muscle. In the present study, we investigated the effects of the chronic administration of L-NAME and L -arginine on 14-week streptozotocin (STZ)-diabetic rat atria. To study these effects, we compared the alterations of inotropic and chronotropic responses to isoprenaline (ISO) on electrically-driven left atria and spontaneously beating right atria. In addition, we compared the blood pressures of rats in all groups. The chronic administration of L-arginine resulted in a significant reduction in blood pressure of the diabetic rats. On the other hand, the chronic nitric oxide synthase inhibition resulted in a significant increase in blood pressure of diabetic animals. To our findings, maximum positive inotropic responses of ISO diminished in STZ-diabetic, L-arginine and L-NAME treated diabetic groups relative to controls but neither the basal contractility of the left atria nor the pD(2)values were altered significantly in all groups. The basal atrial rate and maximum positive chronotropic responses to ISO were found to be significantly lower in treated and untreated diabetic groups, no significant changes were observed in pD(2)values. Our results demonstrate that the changes in inotropic and chronotropic responses in diabetic rat atria were not influenced by the chronic administration of L-arginine and L-NAME treatments.

Reversal effects of L-arginine treatment on blood pressure and vascular responsiveness of streptozotocin-diabetic rats.

In the present study, we examined the reversal effects of L-arginine (L-ARG) treatment in vivo on blood pressure and on vascular responsiveness of chronic diabetic rats. Twelve weeks after streptozotocin (STZ) injection, the systolic blood pressures (SBP) of diabetic groups have been found to be significantly higher compared with that of control groups. L-ARG treatment for 4 weeks, begun 12 weeks after the onset of diabetes, induced a significant fall in SBP of diabetic rats. Maximal contractile response and sensitivity (pD(2)value) of the aortae to phenylephrine (PE) were significantly enhanced in diabetic rats compared with control subjects. Treatment of diabetic rats with L-ARG completely reversed the increases in responsiveness and sensitivity of aortae to PE. The relaxation response to acetylcholine (ACh), but not to sodium nitroprusside (SNP), in diabetic aorta has been found to be significantly decreased when compared with control subjects. The in vivo treatment with L-ARG reversed the decreased ACh responses to the control level. Plasma malondialdehyde (MDA) level of diabetic rats was also significantly higher than control subjects. However, L-ARG treatment normalized the increase in MDA level of plasma of diabetic rats. All of the effects of L-ARG treatment were found to be specific for diabetic rats but not control subjects. These results show that L-ARG treatment in vivo has a reversal effect on impaired vascular responses and increased oxidative stress. The present findings also suggest that oxidative stress that occurred in diabetes might cause or contribute to the development of hypertension by affecting vascular reactivity. On the other hand, the lipid peroxidation-lowering effect of L-ARG may account for its beneficial effect on SBP and vascular responsiveness of diabetic rats.

Troglitazone has no effect on K(ATP) channel opener induced-relaxations in rat aorta and in human saphenous veins from patients with type 2 diabetes.

Troglitazone, a thiazolidinedione derivative, is an oral antidiabetic agent that enhances insulin sensitivity in insulin-resistant states. K(ATP) channels, on the other hand, have important roles protecting cardiovascular system in ischemic and/or hypoxic states. They are also important in the control of vascular tone, and therefore of blood pressure. We tested whether troglitazone can directly affect vascular K(ATP) channel opener-induced relaxations in vitro. 1, 10 or 100 microM troglitazone incubations for 30 min did not alter cromakalim (a K(ATP) channel opener)--induced relaxations in endothelium-denuded aortas from rat, saphenous veins from type 2 diabetic and nondiabetic patients. In addition, we compared the sensitivity to cromakalim in diabetic saphenous veins with that of nondiabetic veins. The concentration-response curve for cromakalim was shifted to the right in diabetic vein. pD2 values for cromakalim were 6.85+/-0.08 vs. 6.61+/-0.04 (p<0.05) in nondiabetic (n:10) and diabetic (n:7) veins respectively. % maximum response of cromakalim was also significantly decreased by 24+/-3% in diabetic veins. However, responsiveness of veins to phenylephrine or sodium nitroprusside were similar in both groups. The results obtained may be clinically useful 1. suggesting that in ischaemic and/or hypoxic insults troglitazone may not worsen vascular dilatation, through K(ATP) channel, in diabetic patients who are more prone to these conditions than healthy people, 2. providing an evidence that diabetes causes an impaired dilatation of human saphenous vein through K(ATP) channels. This may partly be related with diabetes-induced vascular complications, such as vasospasm and even hypertension. Accordingly, since saphenous veins are used as conduit vessels in coronary by-pass graft surgery, the results also suggest that the defective dilatation through K(ATP) channels may play a role on the performance of saphenous vein grafts in type 2 diabetes.

The effects of chronic L-arginine treatment on vascular responsiveness of streptozotocin-diabetic rats.

In this study, the protective effects of L-arginine treatment in vivo on vascular reactivity of streptozotocin (STZ)-induced 12-week-old diabetic rats were examined. Loss of weight, polydipsia, polyphagia, hyperglycemia, hypoinsulinemia, and elevated levels of plasma cholesterol and triglyceride were observed in diabetic rats. L-arginine treatment (1 mg/mL in drinking water) did not significantly affect these metabolic and biochemical abnormalities. Plasma malondialdehyde (MDA) levels in untreated diabetic rats were also significantly higher than untreated controls. However, L-arginine treatment prevented the increase in MDA level of plasma of diabetic rats. Contractile responses, but not sensitivity to noradrenaline (NA), were significantly increased in diabetic rats compared to controls. Treatment of diabetic rats with L-arginine completely prevented the increase in NA responses. Relaxation response to acetylcholine (ACh), but not to sodium nitroprusside (SNP), in diabetic aorta has been found to be significantly decreased as compared with controls. However, there were no significant differences in pD2 values of acetylcholine in either of the groups. L-arginine treatment increased the ACh responses to the control level. All effects of L-arginine on vascular reactivity were found to be specific for diabetic rats and not controls. These results suggest that functional abnormalities occurred in aorta from diabetic rat might at least in part result from L-arginine deficiency, and the lipid peroxidation-lowering effect of L-arginine may account for its protective effect on vascular reactivity of diabetic rats.

The effects of diabetes on beta-adrenoceptor mediated responsiveness of human and rat atria.

The literature on the influence of diabetes on cardiac beta-adrenoceptors is still a matter of controversy. Hence, in the present study, the responsiveness of spontaneously beating right atria from streptozotocin (STZ)-diabetic rats to beta-adrenoceptor agonists were compared with those from non-diabetic controls. The responsiveness of right atria from 8-week diabetic rats to the chronotropic effects of isoprenaline, noradrenaline and fenoterol was found to be unchanged. As the disease progressed, on the other hand, the diabetic atria were found to have decreased responsiveness to the chronotropic effects of noradrenaline. The pD2 value and maximum chronotropic effect of noradrenaline were decreased in 14-week diabetic right atria when compared with those from age-matched controls. A significant decrease in the maximum chronotropic response to isoprenaline with no change in pD2 value was also observed in 14-week diabetes. These results suggest that beta 1--but not beta 2-adrenoceptor mediated chronotropic responses were reduced in the right atria due to the increase in the duration of diabetes. On the other hand, the inotropic responses to beta-adrenoceptor agonists were also assessed on diabetic and nondiabetic human atrial tissue. There were no significant differences in the inotropic responses to each agonists in either of the diabetic and nondiabetic human atrial tissues. The full agonist potency order was isoprenaline > or = fenoterol > noradrenaline.

Calmodulin content and in vitro contractility of duodenum from streptozotocin-induced diabetic rats: effects of insulin therapy and calmodulin antagonism.

The effects of experimental diabetes and insulin treatment on the decreased reactivity of isolated rat duodenum to KCl and calmidazolium, a specific calmodulin antagonist, were examined. After 8 weeks of streptozotocin diabetes, the contractile effect of KCl and the non-competitive antagonistic effect of calmidazolium against KCl on isolated rat duodenum were decreased. Calmodulin levels, as measured by radioimmunoassay, were also found to the decreased in duodenum from streptozotocin-diabetic rats. Neither impaired reactivity to KCl nor decreased calmodulin levels in diabetic rat duodenum were corrected by treatment with insulin (10 IU/kg for 20 days). Following insulin treatment, there was only a partial correction in the antagonistic effect of calmidazolium as shown by the increase in non-competitive antagonist affinity constant.

Improvement of glucose and lipid metabolism in diabetic rats treated with molybdate.

Molybdenum mimics certain insulin actions in vitro. We have investigated the effects of oral administration of Na2MoO4 (Mo) for 8 wk on carbohydrate and lipid metabolism in streptozotocin-diabetic rats. Mo decreased hyperglycemia and glucosuria by 75% and corrected the elevation of plasma nonesterified fatty acids. Tolerance to glucose loads was improved, and glycogen stores were replenished. These effects were not due to a rise of insulinemia. In liver, Mo restored the blunted mRNA and activity of glucokinase and pyruvate kinase and decreased to normal phosphoenolpyruvate carboxykinase values. Finally, Mo totally reversed the low expression and activity of acetyl-CoA carboxylase and fatty acid synthase in liver, but not in white adipose tissue. In conclusion, Mo exerts a marked blood glucose-lowering effect in diabetic rats by an insulin-like action. This effect results in part from a restoration of hepatic glucose metabolism and is associated with a tissue-specific correction of lipogenic enzyme gene expression, both processes being essentially mediated by reversal of impaired pretranslational regulatory mechanisms. These observations raise new therapeutic perspectives in diabetes, particularly in the insulin-resistant condition.

Effect of insulin treatment on smooth muscle calmodulin levels in rats with long-term streptozotocin-diabetes.

Altered responses to several agonists have been reported in various smooth muscles from experimentally-diabetic animals suggesting a defective contractile process of smooth muscle. Recently, decreased smooth muscle calmodulin levels have been reported in streptozotocin-diabetic rats. However, the effectiveness of insulin on the decreased calmodulin levels in diabetic rats has not been questioned. Therefore, the present study was designed to examine the effect of insulin on smooth muscle calmodulin levels from streptozotocin-diabetic rats. Calmodulin levels of the smooth muscle were measured by a radioimmunoassay technique. Streptozotocin diabetes caused a significant decrease in tissue calmodulin levels of smooth muscles. Insulin therapy for 20 days did not correct the changes in calmodulin levels of rat smooth muscles, although it normalised blood glucose in streptozotocin-diabetic rats. These findings suggest that the altered smooth muscle calmodulin may contribute the defective contractile responses in diabetes and these changes may be resistant to insulin therapy.

Oral selenate improves glucose homeostasis and partly reverses abnormal expression of liver glycolytic and gluconeogenic enzymes in diabetic rats.

Selenium is a trace element that exerts certain insulin-like actions in vitro. In this study, we evaluated its in vivo effects on the glucose homeostasis of rats made diabetic and insulin-deficient by streptozotocin. Na2SeO4 was administered ad libitum in drinking water and/or food for 10 weeks. The elevated plasma glucose levels (approximately 25 mmol/l) and glucosuria (approximately 85 mmol/day) of untreated rats were decreased by 50 and 80%, respectively, by selenate treatment. The beneficial effect of selenate was also evident during oral and intravenous glucose tolerance tests: the integrated glucose responses were decreased by 40-50% as compared to those in untreated rats. These effects were not due to an increase in plasma insulin levels. Compared to non-diabetic rats, pancreatic insulin reserves were reduced by more than 90% in treated and untreated diabetic rats. The hepatic activities and mRNA levels of two key glycolytic enzymes, glucokinase and L-type pyruvate kinase were blunted in diabetic rats. They increased approximately two- to threefold after selenate treatment, to reach 40-75% of the values in non-diabetic rats. In contrast, elevated activity and mRNA levels of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase, were reduced by 40-65% after selenate administration. Since selenate induced a moderate decrease in body weight due to an anorexigenic effect, we checked that there was no improvement of glucose homeostasis or hepatic glucose metabolism in an additional group of calorie-restricted diabetic rats, which was weight-matched with the selenate group. In addition, no obvious toxic side-effects on the kidney or liver were observed in the rats receiving selenate. In conclusion, selenate induces a sustained improvement of glucose homeostasis in streptozotocin-diabetic rats by an insulin-like action, which involves partial correction of altered pretranslational regulatory mechanisms in liver metabolism.

Vanadate treatment reverses gastrointestinal complications in the streptozotocin-diabetic rats.

1. Insulin-like effects of vanadium compounds have been reported in various experimental conditions. Effects of vanadate on the decreased beta-adrenergic responsiveness of the rat duodenum due to streptozotocin diabetes were investigated to determine its influence on diabetic gastro-intestinal complications as well as its effects on the carbohydrate metabolism. 2. Administration of sodium orthovanadate to streptozoticin-diabetic rats in drinking water (0.7 mg/ml) for 4 weeks resulted in an improvement of carbohydrate metabolism noticed by increased serum levels of insulin and decreased blood levels of glucose as reported in previous studies. 3. Vanadate treatment of streptozotocin-diabetic rats also corrected the diabetic changes in the beta-adrenergic responsiveness of the rat duodenum to salbutamol suggesting a beneficial effect on the diabetic complications of rat gastro-intestinal tract. The same treatment with vanadate did not cause any alteration in the beta-adrenergic responsiveness of isolated duodenum from non-diabetic rats. 4. From the findings obtained, it is concluded that vanadate possesses an insulin-like effect on the beta-adrenergic responsiveness of the rat gastro-intestinal tract. Since vanadate treatment did not alter the beta-adrenergic responses of isolated duodenum from non-diabetic rats it seems likely that the insulin-like effect of vanadate is dependent on increased responsiveness of the gastrointestinal tract to circulating insulin.

Effect of short and long term streptozotocin diabetes on smooth muscle calmodulin levels in the rat.

Diabetes mellitus is a metabolic disease associated with certain complications which have also been demonstrated in the experimental models of this disease. Altered responses to several agonists have been reported in various smooth muscles from alloxan or streptozotocin diabetic animals. Since these reports revealed a defect in the contractile process of smooth muscles from experimentally-induced diabetes, short and long term effects of diabetes on calmodulin levels in the smooth muscles of aorta, trachea, vas deferens and duodenum were investigated using streptozotocin diabetic rats. In spite of the fact that most of the reports have demonstrated the defective contractions in long term diabetic rats, short term effect (for 1 week) of diabetes on calmodulin levels in the smooth muscles of aorta, trachea, vas deferens and duodenum was also investigated in the present study using streptozotocin diabetic rats to understand whether the changes in calmodulin dependent contractile process begin at an earlier stage of the disease. Tissue calmodulin levels of the smooth muscles were measured by the radioimmunoassay technique using a [125I]-labeled kit. Although rats injected with streptozotocin exerted the characteristics of diabetes such as polyuria, polydipsy, polyphagy and elevated blood glucose levels, unchanged calmodulin levels were found in the rats with short term streptozotocin diabetes. In contrast, long term streptozotocin diabetes (for 8 weeks) was found to cause a significant decrease in tissue calmodulin levels of these four smooth muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of vanadyl treatment on vascular responsiveness of streptozotocin-diabetic rats.

Vanadyl sulphate has been demonstrated to possess insulin-like effects in streptozotocin (STZ) diabetic rats, including the normalization of hyperglycaemia and the prevention of diabetes-induced cardiac dysfunction. However, the effectiveness of vanadyl sulphate on diabetes-related vascular aberrations has not been questioned. Hence, in the present work, we have specifically addressed the question of whether chronic oral vanadyl sulphate treatment has any beneficial effect on diabetes-induced changes in vascular reactivity. Male albino rats were injected with a single intravenous dose of STZ (55 mg/kg). Vanadyl sulphate was administered in the drinking water at a concentration of 1 mg/ml from 7 days after the STZ injection and treatment was maintained for 10 weeks. Vanadyl intake was accompanied by decreased blood glucose and serum insulin levels. The effects of diabetes on vascular smooth muscle function were assessed by the responsiveness of aortae to noradrenaline and KCl. Contractile responses of the diabetic aortae were found to be significantly increased as compared with controls. However, there were no significant differences in pD2 values of the agonists in either of the groups. Treatment of diabetic rats with vanadyl sulphate completely prevented the increases in responsiveness of aortae to noradrenaline and KCl. The effect of diabetes on the fast and slow components of noradrenaline-induced contraction was also examined. Both components of the response to noradrenaline were significantly increased in diabetic aortae. These changes were also prevented by vanadyl sulphate treatment. The data demonstrate that 10-week vanadyl sulphate treatment results in improved vascular reactivity of diabetic rats.

The effect of vanadate on alloxan-diabetic rat atria.

In this study, we examined the effect of vanadate treatment on cardiac changes recognized in diabetic rats. In addition, the possible contribution of thyroid hormones to vanadate's effect on alloxan-diabetic atria was also investigated. Administration of alloxan to rats, as expected, resulted in hyperglycemia; hypoinsulinemia reduced thyroid hormone levels, decreased body weight and depressed cardiac function. Vanadate treatment of diabetic rats normalized blood glucose and serum thyroid hormone levels, neither were serum insulin levels of diabetic animals corrected after vanadate treatment. Vanadate treatment, however, did not affect the body weights of diabetic rats. Spontaneously-beating atria from diabetic rats were found to have decreased rates but increased forces of contractions compared with those from controls. On the other hand, the responsiveness of diabetic atria to both inotropic and chronotropic effects of isoprenaline was found to be decreased. Vanadate treatment resulted in the normalization of these alterations observed in diabetic atria. These results thus indicate that the normalizing effect of vanadate on diabetes-induced hypothyroidism may contribute to its effect in preventing cardiac changes observed at the early stage of diabetes.

Effect of insulin on the decreased beta-adrenergic responses of duodenum and atrium isolated from streptozotocin diabetic rats.

1. Decreased beta-adrenergic responses have been reported in both gastro-intestinal tract and atrium of experimentally-induced diabetic rats. The present study was undertaken to investigate in vitro effects of insulin on decreased beta-adrenergic responses of the duodenum and atrium from streptozotocin-diabetic rats. 2. Insulin incubation (16.67 micrograms/ml) in bathing medium for 5 hr enhanced the decreased beta-adrenergic responses in the diabetic rat duodenum, but not those in the diabetic atrium. Incubation of bovine insulin with anti-bovine insulin antibody in the test-tube inhibited the improving effect of insulin on the decreased beta-adrenergic responses of diabetic rat duodenum. 3. In vitro treatment with the same dose of bovine insulin in bathing medium caused a decrease in the beta-adrenergic responses of the atria from both non-diabetic and diabetic rats. Anti-bovine insulin antibody also abolished the inhibitory effect of insulin on the rat atria. 4. These results strongly suggest that the experimental diabetes affects beta-adrenergic responsiveness of the rat gastro-intestinal tract through a different mechanism from that of the rat myocardium.

The effect of oral vanadyl treatment on the reactivity of tracheal smooth muscle obtained from insulin-dependent diabetic rats.

1. In this study, we investigated the contractile effects of acetylcholine (ACh) and KCl in tracheas obtained from 12-13 wk insulin-dependent (ID)-diabetic rats. 2. The maximum contractile responses to ACh and KCl were significantly increased in ID-diabetic rat tracheas compared with those from controls. But the sensitivity (pD2 values) of ID-diabetic tracheas to these agents were not significantly altered relative to controls. 3. The alterations which occurred in ID-diabetic rats were prevented with oral vanadyl treatment during a 10 wk period.

Basal and histamine-induced gastric acid secretion in alloxan diabetic rats.

1. Effects of alloxan-induced diabetes on the rat gastric acid secretion were investigated using a number of biostatistical models described earlier. 2. Histamine-induced gastric acid secretion was found to be decreased in alloxan-diabetic rats when compared with their age-matched controls. 3. Basal acid secretion was also decreased depending on experimentally-induced diabetes. 4. The above results strongly suggest that alloxan-induced diabetes depresses vagal activity and H2-receptor activity in the stomach.

Beneficial effect of insulin on the decreased gastrointestinal beta-adrenergic responses in streptozotocin-diabetic rats: a contributing role of protein biosynthesis.

The beneficial effect of insulin on the decreased gastrointestinal beta-adrenergic responses in experimentally diabetic rats has been reported. The effects of streptozotocin-induced diabetes and insulin on the isolated rat duodenum, precontracted with bethanechol, were examined in the absence and in the presence of protein synthesis inhibitors in isometric conditions. Streptozotocin-induced diabetes caused a decrease of the beta-adrenergic responses of the rat duodenum. In vitro insulin treatment corrected the decreased beta-adrenergic responses of rat duodenum due to streptozotocin-induced diabetes. In the presence of protein synthesis inhibitors, actinomycin D or cycloheximide, the beneficial effect of insulin on the decreased intestinal beta-adrenergic responses was significantly inhibited. These findings suggest that the beneficial effect of insulin in the rat duodenum might be related to a new receptor synthesis.

Linear modeling of the effect of intravenous histamine infusion on rat gastric acid secretion: a biostatistical evaluation by splitting the time-effect curves.

Lumen perfusion experiments have been widely employed for the evaluation of gastric acid secretion in rats. The advantage of the lumen perfusion models is the simplicity in evaluating the effectiveness of secretagogues and antisecretagogues. There is, however, no efficient methodology for biostatistical modeling of gastric acid secretion in lumen-perfused rats. In order to optimize methodology, we applied a linear regression model after splitting the time-effect curves obtained from histamine-induced gastric acid secretion in rats.