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Biomedical subjects

R K Goyal

Publications and source records attributed to R K Goyal.

At least 73 records · Page 4Linked to original sources
PubMed1998

Effect of chronic treatment with amlodipine in non-insulin-dependent diabetic rats.

We have investigated the effects of amlodipine on streptozotocin-(STZ) induced neonatal non-insulin-dependent diabetes mellitus (NIDDM) rats. NIDDM was induced by intraperitoneal injection of STZ (70 mg kg-1) to 5-day-old rat pups. The animals were weaned at 30 days and maintained with food and water ad libitum for 3 months. Amlodipine (5 mg kg-1 p.o.) was administered for 6 weeks after the animals were confirmed diabetic (3 months after the STZ injection). A group of control animals were also maintained and this group received citrate buffer 5 days after birth. Fasting- and fed-glucose levels in NIDDM rats were significantly higher than control rats. Treatment with amlodipine reduced the elevated fasting- and fed-glucose levels significantly. Results of the oral glucose tolerance test (OGTT) revealed the glucose tolerance is impaired in the NIDDM rats. There was a marked increase in glucose levels after oral administration of glucose in the control NIDDM rats. Increased glucose levels were found to be associated with increased insulin levels. Treatment with amlodipine in the NIDDM rats caused a decrease in insulin release, however, glucose levels were found to be lowered significantly indicating that amlodipine causes an increase in insulin sensitivity. In conclusion, our data indicated that amlodipine increases insulin sensitivity in neonatal-STZ NIDDM rats.

Amlodipine↗
PubMed1998

Effect of long-term treatment with enalapril in streptozotocin diabetic and DOCA hypertensive rats.

We studied the effects of long-term treatment with enalapril (5 mg/kg/day orally) on various biochemical and cardiovascular complications in streptozotocin (STZ) diabetic and deoxycorticosterone acetate (DOCA) hypertensive rats. Female Wistar rats made diabetic or hypertensive or both by streptozotocin (STZ; 45 mg/kg) or deoxycorticosterone acetate (DOCA; 10 mg/kg, p.o., daily) or both. Enalapril (5 mg/kg) was administered daily by the oral route for 6 weeks. At the end of 6 weeks, blood samples were taken to analyze glucose, insulin, and lipids. Blood pressure and heart rate were recorded by a noninvasive technique, and cardiac functions were recorded by Neely's working heart preparation. Injection of STZ produced severe glycosuria (>2%), hyperglycemia, hypoinsulinemia, and loss of body weight. It also produced hypercholesterolemia, hypertriglyceridemia, hypertension, bradycardia, and decreased left ventricular developed pressure (LVDP) and increase in angiotensin-converting enzyme (ACE) in left ventricular tissue. DOCA by itself did not produce any change in blood glucose but reduced serum insulin levels in nondiabetic animals. However, in the diabetic group, DOCA reduced blood sugar levels. Treatment with enalapril prevented an increase in the blood pressure and the heart weight. Decrease in the heart rate, reduction in LVDP, and increase in intracardiac activity were observed in diabetic rats; these were also prevented by enalapril treatment. Enalapril had no effect on plasma glucose and did not modify plasma insulin levels in diabetic animals. The effects of STZ and DOCA together were not additive on the investigated parameters, and enalapril was similarly efficient in diabetic and diabetic hypertensive animals.

Analysis of Variance↗
PubMed1998

Differences in contractile protein content and isoforms in phasic and tonic smooth muscles.

The basis of tonic vs. phasic contractile phenotypes of visceral smooth muscles is poorly understood. We used gel electrophoresis and quantitative scanning densitometry to measure the content and isoform composition of contractile proteins in opossum lower esophageal sphincter (LES), to represent tonic muscle, and circular muscle of the esophageal body (EB), to represent phasic smooth muscle. The amount of protein in these two types of muscles is similar: approximately 27 mg/g of frozen tissue. There is no difference in the relative proportion of myosin, actin, calponin, and tropomyosin in the two muscle types. However, the EB contains approximately 2.4-times more caldesmon than the LES. The relative ratios of alpha- to gamma-contractile isoforms of actin are 0.9 in the LES and 0.3 in EB. The ratio between acidic (LC17a) and basic (LC17b) isoforms of the 17-kDa essential light chain of myosin is 0.7:1 in the LES, compared with 2.7:1 in the EB. There is no significant difference in the ratios of smooth muscle myosin SM1 and SM2 isoforms in the two muscle types. The level of the myosin heavy chain isoform, which contains the seven-amino acid insert in the myosin head, is about threefold higher in the EB compared with LES. In conclusion, the esophageal phasic muscle in contrast to the tonic LES contains proportionally more caldesmon, LC17a, and seven-amino acid-inserted myosin and proportionally less alpha-actin. These differences may provide a basis for functional differences between tonic and phasic smooth muscles.

Actins↗
PubMed1998

Nitric oxide suppresses a Ca(2+)-stimulated Cl- current in smooth muscle cells of opossum esophagus.

Nitric oxide (NO) hyperpolarizes visceral smooth muscles. Using the patch-clamp technique, we investigated the possibility that NO-mediated hyperpolarization in the circular muscle of opossum esophagus results from the suppression of a Ca(2+)-stimulated Cl- current. Smooth muscle cells were dissociated from the circular layer and bathed in high-K+ Ca(2+)-EGTA-buffered solution. Macroscopic ramp currents were recorded from cell-attached patches. Contaminating K(+)-channel currents were blocked with tetrapentylammonium chloride (200 microM) added to all solutions. Raising bath Ca2+ concentration above 150 nM in the presence of A-23187 (10 microM) activated a leak current (IL-Ca) with an EC50 of 1.2 microM at -100 mV. The reversal potential (Erev) of IL-Ca (-8.5 +/- 1.8 mV, n = 8) was significantly different (P < 0.05) from Erev of the background current (+4.2 +/- 1.2 mV, n = 8). Equimolar substitution of 135 mM Cl- in the pipette solution with gluconate significantly shifted Erev of IL-Ca to +16.6 +/- 3.4 mV (n = 4) (P < 0.05 compared with background), whereas replacement of total Na+ with Tris+ suppressed IL-Ca but did not affect Erev (-15 +/- 3 mV, n = 3; P > 0.05). IL-Ca was inhibited by DIDS (500 microM). Diethylenetriamine-NO adduct (200 microM), a NO donor, and 8-bromo-cGMP (200 microM) suppressed IL-Ca by 59 +/- 15% (n = 5) and 62 +/- 21% (n = 4) at -100 mV, respectively. We conclude that in opossum esophageal smooth muscle NO-mediated hyperpolarization may be produced by suppression of a Ca(2+)-stimulated Cl(-)-permeable conductance via formation of cGMP.

Animals↗
PubMed1998

Evidence for NO. redox form of nitric oxide as nitrergic inhibitory neurotransmitter in gut.

A nitric oxide (NO)-like product of the L-arginine NO synthase pathway has been shown to be a major inhibitory neurotransmitter that is involved in the slow component of the inhibitory junction potential (IJP) elicited by stimulation of nonadrenergic, noncholinergic nerves. However, the exact nature of the nitrergic transmitter, the role of cGMP, and the involvement of a potassium or a chloride conductance in the slow IJP remain unresolved. We examined the effects of soluble guanylate cyclase inhibitors LY-83583 and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), potassium-channel blockers and putative chloride-channel blockers diphenylamine-2-carboxylate (DPC) and niflumic acid (NFA) on the hyperpolarization elicited by an NO. donor, diethylenetriamine/NO adduct (DNO), NO in solution, and an NO+ donor, sodium nitroprusside (SNP), in the guinea pig ileal circular muscle. Effects of these blockers on purinergic (fast) and nitrergic (slow) IJP were also examined. DNO-induced hyperpolarization and nitrergic slow IJP were suppressed by LY-83583 or ODQ and DPC or NFA but not by the potassium-channel blocker apamin. In contrast, hyperpolarization caused by SNP or solubilized NO gas and purinergic fast IJP were antagonized by apamin but not by inhibitors of guanylate cyclase or chloride channels. These results demonstrate biological differences in the actions of different redox states of NO and suggest that NO. is the nitrergic inhibitory neurotransmitter.

Aminoquinolines↗
PubMed1998

Oral zinc therapy in diabetic neuropathy.

The present double blind randomized study was conducted on 50 subjects; 20 age and sex matched healthy controls (Group--I); 15 patients of diabetes mellitus with neuropathy who received placebo for 6 weeks (Group--IIA); and 15 patients of diabetes mellitus with neuropathy who were given supplemental zinc sulphate (660 mg) for 6 weeks (Group--IIB). Serum zinc level, fasting blood sugar (FBS) and post prandial blood sugar (PPBS) levels and motor nerve conduction velocity (MNCV) were estimated on day 0 and after 6 weeks in all subjects. Serum zinc levels were significantly low (p < 0.001) in group IIA and IIB as compared to healthy controls (Group--I) at baseline. After 6 weeks the change in pre and post therapy values of FBS, PPBS and MNCV (median and common peroneal nerve) were highly significant (P = < 0.001) for group IIB alone with insignificant change (P = > 0.05) in group IIA. No improvement (P = > 0.05) in autonomic dysfunction was observed in either groups. Therefore, oral zinc supplementation helps in achieving better glycemic control and improvement in severity of peripheral neuropathy as assessed by MNCV.

Administration, Oral↗
PubMed1998

Gastroesophageal reflux disease versus Helicobacter pylori infection as the cause of gastric carditis.

To explore the potential contributions of gastroesophageal reflux disease, as opposed to Helicobacter pylori infection, to the development of gastric carditis, we evaluated gastric carditis (using the criteria of the updated Sydney system for the classification of gastritis), clinical and morphologic features of esophagitis, and H. pylori infection (evaluation of Steiner stains) in biopsy specimens from the gastroesophageal squamocolumnar junction. We correlated clinical, endoscopic, and histologic features in an unselected group of 116 patients. Some degree of carditis was found in 107 (92%) of the patients. The mean age of the patients increased with increasing severity of carditis (P < .05). The various groups of patients with different degrees of carditis did not differ significantly in sex ratio, ethnic background, presence of obesity, percentage having symptoms of gastroesophageal reflux disease (such as heartburn, regurgitation, dysphagia, or odynophagia), endoscopic evidence of esophagitis and columnar epithelium in the distal esophagus, or histologic evidence of active esophagitis. The presence, however, of active gastritis and H. pylori infection in the distal stomach and/or in the cardia was significantly associated with carditis. In patients without carditis, H. pylori was not detected in any cardiac or distal gastric biopsy specimen. In contrast, H. pylori was demonstrated in gastric tissue samples (either from the cardia or distally) of patients with carditis, with the prevalence rate increasing with greater degrees of cardiac inflammation. The H. pylori prevalence rate was 12% in the group with mild carditis, 40% in those with moderate carditis, and 57% in patients with marked carditis (P = .0001). In summary, carditis is commonly found in patients with symptoms related to upper gastrointestinal diseases. From analysis of our study cohort, we concluded that carditis was significantly associated with H. pylori infection and active gastritis but not with symptoms or signs of gastroesophageal reflux disease. These findings suggest that carditis with histologic features similar to those of gastritis in the distal stomach was a sequel of H. pylori infection and represented a part of an H. pylori--associated gastric inflammation.

Adult↗
PubMed1997

Activation of small conductance Ca(2+)-dependent K+ channels by purinergic agonists in smooth muscle cells of the mouse ileum.

1. Whole-cell and single-channel K+ currents were recorded at room temperature (22-24 degrees C), from smooth muscle cells enzymatically dispersed from the mouse ileum, using variations of the patch-clamp technique. 2. Net outward K+ currents recorded through amphotericin-B-perforated patches in response to step depolarizations positive to -50 mV from a holding potential of -80 mV were decreased by up to 70% by external apamin (0.5 microM). Apamin-sensitive whole-cell currents were also recorded from cells perfused internally with 150 nM Ca2+ but not from cells perfused internally with 85 nM Ca2+. 3. Three types of non-inactivating Ca(2+)-sensitive K+ channels were identified in cell-attached and excised patches under an asymmetrical K+ gradient: (i) large conductance (BKCa; approximately 200 pS) channels blocked by 2 mM external TEA; (ii) intermediate conductance (IKCa; approximately 39 pS) channels blocked by 2 mM external TEA and inhibited by external apamin (0.5 microM); and (iii) small conductance (SKCa; approximately 10 pS) channels that were not blocked by 5 mM external TEA but were sensitive to extracellular apamin (0.5 microM). 4. The TEA-resistant SKCa channels were activated by an increase in [Ca2+]i with an EC50 of 1.5 microM and a Hill coefficient of 1.3. 5. P2 purinoceptor agonists 2-methylthioATP (2-MeSATP), 2-chloroATP and ATP (10-50 microM) increased an apamin-sensitive whole-cell outward K+ current. Extrapatch application of 2-MeSATP (20-100 microM) stimulated the apamin-sensitive IKCa and SKCa channels and activated an apamin-sensitive steady outward current at 0 mV. 6. Smooth muscle cells from the mouse ileum possess two apamin-sensitive K+ channels (IKCa and SKCa); of these, the IKCa channels are TEA sensitive while the SKCa channels are TEA resistant. These channels, along with an apamin-sensitive but TEA-resistant steady outward current, may mediate membrane hyperpolarization elicited by purinergic agonists.

Adenosine Triphosphate↗
PubMed1997

Effects of chronic treatment with amlodipine in streptozotocin-diabetic and spontaneously hypertensive rats.

Calcium antagonists have been reported to alter insulin secretion and insulin sensitivity. However, there still exists a controversy over the benefits of calcium antagonists in the conditions when diabetes mellitus and hypertension coexist. In the present study the effects of six-week chronic amlodipine treatment (5 mg kg-1 p.o.) on insulin sensitivity and serum lipid levels in streptozotocin (STZ)-diabetic and spontaneously hypertensive (SH) rats were investigated. Intravenous injection of STZ produced glucosuria (> 2%). hyperglycaemia, hypoinsulinemia, polydipsia, polyphagia, loss of body weight, hypercholesterolemia, hypertriglyceridaemia, hypertension and bradycardia. SH rats were found to have significantly higher insulin levels compared to their Wistar controls. Treatment of rats with amlodipine in diabetic and diabetic-hypertensive animals significantly prevented STZ-induced loss of body weight, hypertension and bradycardia. It also significantly prevented STZ-induced hyperglycaemia in both STZ-diabetic Wistar and SH rats. The insulin levels were decreased in the non-diabetic treated Wistar rats but were unaltered in the non-diabetic SH and the diabetic Wistar and SH rats. There was a significant reduction in cholesterol levels in diabetic Wistar and SH rats. In conclusion the present study revealed beneficial effects of amlodipine treatment in hyperinsulinemic, diabetic and/or hypertensive rats.

Amlodipine↗
PubMed1997

Strain differences in susceptibility to streptozotocin-induced diabetes: effects on hypertriglyceridemia and cardiomyopathy.

OBJECTIVE: Streptozotocin (STZ)-induced diabetes in Wistar rats results in severe hyperlipidemia and a characteristic cardiomyopathy. However, Wistar-Kyoto (WKY) rats made diabetic with a similar dose of STZ did not develop heart dysfunction or hypertriglyceridemia at 12 weeks post-STZ. We investigated whether an apparent resistance of the WKY strain to develop diabetic cardiomyopathy and hypertriglyceridemia following chronic diabetes could be due to a reduced susceptibility to the diabetogenic effects of STZ. METHODS: Adult male WKY and Wistar rats were made diabetic with a moderate (55 mg/kg) or high (75 mg/kg) dose of STZ. At 6 weeks of diabetes, glucose tolerance, cardiac function, pancreatic insulin content and basal and post-heparin plasma lipolytic activity were determined. RESULTS: Administration of a moderate dose of STZ produced cardiac dysfunction in Wistar but not WKY rats at 6 weeks after diabetes induction. The same dose of STZ in WKY rats also resulted in a lesser degree of hyperglycemia and glucose intolerance, and significantly higher pancreatic insulin content relative to Wistar rats. Following a high dose of STZ, the apparent resistance to developing cardiomyopathy was lost in the WKY rats. As well, the WKY rats demonstrated an equal degree of hyperglycemia and glucose intolerance as Wistar rats. However, unlike the Wistar strain, WKY rats did not demonstrate either hypertriglyceridemia or a reduced heparin-releasable plasma lipoprotein lipase (LPL) activity following a high dose of STZ. CONCLUSIONS: These results suggest that the incidence of diabetes-related cardiomyopathy and hypertriglyceridemia in rats may be independently influenced by strain-dependent susceptibilities to the beta-cytotoxic effects of STZ. The absence of hypertriglyceridemia in severely diabetic WKY rats may be linked to the maintenance of a critical level of plasma LPL activity.

Animals↗
PubMed1997

Value of cytology in detecting intestinal metaplasia and associated dysplasia at the gastroesophageal junction.

Tissue sampling is essential for detecting intestinal metaplasia in the distal esophagus (Barrett's esophagus), because symptoms and endoscopy are not reliable in making this diagnosis. The utility of cytology in this process is unknown. All adult patients having elective upper gastrointestinal endoscopy over a 6-month period were invited to participate in a prospective study whose aim was to determine the prevalence of intestinal metaplasia in the distal esophagus in an adult population with diverse upper gastrointestinal symptoms. Clinical data and endoscopic findings were recorded. Brush cytology and biopsy specimens were obtained from both sides of the apparent squamocolumnar junction. The cytology specimens were processed routinely, stained with the Papanicolaou technique, and reviewed blinded to the clinical information and the histological findings in the corresponding biopsy specimens. One hundred fifty-five patients (81 women, 74 men; 137 whites, 11 blacks, 7 others; mean age, 52 years) were included. Glandular epithelium/cells were present on both histology and cytology in 147 specimens. Thirty-two patients (22%) showed intestinal metaplasia on histology. Of the cytology specimens from these 32 patients, 6 contained definite goblet cells (19%), 7 probable goblet cells, and 19 no goblet cells. Goblet cells and probable goblet cells were observed on cytology in 7 and 11 additional specimens, respectively. One was from a patient known to have intestinal metaplasia in the esophagus. Follow-up endoscopy with biopsy was performed in two of these latter 18 patients and did not show intestinal metaplasia. One case of high-grade dysplasia, two of low-grade dysplasia, and three indefinite for dysplasia were diagnosed on histology. All three cases of dysplasia were also identified on cytology. The three indefinite cases on histology were considered reactive in two and unremarkable in one on cytology. Low-grade dysplasia was diagnosed on cytology alone on two cases. Follow-up endoscopy with biopsy was performed in one patient, and low-grade dysplasia was found. Cytology using the Papanicolaou stain is not as sensitive and specific as histology for detecting intestinal metaplasia in the distal esophagus. However, it may be at least as useful as tissue sampling in detecting dysplasia.

Adult↗
PubMed1997

Beneficial effects of clonidine in streptozotocin-induced diabetes and DOCA-hypertensive rats.

This investigation was undertaken to study the effects of chronic treatment with clonidine on cardiovascular complications in streptozotocin-induced diabetes and DOCA-hypertensive rats. Injection of streptozotocin induced glucosuria, hyperglycaemia, hypoinsulinaemia, hypothyroidism, hypercholesterolaemia, hypertriglyceridaemia, bradycardia and a decrease in left ventricular developed pressure (LVDP). DOCA by itself did not induce any change in blood-glucose levels in non-diabetic animals. However, in diabetic animals DOCA significantly reduced blood-glucose levels. Treatment of diabetic and diabetic hypertensive animals with clonidine (25 micrograms kg-1 every day for six weeks) significantly prevented diabetes-induced loss of body weight, bradycardia, cardiac hypertrophy and hypothyroidism. It also partially, but significantly, prevented diabetes-induced hyperglycaemia and hypoinsulinaemia in both diabetic and diabetic-hypertensive animals. There was a significant reduction in diabetes-induced elevation of cholesterol and triglyceride levels and an improvement in LVDP at higher filling pressure in diabetic and diabetic hypertensive animals. This investigation shows that chronic treatment with clonidine produces a number of beneficial effects such as prevention of hyperlipidaemia and hypothyroidism and improvement in cardiomyopathy and glycaemic control in diabetic and diabetic hypertensive rats.

Adrenergic alpha-Agonists↗
PubMed1997

Evidence for alpha 2-adrenoceptor agonist activity of minoxidil.

The present investigation was undertaken to study the mechanism of action of minoxidil using various smooth muscle preparations. Minoxidil (4.7 x 10(-6) M to 4.7 x 10(-4) M) produced a concentration-dependent inhibition of field stimulation-evoked responses in rat anococcygeus muscle and vas deferens. The inhibition produced by minoxidil was antagonized by yohimbine (2.5 x 10(-7) M). Minoxidil (1.4 x 10(-5) M to 4.7 x 10(-4) M) also produced a concentration-dependent relaxation in oestrogen-primed potassium chloride-depolarized rat uterus. These responses were blocked not only by yohimbine but also by glibenclamide (2.02 x 10(-8) M). Our results suggest that minoxidil possesses alpha 2-adrenoceptor agonist activity in addition to potassium-channel-opening activity.

Adrenergic alpha-Agonists↗
PubMed1997

Tyrosine phosphorylation in contraction of opossum esophageal longitudinal muscle in response to SNP.

Sodium nitroprusside (SNP) has been shown to elicit a guanosine 3',5'-cyclic monophosphate (cGMP)-mediated, indomethacin-sensitive contraction of the opossum esophageal longitudinal muscle. We examined the role of tyrosine phosphorylation in the signal transduction pathway of contractions induced by SNP and cGMP in longitudinal muscle strips in vitro. Force of isometric contractions was expressed as the percentage of responses to KCl (73 mM). SNP (100 microM)-induced contractions were 75 +/- 5% before and 3 +/- 2% after 50 microM genistein (P < 0.005) and 86 +/- 16% before and 0 +/- 0% after 50 microM tyrphostin B46. Contractions in response to 8-bromo-cGMP (8-BrcGMP; 1 mM) were 74 +/- 15% before and 3 +/- 2% after genistein (P < 0.01) and 63 +/- 15% before and 18 +/- 4% after tyrphostin B46 (P < 0.05). In contrast, KCl-induced contractions were 82 +/- 8% and 96 +/- 9% of the control value after genistein and tyrphostin B46 treatments, respectively (P > 0.05 for both). Carbachol contractions were partially suppressed by genistein (106 +/- 8% vs. 79 +/- 8%; P < 0.05) but unaffected by tyrphostin B46 (114 +/- 10% vs. 107 +/- 12%; P > 0.05). Western blot analysis revealed a 116-kDa phosphotyrosine protein in the control muscle strips. The level of this protein was increased to 206 +/- 15% of control after SNP treatment. Both genistein and tyrphostin B46 blocked this increase. These studies show that contractions of the esophageal longitudinal muscle induced by SNP and cGMP utilize a signal transduction pathway different from that used by the depolarizing agent KCl and the muscarinic agonist carbachol. Contractions induced by SNP and cGMP involve tyrosine phosphorylation of a protein, possibly identified as a 116-kDa protein, as a key step in the signaling pathway.

Animals↗
PubMed1997

Pathogenesis of peptic ulcer disease and current trends in therapy.

Traditionally drugs used in peptic ulcer have been directed mainly against a single luminal damaging agent i.e. hydrochloric acid and a plethora of drugs like antacids, anticholinergics, histamine H2-antagonists etc. have flooded the market. An increase in 'aggressive' factors like acid and pepsin is found only in a minority of peptic ulcer patients. These factors do not alter during or after spontaneous healing. It is well-known that the gastric mucosa can resist auto-digestion though it is exposed to numerous 'insults' like high concentration of hydrochloric acid, pepsin, reflux of bile, spicy food, microorganisms and at times alcohol and irritant drugs. It is thus evident that the integrity of the gastric mucosa is maintained by defense mechanisms against these 'aggressive' damaging factors. Recently, attention has been focused more on gastroduodenal defense mechanisms leading to the concept of 'Cytoprotection'. The old dictum "no acid--no ulcer" now extends to "if acid--why ulcer"? as a fundamental question. During last decade more information has poured in about the prevalence and changing pattern of the disease, the influence of environmental factors and speculation on the role of a recently characterized bacterial organism, Helicobacter pylori which colonizes in the gastric mucosa, particularly the antral region. This review briefly describes current knowledge about the pathogenesis of peptic ulcer disease and discusses strategies for its treatment.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Effects of chronic ramipril treatment in streptozotocin-induced diabetic rats.

The present investigation was undertaken to study the effects of chronic oral ramipril (1 mg/kg) treatment in streptozotocin (STZ) induced diabetic rats. Single tail vein injection of STZ (45 mg/kg, i.v.) produced a diabetic state exhibiting all the cardinal symptoms such as loss of body weight, polydipsia, polyuria, glucosuria, polyphagia, hypoinsulinaemia and hyperglycaemia. The diabetic state was also found to be associated with bradycardia, hypothyroidism, cardiac depression and cardiomyopathy. Ramipril treatment prevented STZ-induced hypertension, bradycardia, hypothyroidism, hyperchosesterolaemia and partially the cardiomayopathy. Ramipril treatment could not, however prevent STZ-induced loss of body weight, polyuria, polydipsia, polyphagia, hyperglycaemia, hypoinsulinaemia, hypertriglyceridaemia and cardiac depression. Our data suggests that ramipril has a few beneficial effects in the STZ-treated diabetic rats.

Animals↗
PubMed1997

Mechanism of the antihyperlipaemic activity and pharmacokinetics of 2-chloromethyl-5,6,7,8-tetrahydrobenzo(b)thieno[2,3-d]pyrimidin-4(3H)-o ne.

The pharmacokinetics and the mechanism of action of the antihyperlipaemic compound 2-chloromethyl-5,6,7,8-tetrahydrobenzo(b)thieno[2,3-d]pyrimidin-4(3H)-on e (CAS 89587-03-3, LM-1554) have been studied. Serum concentrations were determined by reverse phase HPLC using methanol : water (60 : 40) as the solvent system. The results of pharmacokinetic studies suggest that the compound LM-1554 is poorly absorbed from the gastrointestinal tract after the oral administration in dogs and rabbits. The volume of distribution (Vd) was found to be low. The poor bioavailability (3-4%) and low volume of distribution of the compound LM-1554 suggest the gastrointestinal tract as the site of action for the antihyperlipaemic activity. This hypothesis is substantiated by the observations that the compound was found active in rabbits only when administered orally and found inactive by the parenteral route. Further, the cholesterol levels were found to increase in blood samples collected from the portal vein after oral administration of cholesterol in coconut oil to rats. This increase was found to be prevented by the compound LM-1554. In conclusion, the compound LM-1554 has a potential to be developed as an antihyperlipaemic agent. The mechanism of action of the compound LM-1554 appears to consist in the inhibition of cholesterol absorption in the gastrointestinal tract.

Administration, Oral↗