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We have studied the effect spironolactone (20 mg/kg/day) on cardiovascular complications in neonatal model of diabetes in rats, induced by administering 90 mg/kg streptozotocin (STZ), i.p. in 2 day old rats. Diabetes was checked after 12 weeks. At the end of 8 weeks of treatment, various biochemical and cardiac parameters were measured. STZ produced hyperglycemia, hyperinsulinemia, dyslipidemia, increased creatinine, cardiac enzyme and C-reactive protein (CRP) levels, worsened hemodynamic parameters, cardiac hypertrophy and oxidative stress. Chronic treatment with spironolactone significantly reduced serum glucose levels but did not alter insulin levels. It also significantly prevented the dyslipidemia and reduced elevated Lactate de-hydrogenase, creatinine kinase, CRP and creatinine levels. Chronic treatment with spironolactone prevented STZ-induced hypertension, tachycardia and elevated rate of pressure development and decay. Spironolactone also produced beneficial effect by preventing cardiac hypertrophy as evident from left ventricular collagen levels, cardiac and left ventricular hypertrophic indices and prevented oxidative stress. In conclusion, our data suggests that spironolactone prevents STZ induced metabolic abnormalities and cardiovascular complications in animal model of type 2 diabetes.

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Several experimental, pathological, epidemiological, and clinical studies have clearly depicted that diabetes mellitus results in cardiac functional and structural changes. Diabetic cardiomyopathy results in both structural and functional alterations in the myocardium. Several mechanisms have been implicated in the pathophysiology of diabetic cardiomyopathy. Of these, metabolic disturbances, myocardial fibrosis, small vessel disease, and cardiac autonomic neuropathy are the major players in the pathophysiology of diabetic cardiomyopathy. This review is intended to discuss various such pathophysiological mechanisms of diabetic cardiomyopathy. We have also described the systolic and diastolic dysfunctioning and its corelation to structural changes in diabetes.

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Currently, statins are in lime light due to their pleiotropic effects. One of their pleiotropic effects is on glucose metabolism. Various clinical and preclinical studies were designed to evaluate statins' effect on glucose metabolism. This review describes preclinical and clinical evidences of statins' action on glucose metabolism.

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Effect of chronic treatment with Bis(maltolato)oxovanadium (IV) (BMOV) was studied in streptozotocin (STZ)-induced neonatal non-insulin-dependent-diabetic (NIDDM) rats. Intraperitoneal injection of STZ (90 mg kg(-1)) in Wistar rat pups (day 2 old) produced mild hyperglycemia, impaired glucose tolerance and insulin resistance at the age of 3 months. Treatment with BMOV (0.23 mM kg(-1)) in drinking water for 6 weeks produced a significant decrease in elevated serum glucose levels without any significant change in serum insulin levels in diabetic rats. BMOV treatment significantly decreased integrated area under the glucose curve without any significant change in integrated area under the insulin curve indicating improved glucose tolerance. Treatment also significantly increased K(ITT) value of diabetic rats indicating increased insulin sensitivity. BMOV treatment significantly reduced hypercholesterolemia in diabetic rats. Treatment also significantly decreased serum triglyceride levels in both diabetic and non-diabetic rats. The data suggest that chronic BMOV treatment improves glucose and lipid homeostasis. These effects appear to be due to the insulin sensitizing action of vanadium.

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Recognition of Nitric oxide (NO) as the chemical entity of endothelium-derived relaxing factor (EDRF) has renewed the interest of the scientific community in the last decade. The outcome of research the world over is that the dreaded environmental pollutant is found to be a fundamental physiological mediator and effector. NO is synthesized endogenously by enzymes nitric oxide synthase (NOS) in specialized tissues from its precursor L-arginine. The L-arginine-NO biosynthetic pathway is involved in physiological processes such as vasodilation, memory, neuroprotection, peristalsis, penile erection, immune defense, various endocrine and exocrine secretions in various systems such as cardiovascular, CNS, reproductive and immune system. Small quantities of NO produced by constitutive enzymes mediate these physiological effects. The expression of inducible enzyme or overstimulation of constitutive enzymes leading to production of large quantities of NO is implicated in the cytotoxic effects observed in various disorders like AIDS, cancer, Alzheimer's, arthritis etc. In conclusion, NO is a 'double edged sword' and the challenge before the scientific community is to develop strategies for using it to our advantage.

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We have studied the effects of various angiotensin-converting enzyme (ACE) inhibitors on intraocular pressure (IOP) of rabbits with experimentally induced ocular hypertension and their mechanism of action. Acute ocular hypertension was induced by infusion of 5% glucose (15 ml/kg) through marginal ear vein, whereas chronic glaucoma was induced by injection of alpha-chymotrypsin into the posterior chamber of the eye. IOP was measured by tonometer. All ACE inhibitors were instilled topically in the eye in a sterile solution. The effect of ACE inhibitors also was studied on serum cholinesterase (true and pseudo) and the enzyme ACE in vitro. Enalaprilat, ramiprilat, and fosinopril produced a time-dependent decrease of IOP in both acute and chronic models of ocular hypertension in rabbits. The decrease in IOP was observed for >4 h, and the extent of decrease was comparable to that with both pilocarpine and betaxolol. Prodrugs enalapril and ramipril failed to produced any change in IOP. Losartan also produced a significant decrease in IOP in the chronic model of ocular hypertension in rabbits. All the three ACE inhibitors were found to inhibit ACE activity in aqueous humor. The enzyme cholinesterase was found to be inhibited by enalaprilat, ramiprilat, and fosinopril. However, atropine did not alter the IOP-lowering effect of enalaprilat in rabbits. Indomethacin pretreatment produced slight but significant inhibition of the IOP-lowering effect of enalaprilat in rabbits. Our data suggest that ACE inhibitors enalaprilat, ramiprilat, and fosinopril produce a significant ocular hypotensive effect in acute and chronic models of ocular hypertension in rabbits. Inhibition of ACE in aqueous humor, and in ocular tissues, resulting in reduced angiotensin II formation, could be one of the major mechanisms responsible for the IOP reduction by ACE inhibitors in rabbits.

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Hypertension and diabetes mellitus are associated with hyperinsulinemia and insulin resistance. The present work was undertaken to study the effects of enalapril and nifedipine on insulin sensitivity in spontaneously hypertensive (SH) rats and diabetic rats. Insulin sensitivity was measured by insulin tolerance test using K(ITT) as an index of insulin mediated glucose metabolism. The time to produce 50% fall in initial blood sugar level (T1/2) was significantly higher in non-insulin dependent diabetes mellitus (NIDDM) and SH rats as compared to Wistar control. The mean K(ITT) values were significantly lower in NIDDM and SH rats as compared to Wistar control. Treatment with nifedipine (10 mg/kg) and enalapril (5 mg/kg) for 15 days produced a significant reduction in T1/2. Further, K(ITT) value was found to be significantly increased in SH rats treated with nifedipine or enalapril as compared to control. Our data indicate that NIDDM and SH rats are not only hyperinsulinemic but also insulin resistant. Nifedipine and enalapril treatment produced increase in insulin sensitivity in these animals.

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Our objectives were to determine the accuracy of antenatal sonography for the detection of congenital renal malformations and to characterize the type of malformations, seen in a 3-year prospective study at a university-affiliated maternity hospital. Participants were 31,217 pregnant women, during the study period, and subjects were 65 fetuses in whom renal malformations were detected on antenatal ultrasound. Pelvic ultrasound scans were performed at least once between 20 and 37 weeks' gestation on all pregnant women attending the antenatal clinic of the hospital for the detection of renal malformations. Fetal urinary sampling, diversion procedures, or termination of pregnancy were carried out as required in those detected to have renal anomalies. Postnatal diagnosis was confirmed by sonography or autopsy. Diagnostic procedures and renal surgery were performed postnatally if indicated. Sixty-five fetuses (0.2 per cent) were diagnosed to have congenital renal malformation antenatally at a mean gestational age of 28.4 weeks. A dilated urinary system was seen in 39, cystic renal disease in 15, agenesis/hypoplasia in six, combined lesions in four, and a horseshoe kidney in one. Oligohydramnios was noted in 20 (31 per cent) pregnancies. Multiple congenital malformations associated with renal anomalies were detected in 12 pregnancies. Termination was carried out at 20 weeks in two pregnancies for lethal malformations; fetal urinary sampling was done in two fetuses with obstructed uropathy, and a vesicoamniotic shunt inserted in one. Postnatal ultrasound confirmed a dilated urinary system in 32, cystic renal dysplasia in 15, renal aplasia/hypoplasia in five, combined lesions in six, and a horseshoe and an ectopic kidney in one each. Five infants were found to be normal. There were seven stillbirths and seven neonatal deaths. Radionuclide scans showed obstruction in nine, decreased renal function in six, and absent renal functions in 10 infants. Micturating cystourethrography demonstrated reflux in 11 and a non-refluxing non-obstructive dilated renal system in five babies. Renal surgery was performed in nine infants. The conclusions drawn from this study were that antenatal detection of renal disease is fairly accurate, even in an extremely busy hospital and certain types of malformations reported in other studies were not observed, despite a large cohort.

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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.

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The present investigation was undertaken to study the effects of K+ channel openers in the relaxant responses to various agonists in estrogen primed rat uterus. Adrenaline and isoprenaline produced a dose-dependent relaxation in the estrogen primed rat uterus. The relaxant responses were found to be significantly potentiated when the preparations were exposed to PSS devoid of calcium. The responses to isoprenaline were found to be greater in the preparations depolarized with 40 mM KCl instead of 80 mM KCl. KCl failed to produce any contractile effect in the presence of D-600. Further, the addition of D-600 completely relaxed the KCl depolarized rat uterus. Pinacidil and cromakalim failed to relax 80 mM KCl depolarized rat uterus. However, they produced dose-dependent relaxation in the preparations depolarized with 40 mM KCl. The relaxant responses to pinacidil and cromakalim were competitively blocked by procaine. However, they were not altered by either propranolol or cimetidine. The relaxant responses to isoprenaline and histamine were found to be potentiated by pinacidil and cromakalim. These results indicate that in rat uterus in addition to adenylate cyclase c-AMP, potassium channels are also involved in the relaxant responses to isoprenaline and histamine.

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The present investigation was undertaken to study the interaction of fluoxetine with 5-hydroxytryptamine (5-HT) and noradrenaline (NA) in rat anococcygeus muscle and vas-deferens. In rat anococcygeus muscle responses to NA were significantly potentiated after 30 min and 60 min incubation with fluoxetine (2.9 x 10(-9) M). The responses to 5-HT were however, inhibited after 30 min incubation with fluoxetine in this preparation. On rat vas-deferens also, the responses to NA were potentiated after 30 min incubation with fluoxetine. The response to 5-HT were not altered significantly. In rats pretreated with fluoxetine (5 mg/kg, ip) for seven days, the responses to NA were significantly potentiated in rat anococcygeus muscle. Whereas the responses to 5-HT and tyramine were significantly inhibited. The inhibited responses to 5-HT restored back to normal when the anococcygeus muscle was pre-incubated with NA for 30 min.

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The present study was undertaken to investigate the autoinhibition and desensitization of 5-hydroxytryptamine (5-HT) using another agonist MK-212 on guinea pig ileum. 5-HT and MK-212 produced dose dependent contractions of guinea pig ileum. The responses to MK-212 were reduced in the presence of 5-HT and vice versa. Neither 5-HT nor MK-212 produced any change in the responses to histamine, acetylcholine or KCl. Increase in Ca++ in bathing fluid reversed the desensitization produced by MK-212 or 5-HT. Our data suggest that 5-HT and MK-212 produce desensitization which is specific for serotonergic receptors and possibly involves Ca++ ions.

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