Metformin vs insulin in the management of gestational diabetes: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness of metformin compared with insulin in achieving glycemic control and investigate the maternal and neonatal outcomes in gestational diabetes mellitus. METHODS: We searched four electronic databases from inception through December 2012. Terms for Gestational diabetes/gestational diabetes mellitus/diabetes pregnancy AND/OR Metformin/hypoglycemic drugs/Hypoglycemic Agents/Antidiabetic Medications were used in the search. Two investigators independently reviewed titles and abstracts, performed data abstraction on full articles, and assessed study quality. Meanwhile, manual search of other resources and the search on Google Scholar were also carried out to identify more related articles .Rev Man 5.0 was used to analyze the data. RESULTS: Six randomized clinical trials involving 1420 subjects were included. The current limited data suggested that using metformin in gestational diabetes subjects did not significantly increase adverse maternal outcomes and neonatal outcomes, also with less weight gain and neonatal hypoglycemia, but a higher incidence of premature birth. CONCLUSIONS: Metformin will not increase the incidence of adverse maternal outcomes and neonatal outcomes.

Resveratrol, an activator of SIRT1, upregulates AMPK and improves cardiac function in heart failure.

Reduced AMP-activated protein kinase (AMPK) expression has been shown to play a significant role in the cardiac dysfunction in heart failure. This study was designed to examine the effect of resveratrol, a potent activator of silent information regulator (SIRT1), on cardiac function and AMPK expression in heart failure. Adult male rat left anterior descending arteries were ligated, and they were fed with either a regular diet or a diet enriched with resveratrol. Heart failure was produced by myocardial infarction, and was associated with markedly increased AMPK and SIRT1 protein levels. Resveratrol treatment had a tremendous beneficial effect, both in terms of improving AMPK expression and on cardiac function. Decreased cardiac function and AMPK expression were also found in SIRT1 knockout (+/-) mice. In cultured cardiomyocytes, resveratrol increased AMPK and SIRT1 expressions, and overexpression of SIRT1 was found to be sufficient to activate AMPK in H9c2 cells. In contrast, pretreatment of cardiomyocytes with an SIRT1 antagonist, nicotinamide, blocked these beneficial effects of resveratrol. Therefore, the protective effects of resveratrol were found to be dependent on its ability to activate SIRT1 and improve AMPK expression. These results demonstrated that in heart failure, the enzymatic activity of cardiac SIRT1 is increased, which contributes to increased expression of AMPK, and resveratrol enhances the expression of AMPK and improves cardiac function through the activation of SIRT1.

Blood pressure variability is increased in genetic hypertension and L-NAME -induced hypertension.

AIM: To examine whether the blood pressure variability (BPV) is increased in spontaneously hypertensive rats (SHR) and L-NAME-induced hypertensive rats (NHR). METHODS: BPV was recorded with continuous hemodynamic monitoring in conscious un restrained rats. Time course of L-NAME-induced hypertension was measured by the tail-cuff method. Plasma NO concentration was determined by the method of nitric acid reductase. RESULTS: In both SHR and NHR, systolic and diastolic BPV were significantly increased when compared with their respective controls. In S HR, in crease in diastolic BPV was predominant, whereas in NHR, increase in systolic BP V was predominant. Moreover, increase in systolic BPV in NHR (102 %) was obviously higher than that in SHR (28 %). Chronic administration of L-NAME 1 g/L in drink ing water caused a progressive increase in arterial blood pressure in rats. All rats were hypertensive at 4 weeks after treatment. Plasma NO level was decreased in NHR. CONCLUSION: Increased BPV is a general phenomenon in hypertension. NO is involved in the regulation of BPV.

Reduction of cardiac norepinephrine improves postischemic heart function in stroke-prone spontaneously hypertensive rats.

Although mammalian ventricle is richly supplied with adrenergic nerves, endogenous norepinephrine is not essential to the intrinsic contractility of the normal heart. However, it is not clear whether acute changes in cardiac norepinephrine could alter heart function in genetically hypertensive rats. The purpose of this study was to examine the effect of cardiac norepinephrine reduction on basal and postischemic heart function in stroke-prone spontaneously hypertensive rats (SHRSPs) using an isolated working heart preparation. Hypertrophied hearts of SHRSPs showed higher cardiac norepinephrine content and impaired heart function at 4 months of age as compared with normal Wistar-Kyoto rats. Poor postischemic recovery of heart function observed in SHRSPs was accompanied by large amounts of coronary norepinephrine overflow. Cardiac norepinephrine reduction or depletion did not affect basal heart function in SHRSPs. Considerable reduction in cardiac norepinephrine with acute reserpine injection (5 mg/kg) in SHRSPs significantly improved postischemic recovery of cardiac output, coronary flow, and rate-pressure product. However, complete norepinephrine depletion with reserpine (10 mg/kg) was detrimental to myocardial automaticity and limited the postischemic recovery of systolic function in the hypertrophied hearts. These results suggest that acute reduction in cardiac norepinephrine may be of potential therapeutic importance to postischemic dysfunction in the hypertrophied hearts.

Blood pressure variability and organ damage.

1. Blood pressure variability (BPV) is expressed as the standard deviation of the average blood pressure (BP). Blood pressure variability is increased in hypertensive patients and animals. However, BPV is not necessarily related to the BP level. 2. For nearly any level of 24 h mean BP, hypertensive patients in whom the BPV is low have a lower prevalence and severity of organ damage than patients in whom the 24 h BPV is high. This observation has been confirmed further in spontaneously hypertensive rats with direct pathological analysis for organ damage. 3. In sinoaortic-denervated (SAD) rats, 24 h average BP is normal and BPV is markedly increased. Myocardial damage, renal lesions and vascular remodelling are seen in these animals 4 weeks after SAD. 4. Haemodynamic effects and activation of the renin- angiotensin system are hypothesized to contribute to organ damage induced by increased BPV. 5. Blood pressure variability is of potential importance in antihypertensive therapy.

Effects of six antihypertensive drugs on blood pressure and hypothalamic GABA content in spontaneously hypertensive rats.

In order to investigate the effects of antihypertensive drugs on blood pressure and gamma-amino butyric acid (GABA) content in the hypothalamus and the possible relationship between blood pressure decrease and GABA content changes, blood pressure and GABA contents after chronic (20 weeks) treatments of nitrendipine, atenolol, captopril, hydrochlorothiazide, dihydralazine and prazosin were studied in spontaneously-hypertensive rats (SHR). The acute and subacute (1 week) effects of nitrendipine on GABA contents was also observed in SHR. It was found that 20 week treatments with six different antihypertensive agents produced a decrease in systolic blood pressure and an increase in GABA content. The blood pressure level was significantly correlated with GABA content in the hypothalamus, but not with that in the cortex. Acute treatment with a single dose of nitrendipine, did not alter GABA content. Bicuculline, a GABA receptor antagonist, did not attenuate the hypotensive effect of nitrendipine. In conclusion, chronic treatments by different antihypertensive agents produced an increase of hypothalamic GABA content and a decrease of blood pressure. The increase of GABA content induced by nitrendipine seems likely to be secondary to blood pressure decrease.

Arterial baroreflex deficit induced organ damage in sinoaortic denervated rats.

To verify the independent role of the arterial baroreceptor dysfunction involved in target-organ damage in hypertension, sinoaortic denervated (SAD) rats were used as a model of arterial baroreflex (ABR) deficit. SAD, isolated aortic-denervated (AD), and isolated sinus-denervated (SD) rats were instrumented to record blood pressure (BP), heart rate (HR), BP variability (BPV), HR variability (HRV), ABR function control of heart period (ABR-HP), and BP (ABR-BP). Vascular maximum contractile/relaxant function was determined and organ damage was estimated by observation of morphologic changes. Short-term (postoperative 1 week) SAD caused hypertension and tachycardia in rats. Eighteen weeks after operation, BP and HR values in SAD and SD rats were not different from those in sham-operated rats, but AD rats were hypertensive compared with control group. Although 24-h mean BP values of long-term SAD rats were not different from those of sham-operated rats, 24-h BPV of SAD rats was significantly higher than that of sham-operated rats. Arterial baroreflex function in short-term SAD rats was significantly less than in sham-operated rats, whereas in long-term SAD rats, ABR-HP and ABR-BP were higher than those in short-term SAD rats, but were still significantly lower than those in control groups. At postoperative 18 weeks, baroreflex function in SAD and AD rats was significantly less than function in SD and control groups. SBPmax after phenylephrine and DBPmin after nitroprusside were significantly higher in SAD, AD, and SD rats than in control rats. Baroreflex function was negatively correlated to DBPmin and SBPmax in all denervated rats (n = 44). Some morphologic changes were found 18 weeks after denervation in heart, kidney, and small artery in SAD, AD, and SD rats. Baroreflex function in all denervated rats was negatively related to 24-h BPV values. In contrast, 24-h BPV values in SAD, AD, and SD rats were positively related to organ-damage score. A negative correlation between ABR function and end-organ damage score was found. Arterial baroreflex deficit played an independent and important role in organ-damage in SAD rats with significantly elevated 24-h BPV.

Arterial remodeling in chronic sinoaortic-denervated rats.

The spontaneous variation of blood pressure is defined as "blood pressure variability" (BPV). The chronic sinoaortic-denervated (SAD) rat is a model of high BPV without sustained hypertension. Little is known about vascular remodeling in this model. In the present study, we examined blood pressure, vascular remodeling, and aortic angiotensin II concentration in chronic SAD rats in separate experiments. In experiment 1, intra-arterial blood pressure was continuously recorded in conscious unrestrained rats. The 16-week SAD rats had a significant increase in BPV and no change in the mean level of blood pressure over a 24-h period. In experiment 2, we measured structural changes of seven kinds of arteries by histologic method and computer image analysis and functional changes of thoracic aortas by isolated artery preparation. Structural remodeling after 16-week sinoaortic denervation was characterized by increase in wall thickness, wall area, and ratio of wall thickness to internal diameter, with different changes in internal diameter and external diameter in different arteries, indicating that arterial structural remodeling expresses itself mainly as vascular growth. This vascular growth might be caused by medial smooth muscle cell growth and collagen accumulation. Aortic contraction induced by norepinephrine was potentiated, whereas aortic relaxation induced by acetylcholine was attenuated after sinoaortic denervation. In experiment 3, plasma and aortic angiotensin II concentrations were determined by radioimmunoassay. The former remained unchanged, whereas the latter was significantly increased in 10-week SAD rats. It is concluded that in rats chronic sinoaortic denervation can produce vascular remodeling that might be related to increased BPV and an activated tissue renin-angiotensin system.

The effect of adenosine on blood pressure variability in sinoaortic denervated rats is mediated by adenosine A2a-Receptor.

It is known that adenosine decreases blood pressure (BP) level as well as blood pressure variability (BPV). However, there is little information about the effect of adenosine on BPV. With a computerized analytic system for BP and heart rate (HR) that could sample the data continuously in conscious, freely moving rats, we studied the effects of different agonists and antagonists of adenosine receptors on BPV in sinoaortic denervated (SAD) rats. It was found that both adenosine and 5'-N-cyclopropyl-carboxamidoadenosine (CPCA, a selective adenosine A,-receptor agonist) decreased BPV. whereas N6-cyclopentyladenosine (CPA, a selective adenosine A1-receptor agonist) had no significant effect on BPV. When the rats were pretreated with theophylline (the nonselective adenosine-receptor antagonist), the inhibitory effects of adenosine as well as CPCA on BPV were abolished. Furthermore, it was found that 8-(3-chlorostyryl)caffeine (CSC, a selective adenosine A2a-receptor antagonist), also could prevent such an effect on BPV of CPCA. By itself, however, neither theophylline nor CSC had any influence on BPV. These results suggest that the effect of adenosine on BPV is mediated by adenosine A2a-receptor.

Relationship between baroreceptor reflex function and end-organ damage in spontaneously hypertensive rats.

The purpose of this study was to further illustrate the relationship between baroreceptor reflex sensitivity (BRS) and hypertensive end-organ damage (EOD) and to test the hypothesis that impairment of BRS aggravates EOD in hypertension. We studied baroreflex-mediated changes in heart rate [expressed as baroreceptor sensitivity to heart rate control (BRS(HR))] and blood pressure [expressed as baroreceptor sensitivity to blood pressure control (BRS(BP))] in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) that were used as controls, both at the age of 50-52 wk. Rats were also instrumented to record BP, HR, and BP variability (BPV) in the conscious, unrestrained state. In SHR compared with WKY, BP and BPV were significantly increased, whereas BRS(HR) and BRS(BP) were significantly decreased. SHR had remarkable EOD when compared with WKY (EOD score: 6.3 +/- 2.5 vs. 2.9 +/- 0.8, P < 0.01). Univariate regressive analysis demonstrated that EOD score was increased with BP and BPV and decreased with BRS. In multivariate analysis, EOD score was predicted by greater systolic BP and lower BRS and HR variability. These results indicate that BRS is negatively related to BPV and EOD score, and impaired BRS might be one of the major causes for hypertensive EOD.

Hemodynamic responses to endothelin-1 and endothelin antagonists microinjected into the nucleus tractus solitarius in rats.

The role of endothelin-1 (ET-1) within the nucleus tractus solitarius (NTS) in central cardiovascular control was investigated by local microinjections of ET-1 and ET-receptor antagonists. In urethane-anesthetized Sprague-Dawley rats, a unilateral microinjection of ET-1 (1.0, 3.3, and 10.0 pmol) into the NTS significantly increased arterial pressure, left ventricular systolic pressure, and dP/dt(max) in a dose-dependent manner, and slightly decreased heart rate in a dose-independent manner. The pressor effect lasted >90 min. In normotensive rats, neither PD147953, a selective ETA-receptor antagonist, nor PD142893, a mixed ETA- and ETB-receptor antagonist, microinjected into the NTS elicited any changes in arterial pressure or heart rate. The pressor and bradycardic effects evoked by microinjection of ET-1 into the NTS could be blocked by local pretreatment with PD147953 and completely eliminated by intravenous pretreatment with the ganglionic blocker hexamethonium. The arterial baroreflex sensitivity was almost totally suppressed by microinjection of ET-1 (3.3 pmol) in alpha-chloralose-anesthetized Sprague-Dawley rats. A similar pattern of changes in the hemodynamic variables was elicited by microinjection of ET-1 (3.3 pmol) into the NTS in spontaneously hypertensive rats (SHRs) compared with Wistar-Kyoto (WKY) rats. In SHRs, microinjection of PD142893 did not elicit any changes in arterial pressure or heart rate. These results suggest that ET-1 modulates reflex control of hemodynamics by activation of autonomic nerve via ETA receptors in the NTS, and that the responsiveness of SHRs to ET-1 or PD142893 is similar to that of WKY rats.

Protective effects of silybin and tetrandrine on the outcome of spontaneously hypertensive rats subjected to acute coronary artery occlusion.

The effects of silybin and tetrandrine on the survival of spontaneously hypertensive rats subjected to acute coronary artery occlusion were investigated. The mortality after acute coronary occlusion in spontaneously hypertensive rats (66.7%) was higher than that of control Wistar-Kyoto rats (20%, P < 0.05). Oral administration of silybin (300 mg/kg daily) for 8-12 days reduced mortality in spontaneously hypertensive rats (0, P < 0.01 in comparison with untreated spontaneously hypertensive rats). Administration of tetrandrine 40 mg/kg daily for 8-12 days reduced the mortality to some extent (22.2%, P = 0.051, as compared with control rats). Silybin reduced blood pressure and the incidence of post-occlusion arrhythmias in spontaneously hypertensive rats to the same extent as tetrandrine. Both silybin and tetrandrine decreased the severity of ventricular hypertrophy. Although there were significant decreases in risk zone and infarct zone in silybin- and tetrandrine-treated rats, the ratio of infarct to risk zone was not changed. The results implies that silybin may be beneficial when used in hypertensive patients who develop acute myocardial infarction.

Arterial baroreflex control of heart period is not related to blood pressure variability in conscious hypertensive and normotensive rats.

1. The short-term (within 30 min periods) and the long-term (among 30 min periods) variabilities, expressed as variation coefficients, of blood pressure (BP) and heart period (HP) were studied using a computer analysis of BP recordings in freely moving genetically hypertensive (LH), normotensive (LN) and low BP (LL) rats of Lyon strains at ages 5, 9, 21 and 40 weeks. The baroreflex control of HP was estimated with the slope of the linear relationship between systolic BP (SBP) and HP (SBP-HP slope) computed after phenylephrine and nitroglycerin injections. 2. Short-term variability of BP increased between 5 and 9 weeks of age and then remained stable. Hypertension was accompanied by an increase in both short- and long-term variabilities of diastolic BP in adult rats. 3. A sharp increase in SBP-HP slope was observed between 5 and 9 weeks of age in LN rats. SBP-HP slope of LH rats increased slightly up to 21 weeks but remained lower than that of normotensive controls. 4. The weak inverse correlation existing between SBP-HP slope and BP variability appeared to be mediated by the BP level. In addition, atropine which is known to abolish almost completely the SBP-HP slope, did not increase BP variability. It is concluded that SBP-HP slope is not linearly associated with BP variability in conscious rats.

[Effect of ketanserin on arterial baroreflex-blood pressure control in conscious hypertensive rats].

The effect of ketanserin on arterial baroreflex-blood pressure control (ABR-BP) were studied in conscious freely-moving spontaneously hypertensive rats (SHR) and renovascular hypertensive rats (RVHR). The ABR-BP was measured by using a new method comparing with the pressor responses (in area) to angiotensin II before and after blocking the baroreflex efferent pathway by guanethidine and methyl atropine. It was found that ketanserin enhanced markedly the ABR-BP in both groups of hypertensive rats (SHR: 51% to 74%; RVHR: 59% to 77%). This suggests that the enhancement of ABR-BP may be involved in the anti-hypertensive effects of ketanserin.

[Antihypertensive effects of atenolol and nitrendipine alone or in combination on three hypertensive models of rats].

The antihypertensive effects of atenolol (Ate) or nitrendipine (Nit) alone or in combination (Ate+Nit) were studied in conscious experimental hypertensive rats. The hypotensive effects of single ig of Ate 20 + Nit 10 mg.kg-1 were rapid and persistent in spontaneously hypertensive rats (SHR). In renovascular hypertensive rats (RVHR) and DOCA-salt hypertensive rats (DHR), Ate+Nit (6 + 3, 20 + 10, 60 + 30 mg.kg-1) given ig once a day for 10 d reduced the blood pressure in a dose-dependent manner. But Ate 20 mg.kg-1 or Nit 10 mg.kg-1 alone given ig once a day for 10 d caused no obvious reduction in blood pressure in RVHR, DHR, and SHR q = 1.32. These results revealed that the synergy is present in the antihypertensive action of Ate+Nit.

[Inhibitory effects of neferine and tetrandrine on portal vein and papillary muscle in rats].

To determine the vascular selectivity, the inhibitory effects of verapamil (Ver), neferine (Nef), and tetrandrine (Tet) on the spontaneous contractile force of portal vein and contractile force of the paced papillary muscle of left ventricle were studied in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The vascular selectivity was expressed by the IC50 ratio (IC50 for papillary muscle/IC50 for portal vein). The results showed that the vascular selectivity values of Ver, Nef, and Tet were 1.15, 0.32, and 0.20, respectively in WKY and 0.80, 0.24, and 0.10, respectively in SHR. It is concluded that Nef and Tet, in contrast with Ver which is devoid of selectivity for either tissue, are more liable to inhibit the myocardium than the vascular smooth muscle. In addition, the IC50 value of Tet for inhibition of the portal vein in SHR was nearly 10-fold higher than that in WKY (237 and 27 mumol.L-1, respectively). This indicates that the response of portal vein to Tet is decreased in SHR.