Effects of chronic treatment with a low dose of nicorandil on the function of the rat aorta during ageing

Cervical priming before first-trimester surgical abortion is recommended in certain groups of women. Nitric oxide (NO) donors induce cervical ripening without uterine contractions, but the efficacy and side effects are of concern. To evaluate NO donors for cervical ripening before first-trimester surgical abortion, in terms of efficacy, side effects, and reduction of complications. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and POPLINE. We also searched reference lists of retrieved papers. We contacted experts in the field for information on both published and unpublished trials. Randomised controlled trials comparing NO donors alone or in combination with other methods for cervical ripening in first-trimester surgical abortion. Two review authors independently selected and extracted the data onto a data extraction form. We processed the data using Review Manager (RevMan 5) software. We included 9 studies involving 766 participants. There were no serious complications (infection requiring antibiotic treatment, blood transfusion, complications requiring unintended operation, cervical injury, uterine perforation, death or serious morbidity) in the included trials.NO donors were more effective in cervical ripening when compared with placebo or no treatment. Baseline cervical dilatation before the procedure was higher in NO donors group (mean difference (MD) 0.30, 95% confidence interval (CI) 0.01 to 0.58) The cumulative force required to dilate the cervix to 8 mm (MD -4.29, 95% CI -9.92 to 1.35), headache (risk ratio (RR) 1.73, 95% CI 0.86 to 3.46), abdominal pain (RR 0.87, 95% CI 0.50 to 1.50), or patient satisfaction (RR 0.95, 95% CI 0.84 to 1.07) were not different. More nausea and vomiting occurred in the women who received a NO donor (RR 2.62, 95% CI 1.07 to 6.45).NO donors were inferior to prostaglandins for cervical ripening. The cumulative force required to dilate the cervix to 8 mm to 9 mm was higher (MD 13.12, 95% CI 9.72 to 16.52), and baseline cervical dilatation was less (MD -0.73, 95% CI -1.01 to -0.45) in the NO donor group. However, the probability of dilation greater than 8 mm at three hours was higher in the NO donor group (RR 6.67, 95% CI 2.21 to 20.09). Side effects including headache (RR 5.13, 95% CI 3.29 to 8.00), palpitation (RR 3.43, 95% CI 1.64 to 7.15), dizziness (RR 3.29, 95% CI 1.46 to 7.41), and intraoperative blood loss (MD 33.59 ml, 95% CI 24.50 to 42.67) were also higher. However, abdominal pain (RR 0.33, 95% CI 0.25 to 0.44) and vaginal bleeding (RR 0.14, 95% CI 0.07 to 0.27) were less in the NO donor group. No difference for nausea/vomiting in both groups(RR 1.17, 95% CI 0.94 to 1.46). Patient satisfaction was not different.One trial compared a NO donor with a NO donor plus prostaglandin. The cumulative force required to dilate the cervix to 8 mm was higher (MD 14.50, 95% CI 0.50 to 28.50) in the NO donor group. There was no difference in headache (RR 0.88, 95% CI 0.38 to 2.00), abdominal pain (RR 0.14, 95% CI 0.02 to 1.07), or intraoperative blood loss (MD -50, 95% CI -164.19 to 64.19). NO donors are superior to placebo or no treatment, but inferior to prostaglandins for first-trimester cervical ripening, and associated with more side effects.

Cervical priming before first-trimester surgical abortion is recommended in certain groups of women. Nitric oxide (NO) donors induce cervical ripening without uterine contractions, but the efficacy and side effects are of concern. To evaluate efficacy, side effects and complications of NO donors for cervical ripening before first-trimester surgical abortion. We searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE and POPLINE. We also searched reference lists of retrieved papers. We contacted experts in the field for information on both published and unpublished trials. Randomised controlled trials comparing NO donors alone or in combination with other methods for cervical ripening in first-trimester surgical abortion. Two reviewers independently selected and extracted the data onto a data extraction form. We processed the data using Review Manager (RevMan5) software. We included nine studies involving 766 participants. There were no serious complications (infection requiring antibiotic treatment, blood transfusion, complications requiring unintended operation, cervical injury, uterine perforation, death or serious morbidity) in the trials included.NO donors were more effective in cervical ripening comparing with placebo or no treatment. Baseline cervical dilatation before the procedure was higher in NO donors group (mean difference 0.30, 95% CI 0.01, 0.58) The cumulative force required to dilate the cervix to 8 mm (mean difference -4.29, 95% CI -9.92, 1.35), headache (RR 1.73, 95% CI 0.86, 3.46), abdominal pain (RR 0.87, 95% CI 0.50, 1.50) or patient satisfaction (RR 0.95, 95% CI 0.84, 1.07) were not different. More nausea and vomiting occurred in the women who received a NO donor (RR 2.62, 95% CI 1.07, 6.45).NO donors were inferior to prostaglandins for cervical ripening. The cumulative force required to dilate the cervix to 8-9 mm was higher (mean difference 13.12, 95% CI 9.72, 16.52) and baseline cervical dilatation was less (mean difference -0.73, 95% CI -1.01, -0.45) in the NO donor group. Side effects including headache (RR 5.13, 95% CI 3.29, 8.00), palpitation (RR 3.43, 95% CI 1.64, 7.15), dizziness (RR 3.29, 95% CI 1.46, 7.41) and intraoperative blood loss (mean difference 33.59 ml, 95% CI 24.50, 42.67) were also higher. However, abdominal pain (RR 0.33, 95% CI 0.25, 0.44) and vaginal bleeding (RR 0.14, 95% CI 0.07, 0.27) was less in the NO donor group. Patient satisfaction was not different.One trial compared a NO donor with a NO donor plus prostaglandin.The cumulative force required to dilate the cervix to 8 mm was higher (mean difference 14.50, 95% CI 0.50, 28.50) in the NO donor group. There was no difference in headache (RR 0.88, 95% CI 0.38, 2.00), abdominal pain (RR 0.14, 95% CI 0.02, 1.07) or intraoperative blood loss (mean difference -50, 95% CI -164.19, 64.19). NO donors are superior to placebo or no treatment, but inferior to prostaglandins for first-trimester cervical ripening, and associated with more side effects.

Cervical priming before first-trimester surgical abortion is recommended in certain groups of women. Nitric oxide (NO) donors induce cervical ripening without uterine contractions, but the efficacy and side effects are of concern. To evaluate efficacy, side effects and complications of NO donors for cervical ripening before first-trimester surgical abortion. We searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE and Popline. We also searched reference lists of retrieved papers. We contacted experts in the field for information on both published and unpublished trials. Randomised controlled trials comparing NO donors alone or in combination with other methods for cervical ripening in first-trimester surgical abortion. Two reviewers independently selected and extracted the data onto a data extraction form. We processed the data using Review Manager (RevMan5) software. We included eight studies involving 718 participants. There were no serious complications (infection requiring antibiotic treatment, blood transfusion, complications requiring unintended operation, cervical injury, uterine perforation, death or serious morbidity) in the trials included.NO donors were ineffective in cervical ripening comparing with placebo or no treatment. The cumulative force required to dilate the cervix to 8 mm (mean difference -4.29, 95% CI -9.92, 1.35), baseline cervical dilatation before the procedure (mean difference 0.21, 95% CI -0.12, 0.53), headache (RR 1.73, 95% CI 0.86, 3.46), abdominal pain (RR 0.87, 95% CI 0.51, 1.50) or patient satisfaction (RR 0.95, 95% CI 0.84, 1.07) were not different. More nausea and vomiting occurred in the women who received a NO donor (RR 2.62, 95% CI 1.07, 6.75).NO donors were inferior to prostaglandins for cervical ripening. The cumulative force required to dilate the cervix to 8-9 mm was higher (mean difference 13.12, 95% CI 9.72, 16.52) and baseline cervical dilatation was less (mean difference -0.73, 95% CI -1.01, -0. 45) in the NO donor group. Side effects including headache (RR 5.13, 95% CI 3.29, 8.00), palpitation (RR 3.43, 95% CI 1.64, 7.15), dizziness (RR 3.29, 95% CI 1.46, 7.41) and intraoperative blood loss (mean difference 33.59 ml, 95% CI 24.50, 42.67) were also higher. However, abdominal pain (RR 0.33, 95% CI 0.25, 0.44) and vaginal bleeding (RR 0.14, 95% CI 0.07, 0.27) was less in the NO donor group. Patient satisfaction was not different.One trial compared a NO donor with a NO donor plus prostaglandin. The cumulative force required to dilate the cervix to 8 mm was higher (mean difference 14.50, 95% CI 0.50, 28.50) in the NO donor group. There was no difference in headache (RR 0.88, 95% CI 0.38, 2.00), abdominal pain (RR 0.14, 95% CI 0.02, 1.07) or intraoperative blood loss (mean difference -50, 95% CI -164.19, 64.19). NO donors are inferior to prostaglandins for first-trimester cervical ripening, and associated with more side effects. NO donors are comparable to placebo and no treatment for cervical ripening.

ATP-sensitive potassium channels (K(ATP) channels) regulate vascular tone and cardiac contraction through their action on the membrane potential of smooth muscle cells and cardiomyocytes. Because aging and diseases alter K(ATP) channel activity, many pharmacological treatments aimed at improving their function, therefore cardiovascular function, have been evaluated. Nicorandil, a K(ATP) channel opener, nitric oxide donor and antioxidant, is used as a treatment of angina pectoris and induces vasodilation, blood pressure decrease and cardioprotection in aging as well as after ischemia-reperfusion. Here, using the patch-clamp technique, we have studied the effect a chronic low dose of nicorandil (0.1 mg/kg per day for 2 months), on the activity of cardiomyocyte K(ATP) channels as a function of age, in newborn, 4-, 12- and 24-month old rats. Nicorandil exerted an anti-oxidant and protective action on cardiomyocyte K(ATP) channels, especially in aged animals, leading to restoration of a normal channel activity. These findings could justify further therapeutical applications.

Exogenous intravascular nitric oxide enhances ventricular function after hemodilution with plasma expander

1. Many endothelium-dependent vasodilators hyperpolarize the endothelial cells in blood vessels. It is not known whether these hyperpolarizations are linked to nitric oxide synthesis or to an endothelium-derived hyperpolarizing phenomenon, since most of the vasodilators release both factors. In this context, we first verified that the endothelium-dependent relaxations induced by 5-hydroxytryptamine (5-HT) on pig coronary arteries are due only to the activation of the nitric oxide pathway. Then we studied the effects of 5-HT on membrane potential of endothelial and smooth muscle cells. 2. In the absence of endothelium, 5-HT caused a concentration-dependent contraction of coronary artery strips. No change of the smooth muscle cell membrane potential was observed during contraction to 1 microM 5-HT. 3. In the presence of 1 microM ketanserin to suppress the contractile effect of 5-HT, 5-HT induced concentration-dependent relaxation of endothelium-intact strips precontracted by 10 microM prostaglandin F2 alpha (PGF2 alpha). These relaxations were suppressed by 1 microM NG-nitro-L-arginine, an inhibitor of nitric oxide synthesis, showing that they were produced predominantly by nitric oxide. 4. In the presence of 1 microM ketanserin, 1 microM 5-HT did not change the smooth muscle cell membrane potential of strips precontracted by either 10 microM PGF2 alpha or by 10 microM acetylcholine (ACh). In the same conditions, 1 microM 5-HT caused a weak 2.6 +/- 0.4 mV hyperpolarization, of the endothelial cells. 5. In conclusion, the fact that 5-HT did not change the membrane potential of smooth muscle cells and only weakly hyperpolarized the endothelial cells during relaxations, suggests that in both cell types no electrical events accompany activation of the nitric oxide pathway. This is in contrast to the hyperpolarizations observed in endothelial and smooth muscle cells when the endothelium-derived hyperpolarization factor (EDHF) pathway is activated.

Antisecretory and gastroprotective activities of compounds endowed with H 2 antagonistic and nitric oxide (NO) donor properties

To investigate the effects of nicorandil, an ATP-sensitive potassium (K(ATP)) channel opener with a nitric oxide (NO) donor property, on overactive bladder (OAB) in animal models. Nicorandil is currently used clinically to treat ischaemic heart disease. Three animal OAB models were used: (i) C-fibre mediated bladder overactivity by infusion of a low concentration of acetic acid (AA) into the bladder in female Wistar rats; (ii) bladder outlet obstruction (BOO) created by partial urethral obstruction in female Wistar rats; and (iii) neuronal NO synthase (nNOS) knockout (KO) mice with urinary frequency. The effects of nicorandil and KRN2391, both of which act as K(ATP) channel openers and NO donors, on the OAB models were examined. Cystometry showed that intravesical instillation of nicorandil and KRN2391 successfully inhibited OAB induced by intravesical instillation of AA. In the BOO model compared with untreated BOO rats, both nicorandil (1 and 3 mg/kg, orally) and KRN2391 (1 mg/kg, orally) significantly reduced the voiding frequency. Compared with wild-type mice, nNOS KO mice had urinary frequency with no change in the total urine volume. Nicorandil (3 mg/kg, orally) and KRN2391 (1 mg/kg, orally) significantly reduced the voiding frequency in nNOS KO mice. Our in vivo results show that nicorandil, a K(ATP) channel opener with a NO donor property, can suppress OAB from both neurogenic and myogenic causes. Nicorandil appears to be a promising candidate for clinical use in patients with OAB.

Linking KATP channel activation to p-AKT/mTORC1/eEF2/BDNF axis unravels Nicorandil's promise in countering acetaminophen-induced hepatic encephalopathy in mice.

Cinnamic acid and its derivatives have been studied for a variety of biological properties, including anti-inflammatory, antioxidant, anticancer, antihypertensive, and antibacterial. Many hybrids of cinnamic derivatives with other bioactive molecules have been synthesized and evaluated as nitric oxide (NO) donors. Since NO plays a significant role in various biological processes, including vasodilation, inflammation, and neurotransmission, NO donor groups are incorporated into the structures of already-known bioactive molecules to enhance their biological properties. In this review, we present cinnamic hybrids with NO-donating ability useful in the treatment of several diseases.

In the vasculature it is well established that cGMP is involved in the relaxant response to nitric oxide (NO) and NO donors. However, there is an increasing evidence that alternative/additional pathways that are cGMP-independent may also exist. A key criterion for a response to NO or a NO donor drug to be classified as cGMP-independent is lack of (or incomplete) inhibition by the selective inhibitor of soluble guanylate cyclase, ODQ (1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one). In many blood vessels cGMP-independent mechanisms contribute to the vasorelaxation, and in certain vascular beds cGMP-independent relaxation may be the predominant mechanism of action of NO and NO donors. NO donor drugs that generate NO "spontaneously", like authentic NO (i.e. solutions of NO gas), appear to exhibit a larger component of cGMP-independent vasorelaxation than do those drugs that require bioactivation in the tissue. The long lasting inhibition of responses to vasoconstrictors by S-nitrosothiols, persisting after removal of these NO donors, may be a cGMP-independent process, at least in some vessels. The mechanisms involved in the inhibition of vascular growth by NO and NO donors are predominantly cGMP-independent, as are the mechanisms responsible for the effects of NO donors on apoptosis in vascular smooth muscle and endothelial cells. The ability of NO and NO donors to inhibit platelet aggregation has a significant cGMP-independent component. cGMP-independent pathways are most often, though not exclusively, seen at high concentrations (microM - mM) of NO and NO donors. Hence, in relation to the actions of endogenous NO, these pathways may be particularly important in settings when the inducible isoform of NO-synthase is expressed. Furthermore, cGMP-independent pathways are enhanced in animal models of atherosclerosis and ischaemia. This suggests that it may be possible to target cGMP-independent mechanisms with selected NO donors in disease states.

To investigate the interaction between hydrogen sulfide (H2S)/cystathionine gamma-lyase (CSE) system and nitric oxide (NO)/nitric oxide synthase (NOS) system on cardiac protection in metabolic syndrome (MS) rats. Forty one male Sprague-Dawley rats were randomly divided into 6 groups: control group, MS group, H2S donor group, CSE inhibitor group, NOS inhibitor group, and NO donor group. The MS rat model was established by a high-fat diet of 16 weeks. Rats in control and MS groups were subjected to normal saline and the other four groups were respectively subjected to sodium hydrosulfide (NaHS, 56 μmol/kg), D,L-propargylglycine (PPG, 37.5 mg/kg), Nψ-nitro-L-arginine methyl ester (L-NAME, 18 mg/kg), L-Arginine (500 mg/kg) every day. Four weeks later, the obesity indices, blood sugar of oral glucose tolerance test in each time point (0,30,60, and 120 minutes) and blood lipids (cholesterol, triglyceride, high density lipoprotein, low density lipoprotein) were measured. The computer-based electrophysiological recorder system was used to measure the changes of the left ventricular systolic pressure (LVSP), the left ventricular end diastolic pressure (LVEDP), the maximal rate of pressure increase in the contraction phase (+dP/dtmax), and the maximal rate of pressure decrease in the diastole phase (-dP/dtmax). H2S and NO concentration in plasma and myocardium, as well as CSE, constitutive NOS (cNOS), and inducible NOS (iNOS) activities in myocardium were measured with colorimetric method. Reverse transcription-polymerase chain reaction was used to assess the gene expression of CSE and endothelial NOS (eNOS) mRNAs. Compared with control group, the obesity indices, blood sugar at each time point, and blood lipids significantly increased in MS group (P<0.05). H2S and NO concentration in plasma and myocardium, CSE and cNOS activities in myocardium, the expressions of CSE mRNA and eNOS mRNA, and the myocardial function significantly decreased in MS group (P<0.05). Compared with MS group, NO concentration in plasma and myocardium, cNOS and iNOS activities in myocardium, and the expression of eNOS mRNA significantly increased in CSE inhibitor group (P<0.05). However, activities of cNOS and iNOS in myocardium and the expression of eNOS mRNA were significantly decreased in H2S donor group (P<0.01), while the myocardial function significantly increased (P<0.05). H2S concentration in plasma and myocardium, and the expression of CSE mRNA significantly increased in NOS inhibitor group (P<0.05). However, in NO donor group, the CSE activity in myocardium and the expression of CSE mRNA significantly decreased (P<0.05). And the myocardial function was improved significantly (P<0.05). Both the H2S/CSE and NO/NOS systems appear to have a mutual down-regulation effect on myocardium in MS rats. Meanwhile, exogenous H2S and NO supplement is cardioprotective in rat model of MS.

Longchain n-3 polyunsaturated fatty acids and microvascular reactivity: Observation in the hamster cheek pouch

Cannabinoids Regulate Intestinal Motor Function and Electrophysiological Activity of Myocytes in Rodents

Membrane potential of smooth muscle cells of human allantochorial placental vessels