Preventive treatment with atorvastatin ameliorates endothelial dysfunction of small pulmonary arteries in monocrotaline-induced pulmonary hypertensive rats

This study examined the effects of preventive atorvastatin (Ator) treatment on vasodilatation of small pulmonary arteries (SPAs) in monocrotaline (MCT)-induced pulmonary hypertensive rats. SD rats were randomly assigned to: normal control (Ctr), pulmonary arterial hypertension (PAH), PAH treated with 5 mg/kg/d Ator (LAtor), or 10 mg/kg/d Ator (HAtor). PAH was induced by MCT injection (40 mg/kg, i.p.). Mean pulmonary artery pressure (mPAP), right ventricular hypertrophy index (RVHI%), endothelium-dependent relaxations (EDdRs), and endothelium-independent relaxations (EDiRs) were determined. Four weeks after MCT injection, mPAP was higher in PAH group compared to that in Ctr group, and this effect was suppressed by Ator treatment (PAH: 32.19 ± 0.91 mm Hg vs. LAtor: 19.13 ± 1.01 mm Hg, HAtor: 17.55 ± 0.20 mm Hg, p < 0.05). Similar trend of changes in RVHI% was found in the same way. EDdRs of SPA rings in PAH group were markedly decreased 2 and 4 weeks after MCT injection, while in Ator treated groups, the impairment can only be detected 4 weeks after MCT injection. There were no differences in EDiRs among all groups 1 week after MCT injection. However, 2 weeks and 4 weeks after MCT injection, EDiRs were significantly impaired, while in HAtor and LAtor groups, EDiR was only impaired 4 weeks but not 2 weeks after MCT injection. Preventive treatment with atorvastatin for 2 weeks ameliorated endothelium-dependent and endothelium-independent vasodilative dysfunction in small pulmonary artery rings of MCT-induced PAH rats. It suggests that MCT-induced damage of endothelial function was progressing, and Ator was only beneficial in the early stage of MCT-induced PAH.     

Therapeutic effects of inorganic nitrate and nitrite in cardiovascular and metabolic diseases

Nitric oxide (NO) is generated endogenously by NO synthases to regulate a number of physiological processes including cardiovascular and metabolic functions. A decrease in the production and bioavailability of NO is a hallmark of many major chronic diseases including hypertension, ischaemia–reperfusion injury, atherosclerosis and diabetes. This NO deficiency is mainly caused by dysfunctional NO synthases and increased scavenging of NO by the formation of reactive oxygen species. Inorganic nitrate and nitrite are emerging as substrates for in vivo NO synthase‐independent formation of NO bioactivity. These anions are oxidation products of endogenous NO generation and are also present in the diet, with green leafy vegetables having a high nitrate content. The effects of nitrate and nitrite are diverse and include vasodilatation, improved endothelial function, enhanced mitochondrial efficiency and reduced generation of reactive oxygen species. Administration of nitrate or nitrite in animal models of cardiovascular disease shows promising results, and clinical trials are currently ongoing to investigate the therapeutic potential of nitrate and nitrite in hypertension, pulmonary hypertension, peripheral artery disease and myocardial infarction. In addition, the nutritional aspects of the nitrate–nitrite–NO pathway are interesting as diets suggested to protect against cardiovascular disease, such as the Mediterranean diet, are especially high in nitrate. Here, we discuss the potential therapeutic opportunities for nitrate and nitrite in prevention and treatment of cardiovascular and metabolic diseases.     

Effect of nitric oxide synthase inhibitor (L-NAME) on substance P-induced vasodilatation in the dental pulp

AIM: To investigate the vasodilator mechanisms of pulpal vessels, especially the involvement of nitric oxide (NO), during pulpal inflammation. METHODOLOGY: Eleven cats were prepared for intra-arterial administration of test agents through a lingual artery. The pulpal blood flow was measured by laser Doppler flowmetry from ipsilateral mandibular canine teeth. By using the NO synthase (NOS) inhibitor N(G)-nitro L-arginine methyl ester (L-NAME), the effects of L-NAME on various vasodilators, such as Substance P (SP)-, calcitonin-gene related peptide (CGRP)-, and papaverine-induced vasodilatation, were compared in vivo in 11 feline dental pulps. RESULTS: L-NAME pretreatment potentiates SP-induced vasodilatation for a duration of approximately 5 h. The increase of pulpal blood flow ranged from 91.47 to 109.91%, which was significantly different from SP injection alone (48.79%, P < 0.05). Other vasodilators such as CGRP and papaverine did not respond to L-NAME pretreatment. CONCLUSIONS: This study demonstrates that NOS inhibitor L-NAME administration alone has insignificant effects on pulpal blood flow, although L-NAME pretreatment can potentiate SP-induced vasodilatation, probably via increased activity in the enzyme guanylate cyclase. CGRP and papaverine did not respond to L-NAME pretreatment, indicating that they are not mediated via an endothelium-dependent mechanism.     

Hyperaemic response to cigarette smoking in healthy gingiva

BACKGROUND AND AIM: Cigarette smoking is currently considered as a risk factor for periodontal disease. Controversy exists as to whether the vasoconstrictive property of nicotine is one of the pathogenic mechanisms. To this end we tested the hypothesis that cigarette smoking is causing vasoconstriction in the healthy human gingiva. MATERIALS AND METHODS: Gingival blood flow was continuously measured with laser Doppler flowmetry in healthy (n=13) casual consumers of tobacco. Simultaneously, recordings were made of skin blood flow in the forehead and the thumb as well as heart rate (HR) and blood pressure (BP). In another session infraorbital nerve block anaesthesia (INB) with 1.0 ml of Carbocain without vasoconstrictive additives was used to identify nervously mediated vascular responses to cigarette smoking (n=8). RESULTS: Cigarette smoking induced a modest hyperaemic response in the gingiva that was lower than the relative increases in BP and HR, and the calculated gingival vascular conductance decreased. In the forehead, flow responses were similar to those in the gingiva, while in the thumb a powerful vasoconstriction was observed. During the later part of the 10-min recovery period, BP and HR tended to decrease while blood flow in the gingiva and forehead remained high. INB potentiated the hyperaemic response to cigarette smoking in gingiva. CONCLUSIONS: The present results help to shed some light on the understanding of the vasoactive mechanisms induced by cigarette smoking, and to support the hypothesis that cigarette smoking causes nervously mediated vasoconstriction in the healthy human gingiva. However, the degree of vasoconstriction was far less than in the thumb skin, and in our subjects was overcome by the evoked rise in arterial perfusion pressure. As a consequence, gingival blood flow increased during smoking. It is speculated that small repeated vasoconstrictive attacks due to cigarette smoking may in the long run contribute to gingival vascular dysfunction and periodontal disease.     

The Biological Investigation of Prostacyclin in Preeclamptic Women Seen Reduced Endothelial Function

Objective.?Our aim was to determine the biological investigation of prostacyclin in preeclamptic women seen reduced endothelial vasodilatation by non-invasive technique in vivo.?Methods.?Using a high resolution ultrasound transducer, diameters of brachial arteries were determined after reactive hyperemia in 15 non-pregnant, 20 normotensive pregnant and 20 preeclamptic women. The concentrations of 6-keto-prostaglandin F_1α (6keto-PGF_1α) in plasma and the concentrations of adenosine-3´, 5´-cyclic monophosphate (cyclic AMP) in platelets and serum were measured among the groups.?Results.?Flow-mediated vasodilatation at 1 min after reactive hyperemia was higher in normotensive pregnant than in the non-pregnant or preeclamptic women. The plasma concentration of 6 keto-PGF_1α as well as the serum concentration of cyclic AMP were lower in preeclamptic than those in normotensive pregnant women. The increase in cyclic AMP in the presence of a prostacyclin analogue in platelets was seen at similar levels in all three groups. Conclusion.?From these results, the concentrations of prostacyclin in plasma and cyclic AMP in serum might be low possibly due to reduced production of prostacyclin in preeclamptic women seen reduced endothelial function.     

Endometrial injury in the menstrual cycle prior to assisted reproduction techniques to improve reproductive outcomes

Abstract

Objective: Oral contraceptive pills (OCP) are widely used for treating women with polycystic ovary syndrome (PCOS). Metformin has beneficial effects on insulin resistance and endothelial functions. The aim of this study was to investigate the effects of treatment with drospirenone/ethinyl estradiol (EE) alone or in combination with metformin on the flow-mediated vasodilatation (FMD) and carotid intima media thickness (CIMT) in women with PCOS.

Methods: Fifty women with PCOS (mean age 23?±?5) were randomized to oral treatment of OCP alone (n?=?25) or an OCP combination with metformin (n?=?25) for 6 months. FMD from the brachial artery and CIMT were calculated. The hormonal profile, HOMA-IR score, basal insulin and glucose levels were studied in both groups. Before and after 6 months' treatment, echocardiographic measurements and laboratory tests were also obtained.

Results: After 6 months' treatment we observed a small decrease in FMD in the OCP group (14.9?±?9.4 versus 14.4?±?9.9, p?=?0.801) and a slight increase in the combination group (14.5?±?9.1 versus 15.0?±?8.0, p?=?0.715) but neither of them reached significance. CIMT increased in the OCP group (0.048?±?0.011 to 0.050?±?0.010?cm, p?=?0.433) and decreased slightly in the combination group (0.049?±?0.012, 0.048?±?0.011?cm, p?=?0.833).

Conclusion: We demonstrated that adding metformin to OCP treatment may have beneficial effect on FMD and CIMT that represent vascular function in patients with PCOS. These results suggest that adding metformin to OCP treatment for PCOS could preserve the cardiovascular system and improve it.     

Assessment of early atherosclerotic findings in patients with nasal polyposis

ObjectiveTo investigate early markers of atherosclerosis in patients with nasal polyposis (NP) through measurements of carotid artery intima-media thickness (CIMT), flow-mediated vasodilatation (FMD) of the brachial artery and serum paraoxonase-1 (PON-1) activity.MethodsForty-five patients with NP were included in the study group and 45 healthy individuals in the control group. The diagnosis of patients with NP was predicated on anterior rhinoscopy, endoscopic nasal examination and coronal paranasal sinus computed tomography (CT). Measurements of CIMT and FMD of the brachial artery were performed by high-resolution ultrasonography. Serum PON-1 activity was evaluated by measuring the rate of paraoxon hydrolysis.ResultsMean CIMT values were found to be increased in the NP group compared to the control group. However, mean FMD % values and serum PON-1 activity were significantly lower in the NP group compared to the control group. Moreover; the endoscopic polyps’ scores and paranasal sinus CT scores were positively correlated with CIMT and negatively correlated with FMD % values and PON-1 activity. Disease duration also was positively correlated with CIMT and negatively correlated with FMD % values.ConclusionImpaired FMD, increased CIMT and decreased serum PON-1 activity may be considered to be risk factors for accelerated atherosclerosis in patients with NP who may have subclinical atherosclerosis and be at risk for cardiovascular events in the future.     

Effect of adrenomedullin on the cerebral circulation: relevance to primary headache disorders

Adrenomedullin (ADM) is closely related to calcitonin gene-related peptide, which has a known causative role in migraine. Animal studies have strongly suggested that ADM has a vasodilatory effect within the cerebral circulation. For these reasons, ADM is also likely to be involved in migraine. However, the hypothetical migraine-inducing property and effect on human cerebral circulation of ADM have not previously been investigated. Human ADM (0.08 µg kg⁻¹ min⁻¹) or placebo (saline 0.9%) was administered as a 20-min intravenous infusion to 12 patients suffering from migraine without aura in a crossover double-blind study. The occurrence of headache and associated symptoms were registered regularly 24 h post infusion. Cerebral blood flow (CBF) was measured by ¹³³Xenon single-photon emission computed tomography, mean blood flow velocity in the middle cerebral artery (V_MCA) by transcranial Doppler and the diameter of peripheral arteries by transdermal ultrasound (C-scan). ADM did not induce significantly more headache or migraine compared with placebo ( P  = 0.58). CBF was unaffected by ADM infusion (global CBF, P  = 0.32 and rCBF_MCA, P  = 0.38) and the same applied for the V_MCA ( P  = 0.18). The superficial temporal artery dilated compared with placebo ( P  < 0.001), and facial flushing was seen after ADM administration ( P  = 0.001). In conclusion, intravenous ADM is not a mediator of migraine headache and does not dilate intracranial arteries.     

Endothelial dysfunction in patients with polycythaemia vera

Patients with polycythaemia vera (PV) are at increased risk of developing arterial and venous thromboembolic complications. We investigated whether endothelium-dependent, flow-mediated vasodilatation (FMD) is impaired in PV patients without clinical evidence of artery disease as observed in patients with conventional cardiovascular risk factors. FMD and endothelium-independent, nitroglycerine-induced vasodilatation (NMD) were assessed using high-resolution ultrasound in the brachial artery of 20 patients with PV and 20 sex- and age-matched control subjects (CTL). FMD was markedly impaired in PV patients compared with CTL (7.6 +/- 2.9% versus 11.6 +/- 5.7%, P = 0.009) whereas NMD was similar in both study groups. The impairment of FMD was independently related to the presence of PV (r = -0.434, P = 0.009) and vessel size (r = -0.107, P = 0.038) but was not related to haematocrit values and platelet counts. The results demonstrate that PV is associated with endothelial dysfunction in the pre-clinical phase of arterial disease. However, the precise mechanisms by which PV leads to this altered vascular reactivity remain unclear.