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.     

Histamine receptors in the isolated human middle meningeal artery. A comparison with cerebral and temporal arteries

The subtypes of histamine receptors mediating dilatation of human meningeal arteries have been tested in vitro, using "selective" antagonists, and compared with cerebral and temporal arteries previously examined. Dilatory responses were tested after preconstriction with prostaglandin F2 alpha. Both mepyramine and cimetidine caused a parallel shift to the right of the histamine concentration-response curve, suggesting the presence of both H1- and H2-receptors. Combined treatment with mepyramine and cimetidine caused further displacement of the concentration-response curve to the right. Schild analysis indicated pA2 values of 6.3 for cimetidine and 9.8 for mepyramine in situations of near complete blockade of either of the receptors. Both H1- and H2-receptors seem of importance for the histamine-induced dilatation in meningeal arteries and neither appear to dominate. The data considered in conjunction with our previous findings support the finding that experimental histamine-induced headache due to vasodilatation is intracranial of origin.     

Characterizing the PK/PD relationship for inhibition of capsaicin-induced dermal vasodilatation by MK-3207, an oral calcitonin gene related peptide receptor antagonist

Aims

Calcitonin gene related peptide (CGRP) receptor antagonists are effective acute migraine treatments. A capsaicin-induced dermal vasodilatation (CIDV) model has been developed to provide target-engagement information in healthy volunteers. In the model, CGRP release is provoked after dermal capsaicin application, by activating transient receptor potential vanilloid-type-1 (TRPV1) receptors at peripheral sensory nerves. Laser Doppler imaging is used to quantify CIDV and subsequent inhibition by CGRP receptor antagonists. We sought to evaluate a CGRP receptor antagonist, MK-3207, in the biomarker model and to assess the predictability of the CIDV response to migraine clinical efficacy.

Methods

An integrated population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the exposure−response relationship for CIDV inhibition by CGRP and TRPV1 receptor antagonists. MK-3207 dose−response predictions were made based on estimated potency from the PK/PD model and mean plasma concentrations observed at the doses investigated.

Results

The results suggested that a 20 mg dose of MK-3207 (EC₅₀ of 1.59 nm) would be required to attain the peripheral CIDV response at a target level that was shown previously to correlate with 2 h clinical efficacy based on phase 3 telcagepant clinical data, and that a plateau of the dose−response would be reached around 40–100 mg. These predictions provided a quantitative rationale for dose selection in a phase 2 clinical trial of MK-3207 and helped with interpretation of the efficacy results from the trial.

Conclusions

The integrated CIDV PK/PD model provides a useful platform for characterization of PK/PD relationships and predictions of dose−response relationships to aid in future development of CGRP and TRPV1 receptor antagonists.     

Hepatopulmonary syndrome.

The hepatopulmonary syndrom occurs when pulmonary microvacular dilatation causes hypoxemia in cirrhosis. It is found in between 15-20% of patients with chronic liver diseases and should be considered in the differential diagnosis of dyspnea or abnormal arterial oxygenation in this group. The presence of HPS appears to significantly increase mortality in affected patients with cirrhosis. The mediators of intrapulmonary vasodilatation and HPS are not fully characterized although pulmonary nitric oxide overproduction appears to be a key event in human and experimental models. Contrast echocardiography is the best screening test for pulmonary vasodilatation. Currently there are no effective medical therapies for HPS, although liver transplantation results in reversal of HPS in most cases. However, mortality is higher in patients with HPS undergoing transplantation relative to those without HPS.     

Angiotensin AT1 receptor antagonism normalizes retinal blood flow and acetylcholine-induced vasodiliation in normotensive diabetic rats

Aims/hypothesis The renin angiotensin system is emerging as a potential therapeutic target for diabetic retinopathy. This study examines the effects of angiotensin-converting-enzyme inhibition by captopril and angiotensin AT₁ receptor antagonism using candesartan-cilexetil on retinal blood flow and acetylcholine-stimulated vasodilatation in normotensive diabetic rats.Methods Non-diabetic or streptozotocin-induced diabetic rats were treated for 2 weeks with captopril (100 mg/kg/day) or candesartan cilexetil (2 mg/kg/day). Retinal haemodynamics were measured using video fluorescein angiography. Effects of exogenous acetylcholine on retinal haemodynamics were examined following intravitreal injection. Total retinal diacylglycerol was labelled using diacylglycerol kinase, separated by thin-layer chromatography, and quantified using autoradiography.Results Diabetic rats had prolonged retinal mean circulation time and decreased retinal blood flow compared with non-diabetic rats. Treatment of diabetic rats with either captopril or candesartan blocked the development of these blood flow abnormalities. Intraviteral injection of acetylcholine (10^–5 mol/l) in non-diabetic rats increased retinal blood flow by 53.9±22.0% relative to baseline whereas this response to acetylcholine was blunted in diabetic rats (4.4±19.6%, p<0.001). Candesartan treatment of diabetic rats restored the acetylcholine-stimulated retinal blood flow response to 60.0±18.7% compared with a 56.2+20.1% response in candesartan-treated non-diabetic rats. Total retinal diacylglycerol levels were increased in diabetic rats (3.75±0.98 nmol/mg, p<0.05) compared with non-diabetic rats (2.13±0.25 nmol/mg) and candesartan-treatment of diabetic rats normalized diacylglycerol levels (2.10±0.25 nmol/mg, p<0.05).Conclusion/interpretation This report provides evidence that angiotensin-converting enzyme inhibition and AT₁ receptor antagonism ameliorates retinal haemodynamic dysfunctions in normotensive diabetic rats.Abbreviations ACh acetylcholine - AT appearance time - DAG diacylglycerol - DM diabetic - MCT mean circulation time - NDM non-diabetic - RAS renin angiotensin system - RBF retinal blood flow - STZ streptozotocin     

Vasodilation Responses to Non-Selective α-Adrenergic Blockage of Coronary Bypass Grafts in Diabetic and Non-Diabetic Patients: In Vitro Study

Background: Adrenergic tonus is increased in atherosclerotic coronary arteries. In this study, we aimed to demonstrate in vitro effects of phentolamine, a reversible nonselective alpha (α) adrenergic blocker, on coronary artery bypass grafts (CABG) and compare its effects in diabetic and nondiabetic patients.Methods: A total number of 30 patients (15 diabetic and 15 nondiabetic) who were assigned to elective CABG surgery were enrolled into the study. For both groups of patients, 16 internal mammarian artery (IMA) samples, 16 saphenous vein (SV) samples and 16 radial artery (RA) samples were collected and studied in the tissue bath system. The vasodilatation responses to increasing doses of phentolamine were recorded.Results: When grafts were compared in terms of amount of vasodilatation to phentolamine, IMA had the most prominent vasodilatation followed by RA and SV respectively. Although the vasodilatation responses in nondiabetic patients were numerically higher than diabetic patients, there was no statistically difference between the groups.Conclusion: Phentolamine, a nonselective α adrenergic blocker, is proven to have equal vasodilatory effects in diabetic and nondiabetic CABG grafts and can safely be used both intravenously and topically in the perioperative period.     

Complex vasoactivity of liraglutide. Contribution of three gasotransmitters

BackgroundIncretine hormone glucagon-like peptide-1 (GLP-1) causes dose-dependent relaxation of the thoracic aorta of rats and other arteries via nitric oxide (NO), cAMP and ATP-sensitive potassium channels, however, through a mechanism not thoroughly described. Hereby we aimed to determine the mediators involved in the vasoactive effect of liraglutide.MethodsIsolated rat aortic rings and segments of the femoral artery were mounted in a wire myograph to study the vasoactive effect of liraglutide. Vessels were preincubated either with inhibitors of gasotransmitter-, prostaglandin- or reactive oxygen species-formation, or with inhibitors of protein kinases, potassium channels or the Na⁺/Ca²⁺-exchanger.ResultsAccording to our findings, liraglutide activates endothelial cells and vascular smooth muscle cells leading to the production of NO, carbon monoxide, hydrogen sulphide, superoxide anion, and hydrogen peroxide. Increased production of such relaxing factors promotes the activation of protein kinase– A and –G, resulting in the activation of potassium channels (ATP-sensitive-, voltage-gated-, large-conductance-calcium activated), which profoundly contributes to the activation of the Na⁺/Ca²⁺-exchanger, thereby leading to calcium efflux and smooth muscle relaxation and vasorelaxation.ConclusionsWe reveal the contribution of all gasotransmitters in the vasorelaxation induced by liraglutide. We provide ex vivo evidence that liraglutide is capable of causing vasodilatation in the central and peripherial vessels, thereby supporting the clinical observation that it lowers blood pressure.     

The role of nicorandil in the treatment of myocardial ischaemia

Nicorandil is an anti-anginal agent that has been used in the United Kingdom for over 6 years and is becoming increasingly popular. It induces coronary and peripheral vasodilatation via a dualistic mode of action, mediated by the opening of potassium-ATP channels (K_ATP) and its nitrate effect by stimulation of adenyl cyclase, with an increase in cGMP levels. Comparison to nitrates and other anti-anginal agents have shown it to be of equal efficacy in relieving ischaemic symptoms. Recent evidence suggests a role for nicorandil as a myocardial preconditioning agent but this may be limited by systemic vasodilatation. There is ongoing research into its role in improving the long-term outcome of patients with ischaemic heart disease (IHD). It has been shown to be of proven efficacy in the treatment of IHD and further research will clarify other uses of this agent.