Autonomic and Autacoid Pharmacology最新文献

1 In the present study we have investigated the expression of muscarinic receptors in K562 erythroleukaemic cells and the effects of muscarinic agonist and antagonists on extracellular citrulline levels in these cells, as a marker of nitric oxide (NO) generation.

2 Muscarinic acetylcholine receptors (M₁–M₅) play key roles in regulating many diverse physiological processes. Recent studies suggest that muscarinic receptors mediate some cellular events in haematopoietic cells. Multiple subtypes of muscarinic receptors are expressed in different human cells. NO, a free radical and a signaling molecule, is involved in the regulation of many physiological functions and derived from certain nitric oxide synthases (NOS), which are related to muscarinic receptors.

3 In this study, the presence of M₂, M₃ and M₄ subtypes in K562, an erythroleukaemic cell line, was demonstrated by using the reverse transcriptase-polymerase chain reaction. Moreover, the generation of NO induced by carbachol, a non-selective muscarinic agonist, was investigated by using high-performance liquid chromatography to measure changes in extracellular l-citrulline levels.

4 We found that carbachol enhanced l-citrulline production in K562 erythroleukaemic cells. The effect of carbachol on l-citrulline production was antagonized by atropine and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), while tropicamide had little effect. These results suggest that the muscarinic receptor M₃ subtype may mediate NO signaling in K562 erythroleukaemic cells.

1 Mast cells have classically been regarded as the ‘bad guys’ in the setting of acute myocardial ischaemia, where their released contents are believed to contribute both to tissue injury and electrical disturbances resulting from ischaemia. Recent evidence suggests, however, that if mast cell degranulation occurs in advance of ischaemia onset, this may be cardioprotective by virtue of the depletion of mast cell contents that can no longer act as instruments of injury when the tissue becomes ischaemic.

2 Many peptides, such as ET-1, adrenomedullin, relaxin and atrial natriuretic peptide, have been demonstrated to be cardioprotective when given prior to the onset of myocardial ischaemia, although their physiological functions are varied and the mechanisms of their cardioprotective actions appear to be diverse and often ill defined. However, one common denominator that is emerging is the ability of these peptides to modulate mast cell degranulation, raising the possibility that peptide-induced mast cell degranulation or stabilization may hold the key to a common mechanism of their cardioprotection.

3 The aim of this review was to consolidate the evidence implying that mast cell degranulation could play both a detrimental and protective role in myocardial ischaemia, depending upon when it occurs, and that this may underlie the cardioprotective effects of a range of diverse peptides that exerts physiological effects within the cardiovascular system.

1 The internal anal sphincter (IAS) has a spontaneous tone and is the main contributor to the maintenance of faecal continence. The spontaneous resting tone exhibited by the sphincter can be modified by neurotransmitters from the autonomic and enteric nervous systems.

2 In this review, the influence of the sympathetic and parasympathetic nervous systems on IAS tone are discussed and the putative roles of nitric oxide, carbon monoxide, vasoactive intestinal peptide and adenosine triphosphate in non-adrenergic non-cholinergic transmission are considered.

3 Faecal incontinence is a common condition that places a heavy financial burden on the health service and severely affects patients’ quality of life. Resting anal pressure is reduced in patients with faecal incontinence and agents that increase sphincter tone tend to relieve symptoms. The results of clinical studies of the use of phenylephrine to treat faecal incontinence are reviewed.

4 It is concluded that the IAS is a potential target for drug development for the treatment of faecal incontinence.

1 There is a relationship between hypertension, insulin resistance and an altered plasmatic lipid profile known as ‘metabolic syndrome’. Fructose (F) overload induces in the rat a mild hypertension associated with metabolic alterations such as hyperglycemia, hypertriglyceridemia and insulin resistance, resembling such syndrome.

2 Prostanoids (PR), metabolites of arachidonic acid, include vasoactive substances synthesized and released by the vessel wall. An altered pattern of PR release has been previously found in mesenteric vessels of experimental diabetic rats.

3 This study analyzed the effects of F-overload during different periods (4, 9, 15 and 22 weeks) on PR release in aorta (A) and mesenteric vascular beds (MVB). Animals received tap water (control) or F solution (10% w/v) to drink.

4 Rats with F overload showed significantly higher systolic blood pressure, glycemia and triglyceridemia than controls; but no differences in this parameters were found among periods of treatment either in controls or experimental animals.

5 In A, prostacyclin was decreased at 9, 15 and 22 weeks of treatment when compared to 4 weeks and controls. In MVB, prostacyclin showed different patterns of release in the studied periods of F overload. Prostaglandin (PG) E₂ diminish in MVB at the same extent in all periods. No changes were observed in A. The vasoconstrictor thromboxane was elevated in the MVB at 9 weeks. PGF₂α, also a vasoconstrictor, remains unchanged.

6 In conclusion, F overload provokes in the rat a decrease in the vascular production of vasodilator PR and, in one of the studied periods, an increase in the release of the vasoconstrictor thromboxane, leading to a negative imbalance in the prostacylin/thromboxane ratio. This could be involved in the blood pressure alterations found in this experimental model of metabolic syndrome.

1 Purinergic signalling is involved both in short-term control of vascular tone and in longer-term control of cell proliferation, migration and death involved in vascular remodelling.

2 There is dual control of vascular tone by adenosine 5′-triphosphate (ATP) released from perivascular nerves and by ATP released from endothelial cells in response to changes in blood flow (shear stress) and hypoxia.

3 Both ATP and its breakdown product, adenosine, regulate smooth muscle and endothelial cell proliferation.

4 These regulatory mechanisms are important in pathological conditions, including hypertension, atherosclerosis, restenosis, diabetes and vascular pain.

1 Limiting the impact of ischemia reperfusion-related cell death is of vital importance given the enormous figures of heart related mortality in the world.

2 Coronary heart disease (CHD) is responsible for over 100 000 deaths in the UK each year, and is the most common cause of premature death in the UK and as a whole it is estimated that there are just over 1.5 million men, and 1.1 million women, who have suffered CHD in the form of either angina or myocardial infarction (http://www.heartstats.org).

3 In patients undergoing standard clinical reperfusion treatment today such as thrombolysis, percutaneous coronary angioplasty (primary PCTA), and bypass surgery, there remains an underscored need for novel therapies and strategies to reduce post-ischemic infarct size.

4 This review focuses on some of the intracellular signalling pathways that have been proposed to be coupled to A3 adenosine receptors in order to reduce post-ischemic infarct size, in particular the role of nitric oxide in A3 adenosine receptor-mediated cardioprotection is discussed.

1 The aim of the current study was to characterize the α₁-adrenergic receptors (α₁-ARs) present in the isolated tunica media of aorta, in normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats during the course of ageing and hypertension (rats of 1, 3, 6 and 12 months of age). In all vessels, endothelium was removed.

2 In isolated aortic rings, phenylephrine increased contraction in a concentration- and age-dependent manner and was impaired in old SHR compared with WKY rats.

3 The α₁-AR selective antagonist prazosin showed high affinity (pA₂) in vessels from both rat strains.

4 The potency of the α_1A-AR selective antagonists, RS 100329 (5-methyl-3-[3-[4-[2-(2,2,2,-trifluoroethoxy) phenyl]-1-piperazinyl] propyl]-2,4-(1H)-pyrimidinedione) and 5-methylurapidil in antagonizing aortic phenylephrine-responses was low.

5 The α_1D-AR selective antagonist, BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1 piperazynil] ethyl]-8-azaspiro [4.5] decane-7,9-dione) potently blocked phenylephrine-induced responses in aorta from both strains and at all ages.

6 Adventitia removal decreased E_max in older rats and modified the relative affinity (pD₂), but did not affect the affinity of the selective antagonists.

7 The results suggest that aorta tunica α_1D-AR is the main subtype involved in phenylephrine-induced contraction of rat aorta, while α_1A-AR plays only a minor role.

8 Ageing and hypertension did not modify α₁-ARs in the blood vessel and the tunica adventitia does not seem to participate in contraction, even though α₁-ARs are expressed.