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British Journal of Pharmacology Sep 2009Neuromedin U (NMU) has been paired with the G-protein-coupled receptors (GPRs) NMU(1) (formerly designated as the orphan GPR66 or FM-3) and NMU(2) (FM-4 or hTGR-1).... (Review)
Review
Neuromedin U (NMU) has been paired with the G-protein-coupled receptors (GPRs) NMU(1) (formerly designated as the orphan GPR66 or FM-3) and NMU(2) (FM-4 or hTGR-1). Recently, a structurally related peptide, neuromedin S (NMS), which shares an amidated C-terminal heptapeptide motif, has been identified in both rat and human, and has been proposed as a second ligand for these receptors. Messenger RNA encoding NMU receptor subtypes shows differential expression: NMU(1) is predominantly expressed in peripheral tissues, particularly the gastrointestinal tract, whereas NMU(2) is abundant within the brain and spinal cord. NMU peptide parallels receptor distribution with highest expression in the gastrointestinal tract and specific structures within the brain, reflecting its major role in the regulation of energy balance. The NMU knockout mouse has an obese phenotype and, in agreement, the Arg165Trp amino acid variant of NMU-25 in humans, which is functionally inactive, co-segregated with childhood-onset obesity. Emerging physiological roles for NMU include vasoconstriction mediated predominantly via NMU(1) with nociception and bone remodelling via NMU(2). The NMU system has also been implicated in the pathogenesis of septic shock and cancers including bladder carcinoma and acute myeloid leukaemia. Intriguingly, NMS is more potent at NMU(2) receptors in vivo where it has similar central actions in suppression of feeding and regulation of circadian rhythms to NMU. Taken together with its vascular actions, NMU may be a functional link between energy balance and the cardiovascular system and may provide a future target for therapies directed against the disorders that comprise metabolic syndrome.
Topics: Amino Acid Sequence; Animals; Energy Metabolism; Humans; Ligands; Metabolic Syndrome; Molecular Sequence Data; Muscle, Smooth; Neuropeptides; Vasoconstriction
PubMed: 19519756
DOI: 10.1111/j.1476-5381.2009.00252.x -
American Journal of Physiology. Heart... Nov 2016Serotonin [5-hydroxytryptamine (5-HT)] has a truly fascinating history in the cardiovascular world. Discovered in the blood, 5-HT has long been appropriately regarded as... (Review)
Review
Serotonin [5-hydroxytryptamine (5-HT)] has a truly fascinating history in the cardiovascular world. Discovered in the blood, 5-HT has long been appropriately regarded as a vasoconstrictor. A multitude of in vitro studies of isolated vessels support that addition of 5-HT causes vascular contraction. In only a few cases was 5-HT a vasodilator. Moreover, the potency and threshold of 5-HT causing contraction is increased in arteries from hypertensive vs. normotensive subjects, both animal and human. As such, we and others have hypothesized that 5-HT would contribute to hypertension by elevating arterial tone. In stark contrast to these decades of findings, we observed that a chronic infusion of 5-HT into conscious rats caused a reduction in blood pressure and nearly normalized blood pressure of experimentally hypertensive rats. Going back to the early work of Irvine Page, one of the scientists who discovered 5-HT, reveals an early recognized but never understood ability of 5-HT to reduce systemic blood pressure. Our laboratory, in collaboration with colleagues around the world, has dedicated itself to understanding the mechanisms of 5-HT-induced reduction in blood pressure. This manuscript takes you through a brief history of the discovery of 5-HT, in vitro serotonergic pharmacology of blood vessels, in vivo work with 5-HT and our studies that suggests the venous vasculature, potentially in combination with small arterioles, may be important to the actions of 5-HT in reducing blood pressure. 5-HT has certainly ended up in a place I never expected it to go.
Topics: Animals; Arteries; Blood Pressure; History, 20th Century; History, 21st Century; Humans; Hypertension; Rats; Serotonin; Vasoconstriction; Vasodilation
PubMed: 27663771
DOI: 10.1152/ajpheart.00538.2016 -
AJNR. American Journal of Neuroradiology Oct 2020There is mounting evidence supporting the benefit of intra-arterial administration of vasodilators in diagnosing reversible cerebral vasoconstriction syndrome. We...
BACKGROUND AND PURPOSE
There is mounting evidence supporting the benefit of intra-arterial administration of vasodilators in diagnosing reversible cerebral vasoconstriction syndrome. We prospectively quantified the degree of luminal diameter dilation after intra-arterial administration of verapamil and its accuracy in diagnosing reversible cerebral vasoconstriction syndrome.
MATERIALS AND METHODS
Patients suspected of having intracranial arteriopathy on noninvasive imaging and referred for digital subtraction angiography were enrolled in a prospective registry. Intra-arterial verapamil was administered in vascular territories with segmental irregularities. The caliber difference (Caliber - Caliber) and the proportion of caliber change ([(Caliber - Caliber)/Caliber] × 100%) were used to determine the response to verapamil. The diagnosis of reversible cerebral vasoconstriction syndrome was made on the basis of clinical and imaging features at a follow-up appointment, independent of the reversibility of verapamil. Receiver operating characteristic curve analysis was performed to determine the best threshold.
RESULTS
Twenty-six patients were included, and 9 (34.6%) were diagnosed with reversible cerebral vasoconstriction syndrome. A total of 213 vascular segments were assessed on diagnostic angiography. Every patient with a final diagnosis of reversible cerebral vasoconstriction syndrome responded to intra-arterial verapamil. The maximal proportion of change (< .001), mean proportion of change (= .002), maximal caliber difference (= .004), and mean caliber difference (= .001) were statistically different between patients with reversible cerebral vasoconstriction syndrome and other vasculopathies. A maximal proportion of change ≥32% showed a sensitivity of 100% and a specificity of 88.2% to detect reversible cerebral vasoconstriction syndrome (area under the curve = 0.951). The Reversible Cerebral Vasoconstriction Syndrome-2 score of ≥5 points achieved a lower area under the curve (0.908), with a sensitivity of 77.8% and a specificity of 94.1%.
CONCLUSIONS
Objective measurement of the change in the arterial calibers after intra-arterial verapamil is accurate in distinguishing reversible cerebral vasoconstriction syndrome from other vasculopathies. A proportion of change ≥32% has the best diagnostic performance.
Topics: Adult; Angiography, Digital Subtraction; Female; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Vasoconstriction; Vasodilator Agents; Vasospasm, Intracranial; Verapamil
PubMed: 32943423
DOI: 10.3174/ajnr.A6772 -
Journal of the American College of... Jan 2003
Topics: Coronary Artery Disease; Coronary Circulation; Coronary Stenosis; Humans; Myocardial Infarction; Polymorphism, Genetic; Receptors, Adrenergic, alpha; Risk Factors; Vasoconstriction
PubMed: 12535807
DOI: 10.1016/s0735-1097(02)02703-1 -
British Journal of Pharmacology Jan 2020Endothelium-derived vasoconstriction is a hallmark of vascular dysfunction in hypertension. In some cases, an overproduction of endothelium-derived prostacyclin (PGI )...
BACKGROUND AND PURPOSE
Endothelium-derived vasoconstriction is a hallmark of vascular dysfunction in hypertension. In some cases, an overproduction of endothelium-derived prostacyclin (PGI ) can cause contraction rather than relaxation. Relaxin is well known for its vasoprotective actions, but the possibility that this peptide could also reverse endothelium-derived vasoconstriction has never been investigated. We tested the hypothesis that short-term relaxin treatment mitigates endothelium-derived vasoconstriction in spontaneously hypertensive rats (SHR).
EXPERIMENTAL APPROACH
Male Wistar Kyoto rats (WKY) and SHR were subcutaneously infused with either vehicle (20 mmol·L sodium acetate) or relaxin (13.3 μg·kg ·hr ) using osmotic minipumps for 3 days. Vascular reactivity to the endothelium-dependent agonist ACh was assessed in vitro by wire myography. Quantitative PCR and LC-MS were used to identify changes in gene expression of prostanoid pathways and PG production, respectively.
KEY RESULTS
Relaxin treatment ameliorated hypertension-induced endothelial dysfunction by increasing NO-dependent relaxation and reducing endothelium-dependent contraction. Notably, short-term relaxin treatment up-regulated mesenteric PGI receptor (IP) expression, permitting PGI -IP-mediated vasorelaxation. In the aorta, reversal of contraction was accompanied by suppression of the hypertension-induced increase in prostanoid-producing enzymes and reduction in PGI -evoked contractions.
CONCLUSIONS AND IMPLICATIONS
Relaxin has region-dependent vasoprotective actions in hypertension. Specifically, relaxin has distinct effects on endothelium-derived contracting factors and their associated vasoconstrictor pathways in mesenteric arteries and the aorta. Taken together, these observations reveal the potential of relaxin as a new therapeutic agent for vascular disorders that are associated with endothelium-derived vasoconstriction including hypertension.
Topics: Animals; Dose-Response Relationship, Drug; Endothelium, Vascular; Hypertension; Male; Mesenteric Arteries; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Relaxin; Vasoconstriction
PubMed: 31479151
DOI: 10.1111/bph.14858 -
Critical Care (London, England) 2001Hypoxic pulmonary vasoconstriction continues to attract interest more than half a century after its original report because of persistent mystery about its biochemical... (Review)
Review
Hypoxic pulmonary vasoconstriction continues to attract interest more than half a century after its original report because of persistent mystery about its biochemical mechanism and its exact physiological function. Recent work suggests an important role for pulmonary arteriolar smooth muscle cell oxygen-sensitive voltage-dependent potassium channels. Inhibition of these channels by decreased PO2 inhibits outward potassium current, causing membrane depolarization, and calcium entry through voltage-dependent calcium channels. Endothelium-derived vasoconstricting and vasodilating mediators modulate this intrinsic smooth muscle cell reactivity to hypoxia. However, refined modeling of hypoxic pulmonary vasoconstriction operating as a feedback mechanism in inhomogeneous lungs, using more realistic stimulus-response curves and confronted with direct measurements of regional blood flow distribution, shows a more effective than previously assessed ability of this remarkable intrapulmonary reflex to improve gas exchange and arterial oxygenation. Further studies could show clinical benefit of pharmacological manipulation of hypoxic pulmonary vasoconstriction, in circumstances of life-threatening hypoxemia.
Topics: Acute Disease; Anesthesia; Humans; Hypoxia; Oxygen; Pulmonary Artery; Pulmonary Veins; Respiratory Insufficiency; Vasoconstriction
PubMed: 11299064
DOI: 10.1186/cc989 -
American Journal of Physiology.... Sep 2007Sex differences exist in a variety of cardiovascular disorders. Sex hormones have been shown to mediate pulmonary artery (PA) vasodilation. However, the effects of...
Sex differences exist in a variety of cardiovascular disorders. Sex hormones have been shown to mediate pulmonary artery (PA) vasodilation. However, the effects of fluctuations in physiological sex hormone levels due to sex and menstrual cycle on PA vasoreactivity have not been clearly established yet. We hypothesized that sex and menstrual cycle affect PA vasoconstriction under both normoxic and hypoxic conditions. Isometric force displacement was measured in isolated PA rings from proestrus females (PF), estrus and diestrus females (E/DF), and male (M) Sprague-Dawley rats. The vasoconstrictor response under normoxic conditions (organ bath bubbled with 95% O(2)-5% CO(2)) was measured after stimulation with 80 mmol/l KCl and 1 mumol/l phenylephrine. Hypoxia was generated by changing the gas to 95% N(2)-5% CO(2). PA rings from PF demonstrated an attenuated vasoconstrictor response to KCl compared with rings from E/DF (75.58 +/- 3.2% vs. 92.43 +/- 4.24%, P < 0.01). Rings from M also exhibited attenuated KCl-induced vasoconstriction compared with E/DF (79.34 +/- 3.2% vs. 92.43 +/- 4.24%, P < 0.05). PA rings from PF exhibited an attenuated vasoconstrictor response to phenylephrine compared with E/DF (59.61 +/- 2.98% vs. 70.03 +/- 4.61%, P < 0.05). While the maximum PA vasodilation during hypoxia did not differ between PF, E/DF, and M, phase II of hypoxic pulmonary vasoconstriction was markedly diminished in the PA from PF (64.10 +/- 7.10% vs. 83.91 +/- 5.97% in M, P < 0.05). We conclude that sex and menstrual cycle affect PA vasoconstriction in isolated PA rings. Even physiological increases in circulating estrogen levels attenuate PA vasoconstriction under both normoxic and hypoxic conditions.
Topics: Animals; Estrogens; Female; Male; Menstrual Cycle; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Sex Factors; Vasoconstriction
PubMed: 17595218
DOI: 10.1152/ajpendo.00201.2007 -
Biomedical Papers of the Medical... Dec 2007Humoral systems play an important role in the pathophysiology and development of chronic heart failure (CHF). (Review)
Review
BACKGROUND
Humoral systems play an important role in the pathophysiology and development of chronic heart failure (CHF).
METHODS
We conducted a search of neurohumoral activation in heart failure and its risk in the development of CHF.
RESULTS AND CONCLUSION
Neurohumoral factors may be divided into vasoconstrictive, vasodilative and cytokines. The main vasoconstrictive systems are the renin-angiotensin-aldosterone system (RAAS) and the sympathoadrenal system (SAS). Cytokines include tumour necrosis factor (TNF) alpha and interleukins. The systems of actions are interconnected and they mutually influence their secretion and activities. The possibilities of their detection and assessment for clinical purposes depend on their changes and kinetics in the organism and on the activity of individual metabolites. Apart from their vasoactive effects, the majority of humoral actions also interfere in the process of remodelling, function of the endothelium, blood elements, cardiomyocytes, cells of the smooth muscles, and in immunity as well as inflammatory processes. The rapid development of knowledge on the humoral actions in recent years has made possible their utilisation in diagnostics, treatment and prognosis.
Topics: Cytokines; Heart Failure; Humans; Neurosecretory Systems; Vasoconstriction; Vasodilation
PubMed: 18345252
DOI: 10.5507/bp.2007.035 -
Circulation Journal : Official Journal... Feb 2018The gastroepiploic artery (GEA) plays an important role in the era of multiple arterial revascularization, but spasm is a major matter of concern. The internal thoracic...
BACKGROUND
The gastroepiploic artery (GEA) plays an important role in the era of multiple arterial revascularization, but spasm is a major matter of concern. The internal thoracic artery has been shown to have a strong tendency to spasm in its distal bifurcating part, whereas the segmental difference in vasoreactivity of the GEA has never been performed.Methods and Results:The full length of the GEA obtained from 21 patients undergoing a total gastrectomy was divided into 3 sections: proximal (5 cm from the origin), middle, and distal (5 cm from the end). Concentration-response curves for vasoconstrictors (phenylephrine, prostaglandin F2α, and endothelin-1) and vasodilators (carperitide, nitroglycerin, and nifedipine) were then established using organ baths. All the vasoconstrictors and vasodilators produced concentration-dependent responses in each section. As the concentration of the vasoconstrictors increased, segments at the distal section showed a significantly greater contraction than those at the middle and proximal sections regardless of the type of vasoconstrictor. The effective concentration of drugs that caused 50% of the maximal response for endothelin-1 was significantly greater in the distal section than that in the proximal sections. No significant difference was found in vasodilators-induced relaxation.
CONCLUSIONS
The contractility increases toward to the end of the GEA. Clinically, the distal portion of the GEA should be trimmed off and not be used as an anastomotic site wherever possible.
Topics: Dinoprost; Dose-Response Relationship, Drug; Endothelin-1; Gastroepiploic Artery; Humans; Phenylephrine; Vasoconstriction; Vasoconstrictor Agents
PubMed: 29238009
DOI: 10.1253/circj.CJ-17-0943 -
Experimental Physiology Nov 2006Sympathetic nerves fire in bursts followed by brief periods of quiescence. Periods of quiescence may be a valuable part of coding for different neurotransmitters. We...
Sympathetic nerves fire in bursts followed by brief periods of quiescence. Periods of quiescence may be a valuable part of coding for different neurotransmitters. We compared adrenergic- and non-adrenergic-mediated vasoconstriction with repeating burst patterns versus constant frequency stimulation. Seventeen rats were killed, and the femoral arteries dissected out and mounted in organ tissue baths at 37 degrees C and pH 7.4. Field stimulation was applied to artery rings from five rats at constant frequencies of 2-6 Hz for 144 impulses. In 12 rats, artery rings were stimulated with two burst pattern protocols consisting of repeating pairs, triplets, quadruplets or sextuplets performed using either 8 or 30 Hz as the instantaneous frequency for a total of 144 impulses. All protocols were repeated with the P2 purinergic antagonist pyridoxal-phosphate-6-azophenyl-2'4'-disulphonic acid (PPADs; 0.42 m) or the alpha(1)-antagonist prazosin (1.59 microM). Tension was decreased by the addition of the P2 antagonist PPADs (P < 0.05). Prazosin abolished tension at all constant frequencies (P < 0.05). P2 and alpha(1)-antagonism decreased tension with 8 and 30 Hz burst pattern field stimulation. However, the magnitude of decrease in tension with prazosin was less with burst patterns compared to the same average constant frequencies (P < 0.05). It appears that P2X receptors and alpha(1)-receptors in the femoral artery are sensitive to frequency and patterns of electrical stimulation.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Electric Stimulation; Femoral Artery; Male; Muscle, Skeletal; Prazosin; Purinergic P2 Receptor Antagonists; Pyridoxal Phosphate; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Receptors, Purinergic P2; Receptors, Purinergic P2X2; Vasoconstriction
PubMed: 16973693
DOI: 10.1113/expphysiol.2006.034694