Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the ability of the endothelium of human epicardial coronary arteries to secrete vasorelaxant substances in response to pharmacological stimulation and under basal conditions. In addition, we have attempted to characterise the chemical identity and biochemical pathway for the synthesis of endothelial derived relaxing factor. Human epicardial coronary arteries were removed from patients who were undergoing heart transplantation for reasons other than ischaemic heart disease. Arteries were cut into segments and suspended in 5 ml organ baths containing a modified Tyrodes solution at 37 degrees C, and gassed with a mixture of 95% oxygen and 5% carbon dioxide. Substance P (10(-10) - 10(-7) M) elicited a dose-dependent relaxation of the coronary segments but this action of substance P was dependent upon an intact endothelium. The maximum response of substance P was equivalent to 89 +/- 8.5% of the maximum effect induced by 1 microgram/ml glyceryl trinitrate. This vasorelaxant effect of substance P was unaffected by the presence of 10(-6) M indomethacin. L-NG-monomethyl-arginine (10(-4) M), a specific inhibitor of formation of nitric oxide from L-arginine, antagonised the relaxations induced by substance P, decreasing the maximum response of substance P to 34 +/- 10.5% of the response to glyceryl trinitrate. Upon application, L-NG-monomethyl-arginine caused a further 23.1 +/- 3.0 increase in tension on preconstricted vessels. This increase in tension was reversed with the addition of L-arginine, but was unaffected by D-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of nitric oxide in mediating endothelium dependent relaxations in the human epicardial coronary artery. 170 57

The endothelium modulates coronary vascular tone by the release of endothelium-derived relaxing or contracting substances. The endothelium-derived relaxing factor has been identified as nitric oxide synthesized in endothelial cells from L-arginine. The endothelium can release other relaxing substances such as prostacyclin and a hyperpolarizing factor. Endothelin-1 is a potent vasoconstrictor peptide formed by endothelial cells, and is likely to be the physiologic antagonist of endothelium-derived relaxing factor. Other putative contracting factors include superoxide anions and products of arachidonic acid metabolism. Endothelium-derived relaxing factor is released spontaneously and in response to flow, platelet-derived products (that is, serotonin, thrombin and adenosine diphosphate) and certain autacoids (that is, acetylcholine, bradykinin, histamine, substance P, vasopressin, alpha-adrenergic agonists). A considerable heterogeneity of responses exists among vessels of different size from different anatomic origin and different species. Hypercholesterolemia, atherosclerosis, hypertension and myocardial ischemia or reperfusion, or both, impair endothelium-dependent relaxation. Under normal conditions, endothelium-derived relaxing factor appears to dominate the control of vascular tone of large and small coronary vessels, whereas in disease states, endothelium-derived contracting factors are released. Impairments of endothelial function may be important in the development of various forms of cardiovascular disease.
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PMID:Endothelial control of vascular tone in large and small coronary arteries. 240 18

This study was undertaken to determine whether atherosclerosis impairs relaxations mediated by endothelium-derived relaxing factor (EDRF) in human coronary arteries. Epicardial coronary arteries were obtained from the hearts of cardiac transplantation patients with or without histologically documented coronary atherosclerosis (atherosclerotic arteries were from patients aged 42-55 years, nonatherosclerotic arteries were from patients aged 14-24 years). Transverse strip preparations were mounted in organ baths for isometric tension recording. Tension was induced with prostaglandins F2 alpha. Indomethacin (10(-5) M) was present to prevent possible interference from endogenously formed prostaglandins. The EDRF-mediated relaxations in response to substance P (10(-10) to 10(-8) M), bradykinin (10(-9) to 10(-7) M), and Ca2+-ionophore A23187 (10(-9) to 10(-7) M) were significantly attenuated in atherosclerotic arteries. In deendothelialized tissues these compounds had no effect. In contrast, endothelium-independent relaxations induced by isoprenaline (10(-7) to 10(-5) M) were not affected by atherosclerosis. Atherosclerotic arteries showed also normal relaxations with high concentrations of glyceryl trinitrate (10(-8) to 10(-7) M), but reduced relaxations with a lower concentration of the compound (10(-9) M). Acetylcholine (10(-7) to 10(-6) M) only produced endothelium-dependent relaxations in 8 of 60 arterial preparations (with or without atherosclerosis). In most of the arteries, it was a direct vasoconstrictor (which may have masked EDRF release in many cases). Omission of indomethacin from the bath solution increased the incidence of moderate acetylcholine-induced relaxations (9 of 16 preparations). It is concluded that atherosclerosis attenuates EDRF-mediated vasospasm and myocardial ischemia.
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PMID:Selective attenuation of endothelium-mediated vasodilation in atherosclerotic human coronary arteries. 244 55

Mast cells and their chemical mediators play a role in cardiac and systemic anaphilaxis. Perivascular and cardiac mast cells have been implicated in the pathogenesis of coronary artery spasm, atherosclerosis, myocardial ischemia, and cardiomyopathy. Despite this, nothing is known about the immunological and biochemical characteristics of the human heart mast cell (HHMC). We have isolated and partially purified HHMC and compared them with mast cells isolated from lung (HLMC) and skin (HSMC) tissues. Cross-linking of the high-affinity receptor for IgE (Fc epsilon RI) by a polyclonal anti-Fc epsilon antibody caused the release of preformed (histamine and tryptase) and de novo synthesized mediators [peptide leukotriene C4 (LTC4) and prostaglandin D2 (PGD2)]. The tryptase content of HHMC (19.4 +/- 1.5 micrograms/10(6) cells) was lower than HSMC (33.4 +/- 2.5 micrograms/10(6) cells) and higher than HLMC (10.6 +/- 1.9 micrograms/10(6) cells). Maximal stimulation of HHMC with anti-IgE led to the release of LTC4 (17.5 +/- 5.1 ng/10(6) mast cells) and PGD2 (17.8 +/- 5.0 ng/10(6) mast cells, whereas HSMC synthesized more PGD2 (65.0 +/- 6.8 ng/10(6) mast cells) and much less LTC4 (< 5 ng/10(6) cells). Recombinant human C5a anaphylatoxin and protamine induced histamine release from HHMC and HSMC, but not from HLMC. Substance P and morphine selectively induced the release of histamine from HSMC, but not from HHMC and HLMC. Compound 48/80 caused histamine release from HSMC and HHMC, but not from HLMC. The pattern of mediators synthesized and the responsiveness of HHMC to different secretagogues appear unique providing strong evidence of human mast cell heterogeneity.
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PMID:Human heart mast cells: a definitive case of mast cell heterogeneity. 753 2

Effects elicited by adenosine and substance P on ventricular sensory endings of 14 dorsal root ganglion afferent neurons were studied in situ in anesthetized dogs. Sensory-field application of adenosine (1 microM) increased the activity of these neurons by 179%. Application of a nonspecific adenosine antagonist to epicardial sensory fields suppressed ongoing activity in all 14 neurons by 39%. Application of an A1- or A2-adenosine-receptor antagonist suppressed activity generated by 10 of these neurons by 44 and 59%, respectively. Adenosine applied after A1- or A2-receptor blockade increased activity in 10 neurons by 131 and 145%, respectively, indicating that A1- and A2-receptor effects were not additive. Application of substance P (1 microM) to identified sensory fields increased activity in 12 of these neurons by 169%, whereas application of a substance P-receptor antagonist reduced activity generated by these neurons by 75%. Myocardial ischemia increased activity of nine neurons associated with left ventricular sensory fields by 320%, an effect that was counteracted by the nonspecific adenosine-receptor antagonist. It is concluded that A1- and A2-adenosine receptors, as well as substance P receptors, are present on ventricular epicardial sensory nerve endings of dorsal root ganglion neurons that are tonically active during normal states, becoming further activated during ischemia.
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PMID:Ventricular sensory neurons in canine dorsal root ganglia: effects of adenosine and substance P. 754 44

Several clinical characteristics of angina pectoris are reflected in the nature of the cardiac nervous system. The extent of silent ischemia, the slow onset of angina during the ischemic cascade, the diffuse character of the visceral component of the pain and the referred pain. Of putative myocardial pain messengers so far only adenosine fulfills Lewis criteria for a cardiac pain messenger. Dependent on the pattern of ischemic release, adenosine appears to stabilize or sensitize afferent cardiac nerves with silent or painful ischemia as a result. Through spatio-temporal summation sensitization may result in an alarm whereby the myocardium signals centrally its precarious state. The activity of adenosine-sensitized afferent nerves may become enhanced by additional stimuli such as potassium, protons, substance P and bradykinin. Primary and secondary afferents from the intrinsic and extrinsic intrathoracic cardiac nervous systems project towards the central nervous system via sympathetic and vagal elements. The main part of primary afferents have their cell bodies in extrinsic cardiac ganglia and only a minority in the dorsal root ganglia. No cardiotopical representation exists in the intrathoracic ganglia. The majority of neurons in intrinsic and extrinsic cardiac ganglia are interneurons integrating cardiac inotropic and vasomotor functions on a beat to beat basis. Multisynaptic transmission over secondary afferents may not only delay the anginal pain message; as somatic afferents also connect to the intrathoracic ganglia, these multisynaptic transmissions may also be a basis for referred pain or pain inhibition. Dorsal root afferents appear to convey only excitatory impulses. Probably due to interneurons, cardiac nodose ganglia activities can become either excitatory or inhibitory. Cardiocardiac reflexes occur from the axonal level up to the brain stem cerebral levels. The brain defense system including the basal ganglia and limbic system and the prefrontal but not the sensory cortex are activated during myocardial ischemia indicating its traumatic nature. The reflexogenic nature of angina pectoris is evident as in silent ischemia similar central nervous system activation occurs as in angina pectoris but with less intense prefrontal activation while in Syndrome X more intense activation occurs. Therapeutic interference of the reflex mechanism by sympathectomy, electrical stimulation or pharmacological interventions can counteract angina pectoris and relax the reflexogenic stress and vasomotor drive on the heart.
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PMID:Neurophysiological aspects of angina pectoris. 910 85

At the turn of this century, it was proposed that ischemic cardiac pain might be related to distension of the ventricular wall ("mechanical hypothesis"). Three decades later, it was hypothesized that ischemic pain might be elicited by the intramyocardial release of pain-producing substances induced by ischemia ("chemical hypothesis"). Studies carried out in the past 10 years have given strong support to the chemical hypothesis, because they have consistently shown that adenosine is a mediator of ischemic cardiac pain. Adenosine-induced ischemic cardiac pain is mediated primarily by stimulation of A1 receptors located in cardiac nerve endings and is potentiated by substance P. Conversely, the magnitude and rate of left ventricular dilation during ischemia do not predict the severity of angina. It is worth noting, however, that stretching of epicardial coronary arteries appears to potentiate the severity of angina caused by myocardial ischemia. The nervous activity generated by myocardial ischemia is modulated in intrinsic cardiac, mediastinal, and thoracic ganglia. Then it is further modulated in the central nervous system and projects bilaterally to the cortex, as demonstrated in humans by positron emission tomography, where it is decoded as a painful sensation. The causes responsible for the lack of angina during myocardial ischemia are probably different in patients who present both pain-free and painful myocardial ischemia, in patients with predominantly painless ischemia, and in diabetic patients.
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PMID:New look to an old symptom: angina pectoris. 939 81

We had shown that bradykinin (BK) generated by cardiac sympathetic nerve endings (i.e., synaptosomes) promotes exocytotic norepinephrine (NE) release in an autocrine mode. Because the synaptosomal preparation may include sensory C-fiber endings, which BK is known to stimulate, sensory nerves could contribute to the proadrenergic effects of BK in the heart. We report that BK is a potent releaser of NE from guinea pig heart synaptosomes (EC(50) approximately 20 nM), an effect mediated by B(2) receptors, and almost completely abolished by prior C-fiber destruction or blockade of calcitonin gene-related peptide and neurokinin-1 receptors. C-fiber destruction also greatly decreased BK-induced NE release from the intact heart, whereas tyramine-induced NE release was unaffected. Furthermore, C-fiber stimulation with capsaicin and activation of calcitonin gene-related peptide and neurokinin-1 receptors initiated NE release from cardiac synaptosomes, indicating that stimulation of sensory neurons in turn activates sympathetic nerve terminals. Thus, BK is likely to release NE in the heart in part by first liberating calcitonin gene-related peptide and Substance P from sensory nerve endings; these neuropeptides then stimulate specific receptors on sympathetic terminals. This action of BK is positively modulated by cyclooxygenase products, attenuated by activation of histamine H(3) receptors, and potentiated at a lower pH. The NE-releasing action of BK is likely to be enhanced in myocardial ischemia, when protons accumulate, C fibers become activated, and the production of prostaglandins and BK increases. Because NE is a major arrhythmogenic agent, the activation of this interneuronal signaling system between sensory and adrenergic neurons may contribute to ischemic dysrhythmias and sudden cardiac death.
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PMID:Bradykinin activates a cross-signaling pathway between sensory and adrenergic nerve endings in the heart: a novel mechanism of ischemic norepinephrine release? 1041 75

Calcitonin gene-related peptide (CGRP) and substance P co-exist in capsaicin-sensitive primary sensory neurons and are released from the myocardium after activation of sensory nerve fibres as well as by ischemia in animals. This study was undertaken to try to clarify the potential involvement of immunoreactive (ir) CGRP in anginal pain and myocardial ischemia in humans. One clinical group (n = 87) and one experimental group (n = 14) were studied. The clinical group was admitted to a coronary care unit with suspected or definite acute myocardial infarction (AMI). The experimental group consisted of patients with severe angina pectoris (NYHA III-IV). This group was subjected to atrial pacing up to the appearance of angina pectoris. Mean irCGRP levels at admission for the clinical group with and without AMI showed no significant difference. Neither were any significant differences found in irCGRP concentrations between patients with pain as compared to those without pain or in the group who had had chest pain >30 min before hospital admission as compared to those with chest pain <30 min. Extraction ratios for lactate and irCGRP was calculated in the experimental group. No statistically significant covariance was found between irCGRP extraction ratio and lactate extraction ratio (r(xy) = -0.006) at the time of appearance of angina during atrial pacing. Despite the facts that CGRP may be liberated by a variety of physiological stimuli and may act as a potent vasodilator in the human vasculature, no evidence has been found in this study that CGRP release is increased as a consequence of ischemia or ischemic pain.
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PMID:Acute ischemic chest pain is not associated with increased calcitonin gene-related peptide (CGRP) levels in peripheral plasma nor in the coronary circulation. 1054 Sep 19

The cardiac mechano- and chemoreceptors are broadly distributed in the myocardium and coronary vessels. A portion of these receptors extends over the epicardium and pericardium and therefore can be excited by mechanical or chemical stimuli directly applied to the surface of the heart. Excitation of epicardial receptors by topical application of chemical compounds elicits a variety of reflex cardiovascular responses, without the vascular or systemic effects of the drug administered systemically. A considerable number of studies has used the epicardial sensory field as a tool to delineate the functional characteristics of the cardiac afferent neurones in normal as well as in pathological conditions. In this review we analyze the cardiovascular reflex responses induced by epicardial application of a variety of substances like bradykinin, nicotine, muscarine, isoprenaline, adenosine, potassium chloride, capsaicin, prostaglandins or substance P in physiological models and also in models with acute myocardial ischemia or heart failure. The data highlight the contribution of the epicardial sensory neurites to the overall control of the cardiovascular system and, on the other hand, strengthen the need for further investigations directed to better elucidate the reflex cardiovascular responses that may develop in patients with pericardial abnormalities.
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PMID:Cardiovascular reflex responses induced by epicardial chemoreceptor stimulation. 1072 29


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