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)

Chronic treatment with cyclosporine A (Cx) seems to produce a decreased ability of the endothelium to secrete nitric oxide. However, its effect on the coronary arterial system remains controversial. Therefore, coronary arteries isolated from piglets treated by intramuscular injections of Cx (10 mg/kg/day, IM, for 22 days) were studied in organ baths and compared with those isolated from control animals (IM injections of the Cx solvent). Depolarization-induced contractions (KCl 120 mM) were similar in both groups, whereas the acetylcholine-induced contractions (percent of 120 mM KCl) were enhanced: The area under the curve (AUC) was 245 +/- 51 in the Cx group versus 110 +/- 15 in the control group (p < 0.05). Removal of the endothelium did not significantly modify the acetylcholine-induced contractions in both groups and, therefore, did not attenuate the enhanced responsiveness to acetylcholine in the Cx group. On unrubbed rings contracted with prostaglandin F2 alpha, the endothelium-dependent relaxations from serotonin (in the presence of 1 microM ketanserin) were reduced: The AUC was 479 +/- 24 in the Cx group versus 385 +/- 22 in the control group (p < 0.02). Larger AUC values were also found for bradykinin and substance P in the Cx group: 158 +/- 18 versus 55 +/- 17 (in the control group, p < 0.01) and 198 +/- 8 versus 145 +/- 12 (p < 0.01), respectively. Nevertheless, no alteration in calcium ionophore-induced relaxations was observed: The AUC was 217 +/- 10 in the Cx group and 224 +/- 18 in the control group (NS). Indomethacin incubation (10 microM) did not prevent the impairment in endothelium-dependent relaxations and did not attenuate the cyclosporine-induced augmentation of acetylcholine-induced contractions. Thus, chronic administration of cyclosporine to piglets impairs the coronary endothelial function and produces functional changes in smooth muscle cells. These alterations may play a role in the occurrence of cardiac graft vasculopathy.
Cardiovasc Drugs Ther 1996 Mar
PMID:Coronary vasomotor responses in cyclosporine-treated piglets. 872 66

We investigated the influence of the Ca(2+)-ATPase inhibitor thapsigargin (TG) on the vasorelaxant response to different endothelium-dependent and endothelium-independent relaxing agents in an isolated thoracic aorta preparation of the rabbit, precontracted by norepinephrine (NE). Pretreatment with 100 microM L-arginine methyl ester (L-NAME) an inhibitor of nitric oxide (NO) synthesis, completely prevented acetylcholine (ACh)-induced relaxation; the inactive stereoisomer D-NAME did not modify the effect of ACh. The exposure of the preparations to 1 microM TG induced a slowly developing slight increase in the basal tension during 30-min contact. The same concentration of TG also slightly reduced the response to the subsequent administration of NE. The antagonist effect of TG on the ACh response was concentration dependent in the range between 0.1 and 10 microM. A 30-min pretreatment with 1 microM TG appeared to be sufficient to induce a consistent antagonism of the ACh (0.01-10 microM) concentration-relaxant effect curve, since an increase to 60 min did not produce a further significant increment in the degree of the antagonist effect. The concentration-dependent relaxation induced by substance P (SP 0.1-3 nM) was also significantly antagonized by 1 microM TG. The effect of the calcium ionophore A23187 (0.01-1 microM) was reduced by the Ca(2+)-ATPase inhibitor only at the higher concentrations tested (0.3-1 microM). However, a 30-min contact time with 1 microM TG was completely ineffective in antagonizing the concentration-relaxant response curves to the two nitrovasodilators sodium nitroprusside (SNP 0.1-100 microM) and nitroglycerin (NTG 1-300 nM) and to the cyclic GMP analogue 8-Bromo-cyclic GMP (3-100 microM). The effects of the beta-adrenoceptor agonist isoprenaline (ISO 0.1-10 microM) and of the direct adenylate cyclase activator forskolin (FK 0.01-10 microM) were also completely unaffected by 1 microM TG. These results demonstrate that TG affects the response to agents that induce an endothelium-dependent relaxation through receptor-dependent calcium mobilization. However, they do not support the hypothesis that sarcoplasmic pump activity is essential for the development of a vasorelaxant response to endothelium-independent agents.
J Cardiovasc Pharmacol 1996 Jul
PMID:Thapsigargin inhibits the response to acetylcholine and substance P but does not interfere with the responses to endothelium-independent agents. 879 40

We studied the influence of dietary L-arginine (L-ARG) supplementation on forearm resistance arteries in vivo and the effect of exogenous addition of L-ARG to subcutaneous arteries isolated from gluteal biopsies. Twenty-six healthy males were recruited, and 16 were randomly allocated in a double-blind protocol to receive either oral L-ARG 20 g/day or placebo for 28 days. We examined responses to acetylcholine (ACh), sodium nitroprusside (SNP) and NG-monomethyl-L-arginine (L-NMMA) on forearm resistance arteries using venous occlusion plethysmography performed before and after supplementation of L-ARG (or placebo). L-ARG 20 g/day had no effect on plasma L-ARG levels (% mol based on total amino acid pool; before vs. after L-ARG 3.43 +/- 0.31 vs. 3.76 +/- 0.05), weekly blood pressure (BP) measurements, or plasma biochemical analysis of liver function enzymes, urea, or electrolyte levels. On the other hand, analysis of the major amino acids in plasma showed a significant difference in profile after L-ARG, but not placebo supplementation (Mann Whitney U test, p < 0.05), indicating a domino effect of chronic oral L-ARG supplementation on other amino acids. This may result from a change in appetite and thus protein intake after L-ARG supplementation. At the dose given, neither L-ARG nor placebo had any effect on forearm blood flow (FBF) responses to ACh (area under the dose-response curve, before vs. after L-ARG 1,763 +/- 260.1 vs. 1,862.8 +/- 163.6 U, Student's paired t test; p > 0.05), SNP, or L-NMMA. Gluteal skin biopsies were performed on 10 different untreated subjects. Subcutaneous arteries were isolated and mounted as ring preparations in isometric small vessel myographs. Full concentration-response curves to norepinephrine (NE), ACh, substance P, and a single response to SNP (10 microM) were obtained with and without addition of either L- or D-ARG 10 microM. Both L-ARG [-log EC50 (M) before vs. after arginine 7.12 +/- 0.15 vs. 6.66 +/- 0.16, Student's paired t test, p < 0.005] and D-ARG [-log EC50 (M) before vs. after arginine 7.36 +/- 0.17 vs. 6.85 +/- 0.18; Student's paired t test, p < 0.05] significantly antagonized responses to NE in subcutaneous arteries isolated from healthy humans. With the exception of a subset of vessels in which some endothelial dysfunction was observed, neither of the isomers of arginine had any effect on the responses to ACh, substance P, or SNP. In the subset vessels already described (n = 5), in which responses to ACh were < 90% maximal dilatation, L- but not D-ARG significantly increased the potency to ACh [-log EC50 (M) before vs. after L-ARG 7.42 +/- 0.20 vs. 8.27 +/- 0.28. Student's paired t test, p < 0.05]. We conclude that oral supplementation with L-ARG 20 g/day for 28 days does not affect endothelial function in normal healthy adults, possibly because the dose given in the current study was inadequate or because chronic oral administration leads to dissipation of arginine to other pathways, as evidenced by the change in total amino acid profile but not L-ARG plasma concentration, or because L-ARG cannot improve normal endothelium-mediated vasodilatation. These concepts are supported by our findings that responses to ACh and substance P were not altered by L-ARG in subcutaneous arteries isolated from healthy subjects.
J Cardiovasc Pharmacol 1996 Jul
PMID:Effects of in vivo and in vitro L-arginine supplementation on healthy human vessels. 879 50

We examined endothelium-dependent vasodilator responses in well-developed coronary collateral vessels. Collateral vessels and size-matched normal epicardial coronary arteries were isolated from canine hearts 6 months after a hollow plug had been introduced into the left anterior descending coronary artery (LAD) to stimulate collateral vessel growth. Vessel segments were isolated and studied in organ chambers. After preconstriction with prostaglandin F2 alpha, (PGF2 alpha) responses to the endothelium-dependent vasodilators, acetylcholine (ACh), substance P, and bradykinin (BK), as well as the endothelium-independent vasodilator nitroglycerin (NTG), were measured. The maximum relaxation to ACh was greater in collateral vessels (129 +/- 3.6% of the preconstricted tension) than in normal vessels (110 +/- 6.2%, p < 0.001), although the EC50 value for ACh was not significantly different between collateral and normal vessels. Collateral vessels demonstrated sensitivity to BK similar to that of normal vessels, but the maximal vasodilation achieved was greater in collaterals (138 +/- 4.6% of preconstricted tension) than in normal vessels (108 +/- 5.0%, p < 0.05). Both substance P and NTG produced dose-related relaxation that was similar in collateral vessels and normal arteries. These findings demonstrate that endothelium-dependent relaxation is intact in well-developed coronary collateral vessels.
J Cardiovasc Pharmacol 1996 Oct
PMID:Endothelium-dependent vasodilation in well-developed coronary collateral vessels. 889 71

It has been shown that substance P causes endothelium-dependent vasodilation in the human coronary and forearm vessels. However, the precise mechanism whereby substance P dilates the coronary and peripheral vasculatures is unknown in humans. The aim of this study was to examine whether the vasodilator effect of substance P is mediated by nitric oxide in the human coronary and forearm vessels. Eight patients with normal coronary angiograms were studied for the measurements of coronary blood flow (intracoronary Doppler guide wire and quantitative coronary arteriography) and forearm blood flow (strain-gauge plethysmograph). Intracoronary acetylcholine (10 micrograms/min for 2 min) and substance P (30 and 90 ng/min for 2 min) increased coronary blood flow from the baseline value. Intracoronary infusion of NG-monomethyl-L-arginine (L-NMMA) at 200 mumol significantly attenuated the magnitudes of increase in coronary blood flow induced by both acetylcholine (p < 0.01) and substance P (p < 0.01). Acetylcholine (4, 8, and 16 micrograms/min for 2 min) and substance P (0.8, 1.6, and 3.2 ng/min for 2 min) also increased forearm blood flow in a dose-dependent manner. Intraarterial L-NMMA (8 mumol/min for 5 min) decreased the magnitudes of increase in forearm blood flow induced by acetylcholine (p < 0.01). L-NMMA at the same dosage decreased the increase in forearm blood flow induced by substance P, but the magnitude of the inhibitory effect of L-NMMA on blood-flow responses to substance P was significantly smaller in the forearm than in coronary vessels. It is suggested that endothelium-derived nitric oxide contributes to substance P-induced vasodilation, and that the contribution of nitric oxide to substance P-induced vasodilation is smaller in the forearm than in coronary circulation.
J Cardiovasc Pharmacol 1997 Apr
PMID:Role of nitric oxide in substance P-induced vasodilation differs between the coronary and forearm circulation in humans. 915 66

Estrogen is known to improve in the short term the impaired endothelium-dependent vasodilating responses in postmenopausal women, which may account in part for the beneficial cardiovascular effects of the female hormone. Endothelium-dependent vasodilation is achieved by combined effects of endothelium-derived prostacyclin, nitric oxide (NO), and hyperpolarizing factor. In this study, we investigated our hypothesis that short-term estrogen improves both NO-mediated and non-NO-mediated endothelium-dependent vasodilation in postmenopausal women. The study included 12 postmenopausal women (aged 64 +/- 3 years). The forearm blood flow was measured by strain-gauge plethysmography. The forearm vascular responses to the endothelium-dependent vasodilators, acetylcholine and substance P, were examined before and after intravenous administration of conjugated estrogen and subsequently after intraarterial infusion of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthesis. Short-term estrogen augmented the forearm vasodilating responses to both acetylcholine and substance P. The treatment with L-NMMA almost abolished the augmented response to acetylcholine but did not affect that to substance P. The forearm vascular response to sodium nitroprusside was unchanged by the estrogen administration. These results indicate that estrogen augments (in the short-term) both NO-mediated and non-NO-mediated endothelium-dependent forearm vasodilation in postmenopausal women. Thus the beneficial effect of estrogen on endothelial vasodilator function appears to extend to non-NO-dependent mechanism(s).
J Cardiovasc Pharmacol 1997 Oct
PMID:Short-term estrogen augments both nitric oxide-mediated and non-nitric oxide-mediated endothelium-dependent forearm vasodilation in postmenopausal women. 933 8

Autonomic influences on the heart rate have been the subject of intense research for many decades and are classically devoted to the sympathetic and parasympathetic systems. However, developments over the past few years in our knowledge of the organization of the autonomic nervous system have led to the conclusion that in addition to the classical transmitters, peptidic transmitters are clearly present and have direct or indirect actions on cardiac conduction. Neuropeptides have been found to collocate with each other or with classical transmitters, thereby increasing the variety of chemical signals that a neuron can utilize to communicate with other cells. Neuropeptides can act as neurotransmitters, neuromodulators or neurohormones. Some are produced in endocrine glands and circulate as hormones, while others are contained in cardiac myocytes, neurons, or endothelial cells in proximity to the sinoatrial node and can therefore act in a paracrine or autocrine way on the pacemaker cells to modulate heart frequency. There is evidence supporting such a role, especially for locally situated neuropeptide Y, vasoactive intestinal peptide, calcitonin gene-related peptide, substance P, angiotensin II, natriuretic peptides, endothelins and possibly many others. The role of the peptidic neurotransmitters in the conduction system should not be exaggerated. Nevertheless, neuropeptides certainly represent a new category of neurotransmitters forming a third component of the autonomic nervous system and may have complex actions with potential therapeutic implications in man.
Cardiovasc Res 1998 Mar
PMID:Peptidic regulation of heart rate and interactions with the autonomic nervous system. 965 41

Because chronic hypoxia increases the production of oxygen radicals, we hypothesized that antioxidants attenuate chronic hypoxic pulmonary hypertension. In part 1, we examined the temporal progress in chronic hypoxic pulmonary hypertension in 46 Wistar rats exposed to hypoxia from 0-3 weeks. In part 2, we tested whether antioxidants attenuated chronic hypoxic pulmonary hypertension in 82 rats divided into 10 groups: control, fullerenol-1, U-83836E, dimethylthiourea-1, dimethylthiourea-2, hypoxia, hypoxia + fullerenol-1, hypoxia + U83836E, hypoxia + dimethylthiourea-1, and hypoxia + dimethylthiourea-2. Control animals breathed room air and were injected intraperitoneally with saline for 2 weeks. Fullerenol-1, U-83836E, and dimethylthiourea are antioxidants and were administered intraperitoneally for 2 weeks, except that dimethylthiourea was given either on days 3, 5, and 7 (dimethylthiourea-1), or on days 8, 10, and 12 (dimethylthiourea-2). Hypoxic animals were placed into a hypobaric chamber with a barometric pressure of 380 Torr for 2 weeks. Hypoxia + antioxidant groups were administered antioxidants during hypoxic exposure. We observed a gradual increase in pulmonary artery pressure, the weight ratio of right ventricle to left ventricle plus septum, and hematocrit during the 3 weeks of chronic hypoxia. These hypoxia-induced alterations were significantly attenuated by U-83836E and dimethylthiourea, but not by fullerenol-1. Neither the temporal alterations nor the antioxidant effects can be explained by the change in either tracheal neutral endopeptidase activity or the lung or plasma substance P level, perhaps because of the time lag in sampling. These results indicate that oxygen radicals play an important role in the development of chronic hypoxic pulmonary hypertension.
J Cardiovasc Pharmacol 1998 Nov
PMID:Antioxidants attenuate chronic hypoxic pulmonary hypertension. 982 44

Long-term treatment with eicosapentaenoic acid (EPA) is known to improve impaired endothelium-dependent relaxations of atherosclerotic blood vessels in animals and humans. However, it remains to be determined which mechanisms are involved in this beneficial effect of EPA. In this study, we investigated our hypothesis that EPA improves both nitric oxide (NO)-mediated and non-NO-mediated endothelium-dependent vasodilatation in patients with coronary artery disease. The study included eight patients with documented coronary artery disease. The forearm vascular responses to the endothelium-dependent vasodilator acetylcholine and substance P were examined before and after intraarterial infusion of NG-monomethyl-L-arginine (L-NMMA). Same measurements were repeated after the treatment with EPA (1,800 mg/day) for 6 weeks. The long-term treatment with EPA augmented forearm blood-flow response to both acetylcholine and substance P. Furthermore, acute administration of L-NMMA significantly inhibited the EPA-induced augmented response to acetylcholine but not that to substance P. The forearm vascular response to sodium nitroprusside was unchanged by the EPA treatment. These results indicate that long-term treatment with EPA augments both NO-dependent and non-NO-dependent endothelium-dependent forearm vasodilatation in patients with coronary artery disease. Thus the beneficial effects of EPA appear to extend to non-NO-dependent mechanism(s).
J Cardiovasc Pharmacol 1999 Apr
PMID:Long-term treatment with eicosapentaenoic acid augments both nitric oxide-mediated and non-nitric oxide-mediated endothelium-dependent forearm vasodilatation in patients with coronary artery disease. 1021 35

Activation of the renin-angiotensin-aldosterone system (RAAS) in left ventricular systolic dysfunction is a critically important determinant in the pathophysiologic processes that lead to progression of heart failure and sudden death. Angiotensin II, acting at the specific angiotensin receptor (AT1-R), activates a series of intracellular signaling sequences which are ultimately expressed within the cardiovascular system as vasoconstriction and associated vascular hypertrophy and remodeling. Angiotensin converting enzyme (ACE) inhibition leads to increases in the vasodilatory peptides bradykinin and substance P and at least an initial reduction in angiotensin II concentrations. AT1-R blocking drugs prevent access of angiotensin II to the AT1-R and thus prevent cellular activation. ACE inhibitors have clearly been demonstrated through a large number of clinical trials to increase survival in congestive heart failure, primarily by reducing the rate of progression of left ventricular dilatation and decompensation. However, this beneficial effect diminishes over time. Preliminary short-term clinical studies evaluating the efficacy of AT1-R blocking drugs in the treatment of heart failure have suggested that they elicit similar hemodynamic and neuroendocrine effects as do the ACE inhibitors. The combination ACE inhibitors and AT1-R blocking drugs offer the theoretical advantage of increasing bradykinin while blocking the actions of angiotensin II, and thus possibly show a synergistic effect. Again, preliminary studies have yielded encouraging results that are difficult to interpret because neither ACE inhibitor nor the AT1-R blocking drug doses were titrated to tolerance. Pharmacological manipulation of the RAAS has led to better understanding of its role in heart failure and improved clinical outcomes.
Prog Cardiovasc Dis
PMID:Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in the treatment of heart failure caused by left ventricular systolic dysfunction. 1036 49


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