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Pharmacological reactivity of human epicardial coronary arteries: phasic and tonic responses to vasoconstrictor agents differentiated by nifedipine.

ABSTRACT: 1. Human epicardial coronary artery rings, freshly obtained from cardiac transplantation patients, commonly exhibited phasic contractile activity in vitro. This activity occurred either spontaneously or in response to vasoconstrictor stimulation. 2. Nifedipine pretreatment (1 nM-0.1 microM) reduced both types of phasic contractions in a concentration-dependent manner. At 0.1 microM nifedipine, spontaneous contractions were completely abolished, as were phasic contractions induced by U46619, endothelin-1 or 5-hydroxytryptamine (5-HT). 3. For U46619 (0.1-100 nM), the largest phasic contractions (amplitude peak to trough) occurred over the mid-range of concentrations used (1-10 nM). At higher concentrations (30-100 nM), phasic activity was reduced as the response reached a maximum. Estimated pEC50 values for the upper phasic and lower phasic curves were significantly different (8.71 +/- 0.13 versus 7.90 +/- 0.11; P < 0.05; n = 10). In the presence of nifidepine (0.1 microM), the purely tonic contraction curve to U46619 was similar to the lower phasic curve in the absence of nifedipine (pEC50 = 8.14 +/- 0.06, n = 10). Similar results were obtained for endothelin-1 (0.1-100 nM). 4. Responses to 5-HT (1 nM-3 microM) were more variable. The largest phasic contractions were spread unevenly throughout the concentration-response curve. In the presence of nifedipine (0.1 microM), the curve to 5-HT was significantly depressed in range but not sensitivity (pEC50) when compared with the phasic curves. 5. In conclusion, activation of dihydropyridine-sensitive voltage-operated Ca2+ channels mediated the phasic contractions commonly observed in human epicardial coronary arteries. These contractions amplified the contractile responses to low concentrations of vasoconstrictors. Inhibition of phasic activity by the Ca2+ channel antagonist, nifedipine, allowed the tonic vasoconstrictor profile of human isolated coronary artery to be determined which is important information for the accurate quantitative assessment of vasodilator responses in this tissue in vitro.

SUBMITTER: Stork AP

PROVIDER: S-EPMC1510518 | biostudies-other | 1994 Dec

REPOSITORIES: biostudies-other

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Pharmacological reactivity of human epicardial coronary arteries: phasic and tonic responses to vasoconstrictor agents differentiated by nifedipine.

Stork A P AP Cocks T M TM

British journal of pharmacology 19941201 4

1. Human epicardial coronary artery rings, freshly obtained from cardiac transplantation patients, commonly exhibited phasic contractile activity in vitro. This activity occurred either spontaneously or in response to vasoconstrictor stimulation. 2. Nifedipine pretreatment (1 nM-0.1 microM) reduced both types of phasic contractions in a concentration-dependent manner. At 0.1 microM nifedipine, spontaneous contractions were completely abolished, as were phasic contractions induced by U46619, endo ...[more]

PMID: 7889259

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Project description:IntroductionFibromyalgia (FM) is associated with dysfunctional pain modulation mechanisms, including central sensitization. Experimental pain measurements, such as temporal summation (TS), could serve as markers of central sensitization and have been previously studied in these patients, with conflicting results. Our objective in this study was to explore the relationships between two different protocols of TS (phasic and tonic) and test the associations between these measures and other clinical variables.Materials and methodsIn this cross-sectional analysis of a randomized clinical trial, patients were instructed to determine their pain-60 test temperature, then received one train of 15 repetitive heat stimuli and rated their pain after the 1st and 15th stimuli: TSPS-phasic was calculated as the difference between those. We also administered a tonic heat test stimulus at the same temperature continuously for 30 s and asked them to rate their pain levels after 10 s and 30 s, calculating TSPS-tonic as the difference between them. We also collected baseline demographic data and behavioral questionnaires assessing pain, depression, fatigue, anxiety, sleepiness, and quality of life. We performed univariable analyses of the relationship between TSPS-phasic and TSPS-tonic, and between each of those measures and the demographic and clinical variables collected at baseline. We then built multivariable linear regression models to find predictors for TSPS-phasic and TSPS-tonic, while including potential confounders and avoiding collinearity.ResultsFifty-two FM patients were analyzed. 28.85% developed summation during the TSPS-phasic protocol while 21.15% developed summation during the TSPS-tonic protocol. There were no variables associated TSPS phasic or tonic in the univariable analyses and both measures were not correlated. On the multivariate model for the TSPS-phasic protocol, we found a weak association with pain variables. BPI-pain subscale was associated with more temporal summation in the phasic protocol (ß = 0.38, p = 0.029), while VAS for pain was associated with less summation in the TSPS-tonic protocol (ß = -0.5, p = 0.009).ConclusionOur results suggest that, using heat stimuli with pain-60 temperatures, a TSPS-phasic protocol and a TSPS-tonic protocol are not correlated and could index different neural responses in FM subjects. Further studies with larger sample sizes would be needed to elucidate whether such responses could help differentiating subjects with FM into specific phenotypes.

Project description:BackgroundNumerous literary data indicate that dynorphin A (DYN-A) has a significant impact on cerebral circulation, especially under pathophysiological conditions, but its potential direct influence on the tone of cerebral vessels is obscure. The aim of the present study was threefold: 1) to clarify if DYN-A is present in cerebral vessels, 2) to determine if it exerts any direct effect on cerebrovascular tone, and if so, 3) to analyze the role of κ-opiate receptors in mediating the effect.Methodology/principal findingsImmunohistochemical analysis revealed the expression of DYN-A in perivascular nerves of rat pial arteries as well as in both rat and human intraparenchymal vessels of the cerebral cortex. In isolated rat basilar and middle cerebral arteries (BAs and MCAs) DYN-A (1-13) and DYN-A (1-17) but not DYN-A (1-8) or dynorphin B (DYN-B) induced strong vasoconstriction in micromolar concentrations. The maximal effects, compared to a reference contraction induced by 124 mM K(+), were 115±6% and 104±10% in BAs and 113±3% and 125±9% in MCAs for 10 µM of DYN-A (1-13) and DYN-A (1-17), respectively. The vasoconstrictor effects of DYN-A (1-13) could be inhibited but not abolished by both the κ-opiate receptor antagonist nor-Binaltorphimine dihydrochloride (NORBI) and blockade of G(i/o)-protein mediated signaling by pertussis toxin. Finally, des-Tyr(1) DYN-A (2-13), which reportedly fails to activate κ-opiate receptors, induced vasoconstriction of 45±11% in BAs and 50±5% in MCAs at 10 µM, which effects were resistant to NORBI.Conclusion/significanceDYN-A is present in rat and human cerebral perivascular nerves and induces sustained contraction of rat cerebral arteries. This vasoconstrictor effect is only partly mediated by κ-opiate receptors and heterotrimeric G(i/o)-proteins. To our knowledge our present findings are the first to indicate that DYN-A has a direct cerebral vasoconstrictor effect and that a dynorphin-induced vascular action may be, at least in part, independent of κ-opiate receptors.

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Pharmacological reactivity of human epicardial coronary arteries: phasic and tonic responses to vasoconstrictor agents differentiated by nifedipine.

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Pharmacological reactivity of human epicardial coronary arteries: phasic and tonic responses to vasoconstrictor agents differentiated by nifedipine.

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