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Existence of different alpha(1)-adrenoceptor subtypes in junctional and extrajunctional neurovascular regions in canine splenic arteries.

ABSTRACT: The present study attempted to characterize the alpha(1)-adrenoceptor subtypes mediating vasoconstrictor responses to administered and nerve stimulation-evoked noradrenaline (NA) release in the isolated and perfused canine splenic artery. A previous study demonstrated that periarterial electrical nerve stimulation (30 s trains of pulses at a frequency of 1, 4 or 10 Hz) induced a double peaked vasoconstriction consisting of an initial transient, predominantly P2X-purinoceptor-mediated constriction followed by a prolonged, mainly alpha(1)-adrenoceptor-mediated response in the canine splenic artery. The effects of alpha(1)-adrenoceptor subtype antagonists on neuronally-mediated second peaked vasoconstrictions were analysed. BMY 7378 (10 - 100 nM), a selective alpha(1D)-adrenoceptor antagonist produced a dose-dependent inhibition of the second peak responses at all frequencies used. BMY 7378 (100 nM) reduced these responses by approximately 30%. Exposure of tissues to chloroethylclonidine (CEC, 60 microM), a selective alpha(1B)-adrenoceptor antagonist attenuated the second peak response by approximately 60%, even in the presence of BMY 7378 (100 nM). On the other hand, WB 4101 (100 nM), a selective alpha(1A)-adrenoceptor antagonist potentiated nerve-stimulation-evoked double peaked vasoconstrictions, especially at low frequencies (1 and 4 Hz). Vasoconstrictor responses to administered NA were dose-dependently antagonized by WB 4101 (10 - 100 nM), but were not significantly affected by either BMY 7378 (10 - 100 nM) or by CEC (60 microM). The present results indicate that NA released from sympathetic nerves may junctionally exert its vasoconstrictor effect via activation of postjunctional alpha(1B)- and in part alpha(1D)-adrenoceptors, whereas exogenous NA extrajunctionally activates alpha(1A)-adrenoceptors to produce its vascular action in canine splenic arteries.

SUBMITTER: Yang XP

PROVIDER: S-EPMC1572737 | biostudies-other | 2001 Apr

REPOSITORIES: biostudies-other

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Project description:Background and purposeIn small arteries, small conductance Ca²?-activated K? channels (SK(Ca)) and intermediate conductance Ca²?-activated K? channels (IK(Ca)) restricted to the vascular endothelium generate hyperpolarization that underpins the NO- and PGI?-independent, endothelium-derived hyperpolarizing factor response that is the predominate endothelial mechanism for vasodilatation. As neuronal IK(Ca) channels can be negatively regulated by PKA, we investigated whether ?-adrenoceptor stimulation, which signals through cAMP/PKA, might influence endothelial cell hyperpolarization and as a result modify the associated vasodilatation.Experimental approachRat isolated small mesenteric arteries were pressurized to measure vasodilatation and endothelial cell [Ca²?]i , mounted in a wire myograph to measure smooth muscle membrane potential or dispersed into endothelial cell sheets for membrane potential recording.Key resultsIntraluminal perfusion of ?-adrenoceptor agonists inhibited endothelium-dependent dilatation to ACh (1 nM-10 ?M) without modifying the associated changes in endothelial cell [Ca²?]i . The inhibitory effect of ?-adrenoceptor agonists was mimicked by direct activation of adenylyl cyclase with forskolin, blocked by the ?-adrenoceptor antagonists propranolol (non-selective), atenolol (??) or the PKA inhibitor KT-5720, but remained unaffected by ICI 118 551 (??) or glibenclamide (ATP-sensitive K? channels channel blocker). Endothelium-dependent hyperpolarization to ACh was also inhibited by ?-adrenoceptor stimulation in both intact arteries and in endothelial cells sheets. Blocking IK(Ca) {with 1 ?M 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34)}, but not SK(Ca) (50 nM apamin) channels prevented ?-adrenoceptor agonists from suppressing either hyperpolarization or vasodilatation to ACh.Conclusions and implicationsIn resistance arteries, endothelial cell ??-adrenoceptors link to inhibit endothelium-dependent hyperpolarization and the resulting vasodilatation to ACh. This effect appears to reflect inhibition of endothelial IK(Ca) channels and may be one consequence of raised circulating catecholamines.

Project description:Highlights • Interrater DSC of the NVB was 0.60 and 0.61 for the left and right side respectively.• Interrater DSC of the IPA was 0.59 for the left and right side.• Agreement was best for the inferior half (i.e. prostate apex to midgland) of the NVB.• Agreement improved with MRI optimization and rater training. Background and purpose Radiation damage to neural and vascular tissue, such as the neurovascular bundles (NVBs) and internal pudendal arteries (IPAs), during radiotherapy for prostate cancer (PCa) may cause erectile dysfunction. Neurovascular-sparing magnetic resonance-guided adaptive radiotherapy (MRgRT) aims to preserve erectile function after treatment. However, the NVBs and IPAs are not routinely contoured in current radiotherapy practice. Before neurovascular-sparing MRgRT for PCa can be implemented, the interrater agreement of the contouring of the NVBs and IPAs on pre-treatment MRI needs to be assessed. Materials and methods Four radiation oncologists independently contoured the prostate, NVB, and IPA in an unselected consecutive series of 15 PCa patients, on pre-treatment MRI. Dice similarity coefficients (DSCs) for pairwise interrater agreement of contours were calculated. Additionally, the DCS of a subset of the inferior half of the NVB contours (i.e. approximately prostate midgland to apex level) was calculated. Results Median overall interrater DSC for the left and right NVB was 0.60 (IQR: 0.54 – 0.68) and 0.61 (IQR: 0.53 – 0.69) respectively and for the left and right IPA 0.59 (IQR: 0.53 – 0.64) and 0.59 (IQR: 0.52 – 0.64) respectively. Median overall interrater DSC for the inferior half of the left NVB was 0.67 (IQR: 0.58 – 0.74) and 0.67 (IQR: 0.61 – 0.71) for the right NVB. Conclusion We found that the interrater agreement for the contouring of the NVB and IPA improved with enhancement of the MRI sequence as well as further training of the raters. The agreement was best in the subset of the inferior half of the NVB, where a good agreement is clinically most relevant for neurovascular-sparing MRgRT for PCa.

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Existence of different alpha(1)-adrenoceptor subtypes in junctional and extrajunctional neurovascular regions in canine splenic arteries.

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