PubMed · 15448548
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John Butterworth. 2004. Do alpha agonists increase venous return?. https://doi.org/10.1097/00000542-200410000-00040
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PURPOSE: This study was performed to characterize the substrate specificity and mechanism of the intestinal clonidine transport. METHODS: Uptake of [3H]clonidine into Caco-2 cells was investigated. Interaction with drugs was studied in competition assays. RESULTS: Uptake of [3H]clonidine was linear for up to 2 min, Na+-independent, and insensitive to changes in membrane potential, but strongly H+-dependent. The uptake rate of clonidine was saturable with kinetic parameters of 0.5+/-0.1 mM (Kt) and 16.6+/-1.8 nmol/2 min per mg of protein (Vmax) at an outside pH of 7.5. Many drugs such as clonidine, guanabenz, methamphetamine, imipramine, clomipramine, nortriptyline, quinine, xylazine, ephedrine, and diphenhydramine strongly inhibited the [3H]clonidine uptake with Ki values between 0.15 and 1 mM. CONCLUSIONS: Clonidine is transported by a carrier-mediated process. Substrate specificity and mechanism are very similar to the transport described in blood-brain barrier endothelial cells. The transport characteristics do not correspond to carriers for organic cations of the SLC22 family or the choline transporters CHT1 and CLT1. The system might be identical to the H+/tertiary amine antiporter. It interacts with a large number of both hydrophilic and lipophilic cationic drugs, and also, interestingly, with opiates.
Chemical stimulation of a region extending from the most caudal ventrolateral medulla into the upper cervical spinal cord evoked large sympathetically mediated pressor responses. These responses were not dependent on the integrity of the rostral ventrolateral medulla (RVLM) and may be mediated by glutamatergic neurons embedded in the white matter that project to the thoracic spinal cord. We term this new region the medullo-cervical pressor area (MCPA). This region is distinct from the caudal pressor area, because blockade of the RVLM with muscimol inhibited this pressor response but not that evoked from the MCPA. This is the first study to provide functional evidence for a cardiovascular role for neurons in the cervical spinal cord white matter that innervate sympathetic preganglionic neurons (Jansen and Loewy, 1997). Using retrograde tracing, in combination with immunohistochemistry and in situ hybridization, we identified two groups of spinally projecting neurons in the region. Approximately 50% of neurons in one group were excitatory because they contained vesicular glutamate transporter 1 (VGluT1)/VGluT2 mRNA, whereas the other contained a mixed population of neurons, some of which contained either VGluT1/VGluT2 or GAD67 (glutamic acid decarboxylase 67) mRNA. Despite the fact that activation of the MCPA causes potent sympathoexcitation, it does not act to restore arterial pressure after chemical lesion of the RVLM so that a role for this novel descending sympathoexcitatory region remains to be elucidated.
BACKGROUND: The sympathetic nervous system is frequently activated in hypertension and may modify various aspects of renal function. Whether modulation of the sympathetic nervous system directly influences the development of renal fibrosis is yet to be established. The current study investigates the role of the alpha-1 adrenoceptor on human mesangial cell scarring. METHODS: Human mesangial cells were injured with macrophage-conditioned medium (MPCM) and treated with doxazosin for 1 or 3 days. RESULTS: alpha-1 Adrenoceptor antagonist doxazosin of 2 micromol/l reduced fibronectin protein in MPCM-injured female mesangial cells by 31 +/- 1.03% (P < 0.001) and by 9.5 +/- 0.3% (P = 0.01) in male mesangial cells. The differential response between sexes was significant (P = 0.004). alpha-1B Adrenoceptors were detected in human mesangial cells by reverse transcription-polymerase chain reaction with expression in female cells being 87% higher than in males (P = 0.04). Injury with MPCM reduced alpha-1B adrenoceptor mRNA expression in both cell types. Doxazosin had no effect on the protein levels of transforming growth factor-beta (TGF-beta) or interleukin-1beta (IL-1beta), however, a small reduction in tumour necrosis factor-alpha (TNF-alpha) levels was observed. Doxazosin had no effect on the modulators of matrix turnover matrix metalloproteinases MMP3, MMP9 and tissue inhibitor of matrix metalloproteinases (TIMP-1), although a significant reduction in tissue plasminogen activator (tPA); (36.5 +/- 2.6%, P < 0.001) was observed. Doxazosin caused an up-regulation of kallikrein expression, both at mRNA and protein levels. Co-treatment with the bradykinin B2 receptor antagonist HOE140 was able to attenuate the effects of doxazosin treatment on fibronectin levels. CONCLUSION: These data suggest that inhibition of alpha-1B adrenoceptors in mesangial cells exerts an anti-fibrotic effect in a sex-specific manner via modulation of the kallikrein-kinin/plasminogen activator system.