scholarly journals Purinergic Receptors Regulate Myogenic Tone in Cerebral Parenchymal Arterioles

2012 ◽  
Vol 33 (2) ◽  
pp. 293-299 ◽  
Author(s):  
Joseph E Brayden ◽  
Yao Li ◽  
Matthew J Tavares
Keyword(s):  
Tissue Perfusion ◽  
P2y Receptors ◽  
Fundamental Aspect ◽  
Myogenic Tone ◽  
Resistance Arteries ◽  
Receptor Isoforms ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
The Brain ◽  
Intravascular Pressure

Myogenic tone is a fundamental aspect of vascular behavior in resistance arteries. This contractile response to changes in intravascular pressure is critically involved in blood flow autoregulation in tissues such as the brain, kidneys, and heart. Myogenic tone also helps regulate precapillary pressure and provides a level of background tone upon which vasodilator stimuli act to increase tissue perfusion when appropriate. Despite the importance of these processes in the brain, little is known about the mechanisms involved in control of myogenic tone in the cerebral microcirculation. Here, we report that pharmacological inhibition of P2Y4 and P2Y6 pyrimidine receptors nearly abolished myogenic tone in cerebral parenchymal arterioles (PAs). Molecular suppression of either P2Y4 or P2Y6 receptors using antisense oligodeoxynucleotides reduced myogenic tone by 44% ± 8% and 45% ± 7%, respectively. These results indicate that both receptor isoforms are activated by increased intravascular pressure, which enhances the activity of voltage-dependent calcium channels and increases myogenic tone in PAs. Enhancement or inhibition of ectonucleotidase activity had no effect on parenchymal arteriolar myogenic tone, indicating that this response is not mediated by local release of nucleotides, but rather may involve direct mechanical activation of P2Y receptors in the smooth muscle cells.

scholarly journals PC-PLC/sphingomyelin synthase activity plays a central role in the development of myogenic tone in murine resistance arteries

2015 ◽  
Vol 308 (12) ◽  
pp. H1517-H1524 ◽  
Author(s):  
Joseph R. H. Mauban ◽  
Joseph Zacharia ◽  
Seth Fairfax ◽  
Withrow Gil Wier
Keyword(s):  
Specific Inhibitor ◽  
Intrinsic Property ◽  
Tissue Perfusion ◽  
Pressure Control ◽  
Mesenteric Arteries ◽  
Myogenic Tone ◽  
Resistance Arteries ◽  
Virtual Absence ◽  
Sphingomyelin Synthase

Myogenic tone is an intrinsic property of the vasculature that contributes to blood pressure control and tissue perfusion. Earlier investigations assigned a key role in myogenic tone to phospholipase C (PLC) and its products, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). Here, we used the PLC inhibitor, U-73122, and two other, specific inhibitors of PLC subtypes (PI-PLC and PC-PLC) to delineate the role of PLC in myogenic tone of pressurized murine mesenteric arteries. U-73122 inhibited depolarization-induced contractions (high external K+ concentration), thus confirming reports of nonspecific actions of U-73122 and its limited utility for studies of myogenic tone. Edelfosine, a specific inhibitor of PI-PLC, did not affect depolarization-induced contractions but modulated myogenic tone. Because PI-PLC produces IP3, we investigated the effect of blocking IP3 receptor-mediated Ca2+ release on myogenic tone. Incubation of arteries with xestospongin C did not affect tone, consistent with the virtual absence of Ca2+ waves in arteries with myogenic tone. D-609, an inhibitor of PC-PLC and sphingomyelin synthase, strongly inhibited myogenic tone and had no effect on depolarization-induced contraction. D-609 appeared to act by lowering cytoplasmic Ca2+ concentration to levels below those that activate contraction. Importantly, incubation of pressurized arteries with a membrane-permeable analog of DAG induced vasoconstriction. The results therefore mandate a reexamination of the signaling pathways activated by the Bayliss mechanism. Our results suggest that PI-PLC and IP3 are not required in maintaining myogenic tone, but DAG, produced by PC-PLC and/or SM synthase, is likely through multiple mechanisms to increase Ca2+ entry and promote vasoconstriction.

Diacylglycerol and protein kinase C activate cation channels involved in myogenic tone

2002 ◽  
Vol 283 (6) ◽  
pp. H2196-H2201 ◽  
Author(s):  
Donald F. Slish ◽  
Donald G. Welsh ◽  
Joseph E. Brayden
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Transient Receptor Potential Channels ◽  
Cell Swelling ◽  
Cation Channels ◽  
Myogenic Tone ◽  
Resistance Arteries ◽  
Kinase C ◽  
Intravascular Pressure

The smooth muscle cells of resistance arteries depolarize and contract when intravascular pressure is elevated. This is a central characteristic of myogenic tone, which plays an important role in regulation of blood flow in many vascular beds. Pressure-induced vascular smooth muscle depolarization depends in part on the activation of cation channels. Here, we show that activation of these smooth muscle cation channels and pressure-induced depolarization are mediated by protein kinase C in cerebral resistance arteries. Diacylglycerol, phorbol myristate acetate, and cell swelling activate a cation current that we have previously shown is mediated by transient receptor potential channels. These currents, as well as the smooth muscle cell depolarizations of intact arteries induced by diacylglycerol, phorbol ester, and elevation of intravascular pressure, are nearly eliminated by protein kinase C inhibitors. These results suggest a major mechanism of myogenic tone involves mechanotransduction through phospholipase C, diacylglycerol production, and protein kinase C activation, which increase cation channel activity. The associated depolarization activates L-type calcium channels, leading to increased intracellular calcium and vasoconstriction.

scholarly journals Pregnancy increases myometrial artery myogenic tone via NOS- or COX-independent mechanisms

2012 ◽  
Vol 303 (4) ◽  
pp. R368-R375 ◽  
Author(s):  
Delrae M. Eckman ◽  
Ridhima Gupta ◽  
Charles R. Rosenfeld ◽  
Timothy M. Morgan ◽  
Shelton M. Charles ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Pregnant Women ◽  
High Flow ◽  
Myogenic Tone ◽  
Internal Diameter ◽  
Pregnant Uterus ◽  
Voltage Dependent ◽  
Oxide Synthase ◽  
The Brain

Myogenic tone (MT) is a primary modulator of blood flow in the resistance vasculature of the brain, kidney, skeletal muscle, and perhaps in other high-flow organs such as the pregnant uterus. MT is known to be regulated by endothelium-derived factors, including products of the nitric oxide synthase (NOS) and/or the cyclooxygenase (COX) pathways. We asked whether pregnancy influenced MT in myometrial arteries (MA), and if so, whether such an effect could be attributed to alterations in NOS and/or COX. MA (200–300 μm internal diameter, 2–3 mm length) were isolated from 10 nonpregnant and 12 pregnant women undergoing elective hysterectomy or cesarean section, respectively. In the absence of NOS and/or COX inhibition, pregnancy was associated with increased MT in endothelium-intact MA compared with MA from nonpregnant women ( P < 0.01). The increase in MT was not due to increased Ca2+ entry via voltage-dependent channels since both groups of MA exhibited similar levels of constriction when exposed to 50 mM KCl. NOS inhibition ( Nω-nitro-l-arginine methyl ester, l-NAME) or combined NOS/COX inhibition (l-NAME/indomethacin) increased MT in MA from pregnant women ( P = 0.001 and P = 0.042, respectively) but was without effect in arteries from nonpregnant women. Indomethacin alone was without effect on MT in MA from either nonpregnant or pregnant women. We concluded that MT increases in MA during human pregnancy and that this effect was partially opposed by enhanced NOS activity.

Pavlovian eyeblink conditioning is severely impaired in tottering mice

2020 ◽  
Author(s):  
Nina L. de Oude ◽  
Freek E. Hoebeek ◽  
Michiel M. ten Brinke ◽  
Chris I. de Zeeuw ◽  
Henk-Jan Boele
Keyword(s):  
Neuronal Excitability ◽  
Eyeblink Conditioning ◽  
Learning Task ◽  
Loss Of Function ◽  
Oscillatory State ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
Dependent Learning ◽  
The Brain ◽  
Normal Calcium

Cacna1a encodes the pore-forming α1A subunit of CaV2.1 voltage-dependent calcium channels, which regulate neuronal excitability and synaptic transmission. Purkinje cells in the cortex of cerebellum abundantly express these CaV2.1 channels. Here, we show that homozygous tottering (tg) mice, which carry a loss-of-function Cacna1a mutation, exhibit severely impaired learning in Pavlovian eyeblink conditioning, which is a cerebellar dependent learning task. Performance of reflexive eyeblinks is unaffected in tg mice. Transient seizure activity in tg mice further corrupted the amplitude of eyeblink CRs. Our results indicate that normal calcium homeostasis is imperative for cerebellar learning and that the oscillatory state of the brain can affect the expression thereof.

Calmodulin mediates norepinephrine-induced receptor-operated calcium entry in preglomerular resistance arteries

2005 ◽  
Vol 289 (1) ◽  
pp. F127-F136 ◽  
Author(s):  
Carie S. Facemire ◽  
William J. Arendshorst
Keyword(s):  
Calcium Concentration ◽  
Cyclopiazonic Acid ◽  
Calcium Entry ◽  
Resistance Arteries ◽  
Renal Vasculature ◽  
Resistance Vessels ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
Entry Mechanism

Although L-type voltage-dependent calcium channels play a major role in mediating vascular smooth muscle cell contraction in the renal vasculature, non-L-type calcium entry mechanisms represent a significant component of vasoactive agonist-induced calcium entry in these cells as well. To investigate the role of these non-voltage-dependent calcium entry pathways in the regulation of renal microvascular reactivity, we have characterized the function of store- and receptor-operated channels (SOCs and ROCs) in renal cortical interlobular arteries (ILAs) of rats. Using fura 2-loaded, microdissected ILAs, we find that the L-type channel antagonist nifedipine blocks less than half the rise in intracellular calcium concentration ([Ca2+]i) elicited by norepinephrine. SOCs were activated in these vessels using the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) inhibitors cyclopiazonic acid and thapsigargin and were dose dependently blocked by the SOC antagonists Gd3+ and 2-aminoethoxydiphenyl borate (2-APB) and the combined SOC/ROC antagonist SKF-96365. Gd3+ had no effect on the non-L-type Ca2+ entry activated by 1 μM NE. A low concentration of SKF-96365 that did not affect thapsigargin-induced store-operated Ca2+ entry blocked 60–70% of the NE-induced Ca2+ entry. Two different calmodulin inhibitors (W-7 and trifluoperazine) also blocked the NE-induced Ca2+ entry. These data suggest that in addition to L-type channels, NE primarily activates ROCs rather than SOCs in ILAs and that this receptor-operated Ca2+ entry mechanism is regulated by calmodulin. Interestingly, 2-APB completely blocked the NE-induced non-L-type Ca2+ entry, implying that SOCs and ROCs in preglomerular resistance vessels share a common molecular structure.

Differential effect of desipramine and 2-hydroxydesipramine on depolarization-induced calcium uptake in synaptosomes from rat limbic sites

1995 ◽  
Vol 73 (5) ◽  
pp. 619-623 ◽  
Author(s):  
G. Beauchamp ◽  
P.-A. Lavoie ◽  
R. Elie
Keyword(s):  
Calcium Channel ◽  
Plasma Concentrations ◽  
Cingulate Cortex ◽  
Clinical Activity ◽  
Ca Uptake ◽  
Voltage Dependent ◽  
Dependent Inhibition ◽  
Voltage Dependent Calcium Channels ◽  
A Minor ◽  
The Brain

This study was conducted to investigate the inhibition of synaptosomal 45Ca uptake by desipramine and its major metabolite 2-hydroxydesipramine in the rat hippocampus and cingulate cortex, areas associated with emotional control. A concentration-dependent inhibition of net depolarization-induced 45Ca uptake was observed for desipramine (20–200 μM) in synaptosomes from both sites. However, 20 μM 2-hydroxydesipramine failed to inhibit calcium channel function in either of the two limbic sites; higher concentrations (60 or 200 μM) did produce a minor degree of inhibition in hippocampus synaptosomes. Others have shown that the clinically encountered plasma concentrations of 2-hydroxydesipramine are lower than those of desipramine, and the brain concentration of 2-hydroxydesipramine is therefore not expected to surpass or even reach 20 μM. In view of the previously observed clinical activity of 2-hydroxydesipramine, the present results indicate that calcium channel antagonism may not be the basis for the therapeutic effect of tricyclic antidepressants.Key words: voltage-dependent calcium channels, 45Ca uptake, hippocampus, cingulate cortex, tricyclic antidepressants.

Sign in / Sign up

Export Citation Format

Share Document