Toluene is a cerebral artery constrictor acting via BK channels.

Acute intoxication by toluene usually follows intentional inhalation to achieve a "high", which may lead to repeated use due to toluene's reinforcing properties. In both acute and chronic intoxication brain function is primarily affected. Neuronal and glial elements participate in toluene's reinforcing properties and chronic toxicity, yet the targets underlying acute toxicity remain unknown.

Ethanol's interaction with BK channel α subunit residue K361 does not mediate behavioral responses to alcohol in mice.

Large conductance potassium (BK) channels are among the most sensitive molecular targets of ethanol and genetic variations in the channel-forming α subunit have been nominally associated with alcohol use disorders. However, whether the action of ethanol at BK α influences the motivation to drink alcohol remains to be determined. To address this question, we first tested the effect of systemically administered BK channel modulators on voluntary alcohol consumption in C57BL/6J males.

Commonly used anesthetics modify alcohol and (-)-trans-delta9-tetrahydrocannabinol in vivo effects on rat cerebral arterioles.

Background: Ethyl alcohol and cannabis are widely used recreational substances with distinct effects on the brain. These drugs increase accidental injuries requiring treatment under anesthesia. Moreover, alcohol and cannabis are often used in anesthetized rodents for biomedical research.

Dual-color miniscope imaging of microvessels and neuronal activity in the hippocampus CA1 region of freely moving mice following alcohol administration.

Moderate-to-heavy episodic ("binge") drinking is the most common form of alcohol consumption in the United States. Alcohol at binge drinking concentrations reduces brain artery diameter in vivo and in vitro in many species including rats, mice, and humans. Despite the critical role played by brain vessels in maintaining neuronal function, there is a shortage of methodologies to simultaneously assess neuron and blood vessel function in deep brain regions.

Alcohol and pregnenolone interaction on cerebral arteries through targeting of vascular smooth muscle - and voltage-gated K channels of big conductance.

Despite the significant number of people who may be taking pregnenolone supplements while drinking alcohol (ethanol), the widely documented cerebrovascular actions of pregnenolone and ethanol, and the critical dependence of cerebrovascular function on cerebral artery diameter, there are no studies addressing the effect of pregnenolone + ethanol in combination on cerebral artery diameter. We investigated this by evaluating the effect of this combination on middle cerebral artery diameter in male and female C57BL/6J mice, both and . The use of de-endothelialized, pressurized middle cerebral artery segments allowed us to conduct a concentration-response study of constriction induced by pregnenolone ± ethanol, in which drug action could be evaluated independently of circulating and endothelial factors.

Differential Functional Contribution of BK Channel Subunits to Aldosterone-Induced Channel Activation in Vascular Smooth Muscle and Eventual Cerebral Artery Dilation.

Calcium/voltage-activated potassium channels (BK) control smooth muscle (SM) tone and cerebral artery diameter. They include channel-forming α and regulatory β subunits, the latter being highly expressed in SM. Both subunits participate in steroid-induced modification of BK activity: β provides recognition for estradiol and cholanes, resulting in BK potentiation, whereas α suffices for BK inhibition by cholesterol or pregnenolone.

Cholesterol and PIP Modulation of BK Channels.

Ca/voltage-gated, large conductance K channels (BK) are formed by homotetrameric association of α (slo1) subunits. Their activity, however, is suited to tissue-specific physiology largely due to their association with regulatory subunits (β and γ types), chaperone proteins, localized signaling, and the channel's lipid microenvironment. PIP and cholesterol can modulate BK activity independently of downstream signaling, yet activating Ca levels and regulatory subunits control ligand action.

Interspecies and regional variability of alcohol action on large cerebral arteries: regulation by KCNMB1 proteins.

Alcohol intake leading to blood ethanol concentrations (BEC) ≥ legal intoxication modifies brain blood flow with increases in some regions and decreases in others. Brain regions receive blood from the Willis' circle branches: anterior, middle (MCA) and posterior cerebral (PCA), and basilar (BA) arteries. Rats and mice have been used to identify the targets mediating ethanol-induced effects on cerebral arteries, with conclusions being freely interchanged, albeit data were obtained in different species/arterial branches.

Cerebrovascular Effects of Alcohol Combined with Tetrahydrocannabinol.

Alcohol (ethanol) and cannabis are among the most widely used recreational drugs in the world. With increased efforts toward legalization of cannabis, there is an alarming trend toward the concomitant (including simultaneous) use of cannabis products with alcohol for recreational purpose. While each drug possesses a distinct effect on cerebral circulation, the consequences of their simultaneous use on cerebral artery diameter have never been studied.

Alcohol Use Disorders and Their Harmful Effects on the Contractility of Skeletal, Cardiac and Smooth Muscles.

Alcohol misuse has deleterious effects on personal health, family, societal units, and global economies. Moreover, alcohol misuse usually leads to several diseases and conditions, including alcoholism, which is a chronic condition and a form of addiction. Alcohol misuse, whether as acute intoxication or alcoholism, adversely affects skeletal, cardiac and/or smooth muscle contraction.

BK channel-forming slo1 proteins mediate the brain artery constriction evoked by the neurosteroid pregnenolone.

Pregnenolone is a neurosteroid that modulates glial growth and differentiation, neuronal firing, and several brain functions, these effects being attributed to pregnenolone actions on the neurons and glial cells themselves. Despite the vital role of the cerebral circulation for brain function and the fact that pregnenolone is a vasoactive agent, pregnenolone action on brain arteries remain unknown. Here, we obtained in vivo concentration response curves to pregnenolone on middle cerebral artery (MCA) diameter in anesthetized male and female C57BL/6J mice.

Temporal Requirement for the Protective Effect of Dietary Cholesterol against Alcohol-Induced Vasoconstriction.

Moderate-to-heavy episodic alcohol drinking resulting in 30-80 mM of ethanol in blood constricts cerebral arteries and constitutes a risk factor for cerebrovascular disease. Alcohol-induced constriction of cerebral arteries and has been shown to be blunted by dietary cholesterol (CLR) in a rat model of a high-CLR diet. Such protection has been proposed to arise from the high-CLR diet-driven increase in blood CLR levels and accompanying buildup of CLR within the cerebral artery smooth muscle.

Cholesterol antagonism of alcohol inhibition of smooth muscle BK channel requires cell integrity and involves a protein kinase C-dependent mechanism(s).

Alcohol constricts cerebral arteries via inhibition of voltage/calcium-gated, large conductance potassium (BK) channels in vascular myocytes. Using a rat model of high-cholesterol (high-CLR) diet and CLR enrichment of cerebral arteries in vitro, we recently showed that CLR protected against alcohol-induced constriction of cerebral arteries. The subcellular mechanism(s) underlying CLR protection against alcohol-induced constriction of the artery is unclear.

Enrichment of Mammalian Tissues and Xenopus Oocytes with Cholesterol.

Cholesterol enrichment of mammalian tissues and cells, including Xenopus oocytes used for studying cell function, can be accomplished using a variety of methods. Here, we describe two important approaches used for this purpose. First, we describe how to enrich tissues and cells with cholesterol using cyclodextrin saturated with cholesterol using cerebral arteries (tissues) and hippocampal neurons (cells) as examples.

Cannabinoid Interactions with Proteins: Insights from Structural Studies.

Cannabinoids have been widely used for recreational and medicinal purposes. The increasing legalization of cannabinoid use and the growing success in Medicinal Chemistry of cannabinoids have fueled recent interest in cannabinoid-sensing sites in receptor proteins. Here, we review structural data from high-resolution cryo-EM and crystallography studies that depict phytocannabinoid, endocannabinoid, and synthetic cannabinoid molecules bound to various proteins.

Gestational Age-Dependent Interplay between Endocannabinoid Receptors and Alcohol in Fetal Cerebral Arteries.

Unlabelled: Alcohol (ethanol) is one of the most widely consumed drugs. Alcohol consumption by pregnant women may result in a range of fetal abnormalities termed fetal alcohol spectrum disorders (FASDs). The cerebrovascular system is emerging as a critical target of alcohol in the developing brain.

Regulation of BK Channel Activity by Cholesterol and Its Derivatives.

Cholesterol (CLR) is an essential structural lipid in the plasma membrane of animal cells. In addition, CLR has been widely recognized as a critical modulator of protein function, including ion channels. Voltage- and Ca-gated K (BK) channels control a wide variety of physiological processes, including cell excitability, smooth muscle contractility, sensory perception, neurotransmitter release, and hormone secretion.

Extra-endothelial TRPV1 channels participate in alcohol and caffeine actions on cerebral artery diameter.

Alcohol (ethyl alcohol; ethanol) and caffeine are the two most widely used psychoactive substances in the world. Caffeine and ethanol have both been reported to constrict cerebral arteries in several species, including humans. We have recently shown that application of 10-μM caffeine mixed with 50 mM ethanol to in vitro pressurized cerebral arteries of rats reduced ethanol-induced constriction.

Large conductance voltage- and calcium-gated potassium channels (BK) in cerebral artery myocytes of perinatal fetal primates share several major characteristics with the adult phenotype.

Large conductance voltage- and calcium-gated channels (BK) control fundamental processes, including smooth muscle contractility and artery diameter. We used a baboon (Papio spp) model of pregnancy that is similar to that of humans to characterize BK channels in the middle cerebral artery and its branches in near-term (165 dGa) primate fetuses and corresponding pregnant mothers. In cell-attached patches (K+pipette = 135 mM) on freshly isolated fetal cerebral artery myocytes, BK currents were identified by large conductance, and voltage- and paxilline-sensitive effects.