Coprescription of opioid and naloxone in office-based practice and emergency department settings in the United States.

OBJECTIVES: The objective of the study was to estimate the national rates of naloxone coprescribing with opioids in office-based practice and emergency department (ED) settings in the United States (US). STUDY DESIGN: This study is a cross-sectional study. METHODS: We used the National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey (NHAMCS) datasets to estimate the national rates of naloxone coprescribing with opioids for the period 2014-2016. The analysis was stratified into office-based practice and ED settings. In ED settings, opioid and naloxone could be given to patients while they were in ED or as a prescription at discharge. Patients of all ages were considered for the analysis and sampling weights were applied to estimate national rates. RESULTS: In office-based settings, 7918 sample visits included one or more opioid prescriptions (10.67 per 100 office visits). Of those, one included naloxone as a coprescription. In ED settings, the opioid prescription was given at discharge in 6124 sample visits (9.68 per 100 ED visits). Of those, two included naloxone as a coprescription. On the other hand, opioid was given to patients in the ED in 8811 sample visits (13.57 per 100 ED visits). Of those, 30 included naloxone as a coprescription. CONCLUSIONS: The rates of naloxone coprescribing with opioids were extremely low in office-based and ED settings in the US. Expanding access to naloxone is a key component of the public health response to the opioid crisis. Based on our study findings, promoting the coprescription of naloxone with opioids may provide greater access to naloxone for those who are at risk of opioid overdose.

Cerebral demyelination in children with collagenous colitis.

Collagenous colitis (CC) is a form of microscopic colitis characterized by the presence of inflammatory infiltrate and subepithelial deposition of collagen in the colon and it is a rare condition with a predominant prevalence in the adult population. Only few cases have been reported in children. We report two children with the CC with concomitant neurological manifestations. Both cases demonstrated variable neurological symptoms clinically and significant cerebral demyelination. In both patients, the gastrointestinal manifestations drastically improved with a short course of prednisolone. However, the neurological symptoms were persistent and progressive. To the best of our knowledge, similar association has not been reported in children.

Cellular basis of vasospasm: role of small diameter arteries and voltage-dependent Ca2+ channels.

Constriction of small (100-200 microm) diameter cerebral arteries in response to increased intravascular pressure plays an important role in the regulation of cerebral blood flow. In arteries from healthy animals, these pressure-induced constrictions arise from depolarization of arterial smooth muscle leading to enhanced activity of L-type voltage-dependent calcium channels. Recently, we have observed that pressure-induced constrictions are greatly enhanced in cerebral arteries obtained from a rabbit model of subarachnoid hemorrhage (SAH) due to the emergence of R-type voltage-dependent calcium channels in arterial myocytes. Enhanced pressure-induced constrictions and the resulting decrease in cerebral blood may contribute to the development of neurological deficits in SAH patients following cerebral aneurysm rupture. This work supports the concept that small diameter arteries represent important targets for current treatment modalities (e.g. Hypertensive, Hypervolemic, Hemodilution "triple H" therapy) used in SAH patients. Further, we propose targeting R-type calcium channels, encoded by the gene Ca(v)2.3, as a novel therapeutic strategy in the treatment of SAH-induced cerebral vasospasm.

Acute and chronic effects of oxyhemoglobin on voltage-dependent ion channels in cerebral arteries.

Voltage-dependent potassium (Kv) and calcium (VDCC) channels play an important role in the regulation of membrane potential and intracellular calcium concentration in cerebral artery myocytes. Recent evidence suggests VDCC activity is increased and Kv channel activity is decreased in cerebral arteries following subarachnoid hemorrhage (SAH), promoting enhanced constriction. We have examined the impact of the blood component oxyhemoglobin on Kv and VDCC function in small (100-200 microm) diameter cerebral arteries. Acute (10 min) exposure of oxyhemoglobin caused cerebral artery constriction and Kv current suppression that was abolished by tyrosine kinase inhibitors and a Kv channel blocker. Although short-term oxyhemoglobin application did not directly alter VDCC activity, five-day exposure to oxyhemoglobin was associated with enhanced expression of voltage-dependent calcium channels. This work suggests that acute and chronic effects of oxyhemoglobin act synergistically to promote membrane depolarization and increased VDCC activity in cerebral arteries. These actions of oxyhemoglobin may contribute to the development of cerebral vasospasm following aneurysmal subarachnoid hemorrhage.

Membrane depolarization, elevated Ca(2+) entry, and gene expression in cerebral arteries of hypertensive rats.

Elevated intracellular Ca(2+) ([Ca(2+)](i)) has been implicated in contractile and phenotypic changes in arterial smooth muscle during hypertension. This study examined the role of membrane potential and [Ca(2+)](i) in altered gene expression in cerebral arteries of a rat (Dahl) genetic model of salt-sensitive hypertension. Cerebral arteries from hypertensive animals (Dahl salt-sensitive) exhibited a tonic membrane depolarization of approximately 15 mV compared with normotensive (Dahl salt-resistant) animals. Consistent with this membrane depolarization, voltage-dependent K(+) currents were decreased in cerebral artery myocytes isolated from hypertensive animals. Arterial wall Ca(2+) was elevated in cerebral arteries from hypertensive animals, an effect reversed by diltiazem, a blocker of voltage-dependent Ca(2+) channels. This depolarization-induced increase in [Ca(2+)](i) was associated with increased activation of the transcription factor, cAMP response element binding protein, and increased expression of the immediate early gene c-fos, both of which are reversed by acute exposure to the voltage-dependent Ca(2+) channel blocker nisoldipine. This study provides the first information linking altered Ca(2+) handling to changes in gene expression in cerebral arteries during hypertension.

Computerized controlled-substance surveillance: application involving automated storage and distribution cabinets.

A secondary data-reporting system used to scan the archives of a hospital's automated storage and distribution cabinets (ASDCs) for indications of controlled-substance diversion is described. ASDCs, which allow access to multiple doses of the same medication at one time, use drug count verification to ensure complete audits and disposition tracking. Because an ASDC may interpret inappropriate removal of a medication as a normal transaction, users of ASDCs should have a comprehensive plan for detecting and investigating controlled-substance diversion. Monitoring for and detecting diversion can be difficult and time-consuming, given the limited report-generating features of many ASDCs. Managers at an 800-bed hospital used report-writing software to address these problems. This application interfaces with the hospital's computer system and generates customized reports. The monthly activity recapitulation report lists each user of the ASDCs and gives a summary of all the controlled-substance transactions for those users for the time period specified. The monthly summary report provides the backbone of the surveillance system and identifies situations that require further audit and review. This report provides a summary of each user's activity for a specific medication for the time period specified. The detailed summary report allows for efficient review of specific transactions before there is a decision to conduct a chart review. This report identifies all ASDC controlled-substance transactions associated with a user. A computerized report-generating system identifies instances of inappropriate removal of controlled substances from a hospital's ASDCs.

Role of phospholamban in the modulation of arterial Ca(2+) sparks and Ca(2+)-activated K(+) channels by cAMP.

Phospholamban (PLB) inhibits the sarcoplasmic reticulum (SR) Ca(2+)-ATPase, and this inhibition is relieved by cAMP-dependent protein kinase (PKA)-mediated phosphorylation. The role of PLB in regulating Ca(2+) release through ryanodine-sensitive Ca(2+) release channels, measured as Ca(2+) sparks, was examined using smooth muscle cells of cerebral arteries from PLB-deficient ("knockout") mice (PLB-KO). Ca(2+) sparks were monitored optically using the fluorescent Ca(2+) indicator fluo 3 or electrically by measuring transient large-conductance Ca(2+)-activated K(+) (BK) channel currents activated by Ca(2+) sparks. Basal Ca(2+) spark and transient BK current frequency were elevated in cerebral artery myocytes of PLB-KO mice. Forskolin, an activator of adenylyl cyclase, increased the frequency of Ca(2+) sparks and transient BK currents in cerebral arteries from control mice. However, forskolin had little effect on the frequency of Ca(2+) sparks and transient BK currents from PLB-KO cerebral arteries. Forskolin or PLB-KO increased SR Ca(2+) load, as measured by caffeine-induced Ca(2+) transients. This study provides the first evidence that PLB is critical for frequency modulation of Ca(2+) sparks and associated BK currents by PKA in smooth muscle.

National supply-chain survey of drug manufacturer back orders.

The impact of manufacturer back orders on the supply chain for pharmaceuticals in the institutional setting was studied. A questionnaire was distributed during May and June 2000 to 600 institutional pharmacies affiliated with a major national drug and supply group purchasing organization. The instrument included questions on basic institutional demographics, perceptions about the frequency of manufacturer back orders for pharmaceuticals, the quality of communication with manufacturers and wholesalers about back orders, the two most significant back orders that had occurred in the 12 months preceding the survey, and the reasons for and impact of back orders. A total of 170 usable surveys were returned (net response rate, 28.3%). Reported manufacturer back orders included an array of drug classes, including blood products, antimicrobials, antiarrhythmics, benzodiazepine antagonists, thrombolytics, corticosteroids, and antihypertensives. Respondents perceived significant back orders as increasing in frequency. Communication by manufacturers and wholesalers about back orders was reported to be relatively poor. A raw-material shortage was the most common reason given by manufacturers for back orders (36.5%), followed by a regulatory issue (23.2%). In most cases (92%), medical staff members had to be contacted, indicating an interruption in the normal drug distribution process. In over a third of instances, respondents stated that the back order resulted in less optimal therapy. A survey found that manufacturer back orders for pharmaceuticals were increasing in frequency and that information flow within the supply chain was insufficient to meet the needs of end users.

Targeted disruption of Kir2.1 and Kir2.2 genes reveals the essential role of the inwardly rectifying K(+) current in K(+)-mediated vasodilation.

The molecular bases of inwardly rectifying K(+) (Kir) currents and K(+)-induced dilations were examined in cerebral arteries of mice that lack the Kir2.1 and Kir2.2 genes. The complete absence of the open reading frame in animals homozygous for the targeted allele was confirmed. Kir2.1(-/-) animals die 8 to 12 hours after birth, apparently due to a complete cleft of the secondary palate. In contrast, Kir2.2(-/-) animals are viable and fertile. Kir currents were observed in cerebral artery myocytes isolated from control neonatal animals but were absent in myocytes from Kir2.1(-/-) animals. Voltage-dependent K(+) currents were similar in cells from neonatal control and Kir2.1(-/-) animals. An increase in the extracellular K(+) concentration from 6 to 15 mmol/L caused Ba(2+)-sensitive dilations in pressurized cerebral arteries from control and Kir2.2 mice. In contrast, arteries from Kir2.1(-/-) animals did not dilate when the extracellular K(+) concentration was increased to 15 mmol/L. In summary, Kir2.1 gene expression in arterial smooth muscle is required for Kir currents and K(+)-induced dilations in cerebral arteries.

Inhibition of vascular K(ATP) channels by U-37883A: a comparison with cardiac and skeletal muscle.

1 The aim of this study was to investigate the selectivity of the ATP-sensitive potassium (K(ATP)) channel inhibitor U-37883A (4-morpholinecarboximidine-N-1-adamantyl-N'-1-cyclohexyl). Membrane currents through K(ATP) channels were recorded in single muscle cells enzymatically isolated from rat mesenteric artery, cardiac ventricle and skeletal muscle (flexor digitorum brevis). K(ATP) currents were induced either by cell dialysis with 0.1 mM ATP and 0.1 mM ADP, or by application of synthetic potassium channel openers (levcromakalim or pinacidil). 2 U-37883A inhibited K(ATP) currents in smooth muscle cells from rat mesenteric artery. Half inhibition of 10 microM levcromakalim-induced currents occurred at a concentration of 3.5 microM. 3 Relaxations of rat mesenteric vessels caused by levcromakalim were reversed by U-37883A. 1 microM levcromakalim-induced relaxations were inhibited at a similar concentration of U-37883A (half inhibition, 1.1 microM) to levcromakalim-induced KATP currents. 4 K(ATP) currents activated by 100 microM pinacidil were also studied in single myocytes from rat mesenteric artery, skeletal muscle and cardiac ventricle. 10 microM U-37883A substantially inhibited K(ATP) currents in vascular cells, but had little effect in skeletal or cardiac myocytes. Higher concentrations of U-37883A (100 microM) caused a modest decrease in K(ATP) currents in skeletal and cardiac muscle. The sulphonylurea K(ATP) channel antagonist glibenclamide (10 microM) abolished currents in all muscle types. 5 The effect of U-37883A on vascular inward rectifier (KIR) and voltage-dependent potassium (KV) currents was also examined. While 10 microM U-37883A had little effect on these currents, some inhibition was apparent at higher concentrations (100 microM) of the compound. 6 We conclude that U-37883A inhibits K(ATP) channels in arterial smooth muscle more effectively than in cardiac and skeletal muscle. Furthermore, this compound is selective for K(ATP) channels over KV and KIR channels in smooth muscle cells.

Ontogeny of local sarcoplasmic reticulum Ca2+ signals in cerebral arteries: Ca2+ sparks as elementary physiological events.

Ca2+ release through ryanodine receptors (RyRs) in the sarcoplasmic reticulum is a key element of excitation-contraction coupling in muscle. In arterial smooth muscle, Ca2+ release through RyRs activates Ca2+-sensitive K+ (KCa) channels to oppose vasoconstriction. Local Ca2+ transients ("Ca2+ sparks"), apparently caused by opening of clustered RyRs, have been observed in smooth and striated muscle. We explored the fundamental issue of whether RyRs generate Ca2+ sparks to regulate arterial smooth muscle tone by examining the function of RyRs during ontogeny of arteries in the brain. In the present study, Ca2+ sparks were measured using the fluorescent Ca2+ indicator fluo-3 combined with laser scanning confocal microscopy. Diameter and arterial wall [Ca2+] measurements obtained from isolated pressurized arteries were also used in this study to provide functional insights. Neonatal arteries (<1 day postnatal), although still proliferative, have the molecular components for excitation-contraction coupling, including functional voltage-dependent Ca2+ channels, RyRs, and KCa channels and also constrict to elevations in intravascular pressure. Despite having functional RyRs, Ca2+ spark frequency in intact neonatal arteries was approximately 1/100 of adult arteries. In marked contrast to adult arteries, neonatal arteries did not respond to inhibitors of RyRs and KCa channels. These results support the hypothesis that RyRs organize during postnatal development to cause Ca2+ sparks, and RyRs must generate Ca2+ sparks to regulate the function of the intact tissue.

ATP-sensitive K+ channel activation by calcitonin gene-related peptide and protein kinase A in pig coronary arterial smooth muscle.

1. We used patch clamp to study whole-cell K+ currents activated by calcitonin gene-related peptide (CGRP) in smooth muscle cells freshly dissociated from pig coronary arteries. 2. CGRP (50 nM) activated an inward current at -60 mV in symmetrical 140 mM K+ that was blocked by glibenclamide (10 microM), an inhibitor of ATP-sensitive potassium (KATP) channels. CGRP-induced currents were larger in cells dialysed with 0.1 mM ATP than with 3.0 mM ATP. 3. Forskolin (10 microM) activated a glibenclamide-sensitive current, as did intracellular dialysis with cAMP (100 microM). The catalytic subunit of cAMP-dependent protein kinase (protein kinase A, PKA), added to the pipette solution, activated equivalent currents in five out of twelve cells. 4. CGRP-induced currents were reduced by the PKA inhibitors adenosine 3',5'-cyclic monophosphorothioate, RP-isomer, triethylammonium salt (Rp-cAMPS; 100 microM) and N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulphonamide+ ++ dihydrochloride (H-89; 1 microM), and abolished by inclusion of a PKA inhibitor peptide in the pipette solution. 5. The beta-adrenergic agonist isoprenaline (10 microM) also activated a glibenclamide-sensitive K+ current. 6. CGRP-induced currents were unaffected by the inhibitor of cGMP-dependent protein kinase (PKG) KT5823 (1 microM). Sodium nitroprusside (10 microM) did not activate a glibenclamide-sensitive current in cells held at -60 mV, but did activate an outward current at +60 mV that was abolished by KT5823, or by 100 nM iberiotoxin (an inhibitor of BKCa channels). 7. Our findings suggest that CGRP activates coronary KATP channels through a pathway that involves adenylyl cyclase and PKA, but not PKG.

Ca2+ channels, ryanodine receptors and Ca(2+)-activated K+ channels: a functional unit for regulating arterial tone.

Local calcium transients ('Ca2+ sparks') are thought to be elementary Ca2+ signals in heart, skeletal and smooth muscle cells. Ca2+ sparks result from the opening of a single, or the coordinated opening of many, tightly clustered ryanodine receptor (RyR) channels in the sarcoplasmic reticulum (SR). In arterial smooth muscle, Ca2+ sparks appear to be involved in opposing the tonic contraction of the blood vessel. Intravascular pressure causes a graded membrane potential depolarization to approximately -40 mV, an elevation of arterial wall [Ca2+]i and contraction ('myogenic tone') of arteries. Ca2+ sparks activate calcium-sensitive K+ (KCa) channels in the sarcolemmal membrane to cause membrane hyperpolarization, which opposes the pressure induced depolarization. Thus, inhibition of Ca2+ sparks by ryanodine, or of KCa channels by iberiotoxin, leads to membrane depolarization, activation of L-type voltage-gated Ca2+ channels, and vasoconstriction. Conversely, activation of Ca2+ sparks can lead to vasodilation through activation of KCa channels. Our recent work is aimed at studying the properties and roles of Ca2+ sparks in the regulation of arterial smooth muscle function. The modulation of Ca2+ spark frequency and amplitude by membrane potential, cyclic nucleotides and protein kinase C will be explored. The role of local Ca2+ entry through voltage-dependent Ca2+ channels in the regulation of Ca2+ spark properties will also be examined. Finally, using functional evidence from cardiac myocytes, and histological evidence from smooth muscle, we shall explore whether Ca2+ channels, RyR channels, and KCa channels function as a coupled unit, through Ca2+ and voltage, to regulate arterial smooth muscle membrane potential and vascular tone.

Applying principles of pharmacoeconomic evaluation to perflenapent emulsion, a new echocardiographic contrast agent for use in cardiac function testing.

A pharmacoeconomic evaluation was performed to determine the cost-effectiveness of perflenapent emulsion, a new contrast agent for use in echocardiography. A decision tree analysis was performed on data from the charts of 108 patients who had undergone stress echocardiography without contrast enhancement as part of a cardiac function or wall-motion study. An analysis of a theoretical cohort of patients was conducted to determine shifts in cost associated with enhancement of stress echocardiography with perflenapent emulsion. Outcome was determined by the point at which the clinician was able to determine a treatment course for the patient based on the diagnostic information given. Stress echocardiography without contrast was identified as the most cost-effective path in terms of a conclusive test. Perflenapent emulsion shows a positive cost impact in patients who have had an inconclusive stress echocardiogram without the use of a contrast agent. These results are supported by a sensitivity analysis across a wide range of pricing for perflenapent emulsion, a wide range of cost for a stress echocardiogram, and up to 99% efficacy of contrast-enhanced stress echocardiography.

Gender differences in coronary artery diameter involve estrogen, nitric oxide, and Ca(2+)-dependent K+ channels.

During their reproductive years, women have a much lower incidence of coronary heart disease compared with men of similar age. Estrogen appears to be largely responsible for this decrease in cardiovascular mortality in women. In the present study, isolated pressurized coronary arteries from rats were used to assess the role of gender and circulating estrogen on coronary vascular function. Pressure-induced constrictions ("myogenic tone") were greater (approximately 2-fold) in isolated coronary arteries from estrogen-deficient male or ovariectomized (OVX) rats compared with similar arteries obtained from female rats or OVX rats receiving physiological levels of estrogen replacement (OVX+E group). These differences in coronary artery diameter were abolished by removal of the vascular endothelium or chemical inhibition of NO synthase. The anti-estrogen, tamoxifen, increased pressure-induced constrictions of coronary arteries from female and OVX+E rats. Dilations of pressurized coronary arteries from female and OVX animals to sodium nitroprusside, a nitrovasodilator that generates NO, were reduced by > 50% by iberiotoxin (IBTX), an inhibitor of Ca(2+)-dependent K+ (KCa) channels. Sodium nitroprusside (10 mumol/L) hyperpolarized coronary arteries by 13 +/- 2 mV, an effect that was greatly diminished (approximately 80%) by IBTX. Coronary arteries isolated from female rats produced greater constrictions in response to IBTX and KT 5823, an inhibitor of cGMP-dependent protein kinase, compared with coronary arteries from OVX rats. cGMP-dependent protein kinase increased the activity of KCa channels 16.5 +/- 5-fold in excised membrane patches from smooth muscle cells enzymatically isolated from these small coronary arteries. We propose that physiological levels of circulating 17 beta-estradiol elevate basal NO release from the endothelial cells, which increases the diameter of pressurized coronary arteries. Further, our results suggest that part of the effect of this NO is through activation of KCa channels in the smooth muscle cells of the coronary arteries.

Evidence against the association of the sulphonylurea receptor with endogenous Kir family members other than KATP in coronary vascular smooth muscle.

We used whole-cell patch clamp to record inward rectifier (KIR) and ATP-sensitive (KATP) K+ currents from pig coronary arterial myocytes. KIR currents were blocked by Ba2+ ions with a KD around 3 microM, but were unaffected by 10 microM glibenclamide, and only reduced 16% by 100 microM of the sulphonlyurea (n=4). In contrast, pinacidil-activated KATP currents were over 1000 times more sensitive to glibenclamide, being inhibited with a KD close to 100 nM (n=5). Our findings suggest that the sulphonylurea receptor (SUR) in these cells associates with the appropriate subunits of the Kir family to form KATP channels, but does not show promiscuous association with subunits that form the strong inward rectifier KIR.

A proposed mechanism for the cardioprotective effect of oestrogen in women: enhanced endothelial nitric oxide release decreases coronary artery reactivity.

1. During their reproductive years women have a much lower incidence of coronary heart disease than men of similar age. A cardioprotective effect of circulating oestrogen appears to be responsible for this decrease in cardiovascular mortality in women. 2. Oestrogen can enhance nitric oxide (NO) production by the vascular endothelium, possibly through enhanced production of the enzyme NO synthase. 3. Pressure-induced constrictions in isolated coronary arteries from rats with physiological circulating levels of oestrogen are reduced compared to oestrogen-deficient animals. This difference is abolished by endothelial removal or inhibition of NO synthase. 4. NO through stimulation of guanylyl cyclase increases levels of the cytosolic second messenger cyclic GMP (cGMP) which activates a cGMP-dependent protein kinase in vascular smooth muscle cells. 5. Potassium currents through calcium-activated channels in vascular smooth muscle cells are increased in response to NO or upon exposure to cGMP-dependent protein kinase. 6. In rat coronary arteries dilations to NO are reduced by agents which inhibit calcium-activated potassium channels. NO can also hyperpolarize this tissue, suggesting membrane potential changes are involved in the response to NO. 7. We propose that oestrogen increases NO production leading to more negative membrane potentials and decreased calcium entry in coronary vascular smooth muscle cells.

Barium inhibits the endothelium-dependent component of flow but not acetylcholine-induced relaxation in isolated rabbit cerebral arteries.

An increase in blood flow can cause vasodilation through a local action on the blood vessel wall. We examined the involvement of potassium channels in the relaxation of segments of the rabbit middle cerebral artery to intraluminal infusion of physiological saline. In segments with intact endothelium, intraluminal flow (20 microliters/min) produced a relaxation of 81.7 +/- 3.0% of pre-flow tone. This relaxation was significantly reduced upon endothelium removal (43%, n = 5) or inhibition of nitric oxide synthase (34%, n = 6). Inhibition of nitric oxide synthase had no effect on the relaxation in endothelium denuded preparations. This suggests that the overall response to flow is a combination of endothelium/nitric oxide dependent and smooth muscle components. Barium chloride (10 and 300 microM) reduced flow-induced relaxations by 30 and 61%, respectively, in intact arteries but had no effect following endothelium removal or nitric oxide synthase inhibition. Micromolar concentrations of barium are thought to block selectively the inward rectifier potassium channel. These concentrations of barium were without effect on the relaxation produced by the endothelium-dependent vasodilator acetylcholine. Blockers of other potassium channels, glibenclamide (10 microM, ATP-sensitive K+ channel), charybdotoxin (100 nN) and tetraethylammonium (0.3 mM, Ca(++)-activated K+ channel) and 4-aminopyridine (1 mM, delayed rectifier K+ channel) did not effect either endothelium-dependent or endothelium-independent flow-induced relaxation. Our results suggest that flow-induced shear stress activates endothelial cell inward rectifier potassium channels leading to increased synthesis/release of nitric oxide.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced resistance artery sensitivity to agonists under isobaric compared with isometric conditions.

We have compared the responsiveness of rabbit mesenteric resistance arteries with agonists under isometric and isobaric conditions. When pressurized (60 mmHg), arteries spontaneously reduced their diameter by 18.1%. An equivalent isometric stress did not generate force in a "wire" myograph. Subsequently, much higher concentrations of norepinephrine (NE) and histamine were required to cause isometric contractions than were needed to reduce vascular diameter of pressurized vessels, whereas angiotensin II produced a maintained response only in pressurized arteries. Reducing transmural pressure to 20 mmHg abolished pressure-induced myogenic tone and decreased arterial sensitivity to NE. Under isometric conditions, partial depolarization with KCl increased sensitivity to NE and histamine to within the concentration range effective in pressurized vessels and also "revealed" responses to angiotensin II. The membrane potential of the vascular smooth muscle cells under partially depolarized conditions was similar to that found in vivo and in vessels studied isobarically. These observations demonstrate a fundamental interaction between pressure-induced myogenic tone and the sensitivity of resistance arteries to vasoactive stimuli. This influence was mimicked in isometrically mounted vessels by partial depolarization, indicating a possible pivotal role for membrane potential in determining the reactivity of the resistance vasculature.