Vasoconstrictor stimulus determines the functional contribution of myoendothelial feedback to mesenteric arterial tone.

KEY POINTS: In isolated resistance arteries, endothelial modulation of vasoconstrictor responses to α1 -adrenoceptor agonists occurs via a process termed myoendothelial feedback: localized inositol trisphosphate (InsP3 )-dependent Ca2+ transients activate intermediate conductance Ca2+ -activated K+ (IKCa ) channels, hyperpolarizing the endothelial membrane potential to limit further reductions in vessel diameter. We demonstrate that IKCa channel-mediated myoendothelial feedback limits responses of isolated mesenteric arteries to noradrenaline and nerve stimulation, but not to the thromboxane A2 mimetic U46619 or to increases in intravascular pressure. In contrast, in the intact mesenteric bed, although responses to exogenous noradrenaline were limited by IKCa channel-mediated myoendothelial feedback, release of NO and activation of endothelial small conductance Ca2+ -activated K+ (SKCa ) channels in response to increases in shear stress appeared to be the primary mediators of endothelial modulation of vasoconstriction. We propose that (1) the functional contribution of myoendothelial feedback to arterial tone is determined by the nature of the vasoconstrictor stimulus, and (2) although IKCa channel-mediated myoendothelial feedback may contribute to local control of arterial diameter, in the intact vascular bed, increases in shear stress may be the major stimulus for engagement of the endothelium during vasoconstriction. ABSTRACT: Constriction of isolated resistance arteries in response to α1 -adrenoceptor agonists is limited by reciprocal engagement of inhibitory endothelial mechanisms via myoendothelial feedback. In the current model of feedback, agonist stimulation of smooth muscle cells results in localized InsP3 -dependent Ca2+ transients that activate endothelial IKCa channels. The subsequent hyperpolarization of the endothelial membrane potential then feeds back to the smooth muscle to limit further reductions in vessel diameter. We hypothesized that the functional contribution of InsP3 -IKCa channel-mediated myoendothelial feedback to limiting arterial diameter may be influenced by the nature of the vasoconstrictor stimulus. To test this hypothesis, we investigated the functional role of myoendothelial feedback in modulating responses of rat mesenteric resistance arteries to the adrenoceptor agonist noradrenaline, the thromboxane A2 mimetic U46619, increases in intravascular pressure and stimulation of perivascular sympathetic nerves. In isolated arteries, responses to noradrenaline and stimulation of sympathetic nerves, but not to U46619 and increases in intravascular pressure, were modulated by IKCa channel-dependent myoendothelial feedback. In the intact mesenteric bed perfused under conditions of constant flow, responses to exogenous noradrenaline were modulated by myoendothelial feedback, but shear stress-induced release of NO and activation of endothelial SKCa channels appeared to be the primary mediators of endothelial modulation of vasoconstriction to agonists and nerve stimulation. Thus, we propose that myoendothelial feedback may contribute to local control of diameter within arterial segments, but at the level of the intact vascular bed, increases in shear stress may be the major stimulus for engagement of the endothelium during vasoconstriction.

The prevalence of drugs and alcohol in fatally injured truck drivers.

To assess the impact of alcohol and other drug use in the trucking industry, the National Transportation Safety Board, in collaboration with The National Institute on Drug Abuse investigated fatal-to-the-driver trucking accidents in eight states over a one year period. Comprehensive drug screens were performed on blood specimens collected from 168 fatally injured drivers. One or more drugs were detected in 67% of the drivers and 33% of the drivers had detectable blood concentrations of psychoactive drugs or alcohol. The most prevalent drugs were cannabinoids and ethanol, each found in 13% of the drivers. Cocaine or benzoylecgonine was found in 8% of the cases. Seven percent of the driver's blood specimens contained amphetamine or methamphetamine and 7% contained phenylpropanolamine, ephedrine, or pseudoephedrine. A panel of toxicologists reviewed the accident investigation report and the toxicology findings for each case and determined that impairment due to marijuana use was a factor in all cases where the delta-9-tetrahydrocannabinol concentration exceeded 1.0 ng/mL and that alcohol impairment contributed to all accidents where the blood alcohol concentration was 0.04% wt/vol or greater. In 50 of 56 cases where psychoactive drugs or alcohol were found, impairment due to substance use contributed to the fatal accident.

Long-term use of nicotine vs placebo gum.

Medical patients (n = 315) who wished to quit smoking were randomly assigned in a double-blind manner to receive either nicotine or placebo gum. Subjects were advised to stop gum use by 4 months. Among abstinent smokers, 46% of those receiving nicotine gum and 17% of those receiving placebo gum used the gum beyond the recommended 4-month period. By 10 months after cessation 17% of quitters receiving nicotine gum and 6% receiving placebo gum were still using gum. Gradual reduction of nicotine gum did not result in withdrawal and cessation of nicotine gum did not increase the probability of relapse to smoking or weight gain. We conclude that use of nicotine gum is due, in part, to the effects of nicotine; however, long-term use is uncommon.

Symptoms of tobacco withdrawal. A replication and extension.

Smokers (n = 315) who wished to quit were randomly assigned in a double-blind manner to groups using either nicotine or placebo gum. Self-reported and observed symptoms of tobacco withdrawal were collected before cessation and at follow-ups of 1 to 2 weeks, 1 month, and 6 months. Self-reported and/or observed anger, anxiety, craving, difficulty concentrating, hunger, impatience, and restlessness were the most prominent symptoms of tobacco withdrawal. These symptoms had returned to precessation levels by 1 month except increased weight, hunger, and craving continued for 6 months in many smokers. Nicotine gum decreased most symptoms, including craving and hunger but not weight. Abstinent smokers with more intense withdrawal were not more likely to relapse. Abstinent smokers who gained more weight were less likely to relapse.

Effect of dose on nicotine's reinforcing, withdrawal-suppression and self-reported effects.

Seventy-eight smokers trying to quit were randomly assigned to 0-, 0.5-, 2- and 4-mg doses of nicotine gum and tracked for 9 months. In the 1st week of abstinence, self-administration of gum did not differ by dose (4 mg = 2 mg = 0.5 mg = 0 mg). Higher doses did not more effectively suppress withdrawal than lower doses nor induce more accurate nicotine identification (4 mg = 2 mg = 0.5 mg greater than 0 mg). Higher doses slightly increased ratings of adverse effects in the 1st week (4 mg greater than 2 mg greater than 0.5 mg greater than 0 mg). Over the next 6 months, the two higher doses appeared to support more gum self-administration than the two lower doses (4 mg = 2 mg greater than 0.5 mg = 0 mg) in the subsample of long-term quitters (n = 20). Our results suggest the dose-response curves differ for nicotine gum's reinforcing, withdrawal-suppression and self-reported effects.

The relationship between chronic ethanol exposure and cigarette smoking in the laboratory and the natural environment.

Few studies have examined the association between ethanol use and cigarette smoking topography. In particular, no study has objectively investigated the relationship between chronic ethanol exposure and cigarette smoking. The aim of this study was to quantify the relationship between cigarette smoking and past and current ethanol use. Male and female cigarette smokers (n = 77) between the ages of 30 and 65 years were recruited and grouped as a function of their past and current ethanol use. Group 1 (n = 18) included subjects who were ethanol abstinent for the 3 months prior to the study and had no history of alcohol abuse (as defined by DSM-III criteria). Group 2 (n = 19) included subjects who were current regular ethanol users and had no history of alcohol abuse. Group 3 (n = 20) included subjects who were ethanol abstinent and had a history of alcohol abuse. Group 4 (n = 20) included current regular ethanol users with a history of alcohol abuse. A history of alcohol abuse was associated with an intensified pattern of cigarette smoking. Significant differences were observed for total daily smoke exposure, cigarette number, puff number, total puff and inhalation volume, and the nicotine, tar and carbon monoxide yields of the cigarettes smoked. Increased expired-air carbon monoxide and serum cotinine levels were also observed. Current ethanol use was not associated with an increased cigarette smoking pattern. These data suggest that alcohol abusers are at greater risk of contracting cigarette-related pathology.

Nicotine vs placebo gum in general medical practice.

Three hundred fifteen smokers who attended a family practice clinic and wished to quit smoking were assigned in a random, double-blind manner to receive either nicotine (2 mg) or placebo gum. Smokers initially received brief advice from a physician and nurse, a slide presentation and written materials (29 to 35 minutes), and a single follow-up visit (12 to 20 minutes) one week after cessation. After corrections for marital status and income, 10% of those who received nicotine gum and 7% of those who received placebo gum reported continuous abstinence for 11 months and passed observer and biochemical verification (this difference was not statistically significant). We conclude that, when used in a nonselected group of smokers along with a brief intervention in a general medical practice, the pharmacologic effects of nicotine gum to increase cessation are either small or nonexistent.

Pragmatic procedures for detecting and documenting alcoholism in medical patients.

Although alcoholics are known to utilize a disproportionate amount of medical care, hospital patients are not routinely screened for alcoholism. A sample of 310 randomly selected patients from two hospitals were administered a structured diagnostic interview. More than one-third (35%) of the men and 14% of the women met DSM-III criteria for a current alcohol use disorder and an additional 27% of the men and 9% of the women met criteria for an alcohol use disorder in remission. The practicality and efficiency of structured interviews is discussed along with the potential of a small subset of items to serve as a screen for alcoholism.

Prevalence of tobacco dependence and withdrawal.

In a sample of 1,006 middle-aged male smokers drawn from the general population, 90% (N = 905) fulfilled DSM-III criteria and 36% (N = 362) fulfilled Fagerstrom's criteria for tobacco dependence. Among the 875 who had stopped smoking in the past for at least 24 hours, 21% (N = 184) fulfilled DSM-III criteria and 46% (N = 403) fulfilled the authors' own criteria for tobacco withdrawal. Concordance of results among the criteria for diagnosing tobacco dependence and withdrawal was low. These results suggest that the DSM-III criteria for tobacco dependence are overinclusive and that there is little consensus among the definitions of tobacco dependence and withdrawal.

Physiologic and subjective changes from smokeless tobacco withdrawal.

This study prospectively examined withdrawal symptoms in persons using Copenhagen smokeless tobacco and in persons smoking cigarettes. Smokeless tobacco chewers (N = 16) and cigarette smokers (N = 11) were examined during a 6-day period, during which time a number of measures were administered. Subjects used smokeless tobacco or smoked cigarettes on an ad libitum basis for a 3-day baseline period and then underwent tobacco deprivation. The significant changes that occurred relative to baseline after smokeless tobacco deprivation included decreased heart rate and orthostatic pulse change and increased craving for tobacco, confusion, eating, number of awakenings, and total scores on a withdrawal symptoms checklist for both self-rated and observer-rated measures. There were more changes and changes of greater severity among cigarette smokers.

Minnesota plan for nonsmoking and health: multidisciplinary approach to risk factor control.

In 1981, the Minnesota Department of Health began a long-term program to control risk factors for the major health problems of the State as determined by an expert committee. The methods chosen to initiate programs were social, economic, and epidemiologic background research and a multidisciplinary statewide planning process. Smoking was considered the most important problem. During 1983-84, department staff members analyzed the epidemiology and economics of smoking in Minnesota and reviewed the literature on methods of smoking control. They and a multidisciplinary technical committee prepared a coordinated plan to increase the prevalence of nonsmoking in Minnesota. The 39 recommendations address mass communication and marketing, educational programs in schools, public and private regulation, economic disincentives through taxation, and funding of programs and evaluation of results. The Minnesota Plan for Nonsmoking and Health was released in September 1984. During the first half year, the plan provided material for formation of a coalition of health organizations to promote nonsmoking. In June 1985, the Minnesota Legislature passed the Omnibus Nonsmoking and Disease Prevention Act, which provides $4 million over 2 years for promotion of nonsmoking through education, regulation, and public communications. These intervention activities will be funded by a portion of a 5-cent increase in cigarette excise tax. The foundations have been laid for what may be the most comprehensive statewide nonsmoking program in the United States.

Smoking behavior of type A and type B smokers.

Retrospective surveys have compared smoking between Type A and Type B individuals; however, prospective studies using objective measures have not been reported. In Study 1, we used an ambulatory smoking recorder to compare the smoking behavior of Type A and Type B smokers. Individual smoking behaviors and the derived tobacco and nicotine exposures were similar for Type A and Type B smokers. In Study 2, we compared serum nicotine before and after smoking a cigarette between Type A and Type B smokers. Pre-cigarette and post-cigarette nicotine levels and nicotine boost were similar for Type A and Type B smokers. We conclude that Type A and Type B smokers do not differ in smoking behavior or tobacco and nicotine intake.