Wallace R. Wooles

Ethanol-induced hypertension involves impairment of baroreceptors.

We studied the effect of 12 weeks of ethanol feeding on arterial blood pressure and baroceptor reflex control of heart rate in Sprague-Dawley and Wistar rats. Baroceptor reflex sensitivity and pressor responsiveness were evaluated by evoking graded rises in mean arterial pressure with increasing doses of phenylephrine and angiotensin II. After 12 weeks of ethanol feeding there was a modest increase in mean arterial pressure with no change in heart rate in both strains. When angiotensin II or phenylephrine was used as the pressor agent, baroreceptor reflex curves (relationships between changes in mean arterial pressure and heart rate) of Wistar rats were shifted upward and had a markedly reduced slope compared with those of control rats, suggesting that impairment of baroreceptor reflex control of heart rate had occurred. This effect was less evident in the Sprague-Dawley rats. Ethanol-fed rats had a higher sympathetic activity, since beta-blockade with propranolol decreased heart rate to a greater degree than that seen in control rats. The pressor response curve of phenylephrine was shifted to the right in control rats challenged with ethanol (0.5 g/kg), implying the presence of alpha-blockade. This shift was not present in ethanol-fed rats, showing that tolerance had developed to this effect of ethanol. These findings show that attenuation of baroreceptor reflex function is associated with ethanol-induced hypertension but do not establish whether this is a cause or an effect of the developed hypertension.

Impairment of baroreceptor reflex control of heart rate but not sympathetic efferent discharge by central neuroadministration of ethanol.

We investigated the acute hemodynamic effects of ethanol microinjection into brain areas known to influence cardiovascular function and reflexes. In chloralose-anesthetized rats, ethanol had no effect on baseline mean arterial pressure, heart rate, or sympathetic efferent discharge when microinjected into the nucleus tractus solitarius, the dorsal motor nucleus of the vagus, the rostral ventrolateral medulla, or the posterior hypothalamus. On the other hand, ethanol microinjection into the anterior hypothalamus caused a site-dependent pressor effect and an increase in sympathetic efferent discharge. Baroreceptor heart rate response but not sympathetic efferent discharge response was impaired by ethanol microinjection into the nucleus tractus solitarius, the dorsal motor nucleus of the vagus, and the rostral ventrolateral medulla, suggesting that ethanol involves one or more of these areas in its inhibitory effect on baroreceptor heart rate response and that ethanol has a selective action on baroreceptor reflex control of heart rate. The findings that 1) the effect was dose dependent and 2) injection of ethanol outside of, or an equal volume of cerebrospinal fluid into, the nucleus tractus solitarius had no effect on the response strongly suggest that the observed effect on baroreceptor heart rate response was ethanol mediated. Ethanol microinjection into the dorsal motor nucleus of the vagus impaired the heart rate response, thus raising the possibility that leakage of ethanol to that area from the nucleus tractus solitarius might have contributed to its effect. These findings show that ethanol has a pressor and sympathoexcitatory site of action within the anterior hypothalamus and that it selectively impairs baroreceptor heart rate response via a central site of action; the mechanisms by which ethanol produces these effects remain to be elucidated.

Effect of acute and chronic ethanol on the agonist responses of vascular smooth muscle.

We studied the effect of ethanol in vitro on the response of isolated rat aortas to phenylephrine and angiotensin II. We also examined the effect of chronic ethanol consumption on the phenylephrine response and the effect of ethanol in vitro on that response during the development of ethanol-induced hypertension. In acute experiments the depression of the phenylephrine dose-response produced by ethanol in vitro was greater than that for angiotensin II. Comparing the depression of these agonist dose-responses by ethanol to the depression by the receptor blockers, verapamil, prazosin and saralasin, suggests that ethanol may act like an alpha 1-adrenoceptor blocker. During chronic ethanol consumption two opposing changes occurred: (1) desensitization to phenylephrine during weeks 6-18 and, (2) tolerance to depression by ethanol in vitro during weeks 4-10. These opposing changes may cancel each other which suggests that the hypertension due to chronic ethanol consumption is probably not due to an action of ethanol on the vasculature.

The effect of acute ethanol on dopamine metabolism and other neurotransmitters in the hypothalamus and the corpus striatum of mice

The effect of acute ethanol on the levels of NE, DA and its metabolites DOPAC and HVA, as well as on the levels of GABA, in the corpus striatum and hypothalamus were investigated in mice in the first two hours after acute ethanol administration. There was a marked increase in the concentration of DOPAC and HVA in the corpus striatum from 30 to 120 minutes after a dose of 3.5 g/kg of ethanol even though the concentration of DA was only elevated at 60 minutes after ethanol. A dose of 1.75 g/kg of ethanol did not increase DA levels 60 minutes after administration although it did increase the concentration of DOPAC and HVA at this time. In the hypothalamus a dose of 3.5 g/kg of ethanol did not change the concentration of NE or DA but did produce a marked increase in the levels of DOPAC and HVA at 60 and 120 minutes post ethanol. A lower dose of ethanol, 1.75 g/kg, produced the same effect 60 minutes after ethanol. Ethanol caused a dose-dependent accumulation of DOPA in the corpus striatum after inhibition of DOPA-decarboxylase suggesting an increased synthesis of DA. These data suggest that the increased concentrations of DA metabolites after ethanol is secondary to enhanced DA synthesis and turnover. The concentration of NE and GABA in the hypothalamus and the corpus striatum was unchanged at any time period after ethanol.

Effect of chronically administered methylxanthines on ethanol-induced motor incoordination in mice.

The effect of chronic (10 days) administration of methylxanthines, caffeine, IBMX and theophylline on acute ethanol-induced motor incoordination has been investigated in the mice. In animals that received caffeine, 45 and 90 mg/kg/24 h, ethanol, 1.5 g/kg, produced motor incoordination significantly greater compared to that in the control groups. Significantly greater ethanol-induced motor incoordination was seen in animals fed IBMX, 30 and 60 mg/kg/24 h, compared to controls. Ethanol-induced increased motor incoordination in caffeine and IBMX-fed animals was also associated with significantly greater 3H-R-PIA binding in whole brains compared to tap water controls indicating an increase in brain adenosine binding sites. However neither motor incoordination nor 3H-R-PIA binding was altered in theophylline 75 and 150 mg/kg/24 h, fed animals. The increased motor incoordination associated with increased adenosine binding sites in the brains of caffeine and IBMX-fed animals suggests an involvement of central adenosine mechanisms in the motor incoordinating effect of ethanol and further supports our earlier suggestion for the role of adenosine in some of the central effects of ethanol.

Vasopressin receptors in the area postrema differentially modulate baroreceptor responses in rats

This study examined the effects of microinjection of [Arg8]vasopressin (AVP) into the area postrema (AP) on baroreceptor reflex control of heart rate (HR) and sympathetic efferent discharge (SED) in anesthetized rats. Comparable increments in blood pressure evoked by systemic AVP, as opposed to phenylephrine, were associated with significantly greater reflex bradycardia. Similarly, AVP augmented the baroreflex-mediated sympathoinhibition; however, this effect was evident only with the lower increments in arterial pressure (< 45 mm Hg) i.e. following systemic administration of small doses of AVP. Beyond 45 mm Hg there was no further augmentation of baroreflex-mediated sympathoinhibition showing the non-linearity of the response compared to phenylephrine which was linear over a wide range of induced pressure increases. Microinjection of AVP into the AP produced a differential effect on HR and SED responses to baroreceptor activation by systemically administered phenylephrine, the baroreflex slope of HR response was attenuated whereas that of SED was enhanced. Microinjection of the V1 antagonist AVPX (d(CH2)5Tyr(Me)-AVP) into the AP abolished the inhibitory effect of AVP on the baroreceptor-HR response suggesting that V1 receptors are involved in this response. Further, AVPX inhibited the baroreceptor-SED response suggesting that V1 receptors in the AP are tonically involved in modulating the baroreceptor reflex control of SED. Qualitatively similar but smaller responses were obtained following microinjection of AVP into the nucleus tractus solitarii (NTS) suggesting involvement of neural input from the AP to the NTS in AVP-evoked responses in the AP. It is concluded that the AVP receptors in the AP differentially modulates the baroreceptor reflex control of HR and SED.

Selective sensitization byl-glutamate of baroreflex-mediated bradycardia following microinjection into the rostral ventrolateral medulla

Abstract This study examined the role of l -glutamate receptors in different sites in the rostral ventrolateral medulla (RVL) on baseline mean arterial pressure (MAP), heart rate (HR), sympathetic efferent discharge (SED) as well as baroreflex control of HR and SED. Depending on the site, the hemodynamic responses varied from an increase to a decrease in MAP which was accompanied by a similar or an opposite change in HR; the change in SED correlated positively with the change in MAP. Because injection of the test dose of glutamate (5 nM) into the deepest portion of the RVL produced the most pronounced increases in MAP, which was accompanied by a brisk bradycardia, we decided to investigate the nature of these responses. Dose-related sympathoexcitatory, pressor and bradycardic effects were obtained in response to 1, 3, 5 and 10 nM glutamate. The glutamate antagonist, glutamate diethylester (GDEE) abolished these responses and decreased baseline MAP, HR and SED. That glutamate-evoked bradycardia was baroreceptor-mediated was supported by: (1) the bradycardia was not only eliminated but was also converted to a small but significant tachycardic response in sinoaortic denervated rats and following cardiac muscarinic blockade; (2) glutamate substantially sensitized the baroreceptor HR and had no effect on SED response when tested by phenylephrine; and (3) GDEE abolished the sensitizing action of glutamate on the baroreflex control of HR. We conclude that glutamatergic pathways in the deepest portion of the RVL are tonically active and subserve sympathoexcitatory, pressor and tachycardic effects. Also, glutamate differentially sensitizes the baroreceptor reflex pathways that control HR by mainly activating the vagal component of the reflex, an effect which masks its tachycardic effect.

Survey Results of POPS Use in United States and Canadian Schools of Medicine and Pharmacy

Recent initiatives calling for changes in medical education, such as the General Professional Education of the Physician and Robert Wood Johnson Reports, have recommended alternative teaching approaches to the lecture format. The Patient‐Oriented Problem‐Solving (POPS) exercises, sponsored by the Upjohn Company (Kalamazoo, MI) and made available for pharmacology in 1985, offer one of many possible alternatives to lectures. The technique involves group interactions between four students in a working group, each of whom must, with the aid of their colleagues, arrive at mutual solutions to simulated cases in clinical pharmacology. The exercises are intended to complement and enhance the learning of concepts from lectures, and to help students apply these concepts practically. The system is used extensively by medical, pharmacy, and other health profession schools throughout the United States and also abroad, and many thousands of exercise booklets have been distributed free of charge by the Upjohn Company. Currently, a committee of the American Medical School Pharmacology (AMSP) group, working with Upjohn Company personnel, is responsible for overseeing the writing and educational testing of new and revised exercises. The purpose of this paper is to report the results of a survey of POPS use in medical and pharmacy schools in the United States, Canada, and Puerto Rico, completed in March 1993. The returns indicate continued strong interest in the approach, and the acquired data affirm its value in teaching principles of clinical pharmacology to students in basic pharmacology courses. Detailed data were obtained on patterns of use, and a number of advantages and disadvantages were identified. Priorities for the writing of new POPS exercises were expressed by the respondents. The information acquired will form the basis for planning new and revised POPS exercises in the future.

Protective effect of zinc against ethanol toxicity in mice.

Protection against the lethal effects of ethanol at 4.5 g/kg administered acutely was maximal when zinc was administered 60 min prior to ethanol. The timing of ethanol administration corresponded with elevated plasma levels of absorbed zinc. Protection was inversely related to the dose of zinc employed, as 0.5 mumol provided greater protection than 1.0 mumol, which provided greater protection than 2.0 mumol. Protection against ethanol lethality was greater if zinc was administered 60 min prior to each injection of ethanol. Acute zinc pretreatment did not alter the activity of liver alcohol dehydrogenase (ADH), nor did it alter the blood clearance of ethanol. Chronic zinc administration as ZnCl2, 100 micrograms/ml in the drinking water for 30 d, produced a 25% decrease in hepatic ADH activity, which was accompanied by a similar decrease in the intravascular clearance of ethanol.

The Case Conference Approach to Teaching Clinical Pharmacology

This article analyzes the development of the small group case conference format, historically, elsewhere, and at the authors institution, as a way of introducing second‐year medical students enrolled in a basic pharmacology course to the practicalities, nuances, and challenges of contemporary drug therapy. A number of goals and purposes for these conferences have been identified and incorporated into the development and execution of a plan carried out over the past 14 years. Two examples of the conferences were presented, including an analysis of their teaching features. A listing of the general topics of 40 individual conferences used by the authors was provided. The authors reviewed evidence based on several methods of evaluation that the conferences are enthusiastically accepted by second‐year medical students as an adjunctive approach to teaching both basic and applied clinical pharmacology. In addition, the authors find that the conferences subserve a number of other teaching functions such as problem‐solving, information retrieval and presentation, and peer co‐instruction. The conferences provide a mechanism for faculty‐student interaction and an additional way to evaluate student knowledge and performance beyond the more conventional examination approaches.