Absorption, distribution, metabolism, and excretion of a respirable antisense oligonucleotide for asthma.

EPI-2010 is a respirable antisense oligonucleotide (RASON), which selectively attenuates discordantly overexpressed adenosine A(1) receptors in allergic lung (Nature 1997;385:721). In the present study, aerosolized [(35)S]-labeled EPI-2010 (5 mg exposure; specific activity 0.055 Ci/mmol) was administered to normal rabbits by endotracheal tube to assess biodistribution, route of elimination, and potential cardiovascular toxicity. The animals were killed at 0, 6, 24, 48, and 72 h after inhalation of EPI-2010. Duplicate aliquots from different tissues and samples were solubilized and assessed for radioactivity. Approximately 1.4% of the total aerosolized EPI-2010 was deposited into the lung. The concentration of the drug in the lung at 0, 6, 24, 48, and 72 h was 64.0 +/- 1.5, 67.0 +/- 4.4, 32.0 +/- 3.7, 23.4 +/- 1.4, and 2.1 +/- 0.5 microg equivalents, respectively. Only a small amount of the radioactivity was detected in extrapulmonary tissues. By 72 h, 67.5% of the administered dose was excreted in the urine, which represented the major pathway of elimination. In postlabeling studies, intact full-length EPI-2010 could only be detected in the lung. Autoradiographic analysis after inhalation of [(35)S]-labeled EPI-2010 showed a relatively uniform deposition of drug throughout the lung. The aerosolized EPI-2010 did not have any significant systemic effects on the cardiovascular system as determined by Cardiomax-II analysis. This pattern of distribution and the lack of effect on cardiovascular function support the concept that RASONs offer the potential to safely address respiratory targets for which systemic distribution and systemic bioavailability may be contraindicated.

Intravenous NPY (27-36)-D decreases cardiac output in conscious Sprague-Dawley rats.

Intravenous (IV) administration of NPY (27-36)-D, a substituted carboxyterminal fragment of neuropeptide Y (NPY), decreases mean arterial pressure (MAP) in normo-and hypertensive rats by a mechanism partially involving histamine receptors. The purpose of this study is to further characterize the cardiovascular effects of NPY (27-36)-D. NPY (27-36)-D dose-dependently decreased MAP, cardiac output, and stroke volume without significantly altering peripheral resistance. Myocardial contractility diminished by 151.2 +/- 31.8, 529.6 +/- 182.5, and 495.4 +/- 66.7 mmHg/s2 in rats treated with 300, 500, and 750 nmol/kg NPY (27-36)-D, respectively. Therefore, NPY (27-36)-D modifies MAP, in part, by a reversible negative inotropic effect on the heart.

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.

Hypotensive effects of [D-Tyr27,36, D-Thr32]Neuropeptide Y (27-36).

An analogue of the 10 C-terminal amino acids of neuropeptide Y (NPY) containing three D-isomeric substitutions (27-36-D) has been synthesized and its cardiovascular activity studied in Sprague-Dawley (SD) and spontaneously hypertensive (SHR) rats. Intravenous administration of 1000 nmol/kg 27-36-D decreases MAP in SHR (-59.9 +/- 5.0 mmHg) and SD rats (-44.4 +/- 4.7 mmHg). The hypotension produced by 1000 nmol/kg 27-36-D diminished by 71.2% following pretreatment with the histamine receptor antagonist diphenhydramine, although histamine depletion with compound 48/80 does not significantly alter this hypotension. These data suggest that NPY (27-36)-D produces a profound and sustained hypotension in two strains of rat which is partially attributable to activity at histamine receptors.

Gender-related differences in the baroreceptor reflex control of heart rate in normotensive humans.

The present study investigates the baroreceptor reflex control of heart rate (HR) of normotensive male and female human volunteers under two conditions: bolus- and infusion-evoked elevations of blood pressure by intravenous administration of phenylephrine. Average age and blood pressure were similar in both sexes, but females had a significantly lower heart period (HP; higher HR). A major difference existed between the two sexes when the blood pressure was elevated by the bolus method. Females had a significantly (50%) smaller baroreflex sensitivity (regression coefficient), which inferred a gender-related difference in baroreceptor reflex control of HR. However, because a positive correlation existed between basal HP and baroreflex sensitivity, it was important to investigate whether this difference was related to the significantly lower basal HP in females. This possibility was ruled out because a similar difference still existed when the data were collected from another group of females who had basal HP values similar to those of males. This gender-related difference in baroreceptor reflex control of HR seems to depend on the pattern by which the pressor stimulus is evoked. The baroreceptor HP response to a slowly developing pressor response that was maintained at a steady-state level was very similar in both sexes. Because the HP response to abrupt (bolus-evoked) pressor stimuli mainly reflects the activity of the vagal component, our findings suggest that the cardiac vagal component seems to play a substantially smaller role in the baroreflex-mediated bradycardia in females.

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.

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.

Role of the sympathetic nervous system in ethanol-induced hypertension in rats.

The present study investigated the role of the sympathetic nervous system in the development of ethanol-induced hypertension (EIH) in the rat. Sympathetic nerve activity (SNA) as an index of central sympathetic tone was measured directly from the preganglionic fibers of the greater splanchnic nerve. Four weeks after starting ethanol feeding, and prior to the development of hypertension, SNA of the ethanol-fed rats was significantly greater than that of controls. The increase in SNA was also evident at the early stages of EIH, at 8 weeks, and in fully developed EIH, after 12 weeks of ethanol consumption. Baroreceptor reflex control of heart rate (HR) but not SNA was impaired prior to the development of EIH at 4 weeks. However, at 8 and 12 weeks, baroreflex control of HR and SNA was normal or slightly greater than that of control rats. Because arterial pressure of ethanol-fed rats was significantly higher than that of controls at 8 and 12 weeks, the data suggest that ethanol feeding caused baroreceptor resetting. Pressor responsiveness to phenylephrine was depressed before the development of EIH but was similar to that of control rats following the development of EIH. The data also shows that blood and plasma volumes of ethanol-fed rats at the times that coincided with the pre- and posthypertensive states were similar to those of control rats which suggests that the development of EIH does not involve an increase in plasma volume. It is concluded that an increase in SNA contributes to the development of EIH and that baroreceptor resetting evoked by ethanol feeding plays a permissive role in maintaining an elevated blood pressure in ethanol-fed rats.

Selective sensitization by L-glutamate of baroreflex-mediated bradycardia following microinjection into the rostral ventrolateral medulla.

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.

New triple microbore cannula system for push-pull perfusion of brain nuclei of the rat.

A new miniaturized triple-barreled cannula system has been developed for the push-pull perfusion of a circumscribed area of brain tissue and/or simultaneous microinjection of a drug or other chemical substance at the same site. A three-lumen, microbore glass capillary tube is drawn to a length of 10-15 mm with a tip diameter of 150-190 microM and connected by lengths of PE tubing to a multichannel peristaltic pump. An artificial CSF is then perfused through either one or two tubes at a rate of 5.0-10.0 microliters/min at a selected site. Thus, a pharmacological receptor agonist and/or antagonist, for example, can be delivered simultaneously to the tissue quantitatively to achieve steady-state levels over time. Alternatively, a single volume of a given drug can be micro-injected at the perfusion site during the course of a push-pull perfusion, simply by replacing one push channel with an injection tube. In both cases, aliquots of CSF perfusate from the pull channel(s) are collected on ice for assay by HPLC or other procedures. Because of the diminutive size of the triple-bore cannula system, it is now possible to perfuse an individual nucleus in the hypothalamus or lower brainstem not only with minimal cytopathological damage but also with a punctate dispersion of the perfusion medium. The large number of possible in vivo manipulations which can be undertaken using this cannula system is illustrated experimentally by recovery studies of [14C]glutamate and 45Ca from the nucleus tractus solitarius and hypothalamus of the rat.

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.

Blood ethanol level and physiologic measurements during ethanol-induced hypertension.

Plasma norepinephrine levels and alpha 2-adrenoceptor binding in central nervous system areas involved in blood pressure regulation were determined during the development of ethanol-induced hypertension in rats. Blood pressure was increased after the 4th week of ethanol feeding. Plasma norepinephrine levels of the ethanol-fed group were lower than those of the control group at most time periods studied even though blood pressure was elevated. 3H-Clonidine binding to alpha 2-adrenoceptors was decreased in the anterior and posterior hypothalamus of ethanol-fed rats throughout most of the study. Blood pressure in the ethanol-fed group was elevated when blood ethanol concentration was high, whereas blood pressure in this group was similar to that of the control group when blood ethanol concentration was low. Brain and plasma samples were taken during low blood ethanol which may explain the lack of positive findings. These results suggest that ethanol is a pressor agent and must be present to exert its cardiovascular effects. These findings suggest the importance of blood ethanol concentration at the time of study and also suggest that the blood pressure elevating effects of ethanol may be central rather than peripheral in origin.

Ethanol exhibits alpha receptor blocking-like properties in anesthetized rats.

The ability of ethanol to reduce alpha-adrenergic receptor-mediated pressor responsiveness in vivo was investigated in chloralose-anesthetized male Sprague-Dawley rats. Catheters were inserted in the jugular vein and the femoral artery of rats for the injection of drugs and the measurement of blood pressure, respectively. Dose-response curves for phenylephrine and norepinephrine were constructed by plotting the change in mean arterial pressure following a bolus dose of the agent against the dose of the pressor agent used. Following construction of an initial dose-response curve, animals were challenged with either a 1 g/kg dose of ethanol or an equivalent volume of saline (iv) and the dose-response curves were repeated. Using a similar protocol, pressor responsiveness was evaluated in animals pretreated with either yohimbine (1 mg/kg) or prazosin (3.9 micrograms/kg), a dose sufficient to produce partial blockade of alpha receptor-mediated pressor responsiveness, and then treated with ethanol. Ethanol produced a partial blockade of alpha receptors when the animals were challenged with either phenylephrine or norepinephrine. This blockade produced by ethanol was shown to be similar to that produced by the receptor blocking agents used in this study. To rule out any nonspecific effects of ethanol in reducing vascular reactivity, some animals were challenged with angiotensin II both before and after treatment with ethanol, yohimbine, or prazosin and after both drugs were administered together. Ethanol, as well as the alpha 1- and alpha 2-adrenergic blocking agents tested failed to have any significant effect on angiotensin II-pressor responsiveness, ruling out any nonspecific effect of ethanol on the vasculature. It is concluded, therefore, that ethanol has alpha receptor blocking-like activity in vivo.

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.

Impairment of central mediation of the arterial baroreflex by acute ethanol administration.

We investigated the possibility that the impairment of baroreflex control of heart rate was due to an action of ethanol on the central component of the baroreflex arc. Baroreceptors and baroreceptor afferents were removed from the arc by sino-aortic denervation and the central end of the left aortic depressor nerve was stimulated. Stimulation frequency response curves relating the decreases in blood pressure, heart rate and sympathetic efferent nerve discharge to the frequency of stimulation were constructed before and after the administration of 0.33, 0.66 and 1 g/kg of ethanol administered systemically. Except for a small decrease in blood pressure following the 1 g/kg dose, ethanol administration did not produce any change in baseline heart rate or blood pressure but the frequency response curve of heart rate was reset by the two lower doses of ethanol whereas the dose of 1 g/kg produced frank impairment of baroreflex control. Similarly the dose of 1 g/kg also impaired the depressor response to aortic nerve stimulation whereas it did not impair the baroreflex control of sympathetic efferent discharge. These data suggest a differential effect of ethanol on central pathways that control baroreflex responses. To ensure that the effect of ethanol was not due to an action of ethanol on an end organ, the heart, a separate group of rats were prepared with sino-aortic denervation and the peripheral end of the cut right vagus nerve was stimulated with increasing frequency. Ethanol did not affect the response to stimulation of the vagus nerve showing that the impairment of baroreflex control of cardiovascular variables was primarily of central origin.

A differential action for ethanol on baroreceptor reflex control of heart rate and sympathetic efferent discharge in rats.

The acute effects of ethanol (0.33, 0.66, or 1 g/kg) on baroreflex control of heart rate (HR) and sympathetic efferent discharge (SED) were investigated in chloralose-anesthetized rats. The two higher doses of ethanol caused a progressive and significant increase in baseline SED and a slight increase in HR. That these effects were ethanol mediated is suggested by the absence of any change in blood pressure following ethanol injection in any amount used and the finding that equivolume saline had no effect on any of the tested parameters. On the other hand, the baroreflex slope of the MAP-SED relationship after ethanol was similar to the control (preethanol) value in contrast to a significant decrease in the baroreflex slope of MAP-HR under the same conditions. These findings suggest that the sensitivity of the reflex control of SED was preserved whereas that of HR was impaired after acute ethanol administration. Since these findings were obtained in the same animals, our data suggest that acute ethanol has a differential action on reflex control of SED and HR. Further, the significant increase in SED after moderate and high doses of ethanol suggests an increased central sympathetic tone as recordings were made from preganglionic nerve fibers (splanchnic nerve). The absence of an increase in baseline MAP, in spite of a significant increase in baseline SED following acute ethanol injection, could be explained, at least in part, by an ethanol-evoked reduction in pressor responsiveness to phenylephrine, an alpha-adrenergic agonist.

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.

Acute effects of ethanol on baroreceptor reflex control of heart rate and on pressor and depressor responsiveness in rats.

In rats anesthetized with alpha-chloralose, doses of 0.1, 0.5, and 1 g/kg of ethanol produced an upward shift of baroreflex curves constructed by plotting the heart rate response against mean arterial pressure following evoked rises in mean arterial pressures by phenylephrine or angiotensin II. Whereas the upward shift of baroreceptor curves may be related, at least in part, to a higher base-line heart rate after ethanol, the data showed that the 1 g/kg dose of ethanol significantly depressed baroreflex sensitivity, suggesting that higher doses of ethanol impair baroreflex-mediated bradycardia. The phenylephrine, but not the angiotensin II or the nitroprusside, dose-response curves were shifted to the right after ethanol, indicating a decreased pressor responsiveness and suggesting that ethanol may have alpha-adrenergic blocking activity. This effect was also obtained in conscious rats. That this effect was not influenced by changes in baroreflex sensitivity was supported by the finding that a similar shift of the phenylephrine pressor-response curve was obtained in bilaterally vagotomized and hexamethonium-treated rats. Whether this effect of ethanol on baroreflex control of heart rate was influenced by anesthesia was investigated in conscious rats; the 1 g/kg dose of ethanol that produced the most significant decrease in baroreflex sensitivity was used in these experiments. Ethanol was still able to significantly inhibit baroreflex sensitivity in conscious rats, but the upward shift of the baroreflex curve and the elevated base-line heart rate no longer occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of acute ethanol administration on the baroreceptor reflex control of heart rate in normotensive human volunteers.

The effects of acute ethanol administration on blood pressure, heart rate and the baroreceptor reflex control of heart rate were studied in normotensive subjects who served as their own control. Baroreceptor reflex control of heart rate was measured by two methods: the ramp method and the steady state method. None of the doses of ethanol had any effect on blood pressure during the observation period, except for the highest dose where a slight elevation was evident for a short period of time. On the other hand, the heart rate showed a slight but consistent dose-related increase. In general, ethanol attenuated the baroreceptor mediated bradycardia but this effect was dependent on the way in which blood pressure was elevated. A dose-related impairment of baroreceptors was evident when the ramp method was used, i.e. ethanol significantly depressed baroreflex sensitivity, expressed as delta heart period (HP)/delta mean arterial pressure (MAP). In contrast, delta HP/delta MAP was not influenced by ethanol when the steady state method was used. However, the steady state baroreflex curves were reset about a higher median blood pressure (MAP50), suggesting that the baroreceptors will be operative at higher blood pressure levels after ethanol. The pressor responsiveness was also influenced differently by ethanol depending on the method of injecting phenylephrine. An increase in pressor responsiveness was evident, though not dose-related, after ethanol only when blood pressure was elevated by the ramp method, suggesting that the inverse relationship between baroreflex sensitivity and pressor responsiveness is more prominent with the ramp method and/or when impairment rather than resetting of baroreceptors occurs. That the decrease in baroreflex sensitivity and the increase in MAP50 were related to peak ethanol levels in blood and that the blood pressure was not influenced by ethanol strongly suggest these effects were ethanol mediated. The weakened buffering action of the baroreflexes would be expected to favour the development of higher blood pressure.

Behavioral interactions of ethanol and methylxanthines.

The effect of the methylxanthines caffeine, theophylline and isobutylmethylxanthine (IBMX) on ethanol-induced ataxia and loss of righting reflex was investigated in three strains of mice. A significant potentiation of ethanol-induced ataxia was produced in all strains of mice at 20, 45 and 75 min after ethanol in mice pretreated with 62.5 mg/kg caffeine and 12.5 mg/kg IBMX. In mice pretreated with 40 mg/kg caffeine potentiation of ethanol-induced ataxia was observed only at 20 min after ethanol. Theophylline pretreatment produced no alteration in ethanol-induced ataxia. The results of methylxanthine pretreatment on ethanol-induced ataxia were similar, regardless of a shorter (10 min) or longer (75 min) pretreatment time. The methylxanthines produced no effect on motor coordination or behavior when administered separately. Although ethanol-induced loss of righting reflex was shortened by theophylline, neither caffeine nor IBMX altered the duration of loss of righting reflex. It is possible that inhibition of adenosine uptake, a known effect of the methylxanthines, may be a more likely explanation for the modulation of the behavioral effects of ethanol.