Preoperative assessment of adenylylcyclase activity as a functional marker of islet cell quality after transplantation in rats

To determine the potential value of measuring adenylylcyclase activity as a pre-transplant functional marker of pancreatic islet cell quality, a production rate of adenosine 3':5'-monophosphate was measured with a fluorometric assay in rat islet cells before transplantation. Islets were stored for different periods of time (0 to 96 hours) and in different preservation solutions. The adenylylcyclase activities of islets stored in University of Wisconsin (UW) solution for 3 hours after isolation were significantly higher than those stored in Hanks' balanced salt solution. Similarly, the adenylylcyclase activities of islets stored for more than 24 hours in UW solution decreased significantly with prolonged storage time. Preoperative adenylylcyclase activity was compared with post-transplant islet function in a rat model of diabetes. Transplant success was evaluated by measuring blood glucose level and body weight. Although all transplants were ultimately successful in this study, the rate at which they achieved euglycemia varied, and this is the property that correlated with pre-transplant basal or forskolin-stimulated adenylylcyclase activity. Additional studies showed that it was feasible to measure adenylylcyclase activity in human islet cells. We conclude that preoperative measurement of basal and stimulated adenylylcyclase activity may provide a useful clinical marker for assessing islet cell quality and differences in preservation media and may predict transplant success. Based on these data, additional studies evaluating the feasibility of using adenylylcyclase activity as a research and clinical marker of islet cell viability are warranted.     

Pharmacokinetics and haemodynamic effects of felodipine as monotherapy in hypertensive patients

The acute and steady-state pharmacokinetics and dynamics of felodipine as monotherapy have been studied in 12 hypertensive patients. Felodipine was acutely administered by a constant infusion, 1.5 mg over a 30-min period, or as a 10-mg tablet. Chronic administration was performed on a fixed dose of 10 mg b.i.d. for 28 days. The systemic availability of felodipine after the acute dose was 15%, and at steady state 12% (N.S.), with a 3-fold variation between patients. The mean plasma clearance was 0.6 L/h. The half-life measured in the 4- to 10-h interval after dose was about the same: 3.4, 3.2, and 3.3 h after the i.v. dose, the acute oral dose, and at steady state, respectively. The mean terminal half-life was 24.5 h after the oral dose at steady state. Both the intravenous and the oral doses of felodipine decreased the diastolic blood pressure for about 8 hours after dosing. The reduction in diastolic blood pressure was about 20 mmHg 1 to 2 hours after dose. Supine diastolic blood pressure was significantly reduced up to 48 h after dose at steady state. Maximum reduction of diastolic blood pressure (-22 mmHg) already occurred on the first day of treatment, while systolic blood pressure was further decreased during chronic treatment. There was a correlation between the individual maximum decrease in diastolic blood pressure after the acute oral dose with that after repeated administration (r2 = 0.70, p less than 0.01). Changes in heart rate were non-significant at steady state.     

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.     

Adenylylcyclase gene transfer increases function of the failing heart

A persistent question in cardiovascular gene transfer concerns whether an exogenously delivered gene can increase function of the failing heart. Here we test the hypothesis that intracoronary delivery of adenovirus encoding adenylylcyclase type VI (Ad.ACVI) in the setting of active heart failure will increase function of the failing heart. As a model of heart failure, we used transgenic mice with dilated and poorly functioning hearts resulting from cardiac-directed expression of Galphaq.Galphaq mice with equivalent pretreatment impairment in left ventricular (LV) function (echocardiography) received 2.5x1010 viral particles of Ad.ACVI or Ad.EGFP (enhanced green fluorescent protein), or saline, by indirect intracoronary delivery. Serial echocardiograms obtained before and 14 days after gene transfer showed that Ad.ACVI increased LV ejection fraction (p<0.01) and velocity of circumferential fiber shortening (p<0.03). Detailed measurements in isolated hearts showed that ACVI gene transfer increased LV positive dP/dt (p=0.02) and LV negative dP/dt (p=0.01). Gene transfer was confirmed by polymerase chain reaction. These data show that, in an animal model that mimics key aspects of clinical congestive heart failure, cardiac gene transfer of ACVI increases function of the failing heart.     

Plasma levels and effects of metoprolol on blood pressure and heart rate in hypertensive patients after an acute dose and between two doses during long-term treatment.

Plasma levels and the effect of orally administered metoprolol on the resting arterial blood pressure and heart rate have been studied during acute and steady-state conditions in patients with mild hypertension. The patients receiving an 80-mg dose had a mean maximum plasma level of about 100 ng/ml plasma in single-dose studies and about 140 ng/ml plasma during steady-state conditions. The corresponding values for the patients on the 50-mg dose were about 60 and 100 ng/ml plasma, respectively. The maximum concentrations were reached 1 hr after administration. After the single dose the elimination half-life of metoprolol in plasma was 4.3 plus or minus 0.7 hr in the patients receiving the 80-mg dose and 3.8 plus or minus 0.3 hr in the other group. The difference was not statistically significant. The elimination half-life in the plasma was about the same in the single-dose study and during steady state in both groups. The morning dose induced a decrease of the systolic blood pressure whereas the diastolic blood pressure was not significantly different from that recorded immediately before administration of metoprolol. For the 80-mg dose the systolic pressure dropped from 167 plus or minus 4 to 146 plus or minus 4 mm Hg in the single dose study and from 160 plus or minus 8 to 140 plus or minus 4 mm Hg at steady state. The corresponding values for the 50-mg dose were 150 plus or minus 3 to 135 plus or minus 3 mm Hg and 144 plus or minus 3 to 138 plus or minus 3 mm Hg, respectively. In experiments with placebo the systolic blood pressure was not significantly changed. There was no correlation between the plasma levels and the effect on the systolic blood pressure. Both doses of metoprolol markedly reduced the heart rate after the single dose as well as at steady state. The effect was linearly related to the logarithm of the plasma concentration, and the relationship was virtually the same as obtained previously for the effect on exercise heart rate in healthy volunteers.     

Effect of digoxin on physical performance in healthy man

Summary. The effect of digoxin on the maximal oxygen uptake, the heart rate reaction during submaximal and maximal bicycle exercise and the isokinetic skeletal muscle strength in the thigh was investigated in nine well-trained healthy young men. A daily dose of digoxin of 0·50 mg for 2 weeks, giving a steady state serum digoxin concefltration of 1·0 ± 0·2 nmol/l, did not significantly change maximal oxygen uptake or isokinetic muscle strength. However, the heart rate at rest and during exercise, both at submaximal and maximal levels, decreased significantly during digoxin administration.     

Lactation as a model for naturally reversible hypercorticalism plasticity in the mechanisms governing hypothalamo-pituitary- adrenocortical activity in rats.

Steady state levels of hypothalamic expression of the genes encoding corticotropin-releasing hormone (CRH), proopiomelanocortin (POMC), arginine vasopressin (AVP), and oxytocin (OT) were studied in rats to investigate the mechanisms underlying the transitions between hypercorticalism during lactation and normocorticalism upon weaning. During lactation, CRH mRNA levels and blood titers of adrenocorticotropin (ACTH) were found to be significantly reduced, although POMC mRNA levels in the anterior pituitary were not significantly different from those found in cycling virgin (control) rats; during all phases of lactation, an inverse relationship was observed between the blood levels of ACTH and corticosterone (CORT). Plasma prolactin (PRL) concentrations were elevated approximately 30-fold during lactation. Whereas steady state levels of OT mRNA were markedly increased throughout lactation, those of AVP mRNA were only transiently (initially) elevated, and the blood levels of these hormones were not significantly altered in lactating as compared with cycling virgin and postlactating rats. CRH and POMC gene expression and blood levels of ACTH, CORT, and PRL were normalized within 1-3 d of removal of suckling pups. The temporal relationships between the biosynthetic profiles of the various peptide hormones and the patterns of ACTH and CORT secretion during the two physiological states suggest that lactation-associated hypercorticalism does not merely result from increased ACTH secretion; although still not well substantiated at this time, the evidence points to contributory roles of PRL, OT, and AVP in the hypercorticalismic state found during lactation.     

Downregulation of cardiac guanosine 5'-triphosphate-binding proteins in right atrium and left ventricle in pacing-induced congestive heart failure.

The extent to which congestive heart failure (CHF) is dependent upon increased levels of the cardiac inhibitory GTP-binding protein (Gi), and the impact of CHF on the cardiac stimulatory GTP-binding protein (Gs) and mechanisms by which Gs may change remain unexplored. We have addressed these unsettled issues using pacing-induced CHF in pigs to examine physiological, biochemical, and molecular features of the right atrium (RA) and left ventricle (LV). CHF was associated with an 85 +/- 20% decrease in LV segment shortening (P < 0.001) and a 3.5-fold increase (P = 0.006) in the ED50 for isoproterenol-stimulated heart rate responsiveness. Myocardial beta-adrenergic receptor number was decreased 54% in RA (P = 0.004) and 57% in LV (P < 0.001), and multiple measures of adenylyl cyclase activity were depressed 49 +/- 8% in RA (P < 0.005), and 44 +/- 9% in LV (P < 0.001). Quantitative immunoblotting established that Gi and Gs were decreased in RA (Gi: 59% reduction; P < 0.0001; Gs: 28% reduction; P < 0.007) and LV (Gi: 35% reduction; P < 0.008; Gs: 28% reduction; P < 0.01) after onset of CHF. Reduced levels of Gi and Gs were confirmed by ADP ribosylation studies, and diminished function of Gs was established in reconstitution studies. Steady state levels for Gs alpha mRNA were increased in RA and unchanged in LV, and significantly more GS alpha was found in the supernatant (presumably cytosolic) fraction in RA and LV membrane homogenates after CHF, suggesting that increased Gs degradation, rather than decreased Gs synthesis, is the mechanism by which Gs is downregulated. We conclude that cardiac Gi content poorly predicts adrenergic responsiveness or contractile function, that decreased Gs is caused by increased degradation rather than decreased synthesis, and that alterations in beta-adrenergic receptors, adenylyl cyclase, and GTP-binding proteins are uniform in RA and LV in this model of congestive heart failure.     

Clinical pharmacology of doxazosin in patients with essential hypertension

Doxazosin is a new quinazoline derivative that, like prazosin, has selectivity for alpha 1-receptors. A three-way crossover, randomized, open study in 18 patients with essential hypertension was conducted to investigate the clinical pharmacokinetics of 2, 4, and 8 mg doxazosin at steady state. The pharmacokinetics of the initial 2 mg dose was also studied. Doxazosin showed linear pharmacokinetics. Increases in doses from 2 to 8 mg (steady state) produced proportional increases in doxazosin serum levels (maximum plasma drug concentration [Cmax] minimum plasma drug concentration [C min], and O-24-hour area under the curve [AUC(p-24)], whereas half-life (t1/2) (19.4, 18.7, and 19.7 hours, respectively), volume of distribution (3.4, 3.4, and 3.6 L/kg, respectively), clearance from serum (2.2, 2.2, and 2.1 ml/min/kg, respectively), and degree of protein binding (1.2%, 1.0%, and 1.0% unbound, respectively) were dose independent. Similar t1/2 and time to reach peak concentration (tmax) were obtained with 2 mg initial dose and 2 mg steady state. alpha 1-Acid glycoprotein levels were unchanged during doxazosin treatment. Doxazosin lowered supine and standing systolic and diastolic blood pressure. The blood pressure reduction was associated with an increase in heart rate. Peak hypotensive and tachycardic effects occurred 5.7 +/- 0.1 hours after administration, whereas Cmax was achieved at 2.4 +/- 0.7 hours (tmax). Greater decreases in systolic blood pressure and increases in heart rate were seen in standing than in supine position. The reduction in standing systolic and diastolic blood pressure with 8 mg was greater than with 2 mg (P less than 0.05); however, the increases in heart rate were not different. Dizziness, headaches, and dry mouth were the most frequent side effects. This study indicates that doxazosin shows linear pharmacokinetics between 2 and 8 mg and that because of its long t1/2, once-a-day administration should be adequate for the treatment of hypertension.     

喉鳞癌术后淋巴引流规律及失败模式分析

目的分析喉鳞癌术后颈部淋巴结转移规律,以及局部复发、区域淋巴结转移模式,探讨喉癌放疗临床靶区的勾画。 方法回顾性分析2012年7月至2018年11月山东省肿瘤医院收治的123例喉鳞癌患者资料,包括初诊手术切除以及术后进展在我院接受挽救性手术的患者。根据术后病理分析颈部各淋巴结区淋巴结转移率（LMR）。根据随访结果分析初次治疗后局部、区域、远处失败模式,颈部淋巴结失败区域分布及对应的LMR,分析局部复发、区域淋巴结转移的潜在影响因素。 结果II、III、IV、VI区LMR分别为42.86%、41.67%、27.27%、25.00%,未发现I、V和VII区转移。中位随访15个月,中位疾病无进展生存为16个月［95%可信区间（CI）：8.9~23.1个月］。失败模式分别为：局部复发31例（35.23%）,区域淋巴结转移22例（25.00%）,远处转移9例（10.23%）。淋巴结失败区域分布及LMR分别为II区63.63%,III区36.36%,IV区18.18%,VI区13.63%。单因素分析显示：是否行淋巴结清扫术（χ²=25.87,P＜0.001）、术后是否行颈部预防性照射（χ²=39.31,P＜0.001）是区域淋巴结转移的影响因素;手术方式（χ²=14.02,P=0.007）和术后辅助放射治疗（χ²=15.92,P＜0.001）是局部复发的影响因素。Cox回归模型多因素分析显示,颈部未行预防性照射是区域淋巴结转移的独立预测因素（OR=1.385,95%CI：1.264~12.62,P=0.018）。 结论喉鳞癌淋巴结常见转移部位依次为II、III区,其次为IV、VI区,I、V和VII区在本回顾性研究中未发现转移。失败模式主要为局部复发,其次为区域淋巴结转移,通过颈部预防性照射可降低淋巴结转移率。     

A controlled trial of music and pre-operative anxiety in Chinese men undergoing transurethral resection of the prostate

AIM OF THE STUDY: To test the effects of music intervention on pre-operative anxiety in Chinese males undergoing transurethral resection of the prostate. RATIONALE: No studies have measured the effects of music intervention in reducing pre-operative anxiety for patients with transurethral resection of the prostate (TURP). Previous studies have examined the effects of music on pre-operative anxiety but have not examined the possible effects of the presence of a carer as an independent variable in pre-operative anxiety levels of patients in addition to the music intervention. The cultural validity of applying a music intervention to the reduction of pre-operative anxiety was also investigated. DESIGN: A quasi-experimental design with three groups: music intervention, nurse presence and control group. METHOD: Thirty patients having TURP were randomly assigned (n = 10 each group) to one of the three groups. Pre- and post-test measures of systolic and diastolic blood pressure, heart rate and state anxiety using the Chinese State-Trait Anxiety Inventory (C-STAI) were obtained for the three groups. RESULTS: The findings showed that the music intervention significantly reduced all blood pressure levels for the patients. A reduction in state anxiety level was also found for the music intervention group. No significant reductions in blood pressure, heart rate and state anxiety level were found in the nurse presence and control groups. CONCLUSION: The results support the cross-cultural validity of using a music intervention in pre-operative anxiety reduction, in this case for TURP patients waiting in the theatre holding area.     

Ivabradin

The heart rate at rest is closely associated with total and, in particular, cardiovascular mortality. The reduction in mortality due to treatment with cardiovascular drugs seems to be partly linked with their ability to reduce the heart rate. Both the pathophysiology of angina pectoris in coronary heart disease as well as the development of cardiac insufficiency with reduced left ventricular function are closely associated with resting pulse rate. Therefore, a selective reduction in heart rate is viewed as an interesting therapeutic principle. Such a reduction can be achieved with the new, specific If-channel blocker ivabradine. Ivabradine inhibits the spontaneous depolarisation in the sinus node and thereby reduces heart rate. Other cardiac parameters such as intracellular cAMP or the inotropic state are not influenced. Recent clinical studies allow the application of ivabradine as an alternative agent in patients with stable angina pectoris who do not tolerate beta-blockade. Pending ongoing studies, ivabradine might also be useful for other cardiovascular diseases such as heart failure or rhythm disorders.     

The influence of salt intake on the metabolic acidosis of chronic renal failure

The influence of dietary salt on the levels of plasma bicarbonate and on the characteristics of bicarbonate reabsorption was studied in experimental chronic renal failure. Chronic renal failure was produced in rats by sequential partial nephrectomies. The control group received a diet constant in salt content throughout the progression of renal failure; the other group (PRNa), at each stage of renal failure, received salt intake reduced in direct proportion to the fall in glomerular filtration rate (GFR). In the steady state, the quantities of urinary sodium closely approximated intake in obth groups of animals. The adaptive increased natriuresis per nephron exhibited by the control animals was prevented in the PRNa animals. The PRNa group had (a) higher plasma bicarbonate levels, (b) increased bicarbonate thresholds, and (c) increased maximal tubular reabsorptive capacity for bicarbonate. As renal failure progresses, dietary salt can become a determining factor of the levels at which plasma bicarbonate is maintained. Proportional reduction of dietary salt results in bicarbonate conservation in rats with experimental progressive renal failure.     

心力衰竭病人前列腺素E1治疗效果与其受体水平的相关性研究

目的 观察前列腺素E1(PGE1)对心力衰竭病人的治疗效果,同时通过血小板上EP 受体改变,探讨其可能机制.方法 86 例病人被随机分为两组:常规治疗组(A 组)48 例,PGE1 治疗组(B 组)38 例.常规治疗组采用目前常规抗心力衰竭治疗,而治疗组加用了PGE1 20 μg 于5%葡萄糖注射液稀释后泵静注14 d 为1 个疗程.以治疗前后心功能改善作为判断标准,同时用PCR 法测定血小板上EP 受体改变.结果 B 组总有效率为92.11%,显著高于A 组75.00%,差异有统计学意义(χ2=3.86,P<0.05);PGE1 治疗的慢性阻塞性肺病、高血压和冠心病病人疗效比较,差异无统计学意义(χ2=0.50,P＞0.05);B 组治疗后EP2 和EP4 水平显著增高,与治疗前比较,差异有统计学意义(t 分别=7.86、3.92,P 均<0.05).结论 PGE1 对慢性阻塞性肺病、高血压和冠心病所致的心力衰竭有较好的疗效,其机制可能与治疗后EP2 和EP4 受体表达增加有关.     

A study of adaptive responses in cell signaling in migraine and cluster headache: correlations between headache type and changes in gene expression

The project was an investigation into whether changes in the expression of G-proteins underlie altered cell signaling in migraine and cluster headache. The basis for this assumption is that altered physiological responses are seen in migraineurs and that differences in cell signaling are detected biochemically in various cell types isolated from peripheral blood. Levels of three G-protein mRNAs—Gsα, Giα, and Gqα were quantified in lymphocytes from clinically well-defined migraine and cluster headache patients and correlated with headache type and influence of drug treatment. Giα mRNA was reduced by 50% in all migraine patients compared with control subjects; similarly in patients with or without aura, in patients with a migraine headache at the time of sampling, and patients in a quiescent state. No reduction in the levels of Gsα or Gqα mRNA were seen in migraine patients. A smaller reduction was seen in cluster headache patients, most marked in those without medication. Levels of Gsα. mRNA were significantly reduced in cluster headache patients compared with migraine patients. The marked down-regulation of Giα mRNA in migraine, whether quiescent or acute, indicates either an adaptive response to headache in this group of patients or that low levels of Giα mRNA make individuals more susceptible to migraine.     

Myocardial gene expression of leukaemia inhibitory factor, interleukin-6 and glycoprotein 130 in end-stage human heart failure

BACKGROUND: Studies in different animal models and plasma analyses in humans suggest that members of the interleukin-6 (IL-6) cytokine family may be involved in the pathogenesis of congestive heart failure (CHF). Accordingly, we have examined IL-6-related cytokines in chronic CHF in humans by analysing gene and protein expression in myocardium derived from patients with end-stage heart failure and donor hearts. METHODS: Gene expression of cytokines/receptors of the IL-6 family was documented in myocardial samples using cDNA array hybridization and RNase protection assays. Immunohistochemistry was used to detect leukaemia inhibitory factor (LIF), IL-6 and glycoprotein 130 (gp130) in myocardial tissues. RESULTS: Myocardial gene activity was documented for the majority of IL-6 family cytokines and their receptors. Immunohistochemical analysis localized IL-6, LIF and their common receptor subunit gp130 to myocytes and vascular smooth muscle cells. LIF mRNA levels were enhanced in the left ventricles of CHF patients relative to the left ventricles of donor hearts (patients 4.6 +/- 4.7 vs. donors 0.3 +/- 0.3, P < 0.005). Myocardial IL-6 and gp130 mRNA levels were not statistically different between patients and donors, but in contrast to LIF mRNA expression in heart explants, gp130 mRNA levels were significantly higher in left atrium compared with left ventricle in both patients and donors. CONCLUSIONS: Both mRNA and proteins of gp130 and its ligands IL-6 and LIF are expressed in both nonfailing and failing human myocardium. The elevated LIF mRNA levels in left ventricles from patients with end-stage heart failure suggest a role for LIF in the pathogenesis of CHF.     

Promotion of mouse fibroblast collagen gene expression by mast cells stimulated via the Fc epsilon RI. Role for mast cell-derived transforming growth factor beta and tumor necrosis factor alpha

Chronic allergic diseases and other disorders associated with mast cell activation can also be associated with tissue fibrosis, but a direct link between mast cell mediator release and fibroblast collagen gene expression has not been established. Using in situ hybridization, we show that the elicitation of an IgE-dependent passive cutaneous anaphylaxis (PCA) reaction in mice results in a transient, but marked augmentation of steady state levels of type alpha-1 (I) collagen mRNA in the dermis. While peak levels of collagen mRNA expression in the skin are observed 16-24 h after mast cell activation, substantial numbers of dermal cells are strongly positive for collagen mRNA at 1 and 2 h after antigen challenge, before circulating inflammatory cells are recruited into the tissues. Furthermore, experiments in mast cell- reconstituted or genetically mast cell-deficient WBB6F1-W/Wv mice demonstrate that the increased expression of collagen mRNA at sites of PCA reactions is entirely mast cell dependent. In vitro studies show that the supernatants of mouse serosal mast cells activated via the Fc epsilon RI markedly increase type alpha-1 (I) collagen mRNA levels in mouse embryonic skin fibroblasts, and also upregulate collagen secretion by these cells. The ability of mast cell supernatants to induce increased steady state levels of collagen mRNA in mouse skin fibroblasts is markedly diminished by absorption with antibodies specific for either of two mast cell-derived cytokines, transforming growth factor beta (TGF-beta 1) or tumor necrosis factor alpha (TNF- alpha), and is eliminated entirely by absorption with antibodies against both cytokines. Taken together, these findings demonstrate that IgE-dependent mouse mast cell activation can induce a transient and marked increase in steady state levels of type alpha-1 (I) collagen mRNA in dermal fibroblasts and that mast cell-derived TGF-beta 1 and TNF-alpha importantly contribute to this effect.     

Ventilatory response to intravenous methionine enkephalin in awake dogs

In conscious, microfilaria-free, adult mongrel dogs, i.v. bolus administration of methionine enkephalin (Met5-ENK) produced a transient elevation of both inspiratory minute ventilation (VI) and heart rate (HR). Both VI and HR increased progressively with increasing doses of Met5-ENK over the range of 6 to 18 micrograms/kg, thereafter plateauing at doses up to 36 micrograms/kg. Maximum changes in VI and HR occurred within 30 to 45 sec after injection, both variables returning to control levels in approximately 2 min. In four out of five dogs, mean inspiratory flow (tidal volume/inspiratory time), and consequently, tidal volume, accounted for this enkephalin-mediated increase in ventilation. In one of the dogs, respiratory rate, rather than tidal volume, increased after Met5-ENK. This change in respiratory rate was due to an increase in "effective timing" of the respiratory cycle, the latter defined as the ratio of inspiratory time to total respiratory time. Despite significant changes in VI and HR, neither end tidal oxygen nor carbon dioxide levels were significantly different from control after i.v. injections of Met5-ENK. Pretreatment with naltrexone methylbromide, a quaternary opiate antagonist that does not cross the blood-brain barrier, abolished all enkephalin-induced changes in VI and HR, thus suggesting that systemic enkephalins modulate ventilation via opiate receptors outside the blood-brain barrier. Activation of these receptors produce an increase in both cardiovascular and respiratory activity, as one might expect during stress conditions. These data further support a potential role for peripheral enkephalins as excitatory stress hormones.