Cardiac structure and exercise blood pressure in urban and rural Canadian men of Icelandic descent.

The objective of the study was to determine the relationship between exercise systolic blood pressure (ESBP), during bicycle ergometry, and echocardiographically determined left ventricular structure in rural and urban Canadian men of Icelandic descent. The study was cross-sectional in design. The settings were urban Winnipeg and the rural Interlake District in the province of Manitoba, Canada. Subjects were adult male volunteers from families of wholly Icelandic descent. The subjects were 30 to 60 years of age and had supine blood pressure < 160/95 mm Hg. Anthropomorphic measurements, echocardiography and sphygmomanometry, at rest and during bicycle ergometry, were performed on all subjects. Prevalence of exaggerated ESBP (> or = 200 mm Hg) and left ventricular hypertrophy (LVH) was not significantly different in the two groups. In all but one individual LVH was classified as eccentric hypertrophy. In both urban and rural subjects with exaggerated ESBP, left ventricular mass index (LVMI) was greater than in those subjects without exaggerated ESBP. The LVMI correlated with ESBP at the highest workloads (> or = 150 W). Multivariate analysis of all subjects showed that cardiac index, ESBP, body mass index, and low exercise heart rate were predictive of LVMI. There was no significant difference in prevalence of ESBP or LVH between urban and rural Manitobans of Icelandic descent. However, LVMI levels were lower, and values for ESBP greater, in the rural group compared with the urban group. Within each of the two groups there was a positive association between ESBP and LVMI; hence, the study supports findings of our previous investigation showing evidence of early target organ effects in normotensive men with an exaggerated ESBP.

Relevance of classification by size to topographical differences in bronchial smooth muscle response.

To investigate heterogeneity of airway smooth muscle response, we studied strips of large and small branches from third- to sixth-generation bronchi obtained from ragweed antigen-sensitized and control dogs. The response to electrical field stimulation and carbamylcholine chloride was greater in strips from larger branches of the same generation when expressed as "tissue stress" (force per unit cross-sectional area of the whole tissue), whereas no difference emerged with use of the more appropriate "smooth muscle stress" (force per unit cross-sectional area of the muscle tissue). The response to histamine was significantly higher in small branches than in large ones, and histamine sensitivity [mean effective concentration (EC50)] was 7.79 x 10(-6) [geometric standard error of the mean (GSEM) 1.20] and 1.49 x 10(-5) M (GSEM 1.14), respectively (P < 0.01). Strips from control and sensitized animals at each site and strips from different generations did not show any significant difference. When we clustered our preparations according to dimensions, the response to histamine was significantly higher in small bronchi than in large ones and histamine EC50 was 8.95 x 10(-6) (GSEM 1.17) and 1.57 x 10(-5) M (GSEM 1.18), respectively (P < 0.05). We conclude that evaluation of muscle response in different tissues requires appropriate normalization. Furthermore, classification into generations is inadequate to study bronchial responsiveness, inasmuch as major differences originate from airway size.

Echocardiographic indices and their relationship to the blood pressure response to ergometric exercise in apparently healthy men.

The relationship between atrial and ventricular echocardiographic abnormalities and ergometric exercise systolic blood pressure was studied in 77 apparently healthy men, of whom the majority (77%) were normotensive (resting blood pressure less than 140/90 mmHg), and the remainder (23%) borderline hypertensive (resting systolic blood pressure 140 to 159 mmHg and/or diastolic blood pressure 90 to 95 mmHg). Four categories of exercise systolic blood pressure were defined (less than 190, 190 to 199, 200 to 209 and greater than or equal to 210 mmHg). Left ventricular mass and left atrial dimension were measured by M-mode echocardiography and divided by body surface area to derive the left ventricular mass index and the left atrial dimension index. The prevalence of left ventricular hypertrophy, defined as a left ventricular mass index greater than or equal to 125 g/m2, was 11%. Two key findings were the much higher prevalence of left atrial enlargement, defined as left atrial dimension index greater than or equal to 2 cm/m2 at 23%, and the fact that left atrial enlargement occurred in the absence of left ventricular hypertrophy in the majority of subjects, whereas occurrence of left ventricular hypertrophy in the absence of left atrial enlargement was rare. This is consistent with the view that left atrial enlargement is a common precursor of left ventricular hypertrophy. Multivariate analysis showed exercise systolic blood pressure and cardiac index to be independent predictors of left atrial dimension index and left ventricular mass index (R2 for statistical models was 0.38 [P less than 0.0001] and 0.47 [P less than 0.0001], respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise blood pressure and echocardiographic abnormalities in genetically comparable populations.

OBJECTIVE: To determine the relationship between the systolic blood pressure response to exercise and the echocardiographic dimensions of the left atrium and ventricle in two geographically separate, but genetically comparable, populations. DESIGN AND SETTING: The study was cross-sectional. The settings were two semirural communities, one in Iceland and one in Manitoba. SUBJECTS: Individuals from families where there had been no intermarriage with non-Icelandic individuals were eligible. Of the 200 eligible men in Manitoba and the 150 men in Iceland, 157 and 121 men, respectively, agreed to participate. In the majority of cases, those who chose not to participate stated that work commitments prevented them from taking part. The subjects were aged 25 to 63 years and had blood pressure less than 160/95 mmHg at rest. INTERVENTIONS: Blood pressure was taken at rest and during standardized bicycle ergometry. Left ventricular and atrial echocardiography was performed on a selected number of subjects. MAIN RESULTS: The Canadians of 'pure' Icelandic descent had a higher prevalence of exaggerated exercise systolic blood pressure (ESBP), left atrial enlargement (LAE) and left ventricular hypertrophy (LVH) than native Icelanders. Given their genetic similarity, it is suggested that the difference between the two groups is due to environmental factors. Within each group, subjects with exaggerated ESBP had a significantly greater left atrial dimension index and left ventricular mass index than subjects without an exaggerated ESBP. The relationship of ESBP with left atrial dimension index and left ventricular mass index was independent of age, body mass index and resting blood pressure. LVH was of the eccentric type and was absent in the majority of cases with LAE; however, LAE was present in nearly all LVH cases. CONCLUSIONS: This study demonstrates that an exaggerated ESBP in individuals with resting blood pressure less than 160/95 mmHg is not an innocuous finding it is associated with demonstrable cardiac abnormalities (LAE and LVH). Furthermore, it is proposed that the presence of LAE, with or without LVH, may add to the value of an exaggerated ESBP in identifying individuals at increased risk of developing sustained resting essential hypertension.

The relationship of serum ferritin with sex and exercise in Canadians of Icelandic descent: implications for prevention of coronary artery disease.

OBJECTIVE: To investigate the relationship of serum ferritin with sex and exercise. DESIGN AND SETTING: A cross-sectional design study carried out in Winnipeg, Manitoba. SUBJECTS: Urban Canadians of Icelandic descent, aged 21 to 60 years, took part in this investigation. Subjects were stratified by age, sex and menstrual status. INTERVENTIONS: Venous blood samples from fasting subjects were drawn for serum ferritin, hemoglobin and hematocrit analyses. Various anthropomorphic measurements were taken, and subjects underwent submaximal cycle ergometry testing. A health and lifestyles questionnaire and a four-day prospective food record were administered. MAIN RESULTS: Mean serum ferritin levels obtained were 187.93 and 47.84 micrograms/L for males and females, respectively. Mean serum ferritin levels were 33.06 micrograms/L and 71.14 micrograms/L for premenopausal and postmenopausal females, respectively. The mean weekly consumption of alcohol was 190 mL/week and 80 mL/week for males and females, respectively. The mean dietary intake of iron was 27.3 and 18.9 mg/day for males and females, respectively. Males, but not females, who exercised 45 mins or more per week had significantly lower levels of serum ferritin than their sedentary counterparts. In males, hemoglobin, hematocrit and the consumption of alcohol were positively correlated with serum ferritin, while exercise time was negatively correlated with serum ferritin. A trend towards lower serum ferritin levels at higher workloads was observed in males, but did not reach statistical significance. In females, age and dietary intake of iron were found to be positively correlated with serum ferritin, while history of anemia, menstrual status and workload were negatively correlated with serum ferritin. CONCLUSIONS: These findings suggest that regular aerobic exercise may decrease iron stores in the body. This may be clinically significant since high serum ferritin has been cited as a risk factor for coronary artery disease.

Plasma fatty acids and lipids in two separate, but genetically comparable, Icelandic populations.

Levels of serum lipids and lipoproteins, and the fatty acid composition of plasma phospholipids, were measured in two genetically comparable, but widely separated, populations. The 1975 mortality rates for ischemic heart disease were significantly higher in one of these populations, the Manitoban residents of pure Icelandic descent, than in the other, a rural population from Northeastern Iceland. Two study populations, Icelanders and Icelandic-Canadians, were drawn from these larger populations. The study populations were matched for age and sex and divided into three age groups, 20-39, 40-59, and 60-69 years. In comparison to the Icelandic-Canadians, the Icelanders exhibited significantly higher levels of total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, but lower triglyceride levels. Their plasma phospholipids contained significantly lower levels of saturated fatty acids (SFA), monounsaturated fatty acids, and n-6 polyunsaturated fatty acids (PUFA); but their n-3 PUFA levels were three times as high. It was additionally found that fatty acid composition of plasma phospholipids differed among Icelanders of different ages. SFA levels were significantly lower, and n-6 PUFA levels significantly higher, in the 20-39 year group than in the 60-69 year group, possibly due to different dietary fat consumption patterns between generations. No corresponding age-related difference in the fatty acid composition of plasma phospholipids was found in the Icelandic-Canadian study population. As the Icelandic and Icelandic-Canadian groups are assumed to be genetically similar, the biochemical differences between them are evidently due to environmental, probably dietary, differences. The findings indicate that n-3 PUFA may be cardioprotective in the context of an otherwise atherogenic diet.

Cardiovascular risk factors and relatedness in an Icelandic subpopulation.

Theoretical and empirical studies suggest adverse effects of inbreeding on general vigour. The genetic architecture of physiological and biochemical cardiovascular risk factors is, furthermore, an unsolved issue. Our aim with this study is to investigate potential effects of inbreeding on stated risk factors in a relatively well demarcated Icelandic subpopulation. We used genealogical records to calculate coefficient of inbreeding and estimated the potential association of the coefficient with stated risk factors with known statistical methods. The results suggest absence of inbreeding depression with exception of HDL cholesterol.

Comparison of portal vein responsiveness in Tris, HEPES or bicarbonate-phosphate buffered media.

The effects of using Tris or HEPES buffered solutions instead of bicarbonate-phosphate buffered solution on the spontaneous activity of the rat portal vein were studied. The effect of the solution buffered with Tris on the spontaneous contractile activity was a minor change in amplitude and frequency, increasing the integrated isometric force by about 20%. A small increase in the mechanical response to variations in [Ca2+]0 (1.0-2.5 mM) was also observed. The response to field stimulation of intramural nerves was significantly lowered in Tris but the response to exogenous noradrenaline was not affected. HEPES buffer does not significantly affect the spontaneous activity, the concentration-effect curve for Ca2+, the response to field stimulation or to exogenous noradrenaline. Transient changes in the spontaneous activity and the resting membrane potential were observed when the solution was changed from Krebs to Tris (or HEPES) solution or vice versa. These changes disappear if the Tris or HEPES solutions were aerated with 4% CO2 in O2 (at pH 7.4) instead of pure O2. A small change in extracellular pH (+/- 0.2 pH units) significantly affects the spontaneous activity. A change in pH may be the reason for the observed effects in the different buffer media.

Spontaneous activity of rat portal vein at normal and elevated hydrostatic pressure.

The effects of high hydrostatic pressure on the spontaneous contractile activity of isolated rat portal veins were studied. During compression, an increase of activity was seen, whereas stable elevated hydrostatic pressure gave a decrease of both frequency and time-integrated force. Decompression further reduced the activity, but all changes were reversible upon return to control pressure. During sustained high pressure the frequency of contractions was reduced by 15.9% at 25 atm, 26.4% at 50 atm, and 45.8% at 100 atm. The corresponding reductions in integrated active force were 13.7%, 16.7%, and 40.7%, respectively. Contractions caused by electrical stimulation of nerve endings left in the preparation were reduced by 44.1%, and potassium contractures were reduced by only 15.3% at 100 atm. It is concluded that inhibition of activity in rat portal vein at high hydrostatic pressure is due in part to effects on the smooth muscle membrane.

Stimulatory effects of Ba2+ on contractile activity in the smooth muscle of the rat portal vein.

The effects on mechanical activity in rat portal vein of adding Ba2+, Sr2+ or Mg2+ (0.3--10 mM) to a tris-buffered solution (Na-tris) with 2.5 mM Ca2+ was investigated and compared to the effects of addition of Ca2+. Ba2+ induced a continuous tetanical activity and increased integrated force from threshold (0.3 mM) to sevenfold (10 mM). Addition of Sr2+ and Ca2+ had only minor effects on mechanical activity, whereas Mg2+ in increasing concentrations exerted an inhibitory effect. Contractures were elicited in K+-high tris solution with 2.5 mM Ca2+. The amplitudes of the contractures were not affected by added Mg2+, whereas Ca2+, Sr2+, and Ba2+ increased contracture force to some extent, the increase being highest for Ba2+ (twofold in 10 mM). Sucrose gap recordings of electrical and mechanical activity showed that added Ba2+ (0.3 mM) to Na-tris with 2.5 mM Ca2+ increased spike discharge and force/spike, the latter almost twofold. A corresponding addition of 0.3 mM Ca2+ had no effect. The effects of adding Sr2+ are very similar to that of added Ca2+, Mg2+ decreased spontaneous mechanical activity. Relaxation rates after K-contractures with 2.5 mM Ca2+, Ba2+, or Sr2+ were determined. No difference was found after K-tris with Ca2+ or Ba2+, whereas the veins relaxed faster after K-tris with Sr2+. We conclude tht Ba2+ acts as a constrictor of the smooth muscle in rat portal vein partly by initiating an increased spike discharge, and partly by increasing the entry or release of Ca2+ per spike, whereas the removal of Ca2+ is unaffected.

Membrane potential in smooth muscle cells from hypertrophic rat portal vein.

Portal hypertension was induced in rats by partial ligation of the hepatic branches of the portal vein. After 5 days the vein was removed and mounted in vitro. In contrast to control (C) veins, hypertensive (H) vessels were almost devoid of spontaneous contractions. Microelectrode recordings showed that the smooth muscle cells of H vessels were hyperpolarized. If [K+]o was increased, or if Ba2+ was added spontaneous activity could be initiated in H vessels. A relation in H cells between hyperpolarization and increased aerobic glycolysis (suggesting an increased electrogenic Na+-K+-pumping) is proposed.

Effects of isoprenaline and dibutyryl-C-AMP on the electrical and mechanical activity of the rabbit myometrium.

Mechanical and electrical responses of spontaneously contracting muscle strips from oestrogen dominated rabbit uterus were investigated by the sucrose gap method. The effects of isoprenaline and dibutyryl-c-AMP in the presence and absence of propranolol were tested. It has been shown previously that the beta-adrenoceptor agonist isoprenaline inhibits the spontaneously contracting uterus even in the presence of the beta-blocker propranolol. The rise in c-amp which is caused by isoprenaline, is, however, blocked by propranolol. The aim of this investigation was to study further the role of c-AMP in the isoprenaline-induced relaxation of the uterus. Isoprenaline (10(-6) M) consistently abolished spikes and mechanical contractions, usually accompanied by hyperpolarization. Propranolol (3 X 10(-6) M) markedly reduced the incidence of hyperpolarization, but did not affect the other actions of isoprenaline. Hyperpolarization does not seem to be a prerequisite for inhibition of uterine contraction. Dibutyryl-c-AMP mimicked the actions of isoprenaline. No positive evidence to support a hypothesis of a c-AMP-independent mechanism was found. Therefore a possible explanation of the results could be that isoprenaline increases c-AMP in a small intracellular pool, mediating electrical and mechanical responses but not influenced by propranolol.

The effects of variations in extracellular magnesium concentration on electrical and mechanical activity in rat portal vein.

The effects of various concentrations of extracellular Mg2+ on electrical and mechanical activity of the rat portal vein were studied. The integrated spontaneous contractile activity in the preparation was largest in Mg2+-free solution, decreased to about 50% at 1.2 mM Mg2+ and was almost completely abolished at 10 mM Mg2+. Each spontaneous contraction became smaller whereas contraction frequency was less affected. Sucrose gap recordings showed that the reduced spontaneous mechanical output was associated with decreased electrical activity on increasing [Mg2+]0. Increasing [K+]0 from 6 to 12 mM normalized the spontaneous mechanical activity in 10 mM Mg2+ solution. Local registration of electrical activity with 3 extracellular glass capillary electrodes showed that inactive areas developed at the high Mg2+ concentrations. These findings indicate that Mg2+ exerts a hyperpolarizing action on the smooth muscle cell membrane and, at the highest concentration, interferes with intercellular propagation. [Mg2+]0 in the range of 0-10 mM had no effect on the amplitude of K+ (122 mM) contractures at [Ca2+]0 greater than 0.5 mM. At [Ca2+]0 less than or equal to 0.5 the amplitude diminished with increasing [Mg2+]0. The latter observation indicates that Mg2+ can interfere with the Ca2+-permeability of the depolarized cell membrane. 1 mM EDTA in Na-tris 0 mM Mg2+ and 0 mM Ca2+ seemed to lower intracellular Mg2+ below the minimum concentration needed for contractile activity.

Quantitative aspects of electrical and mechanical responses to anisosmolar solutions in the smooth muscle of the rat portal vein.

The electrical and mechanical activity of the rat portal vein were studied quantitatively under prolonged exposure to solutions in which osmolality was varied by changes in sucrose content. Reducing osmolality by 15 or 30 mosm/kg below the control value of 290 mosm/kg caused enhanced electrical and mechanical activity whereas hyperosmolality up to 390 mosm/kg led to inhibition as demonstrated earlier. These responses faded under prolonged exposure. In hypoosmolality integrated mechanical activity returned to control after about 10-15 min while spike activity remained somewhat increased. Prolonged hyperosmolality was associated with return of spike discharge towards control frequency whereas the integrated contractile force reverted from initial inhibition to levels above control after some 10-15 min. Therefore, the integrated force per spike was increased by prolonged hyperosmolality and decreased by hypoosmolality. Variation in osmolality had similar effects on the amplitude of K+ contractures. The time course of the osmotic responses are discussed in relation to the dynamic effects of passive stretch and shortening in the portal vein. The relation that may exist between "intropic" effects of osmolality and the contractures obtained in strongly hypertonic media is considered.

The effect of hypoxia on mechanical and electrical properties of smooth muscle from the rat portal vein.

The effect of hypoxia on the electrical and mechanical activity of rat portal vein smooth muscle were investigated using intracellular microelectrode technique in combination with contraction force measurements. In control conditions the "resting" potential of the muscle cells was -58.0 +/- 0.1 mV (mean +/- S.E.). Bursts of action potentials, 5-10s long, appeared at regular intervals (2-3/min) in association with phasic contractions. In hypoxia (PO2 at about 10 mm Hg) there was a marked decrease in force and, often, a moderate increase in rate of the spontaneous contractions. Electrically, these changes corresponded to a decrease in length and an increase in frequency of the bursts of action potentials. The general level of membrane polarization and individual action potentials were not affected. In prolonged hypoxia there was a tendency towards dissociation of the electrical and mechanical activities. Increasing [K+]0 or reducing [Na+]0 produced a restoration of the hypoxically depressed force development. Qualitatively similar results with respect to the depression of myogenic activity by hypoxia, and its alleviation in decreased [K+]0 and reduced [Na+]0, were obtained in low Ca (1 mM) solutions. The effects of hypoxia, and their variation with [K+]0 and [Na+]0, could be explained on the basis of pH dependent electro-mechanical uncoupling.

Effects of high hydrostatic pressure on rat atrial muscle.

Muscle preparations from rat atria were hydraulically compressed in circulating Tris-buffered solution kept at 37 degrees C. Spontaneously beating preparations decreased their beating frequency with 37.3 +/- 13.5 beats/min (22.3% +/- 6.7%, P less than 0.001) and increased their force with 2.3 +/- 1.1 mN (48.6% +/- 17.5%, P less than 0.001) when they were compressed to 10 MPa (100 atm). Decompression gave values not significantly different from precompression control values. The increase in force could in part be explained by the hyperbaric bradycardia and negative force-frequency relation. The remaining force increase seemed to be an effect of the increase in hydrostatic pressure. Changes in action potential duration and Ca2+ availability for the contractile machinery are discussed as possible mechanisms. Electrically driven preparations increased their contraction force at compression if the stimulus strength was at least 175% of the threshold. At lower stimulus levels just above threshold and at higher frequencies, inconsistent results were obtained at pressure.

The Schultz-Dale response of sensitized canine bronchial smooth muscle.

We wished to determine why in vitro agonist dose-response curves show reduced leftward shift (1/2-1 log dose units) in sensitized canine airway smooth muscle compared to curves elicited in vivo (2-3 log dose unit). The Schultz-Dale response was studied in sensitized dog tracheal (TSM) and bronchial (BSM) smooth muscle. Sensitized TSM challenged with specific antigen showed greater mechanical response, but only on exposure to 300 micrograms/ml; BSM responded to concentrations of ragweed as low as 0.001 microgram/ml. This result resolved the problem cited at the outset. Control TSM and BSM showed no response. The response in BSM is mediated through histamine release, and to a smaller extent by acetylcholine. With challenge release of histamine and acetylcholine increased significantly in sensitized airway smooth muscle. Integrated contractile responses obtained with high and low concentrations of antigen showed a dose-response relationship. Increased sensitivity of BSM to antigen compared to TSM indicates the former is the preparation of choice for study of allergic bronchoconstriction.

Relative contribution of superficially bound and extracellular calcium to activation of contraction in isolated rat portal vein.

The spontaneous electrical and mechanical activity of the isolated rat portal vein is abolished after only 2-3 min in nominally Ca-free medium, and after 5-6 min there is no contractile response to depolarizing (122 mM K+), Ca-free solution. In the present study we have examined the electrical and mechanical responses of the portal vein to depolarization with simultaneous readministration of Ca2+ (2.5 mM) after periods of variable length in Ca-free standard solution. After 30 to 60 min of Ca depletion a slow contracture occurred in response to the high-K+ solution with 2.5 mM Ca2+. When the period in Ca-free medium was reduced below 30 min an early, faster phase appeared in the contracture response, and this phase was more rapid the shorter the time of Ca depletion. It is suggested that the slow contracture obtained after 30 min or more uses mainly extracellular Ca for activation and that the faster phase seen after shorter periods of Ca depletion is due to release of superficially bound Ca. This latter pool of tissue bound Ca does not alone produce contraction in response to depolarization, suggesting that extracellular Ca is required to trigger the release perhaps through a regenerative process.

Rate-dependent myogenic response of vascular smooth muscle during imposed changes in length and force.

A recent study of electrical and mechanical responses to stretch in isolated vascular smooth muscle revealed a clear-cut and graded influence of the rate of change in length, dL/dt (Johnansson and Mellander, 1975). This myogenic "dynamic" response at high rates of stretch was much more pronounced than the "static" response to constant, increased (+40%) length. In this previous study the mechanical responses were recorded as active force. In view of the fact that myogenic reactions in vivo must be associated with changes in vessel caliber, it was considered of interest to investigate the responses to stretch also in smooth muscle undergoing active shortening. In the present study, as in the one referred to above, electrical and mechanical activity in the isolated rat portal vein was studied by the sucrose gap method. However, in the present experiments the mechanical responses were recorded not only as active force but also as active shortening, making possible a comparison of the myogenic responses under these two types of smooth muscle contraction. Dynamic passive stretch was found to be associated with marked increase in spike discharge and mechanical activity under both these experimental conditions and the quantitative relation between spike discharge and rate of passive stretch (or shortening) was similar. Thus, active shortening of the smooth muscle did not interfere with the ability of the vessel to respond myogenically to passive stretch. A further analysis of the results suggested that, for the preparations as a whole, the dynamic excitatory response was more closely related to the rate of change of passive force, dP/dt, than to dL/dt.

Responses to ions and vasoconstrictor agents and changes of potassium fluxes in vascular smooth muscle during hypoxia.

An inhibitory effect of hypoxia (Po2 less than 5 mmHg) on electrical and mechanical activity of the smooth muscle of the rat portal vein has been described by Hellstrand, Johansson & Norberg (1977). The present study using the sucrose gap method confirmed their finding that spontaneous activity was completely (or almost completely) abolished by the low Po2. Increased [K+]0 from 6 to 24 mM or decreased [Na+]0 from 137.5 to 76.5 mM reinitiated electrical and mechanical activity during hypoxia. If muscle activity had already been increased by 24 mM K+ or 76.5 mM Na+ solutions in the aerobic situation, switching to hypoxia caused only partial inhibition. In hypoxic solutions of such altered ionic composition a gradual increase in muscle activity with time was seen especially in the low Na+-solution. Stimulating agents such as noradrenaline, acetylcholine, 4-aminopyridine, and Ba2+ could reinitiate spike activity and contractions under hypoxic conditions. Ouabain stimulated the activity in normoxia but no effect was seen in hypoxia. Uptake and washout of 42K+ was studied. No difference in uptake was found between normoxic and hypoxic conditions. The rate of 42K+ efflux was decreased under hypoxia. A similar decrease was produced by Mn2+ (0.4 mM) which, like hypoxia abolished phasic muscle activity. In both cases the reduction in 42K+ efflux may just reflect the elimination of action potentials. It is concluded from these results that profound hypoxia exerts its inhibitory effect on the smooth muscle to a large extent through membrane mechanisms responsible for pacemaker activity or spike generation. The electrophysiological response may be secondary to change in intracellular [Na+] or [Ca2+].