Dose-kinetics of pancreatic alpha- and beta-cell responses to a protein meal in normal subjects

A protein meal is well known to induce a prompt secretion of insulin and glucagon. However, the data regarding the dose-response relationship between the protein meal and the insulin and glucagon responses are sparse. This study assessed the effects of ingestion of protein meals of varying amounts on plasma glucose [S], insulin [I], and glucagon [G] concentrations in eight normal subjects. Protein meals were administered after an overnight fast in a randomized sequence at intervals of 10 days in four different quantities: 250 mg/kg body weight (BW) (A), 500 mg/kg BW (B), 1 g/kg BW (C), and 2 g/kg BW (D). Mean S levels were not significantly altered following A, B, or C, although significant decreases in S responses were noted after C and D as reflected by absolute changes (delta) and/or the cumulative responses (CR) and the areas under the curve (sigma). Mean I increased promptly to peak concentration by 30 minutes, although in individual subjects the peak was achieved either at 30 or 60 minutes following all protein meals. The increase was progressively greater and the return was delayed with increasing quantities resulting in progressive elevations in delta I and percent increase from basal concentration (%), as well as CRI and sigma I. G increased following all protein meals as well. The mean peak G concentrations were achieved by 90 minutes, although in individual subjects the peak G was reached at 90 or 120 minutes, a significant delay in comparison to the peak I levels. G returned to base line only following ingestion of A during the study period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Coexpression of receptors for adrenomedullin, calcitonin gene-related peptide, and amylin in pancreatic beta-cells

Three receptors have been characterized by their ability to bind adrenomedullin (AM): L1, RDC1, and CRLR. Immunohistochemical analysis and RT-PCR showed that all three receptors are expressed by the insulin-producing cells of the islets of Langerhans. RDC1 and CRLR in the presence of particular modifying proteins can also bind calcitonin gene-related peptide (CGRP). Such data suggest that the inhibitory effect caused by both AM and CGRP on insulin secretion is mediated by a direct interaction with the beta-cell. We also identified receptors for amylin, the third member of the AM peptide family, in mouse insulin-secreting cells. The beta-cells located closer to the periphery of the islets had a stronger immunoreactivity for the AM/ CGRP receptors. This observation could be related to a paracrine mechanism, given the proximity of AM- and CGRP-secreting cells (F and delta-cells, respectively), which are located at the periphery of the islets. Interestingly, the smooth muscle cells in the pancreatic vasculature expressed only RDC1, which is in agreement with physiological data showing that AM functions in the cardiovascular system are mainly mediated through a CGRP1 receptor. These data further implicate AM and the other components of its peptide family as important regulators of insulin release.     

Effects of melatonin on the thermoregulatory responses to intermittent exercise

We examined the effects of a single 2.5-mg dose of melatonin on the thermoregulatory and circulatory responses to intermittent exercise at a room temperature of 27.2+/-0.4 degrees C (mean+/-S.D.), a relative humidity of 55+/-3% (mean+/-S.D.), and a light intensity of 200-300 lux. In a double-blind cross-over study, six male participants ingested either melatonin or placebo at 11:45 hr. Participants then rested in a semi-supine position for 75 min and completed an intermittent running protocol for 66 min at alternating intensities of 40, 60 and 80% of maximal oxygen uptake. Rectal and mean skin temperature, heart rate, blood pressure, skin blood flow, subjective alertness and sleepiness, ratings of perceived exertion (RPE) and thermal strain were recorded. No effects of melatonin were found on these variables measured during the resting period (P>0.10). During exercise, melatonin was found to moderate the increase in rectal temperature by approximately 0.25 degrees C (P=0.050) and magnify the increase in skin blood flow (P=0.047). Postexercise systolic blood pressure was 7.8+/-2.5 mmHg (mean+/-S.D.) lower than before the exercise in the melatonin trial; a change which differed significantly to that in the placebo trial (P=0.018). Melatonin did not influence subjective alertness and sleepiness before or after exercise and did not change the responses of mean skin temperature, RPE and thermal strain during the exercise (P>0.10). In summary it is apparent that a 2.5-mg dose of melatonin has hypothermic, but not soporific, effects during 66 min of intermittent exercise performed under moderate heat stress. Whether such effects improve endurance athletic performance in hot conditions remains to be confirmed. Our data also suggest that postexercise systolic hypotension is more marked after ingestion of melatonin.     

Plasma atrial natriuretic peptide, aldosterone, and plasma renin activity responses to gradual changes in dietary sodium intake

The present study examines the responses of plasma atrial natriuretic peptide (ANP), aldosterone and plasma renin activity to small alterations in dietary sodium intake. Six normotensive subjects were equilibrated on a low sodium intake of 10 mmol/day for 4 days. Dietary sodium intake was then increased gradually by 50 mmol/day to a maximum of 350 mmol/day over a 7 day period. With the gradual increase in sodium intake there were progressive increases in urinary sodium and cumulative sodium balance. These were associated with gradual increases in plasma ANP and reductions in both plasma aldosterone and plasma renin activity. During the study there were no significant changes in blood pressure, urinary potassium and creatinine clearance. This study demonstrates a marked sensitivity of the responses of both the ANP and the renin-aldosterone system to small changes in sodium intake and points to their importance in the renal adaptations to small alterations in dietary sodium intake.     

Treatment of patients with pancreatic endocrine tumours using a new long-acting somatostatin analogue symptomatic and peptide responses.

Seven patients with gut and pancreatic endocrine tumours have been treated with a long acting somatostatin analogue (SMS 201-995), given as a twice daily subcutaneous injection. This produced dramatic improvement in their endocrine related symptoms, in association with a fall in circulating tumour peptides. One of these patients has now been treated for seven months with this analogue which has controlled his previously life threatening diarrhoea caused by a malignant VIP secreting tumour. He gives his own injections twice daily, and has returned to a full and active life. This is a promising agent both for acute treatment of peptide hypersecretion, and for the long term management of some patients who are unresponsive to other available therapy.     

Hormonal and metabolic responses of untrained, moderately trained, and highly trained men to three exercise intensities

Untrained, moderately trained (runners, 15 to 25 mi/wk), and highly trained (runners, greater than 45 mi/wk) men participated in graded treadmill exercise at 50%, 70%, and 90% of their maximal oxygen consumption to quantify the relation between intensity of exercise and sympathetic nervous system and metabolic responses. Sympathetic system activation was noted at all intensities tested and was proportional to the relative exercise intensity. The magnitudes of the norepinephrine (NE) and epinephrine (E) responses were similar in all three groups of men at each relative exercise intensity and correlated with the magnitudes of change in levels of circulating plasma adrenocorticotropin hormone, cortisol, lactate (La), phosphate (Pi), and glucose (GI). The magnitudes of change in concentrations of La, Pi, and GI were also similar for the three groups at each relative exercise intensity. In contrast, a lower degree of sympathetic system activation in response to a given absolute workload was noted in the moderately and highly trained men as compared to that of the untrained men. Sympathetic and metabolic responses to exercise are similar under conditions of comparable relative exercise intensities, regardless of conditioning level. The sympathetic-adrenal medullary system is more sensitive to exercise than the hypothalamic-pituitary-adrenal axis. For a given absolute workload, the degree of activation significantly lower in trained individuals.     

Glucoregulatory effects and prolonged duration of action of davalintide: a novel amylinomimetic peptide

Aims: Davalintide is a second‐generation amylinomimetic peptide possessing enhanced pharmacological properties over rat amylin to reduce food intake in preclinical models. The current experiments in rats describe additional glucoregulatory actions of davalintide consistent with amylin agonism, and explore the duration of action of these effects. Methods: Subcutaneous (SC) injection of davalintide slowed gastric emptying with equal potency to amylin (ED₅₀'s = 2.3 and 4.1 µg/kg). This effect was maintained for 8 h with davalintide, but not amylin. Intraperitoneal injection of davalintide also reduced food intake with a potency similar to amylin (ED₅₀'s = 5.0 and 11.3 µg/kg). Consistent with amylin agonism, davalintide (10 µg/kg, SC) suppressed the plasma glucagon response over 90 min following an intravenous arginine bolus in anaesthetized rats. The elimination t_1/2 of davalintide (200 µg/kg, SC) was 26 min, similar to the t_1/2 of amylin, suggesting that pharmacokinetic‐independent mechanisms contribute to davalintide's enhanced duration of action. Binding kinetic studies using ¹²⁵I davalintide revealed no appreciable dissociation from the amylin nucleus accumbens receptor after 7 h while ¹²⁵I rat amylin did dissociate from this receptor (K_off = 0.013/min). Sustained SC infusion of davalintide (275 µg/kg/day) or amylin (300) decreased plasma glucose after an oral glucose challenge at 2 weeks (by 27 and 31%) and suppressed gastric emptying at 3 weeks (by 29 and 47%), demonstrating durable glucoregulatory actions of both peptides. Conclusions: These data show glucoregulatory properties of davalintide consistent with amylin agonism and suggest that slowed receptor dissociation plays a role in davalintide's prolonged pharmacodynamic actions.     

Glucoregulatory, hormonal, and metabolic responses to endotoxicosis or cecal ligation and puncture sepsis in the rat: a direct comparison

This study characterized the cecal ligation and puncture (CLP) model of sepsis and the bolus endotoxin model of sepsis in rats with regard to specific hormonal, metabolic, and glucoregulatory changes which occur during the early, compensatory phases of sepsis. Plasma levels of glucose, lactate, insulin, and glucagon were measured during the initial 5 hr of endotoxicosis and CLP sepsis. During this time period, endotoxic and CLP septic rats displayed similar metabolic changes, particularly hyperglycemia, hyperlactacidemia, hyperinsulinemia, and hyperglucagonemia relative to their respective control groups. The metabolic and hormonal similarities observed between these two models of sepsis are consistent with the concept that endotoxin plays a role as a mediator of human and animal sepsis.     

Skin peptide tyrosine-tyrosine, a member of the pancreatic polypeptide family: isolation, structure, synthesis, and endocrine activity.

Pancreatic polypeptide, peptide tyrosine-tyrosine (PYY), and neuropeptide tyrosine (NPY), three members of a family of structurally related peptides, are mainly expressed in the endocrine pancreas, in endocrine cells of the gut, and in the brain, respectively. In the present study, we have isolated a peptide of the pancreatic polypeptide family from the skin of the South American arboreal frog Phyllomedusa bicolor. The primary structure of the peptide was established as Tyr-Pro-Pro-Lys-Pro-Glu-Ser-Pro-Gly-Glu10-Asp-Ala-Ser-Pro-Glu-Glu- Met-Asn- Lys-Tyr20-Leu-Thr-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu30-Val-Thr- Arg-Gln-Arg-Tyr-NH2 . This unusual peptide, named skin peptide tyrosine-tyrosine (SPYY), exhibits 94% similarity with PYY from the frog Rana ridibunda. A synthetic replicate of SPYY inhibits melanotropin release from perifused frog neurointermediate lobes in very much the same way as NPY. These results demonstrate the occurrence of a PYY-like peptide in frog skin. Our data also suggest the existence of a pituitary-skin regulatory loop in amphibians.     

Pancreatic beta-cell secretion after oral glucose and intravenous glucagon: different responses to dietary control of plasma glucose in newly diagnosed patients with NIDDM

Pancreatic beta-cell secretion after oral glucose or intravenous glucagon stimulation was studied in newly diagnosed patients with non-insulin-dependent diabetes mellitus (NIDDM) before and after glycemic control by diet treatment alone. Insulin secretion to oral glucose showed significant improvement, while C-peptide release by glucagon showed no significant difference before and after diet treatment. The finding suggests that pancreatic beta-cell response to oral glucose varies with different metabolic states, but this is not so after glucagon stimulation in NIDDM patients.     

Basal and stimulated plasma levels of pancreatic amylin indicate its co-secretion with insulin in humans

Summary Amylin is a 37-amino acid pancreatic polypeptide, probably involved in the pathophysiology of Type 2 (non-insulin-dependent) diabetes mellitus. We have determined amylin in human plasma by extraction-based radioimmunoassay (Sep-Pak C18). Of 23 healthy control subjects plasma amylin was determined as 11.9+-3.5 ng/l. Of 27 patients with Type 2 diabetes receiving insulin the amylin levels were lower, and in 16 patients with Type 2 diabetes on oral medication they were higher than in the control subjects: 8.2+-4.4 ng/l (p<0.01) vs 18.8+-9.9 ng/l (p<0.05). In 14 Type 1 (insulin-dependent) diabetic patients we found extremely low mean amounts of amylin: 2.9+-1.9 ng/l (p<0.002). Thus, basal amylin appears to be associated with the capacity to release insulin. An oral glucose load stimulated the release of amylin, this was more pronounced in patients with Type 2 diabetes than in healthy subjects. An excellent correlation of mean amylin with mean insulin concentrations was obtained (r=0.949). In patients with Type 2 diabetes amylin was reduced congruent to a decrease in C-peptide during a hyperinsulinaemic, euglycaemic glucose clamp experiment (r=0.971 for linear correlation between C-peptide levels and amylin). We conclude, that amylin and insulin are co-secreted in humans, and that the amylin release is under feedback-control by insulin.     

不同强度运动康复对冠心病心绞痛的影响分析

目的研究不同强度运动康复对冠心病心绞痛的影响,为临床冠心病心绞痛早期开展康复锻炼提供依据。方法将2014-05~2016-05入院的120例入选患者随机分为对照组、中等强度运动康复组及高强度运动康复组,每组40例。对照组给予常规口服抗栓、抗凝、调脂、扩冠药物治疗;中等强度运动康复组在上述常规治疗基础上进行中等强度康复运动;高强度运动康复组在上述常规治疗基础上进行高强度康复运动。6周为一个疗程。疗程结束时通过西雅图心绞痛量表对患者进行5个纬度的评定以及心电图疗效评定。结果 6周疗程结束时,与对照组比较,康复运动组的躯体活动受限程度、心绞痛稳定状态、心绞痛发作情况、治疗满意程度、疾病认知程度明显为优,心电图心肌缺血程度有明显改善,且高强度运动康复组较中等强度运动康复组改善更为明显,差异有统计学意义(P0.05)。结论运动康复治疗对于冠心病心绞痛心电图的改善及生活质量的提高有肯定的作用,且改善程度与运动强度有关。     

Work intensities of different modes of exercise testings in clinical use.

Several different exercise testings with treadmill, bicycle ergometer and two-step were carried out by healthy Japanese men to study oxygen consumption per minute and circulatory responses. Stress imposed on the heart by dynamic leg exercise varied depending on the mode of exercise even if energy expenditure expressed in VO2 was identical. This should be fully taken into consideration in comparison of results of different modes of exercise testing. For estimation of VO2 during treadmill slope walk, an equation was derived by multiple regression analysis with use of belt speed and slope as independent variables.     

Effects of aging on cardiorespiratory responses to brief and intense intermittent exercise in endurance-trained athletes

The aim of this study was to investigate the effects of aging on athletes' cardiorespiratory responses to a brief intense intermittent effort, using the force-velocity test as an exercise model. Twelve young athletes (24.8 +/- 1.3 years) and twelve master athletes (65.1 +/- 1.2 years) with similar heights, body masses, and endurance training schedules participated in this study. They performed both a maximal graded exercise and the force-velocity tests. The force-velocity test consisted of the repetition of 6-second sprints against increasing braking forces with 5-minute recovery periods. None of the subjects presented abnormal electrocardiogram responses to the tests. During the force-velocity test, the heart rate magnitudes of response in all subjects were correlated to the corresponding sprint power output (p < .001), with higher values for the young athletes (p < .001). Both groups had similar systolic blood pressure peaks of response during the force-velocity test. Both groups had similar preexercise and end-of-recovery oxygen consumption (VO2), but the young athletes had higher peaks of response (p < .001). The VO2 magnitudes of response increased during the test (p < .01) in all subjects, with higher values for the young athletes (p < .001). There was a positive correlation between the VO2 magnitude of response and (1) the corresponding sprint power output (R = .58,p < .001) and (2) the corresponding number of sprint repetitions (R = .29, p < .02). The young athletes had higher end-of-recovery and peak carbon dioxide production (VCO2) responses than the master athletes (p < .001). Pulmonary ventilation (V(E)) peaks of response to the sprints were higher in the young athletes (p < .001). There was a positive relation between the V(E) and VCO2 peaks of response (R = 84,p < .001). In both groups the peak heart rate, VO2, VCO2, and V(E) values attained during the force-velocity test represented similar percentages of the maximal values reached at exhaustion of maximal graded exercise. These results showed that aging does not alter the percentage of the cardiorespiratory response to a brief intense intermittent exercise such as the force-velocity test. Moreover, the arterial blood pressure response is not significantly altered, whereas the vasodilatatory response is.     

Glucagon-like peptide-1: a major regulator of pancreatic beta-cell function

Glucagon-like peptide-1 (GLP-1) is a gut hormone synthesized by post-translational processing in intestinal L-cells, and it is released in response to food ingestion. GLP-1 stimulates insulin secretion during hyperglycemia, suppresses glucagon secretion, stimulates (pro)-insulin biosynthesis and decreases the rate of gastric emptying and acid secretion. GLP-1 has also been shown to have a pro-satiety effect. In addition, it has been demonstrated that a long-term infusion with GLP-1, or exendin-4, a long-acting analog of human GLP-1, increases beta-cell mass in rats. In conclusion, GLP-1 appears to regulate plasma glucose levels via various and independent mechanisms. GLP-1 is an excellent candidate option for the treatment of patients with type 2 diabetes mellitus.     

Acute changes in endocrine and fluid balance markers during high-intensity, steady-state, and prolonged endurance running: unexpected increases in oxytocin and brain natriuretic peptide during exercise

Maintenance of fluid homeostasis during periods of heightened physical stress can be best evaluated in humans using exercise as a model. Although it is well established that arginine vasopressin (AVP), aldosterone and atrial natriuretic peptide (ANP) are the principle hormones regulating fluid balance at rest, the potential contributions of other related endocrine factors, such as oxytocin (OT) and brain natriuretic peptide (BNP), have not been well described during exercise. Seven endurance-trained runners completed three separate running trials: a maximal test to exhaustion (high intensity), a 60-min treadmill run (steady state), and a 56 km ultramarathon (prolonged endurance exercise). Statistically significant pre- to post-run increases were found only following the ultramarathon in [AVP](p) (1.9 vs 6.7 pg/ml; P<0.05), [OT](p) (1.5 vs 3.5 pg/ml; P<0.05), [NT-proBNP](p) (23.6 vs 117.9 pg/ml; P<0.01), [interleukin 6](p) (4.0 vs 59.6 pg/ml; P<0.05), [cortisol](p) (14.6 vs 32.6 microg/ml; P<0.01), [corticosterone](p) (652.8 vs 3491.4 ng/ml; P<0.05) and [11-deoxycortisol](p) (0.1 vs 0.5 microg/ml; P<0.05) while a significant post-run increase in [aldosterone](p) was documented after high-intensity (4.9 vs 12.5 ng/ml; P<0.05), steady-state (6.1 vs 16.9 ng/ml; P<0.05) and prolonged endurance running (2.6 vs 19.7 ng/ml; P<0.05). Similarly, changes in fluid balance parameters were significantly different between the ultramarathon versus high-intensity and steady-state running with regard to plasma volume contraction (less % contraction), body weight loss (increased % weight loss), plasma [Na(+)] Delta (decreased from baseline), and urine osmolality Delta (increase from baseline). Hypothetically driven relationships between [OT](p) and [AVP](p) (r=0.69; P<0.01) and between [NT-proBNP](p) Delta and plasma [Na(+)] Delta (r=-0.79; P<0.001)--combined with the significant and unexpected pre- to post-race increases after prolonged endurance exercise--allows for possible speculation that OT and BNP may assist their better known companion hormones (AVP and ANP) in the regulation of fluid balance during conditions of extreme physical stress.     

Unresolved challenges with insulin therapy in type 1 and type 2 diabetes: potential benefit of replacing amylin,a second beta-cell hormone

Current insulin therapy still fails to safely restore near-normoglycemia in the majority of patients. Among the barriers to achieving tight long-term glycemic control with insulin in both type 1 and type 2 diabetes are an increased risk of hypoglycemia, undesired weight gain, and a failure to normalize postprandial hyperglycemia and excessive unpredictable diurnal glucose fluctuations. Amylin is a second beta-cell hormone that is cosecreted with insulin in response to meals, and is deficient in patients with type 1 and insulin-requiring type 2 diabetes. Preclinical studies indicate that amylin acts as a neuroendocrine hormone that complements the effects of insulin in postprandial glucose regulation by suppressing postprandial glucagon secretion and slowing the rate of nutrient delivery from the stomach to the small intestine. Human amylin is not optimal for replacement therapy because of its propensity to aggregate; thus, pramlintide, a soluble, nonaggregating synthetic peptide analog of human amylin, was developed that has potency at least equal to that of human amylin. In clinical studies, subcutaneous injections of pramlintide prior to meals, in addition to insulin therapy, significantly reduced postprandial glucose excursions and lowered HbA(1c) levels in patients with type 1 and type 2 diabetes. The improvement in long-term glycemic control was associated with a significant reduction in body weight and occurred without increases in total daily insulin use or in overall severe hypoglycemia event rates. Because of this unique spectrum of clinical effects, amylin replacement with pramlintide as an adjunctive therapy to insulin is a promising approach that may fulfill some of the unmet clinical needs of insulin-using patients with type 1 and type 2 diabetes.     

Renal and endocrine responses to a renin inhibitor, enalkiren, in normal humans

Interpretation of renin-angiotensin blockade with angiotensin converting enzyme inhibitors is potentially confounded by their multiple effects. We used a selective renin inhibitor (enalkiren, A-64662) to explore the renal and endocrine effects of angiotensin II in healthy men. Each received 90-minute enalkiren infusions at 2-day intervals, on a low (10 mmol, 16 subjects) and high (200 mmol, 12 subjects) salt diet. Plasma renin activity, immunoreactive plasma angiotensin II and aldosterone concentrations, inulin, and p-aminohippurate clearance were measured by standard methods. Plasma renin activity fell at 0.1 micrograms/kg, but the threshold for biologic effect was 256 micrograms/kg, where plasma immunoreactive angiotensin II and aldosterone concentration fell, and renal plasma flow rose (p less than 0.01). The maximal renal vascular response (+152 +/- 23 ml/min/1.73 m2) occurred at 512 micrograms/kg (p less than 0.01). Diastolic and mean blood pressure fell modestly but significantly (p less than 0.05). Responses were limited on a high salt diet. We confirm that conventional plasma renin activity measurement is misleading in humans receiving a renin inhibitor. The renal vascular response to renin inhibition in this study appeared to substantially exceed reported responses to angiotensin converting enzyme inhibition, perhaps reflecting a crucial and relatively inaccessible intrarenal locus.     

Physical responses to different modes of interval exercise in patients with chronic heart failure--application to exercise training

METHOD: In exercise training with chronic heart failure patients, workingmuscles should be stressed with high intensity stimuli withoutcausing cardiac overstraining. This is possible using intervalmethod exercise. In this study, three interval exercise modeswith different ratios of work/recovery phases (30/60 s, 15/60s and 10/60 s) and different work rates were compared duringcycle ergometer exercise in heart failure patients. Work ratefor the three interval modes was 50% (30/60 s), 70% (15/60 s)and 80% (10/60 s) of the maximum achieved during a steep ramptest (increments of 25 w/l0s) corresponding to 71, 98 and 111watts on average. Metabolic and cardiac responses to the threeinterval exercises were then examined including catecholaminelevels and perceived exertion. Parameters measured during intervalexercise were compared with an intensity level of 75% peak VO₂,determined during an ordinary ramp exercise test (incrementsof l2·5 W. min^–1). RESULTS: () (1) In all three interval modes, VO₂, ventilation and lactate did not increase significantlyduring the course of exercise. Mean values during the last workphase were between 754 ± 30 and 803 ± 46 ml. min^–1for VO₂, between 26 ± 3 and 28 ± 11. min^–1for ventilation and between 1·24 ±0·14and l·29 ± 0·10 mmol.1^–1 for lactate.(2) In mode 10/60 s, heart rate and systolic blood pressureincreased significantly (82 ± 485 ± 4 beats. min^–1;124 ± 5134 ± 5 mmHg; P<0·05 each), whilein mode 15/60 s catecholamines increased significantly (norepinephrine0·804 ± 0·0891·135 ± 0·094nmol. 1^–1; P<0·008; epinephrine 0·136± 0·012 0 193 ± 0·019 nmol. 1^–1;P<0·005). (3) In all three modes, rating of leg fatigueand dyspnoea increased significantly during exercise but remainedwithin the range of values considered ‘very light to fairlylight’ on the Borg scale. (4) Compared to an intensitylevel of 75% peak VO₂, work rate durrng interval work phaseswas between 143 and 221%, while cardiac stress (rate-pressureproduct) was significantly lower (83–88%). CONCLUSION: All three interval modes resulted in physical response in anacceptable range of values, and thus can be recommended.