Similar Increase In Cardiac Output Research Articles

Smooth Muscle PPARγ Mutation Causes Impaired Renal Blood Flow and Salt‐Sensitive Hypertension

Failure to vasodilate in systemic and renal vasculature in response to salt loading is a hallmark of salt sensitivity in hypertensive humans and experimental models. Human subjects carrying dominant negative mutations in PPARγ exhibit hypertension while global PPARγ activation consistently lowers blood pressure (BP). To determine whether tissue‐specific actions of PPARγ regulate vascular function, salt sensitivity and BP, we studied mice specifically expressing a human hypertension‐causing mutation in PPARγ (P467L) selectively in smooth muscle (S‐P467L). S‐P467L transgenic mice and non‐transgenic littermate controls (NT) were fed regular diet (0.4% salt) or high salt (HS) diet containing 4% salt for 4 weeks. Salt induced marked elevations in systolic BP in S‐P467L mice (136±4 mmHg salt n=6 vs 121±3 mmHg regular diet n=7, p<0.01, two‐way ANOVA), but not in NT mice (121±4 mmHg salt n=4 vs 116±4.0 mmHg regular diet n=5). Because salt induced similar increases in cardiac output in S‐P467L and NT animals, the pressor effect of salt intake in S‐P467L mice was not due to a larger fluid volume, but likely higher peripheral vascular resistance. In keeping with this, HS‐fed S‐P467L mice, but not NT controls, exhibited severe impairment in acetylcholine (ACh)‐ and sodium nitroprusside (SNP)‐induced vasorelaxation in carotid artery (Maximal relaxation at 30 μM ACh: S‐P467L 31±4.9% n=4 vs. NT 90±1.8% n=6, p<0.01; Maximal relaxation to 30 μM SNP: S‐P467L 38±2.8% n=4 vs. NT 89±2.6% n=6, p<0.01, two‐way ANOVA Repeated Measurements) and in cerebral basilar artery (Maximal relaxation at 100 μM ACh: S‐P467L ‐3.2±9.3% n=7 vs. NT 57±5.9% n=5, p<0.01). Importantly, salt‐induced vascular dysfunction rapidly developed in S‐P467L mice after receiving HS diet for only 3 days, preceding BP elevations. The impaired vasorelaxation in HS‐fed S‐P467L mice was associated with smaller renal artery diameter (S‐P467L 322±21 μm n=6 vs NT 389±22 μm n=5, p<0.05 two‐way ANOVA) and blunted renal blood flow (S‐P467L 36±3.6 μL/min/g n=6 vs. NT 50±6.4 μL/min/g n=5, p<0.05). These changes were not caused by differences in circulating renin‐angiotensin levels or renal sympathetic nerve activity between the two strains. Preliminary data indicated that during the 3rd week of HS diet, S‐P467L mice produced 36% less nitrate/nitrite in 24 hour urine compared to NT controls, which suggested blunted renal bioavailability of nitric oxide, a potent inhibitor of Na‐K‐2Cl cotransporter (NKCC2). This was associated with a declined capacity of HS‐fed S‐P467L mice to excrete an acute volume challenge, which was rescued by an NKCC2 inhibitor furosemide, but not by the Na‐Cl‐cotransporter inhibitor hydrochlorothiazide. Our data support the novel concept that smooth muscle PPARγ regulates systemic vascular resistance, renal perfusion and tubular sodium transport, and loss of these protective actions of PPARγ predisposes to salt sensitivity and hypertension.Support or Funding InformationDr. Jing Wu is supported by an American Heart Association Postdoctoral Fellowship (17POST33660685). This project is funded by R01 HL125603 and R01 HL131689 to Dr. Curt Sigmund.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impaired Dynamic Cerebral Autoregulation to Postural Stress Following Concussive Injuries in Adolescents

Concussions disproportionately affect adolescents and ongoing maturation places this population at increased risk for prolonged recovery and long‐term impairments in neurologic functioning. Although cerebrovascular impairments are believed to contribute to concussion symptoms and recovery, little information exists regarding brain vasomotor control in adolescent concussion, particularly during rapid changes in blood pressure that demand a dynamic cerebral autoregulatory response. The current investigation tested the hypothesis that adolescent concussion is marked by impaired dynamic cerebral autoregulation (CA). Twenty‐two adolescents diagnosed with a concussion (CONC; 13 females; 15 ± 1 years; 26 ± 20 days post‐injury, SCAT3 symptom score = 12 ± 6) and twenty‐seven healthy controls (CTRL; 15 females; 14 ± 2 years; SCAT3 symptom score = 6 ± 4) completed two repeated sit‐to‐stand trials. CONC were followed through their rehabilitation for up to 12‐weeks. Arterial blood pressure (ABP), cerebral blood flow velocity (CBFV), end‐tidal carbon dioxide partial pressure (PetCO2), and heart rate (HR) were measured continuously with finger photoplethysmography (Finapres Medical Systems BV), transcranial Doppler ultrasound (Multigon Industries), a gas analyzer (AD Instruments), and a standard 3‐lead electrocardiogram (ECG), respectively. Furthermore, cardiac output (CO) was provided via the Model flow algorithm and cerebrovascular resistance (CVR) was calculated. The rate of the drop in CVR relative to the change in ABP provided the rate of regulation (RoR). The drop in ABP with standing was similar between CONC and CTRL (25 ± 8 vs. 24 ± 7 mmHg; p = 0.62) although the time to ABP nadir was longer in CONC compared with CTRL (7.2 ± 1.1 vs. 6.1 ± 1.3 sec; p = 0.002). Similarly, time to CBFV nadir was longer in CONC compared with CTRL (5.9 ± 1.4 vs. 4.4 ± 2.0 sec; p = 0.003). Compared to CTRL, RoR was reduced in CONC at study entry (0.21 ± 0.06 vs. 0.16 ± 0.04 sec−1; p = 0.005). However, at the time of CONC final visit (SCAT3 symptom score = 4 ± 5), RoR improved to levels similar to CTRL (0.20 ± 0.08 vs. 0.21 ± 0.06 sec−1; p = 0.55). During sitting and standing, CONC and CTRL had similar PetCO2. The change in heart rate with standing was similar between CONC and CTRL (30 ± 6 vs. 26 ± 9 bpm; p = 0.09) although the time to peak HR was longer in CONC compared with CTRL (10.8 ± 2.5 vs. 9.4 ± 2.0 sec; p = 0.004). Furthermore, a similar increase in CO was witnessed with standing in CONC and CTRL (1.4 ± 1.6 vs. 1.7 ± 0.7 L/min; p = 0.28). Impairments in dynamic CA are evident in adolescents following a concussive injury which recover in accordance with clinical symptoms. Therefore, RoR may aid decisions regarding diagnosis, rehabilitation, and recovery of adolescent concussion.Support or Funding InformationResearch supported by the Children's Health Research Institute (London, Canada).

Effect of Increased Blood Flow on Pulmonary Circulation Before and During High Altitude Acclimatization.

Pulmonary artery catheter determined that systolic Ppa (mean ± SEM) was increased from 20 ± 1 at SL to 27 ± 2 mmHg at HA3 (p < 0.01). Echocardiography assessed that systolic Ppa remained equally increased throughout acclimatization (26 ± 2, 25 ± 2, 25 ± 2, and 24 ± 2 mmHg at HA1-HA4; p = 0.93) and returned to baseline upon return (17 ± 2, 18 ± 1 mmHg at SL, SL2; p = 0.3). The same was shown for PVR. Right heart function remained unaffected. Thigh cuff release maneuvers at SL and HA3 resulted in similar increase in cardiac output (2.5 ± 0.5 and 2.2 ± 0.4 L/min; p = 0.61) without affecting mean Ppa. Prolonged altitude exposure leads to a persistent increase in Ppa and PVR without affecting right heart function and is fully reversible within 1 week after return to SL. The thigh cuff release maneuver-induced increase in cardiac output suggests a preserved ability of pulmonary circulation to cope with sudden remarkable increase in pulmonary blood flow throughout acclimatization.

Epinephrine opens intrapulmonary arteriovenous anastomoses in healthy humans at rest

During exercise or while breathing hypoxic gas mixtures large diameter intrapulmonary arteriovenous anastomoses (IPAVA) open and can be detected with saline contrast echocardiography (SCE). The mechanisms regulating these vessels remain unknown, but both of these conditions activate the sympathetic nervous system and increase plasma catecholamine concentrations. We hypothesized that exogenously increasing the plasma epinephrine concentration would open IPAVA. Using SCE, we studied 5 subjects at rest, before and after continuous infusions of epinephrine at 20, 40, 80, 160, and 320 ng/kg/min for 3 min each. Cardiac output (Q) and pulmonary artery systolic pressure (PASP) were measured using ultrasound. Bubble scores (0–5) increased in a dose‐dependent fashion in all subjects to a max score ranging from 2–4. Q and PASP doubled at the highest infusion rate. After a 30 min break, epinephrine infusions were repeated while subjects breathed 100% O2 and bubble scores did not increase despite similar increases in cardiac output and PASP. These data demonstrate that during exercise or when breathing hypoxic gas mixtures the sympathetically‐mediated release of epinephrine may directly open IPAVA independent of changes in cardiac output or PASP. Mechanisms responsible for hyperoxia‐mediated closure remain elusive.Support: Eugene Evonuk Graduate Fellowship in Exercise &amp; Environmental Physiology

Age and Attenuated Exercise Hyperemia: Partitioning the Contributors

The influence of age on the central and peripheral contributors to exercise induced hyperemia is unclear. PURPOSE: Utilizing a reductionist approach, we compared the peripheral and central responses to passive limb movement (exercise without an increase in metabolism) in 11 old (68±7 years of age) and 10 young (25±3 years of age) healthy subjects. METHODS: Cardiac output (CO), heart rate (HR), stroke volume (SV), mean arterial pressure (MAP), and femoral blood flow of the passively moved leg were evaluated second by second during 3 min of passive knee extension at a rate of 1 Hz. RESULTS: In the older subjects CO, SV, HR, and femoral blood flow increased by 15%, 7%, 8% and 97% respectively. The young subjects displayed similar increases in CO, SV, and HR (15%, 6%, and 12% respectively). However, the young subjects displayed a greater increase in femoral blood flow (136%) compared to the older subjects. The difference with age in the hyperemic response to the passive leg movement with age can be explained by a greater increase in antegrade blood flow (103%) and smaller increase in retrograde blood flow (165%) in the young compared to the old subjects (74% and 204% respectively). CONCLUSIONS: Thus, in agreement with previous reports of attenuated exercise induced hyperemia with age, it appears that the difference is unrelated to central responses to limb movement, is peripheral in nature, and is not dependent upon metabolism. Funding: NIH PO1 HL-091830

Acute Hemodynamic Efficacy of a 32-ml Subcutaneous Counterpulsation Device in a Calf Model of Diminished Cardiac Function

The acute hemodynamic efficacy of an implantable counterpulsation device (CPD) was evaluated. The CPD is a valveless single port, 32-ml stroke volume blood chamber designed to be connected to the human axillary artery using a simple surface surgical procedure. Blood is drawn into the pump during systole and ejected during diastole. The acute hemodynamic effects of the 32-ml CPD were compared to a standard clinical 40-ml intra-aortic balloon pump (IABP) in calves (80 kg, n = 10). The calves were treated by a single oral dose of Monensin to produce a model of diminished cardiac function (DCF). The CPD and IABP produced similar increases in cardiac output (6% CPD vs. 5% IABP, p > 0.5) and reduction in left ventricular external work (14% CPD vs. 13% IABP, p > 0.5) compared to DCF (p < 0.05). However, the ratio of diastolic coronary artery flow to left ventricular external work increase from DCF baseline (p < 0.05) was greater with the CPD compared to the IABP (15% vs. 4%, p < 0.05). The CPD also produced a greater reduction in left ventricular myocardial oxygen consumption from DCF baseline (p < 0.05) compared to the IABP (13% vs. 9%, p < 0.05) despite each device providing similar improvements in cardiac output. There was no early indication of hemolysis, thrombus formation, or vascular injury. The CPD provides hemodynamic efficacy equivalent to an IABP and may become a therapeutic option for patients who may benefit from prolonged counterpulsation.

Sympathoexcitation Increases the QT/RR Slope in Healthy Men: Differential Effects of Hypoxia, Dobutamine, and Phenylephrine

Dynamic ventricular repolarization assessed by QT/RR slopes studies the effects of modifications in cardiac repolarization independently of variations in RR interval (RR). The effects of changes in sympathetic and vagal activity on the QT/RR slope are controversial. We tested the hypothesis that sympathoexcitation is an important determinant of the QT/RR slope. We compared the effects of a reflex sympathetic activation in response to hypoxia, to the direct effects of the infusion of the beta-adrenergic agent dobutamine, on the QTa (apex) and QTe (end)/RR slopes. Dobutamine was titrated to obtain similar increases in cardiac output than with hypoxia. Cardiac vagal activity was estimated by rMSSD and pNN50. In a second group of healthy subjects, we assessed the effect of a reflex cardiac vagal activation in response to phenylephrine infusion on the same variables. We observed a similar increase in QTa and QTe slopes during hypoxia and dobutamine (both P < 0.017 vs. normoxia), despite divergent changes in cardiac vagal activity, as rMSSD and pNN50 decreased with hypoxia compared to normoxia (P < 0.001) but increased during dobutamine infusion compared to hypoxia (P < 0.017). In contrast, these slopes did not change during the rises in rMSSD and pNN50 elicited by phenylephrine (P > 0.7). Beta-adrenergic stimulation induces comparable increases in the QT/RR slopes than hypoxia, but in the presence of a larger cardiac vagal activity. Vagal cardiac activation by phenylephrine does not change the QT slopes. This reveals that the sympathetic system is an important determinant of QT/RR dynamicity in healthy men.

Levosimendan: A New Inodilatory Drug for the Treatment of Decompensated Heart Failure

Levosimendan is a new calcium sensitizer developed for the treatment of congestive heart failure. Experimental studies indicate that levosimendan increases myocardial contractility and dilates both the peripheral and coronary vessels. Its positive inotropic effect is based on calcium-dependent binding of the drug to cardiac troponin C. It also acts as an opener of ATP-dependent potassium channels in vascular smooth muscle, thus inducing vasodilation. Although levosimendan acts preferentially as a calcium sensitizer it has also demonstrated selective phosphodiesterase III inhibitory effects in vitro. However, this selective inhibition does not seem to contribute to the positive action at pharmacologically relevant concentrations. Levosimendan has an active metabolite, OR-1896. Similarly to levosimendan, the metabolite exerts its positive inotropic and vasodilatory effects on myocardium and vasculature. The elimination half-life of levosimendan is about 1 hour. Thus, with intravenous administration, the parent drug rapidly disappears from the circulation after the infusion is stopped. The active metabolite, however, has a half-life of approximately 80 hours, and can be detected in circulation up to 2 weeks after stopping a 24-hour infusion of levosimendan. The intravenous formulation of levosimendan has been studied in several randomized comparative studies in patients with decompensated heart failure. Both patients with ischemic and non-ischemic etiology have participated in the studies. Levosimendan produces significant, dose-dependent increases in cardiac output, stroke volume and heart rate, and decreases in PCWP, mean blood pressure, mean pulmonary artery pressure, mean right atrial pressure and total peripheral resistance. With a loading dose, the effects on PCWP and cardiac ouput are seen within few minutes. There is no sign of development of tolerance even with a prolonged infusion up to 48 hours. Cardiac performance is improved with no significant increases in oxygen consumption or potentially malignant rhythm disorders. Due to the formation of an active metabolite, the hemodynamic effects are maintained up to several days after stopping levosimendan infusion. Compared to dobutamine, levosimendan produces similar increase in cardiac output but profoundly greater decrease in pulmonary capillary wedge pressure. On the contrary to dobutamine, the hemodynamic effects are not attenuated with concomitant beta-blocker use. Levosimendan has been shown to have favourable effects on symptoms of heart failure superior to placebo and at least comparable to dobutamine. Mortality and morbidity in levosimendan treated patients has been shown to be significantly lower when compared to dobutamine or placebo treated patients. The most common adverse events associated with levosimendan treatment are headache and hypotension, as a likely consequence of the vasodilating properties of the compound. In conclusion, levosimendan offers a new effective option for the treatment of acutely decompensated heart failure. Unlike traditional inotropes, levosimendan seems also to be safe in terms of morbidity and mortality.

Influence of Different Atrioventricular and Interventricular Delays on Cardiac Output During Cardiac Resynchronization Therapy

Restoration of the atrioventricular (AVD) and interventricular (VVD) delays increases the hemodynamic benefit conferred by biventricular (BiV) stimulation. This study compared the effects of different AVD and VVD on cardiac output (CO) during three stimulation modes: BiV-LV = left ventricle (LV) preceding right ventricle (RV) by 4 ms; BiV-RV = RV preceding LV by 4 ms; LVP = single-site LV pacing. We studied 19 patients with chronic heart failure due to ischemic or idiopathic dilated cardiomyopathy, QRS >/= 150 ms, mean LV end-diastolic diameter = 78 +/- 7 mm, and mean LV ejection fraction = 21 +/- 3%. CO was estimated by Doppler echocardiographic velocity time integral formula with sample volume placed in the LV outflow tract. Sets of sensed-AVDs (S-AVD) 90-160 ms, paced-AVDs (P-AVD) 120-160 ms, and VVDs 4-20 ms were used. BiV-RV resulted in lower CO than BiV-LV. S-AVD 120 ms and P-AVD 140 ms caused the most significant increase in CO for all three pacing modes. LVP produced a similar increase in CO as BiV stimulation; however, AV sequential pacing was associated with a nonsignificantly higher CO during LVP than with BiV stimulation. CO during BiV stimulation was the highest when LV preceded RV, and VVD ranged between 4 and 12 ms. The most negative effect on CO was observed when RV preceded LV by 4 ms. Hemodynamic improvement during BiV stimulation was dependent both on optimized AVD and VVD. LV preceding RV by 4-12 ms was the most optimal. Advancement of the RV was not beneficial in the majority of patients.

Comparison of hemodynamic performances of St. Jude Medical and Carbomedics 21 mm aortic prostheses by means of dobutamine stress echocardiography

Dobutamine stress Doppler echocardiography was used to compare the hemodynamic performance of two small aortic bileaflet prostheses. Nineteen patients (14 female, mean age 64 years) who had undergone aortic valve replacement with 21 mm bileaflet valve prostheses (St. Jude Medical valve, n = 9, or CarboMedics valve, n = 10) were studied. Dobutamine infusion was started at a rate of 5 μg · kg -1 · min -1 and increased to 10 and 20 μg · kg -1 · min -1 at 15-minute intervals. Under maximum stress, heart rate and cardiac output increased by 70% and 120%, respectively, and mean arterial blood pressure decreased by 9%. Pulsed-wave and continuous-wave Doppler studies were performed at rest and at the end of each stage. Velocity ratio, effective orifice area, performance index, and discharge coefficient of the valve were calculated, and peak and mean velocities and pressure drops across the prostheses were measured. Dobutamine infusion produced similar increases in cardiac output in all patients. Effective orifice areas, discharge coefficients, and performance indexes were comparable for the two valve groups both at rest and maximum stress. Transvalvular velocities and pressure drops were also similar in the two valve groups. Transvalvular pressure drops were also comparable in patients with large body surface area. Dobutamine stress echocardiography is useful in the evaluation of the hemodynamic performance of prosthetic heart valves. St. Jude Medical and CarboMedics 21 mm prostheses have equally favorable hemodynamic performances in most patients under conditions of high cardiac output. (J T HORAC C ARDIOVASC S URG 1996;111:408-15)

Doppler echocardiography evaluation of the CarboMedics valve in patients with small aortic anulus and valve prosthesis–body surface area mismatch

A Doppler echocardiographic study was performed to evaluate the hemodynamic performances of small diameter CarboMedics aortic valves (CarboMedics, Inc., Austin, Tex.) in patients with a mismatch between the prosthetic valve and body surface area. Fourteen patients receiving either a 19 mm (n = 7) or a 21 mm valve (n = 7) prosthesis were studied. Only patients with a body surface area greater than 1.65 m2 were included in the study. Pulsed and continuous wave Doppler echocardiography was performed at rest and 2 minutes after treadmill exercise with the Bruce protocol. Peak and mean gradients across the valve prosthesis were estimated; effective orifice area, performance index, and discharge coefficient of the valve prosthesis were calculated. All patients achieved a significant increase in heart rate, systolic blood pressure, and cardiac output with exercise. Mean gradients ± standard deviation of the mean at rest and 2 minutes after exercise were 20.1 ± 7.1 mm Hg and 21.8 ± 9 mm Hg for the 19 mm prosthesis and 12.3 ± 3.4 mm Hg and 15.9 ± 3.9 mm Hg for the 21 mm prosthesis. The 19 mm valve prosthesis significantly increased the effective orifice area with exercise (1.02 ± 0.2 versus 1.20 ± 0.3; p < 0.05), whereas it was almost unmodified for the 21 mm valve (1.38 ± 0.2 versus 1.39 ± 0.3; p = not significant). Therefore, despite a similar increase in cardiac output with exercise, only the 21 mm valve prosthesis showed a significant increase in peak (25.4 ± 5.2 versus 34.9 ± 8.1 mm Hg) and mean gradient (p < 0.01). We conclude that small diameter CarboMedics valves have satisfactory hemodynamic performances even after strenuous exercise in patients with large body surface areas. The hemodynamic performances of the 19 mm valve prosthesis seem to be optimized with exercise. (J THORAC CARDIOVASC SURG 1994;108:57-62)

Cardiovascular responses during static exercise. Studies in patients with complete heart block and dual chamber pacemakers.

During static exercise in normal subjects, the mean arterial pressure increases as a result of an increase in heart rate and thereby cardiac output with no significant change in stroke volume or systemic vascular resistance. We hypothesized that if one component of the blood pressure response to static exercise, ie, heart rate, were fixed, plasticity of the neural control mechanisms during exercise would allow for preservation of the blood pressure response by alternative mechanisms. Thirteen patients 20 to 68 years old with structurally normal hearts, complete heart block, and dual chamber pacemakers performed static exercise during three conditions: (1) normal dual chamber sensing and pacing mode, (2) heart rate fixed at the resting value obtained in the DDD mode of 78 +/- 4 beats per minute, and (3) heart rate fixed at the peak value obtained during exercise in the DDD mode of 94 +/- 4 beats per minute. Heart rate, blood pressure, and cardiac output were measured and stroke volume and systemic vascular resistance were calculated at rest and at 1 and 5 minutes during static one-leg extension at 20% of maximal voluntary contraction. The mean arterial pressures at rest and at 5 minutes were higher when the heart rate was fixed at the faster peak exercise heart rate. In the DDD mode, heart rate increased by 16 beats per minute and cardiac output by 1.1 L/min, with a resultant 25 mm Hg increase in mean arterial pressure at 5 minutes with no change in the stroke volume or systemic vascular resistance. In both fixed heart rate pacing modes, mean arterial pressure increased by 24 mm Hg when the heart rate was fixed at the resting heart rate and by 25 mm Hg when the heart rate was fixed at the faster peak exercise heart rate pacing modes associated with an increase in stroke volume, with similar increases in cardiac output. During static exercise there was no change in systemic vascular resistance from the resting value in any pacing mode. When heart rate is fixed in the presence of normal left ventricular function, the mean arterial pressure increases normally during static exercise because of an increase in stroke volume with no change in the systemic vascular resistance.

Systemic and renal actions of dopexamine and dobutamine during endotoxin shock in the rat

Acute renal failure is a complication of endotoxin shock caused by decreased renal blood flow and nephrotoxic effects of endotoxin. We hypothesized that dopexamine (DX), a new dopamine and β2 receptor agonist that lacks α-adrenergic vasoconstrictor action, might prevent acute renal failure during shock by its vasodilator action on the renal circulation and not as a result of a concomitant increase in cardiac output (CO). We thus compared the action of DX with that of dobutamine (DB; β1-agonist, no renal effects) administered in such a dose that it caused a similar increase in CO. Shock was induced in anesthetized (sodium pentobarbital) rats by infusion (2 mL/kg/h) of endotoxin ( Escherichia coli 0127138, 10 mg/kg) from t = 0 to t = 60 minutes; experiments ended at t = 135 minutes. Dopexamine (3.10 −8 mol/kg/min; DX group, n = 8) or DB (10 −8 to 10 −7 mol/kg/min; DB group, n = 8) was infused from t = −30 to t = 135 minutes; a third group only received endotoxin (ES group, n = 8). Glomerular filtration rate (GFR) and renal plasma flow (RPF) during shock were calculated from plasma double exponential disappearance rate from t = 90 to t = 135 minutes of 125I thalamate and 131I hippurate, respectively. In renal biopsies, we also measured lactate, glucose, ATP, phosphocreatine concentration (CrP), energy charge ([ATP + 0.5 ADP]/[ATP + ADP + AMP]) and the number of leukocytes per 50 glomeruli at t = 135 minutes. In the ES group, CO was low (approximately 55 mL/min) and serum lactate was high (approximately 5 mmol/L, indicative of shock); RPF and GFR were 1.28 ± 0.31 and 0.46 ± 0.07 mL/min/100 g body weight, respectively. Cardiac output in the DX and DB groups was higher (by approximately 45%) than in the ES group due to a greater stroke volume, but RPF and GFR were significantly higher only in the DX group (by 140% and 76%, respectively). Dopexamine and DB improved renal metabolism to the same extent; the accumulation of leukocytes during endotoxemia was not prevented in either group. The major action of DX thus seems to be an increase in RPF that cannot be attributed to restored CO alone, but also to decreased renal vascular resistance. Acute renal failure was prevented by DX in this way.

Hemodynamic Effects of Ibopamine

The hemodynamic effects of the oral dopaminergic agonist dopamine were evaluated in patients with chronic heart failure. The peak activity occurred between the first and the second hour after administration of ibopamine and lasted for 3 to 6 h. Compared to intravenous dopamine (6 pg/kg/min), oral ibopamine 200 mg three times daily induced similar increases in cardiac output (34%) and stroke volume (37%) and a similar decrease in systemic vascular resistance (30%). Neither drug changed the left heart filling pressure during the study. In long-term studies a favourable hemodynamic effect of ibopamine was also demonstrated in patients with cardiomyopathy and congestive heart failure which was maintained over several weeks. These results suggest that ibopamine may hold beneficial potential in the long-term treatment of patients with congestive heart failure.

Comparison of vascular response of different locations of the gastrointestinal tract to isoproterenol and nifedipine

In the present study we have compared the effect of intravenous infusion of a calcium channel blocker, nifedipine (1.0 micrograms.kg-1.min-1 for 20 min), with that of isoproterenol (0.1 micrograms.kg-1.min-1 for 20 min) on the hemodynamic parameters and the vascular response of different locations and tissue layers of the gastrointestinal tract. Heart rate increased with isoproterenol but not with nifedipine. Both agents caused a similar increase in cardiac output and a similar fall in mean arterial pressure. After 20 min infusion, nifedipine increased the blood flow of the axillary artery, but isoproterenol had no such effect. Isoproterenol caused vasodilation of the mucosa in the antrum but not in the fundus and the body of the stomach or in the duodenum, jejunum, mid small intestine, ileum, and colon. The mucosal effect of nifedipine was similar, except that it also caused vasodilation in the small bowel and in the ascending colon. Nifedipine caused vasodilation of the muscularis throughout the gastrointestinal tract, but isoproterenol had no such effect. These differences are discussed in relation to the mechanism of action of these two vasodilators. It is suggested that the vascular response of different locations and tissue layers of the gastrointestinal tract to vasodilators is locally regulated by a variety of mechanisms may include beta- and alpha-receptor density and (or) sensitivity, angiotensin II activity, and metabolic need of the tissues.

Effects of Pentastarch and Albumin Infusion on Cardiorespiratory Function and Coagulation in Patients with Severe Sepsis and Systemic Hypoperfusion

Twenty consecutive patients with severe sepsis were randomized to fluid challenge with 5% albumin or 10% low MW hydroxyethyl starch (pentastarch) solutions. Fluid challenge was administered iv as 250 ml of test colloid every 15 min until the pulmonary artery wedge pressure (WP) was greater than or equal to 15 mm Hg or a maximum dose of 2000 ml was infused. Hemodynamic, respiratory, and coagulation profiles were measured before and after fluid infusion. The amount of colloid required to achieve a WP of 15 mm Hg was comparable between groups. Both colloid infusions resulted in similar increases in cardiac output, stroke output, and stroke work. The effect of fluid infusion with pentastarch on coagulation was not significantly different from albumin, although pentastarch was associated with a 45% decrease in factor VIII:c. We conclude that pentastarch is equivalent to albumin for fluid resuscitation of patients with severe sepsis.

Cardiac and hemodynamic profile of the new cardiotonic agent, DPI 201-106, in the conscious dog

The cardiac and hemodynamic effects of increasing doses (0.1–3 mg/kg i.v.) of the novel cardiotonic agent, DPI 201-106 (DPI), were investigated over a 60 min period in conscious dogs chronically instrumented for the measurement of arterial pressure, heart rate, left ventricular pressure (LVP), LV (+) dP/dt max and cardiac output. LV (+) dP/dt max, cardiac output and stroke volume were significantly increased by DPI whereas the total peripheral resistance was significantly decreased. These effects were dose-dependent in intensity and in duration. The mean arterial pressure and heart rate remained unaffected, except by the 3 mg/kg dose, which increased them slightly. Autonomic blockade with hexamethonium, atropine and propranolol did not alter the positive inotropic properties of DPI but unmasked its intrinsic bradycardic effect. At equipotent positive inotropic doses, DPI (0.3 mg/kg), milrinone (40 μg/kg) and dobutamine (5 μg/kg per min) induced similar increases in cardiac output and similar decreases in total peripheral resistance, but only dobutamine and milrinone accelerated the heart rate, whereas ouabain (17.5 μg/kg) induced a strong rise in the total peripheral resistance and markedly lowered the heart rate and cardiac output. After coadministration of DPI and ouabain, LV (+) dP/dt max was further increased whereas the ouabain-induced bradycardia, the rise in the total peripheral resistance and the decrease in cardiac output were reinforced, halved and unaltered, respectively. We conclude that (a) DPI exhibits potent and direct positive inotropic properties, associated with a peripheral vasodilating action, and almost no positive chronotropic effects, and (b) coadministration of DPI and ouabain results in synergistic positive inotropic effects.

Effects of pentastarch and albumin infusion on cardiorespiratory function and coagulation in patients with severe sepsis and systemic hypoperfusion

Twenty consecutive patients with severe sepsis were randomized to fluid challenge with 5% albumin or 10% low MW hydroxyethyl starch (pentastarch) solutions. Fluid challenge was administered iv as 250 ml of test colloid every 15 min until the pulmonary artery wedge pressure (WP) was greater than or equal to 15 mm Hg or a maximum dose of 2000 ml was infused. Hemodynamic, respiratory, and coagulation profiles were measured before and after fluid infusion. The amount of colloid required to achieve a WP of 15 mm Hg was comparable between groups. Both colloid infusions resulted in similar increases in cardiac output, stroke output, and stroke work. The effect of fluid infusion with pentastarch on coagulation was not significantly different from albumin, although pentastarch was associated with a 45% decrease in factor VIII:c. We conclude that pentastarch is equivalent to albumin for fluid resuscitation of patients with severe sepsis.

Increase in oxygen supply during experimental septic shock: the effects of dobutamine versus dopexamine

Dobutamine and dopexamine are synthetic adrenergic agents that can efficiently increase cardiac out-put and oxygen supply with little effect on arterial pressure. We compared the effects of these two drugs during experimental septic shock induced by endotoxin infusion in 12 mechanically ventilated dogs. In each animal, dobutamine and dopexamine were administered blindly in a successive and ran domized order at a dose of up to 4 μg/kg/min, while filling pressures were maintained at the baseline level by concurrent fluid administration. Dobutamine and dopexamine administration resulted in a significant and similar increase in cardiac output due to increases in stroke volume and heart rate. Because the arterial pressure increased with dobutamine and not with dopexamine, the left ventricular stroke work increased more with dobutamine and the systemic vascular resistance decreased more with dopexamine. Accordingly, dobutamine has a more pronounced inotropic action and dopexamine has a stronger vasodilating action.Dopexamine also improved arterial oxygenation, possibly by a bronchodilating effect.

Endothelin produces pulmonary vasoconstriction and systemic vasodilation

Endothelin is a newly described polypeptide derived from endothelial cells. The effects of porcine endothelin on the pulmonary vascular bed and systemic vascular bed were investigated in the anesthetized, intact-chest cat under conditions of constant pulmonary blood flow and left atrial pressure. Intralobar bolus injections of porcine endothelin (100-1000 ng) produced a mild vasoconstrictor response in the pulmonary vascular bed. The pulmonary vasoconstrictor response to endothelin was not altered when pulmonary vasomotor tone was increased by infusion of U46619. In contrast to this mild pulmonary vasoconstrictor response, endothelin decreased systemic arterial pressure. Moreover, injections of porcine endothelin into the right and left atria produced similar reductions in aortic pressure as well as similar increases in cardiac output and decreases in systemic vascular resistance. The systemic vasodilator response to porcine endothelin was not affected by beta 2-adrenoceptor blockade. The present data suggest that endothelin does not undergo significant first-pass pulmonary metabolism. The pulmonary vasoconstrictor response to bolus injections of porcine endothelin is not altered by changes in pulmonary vasomotor tone. In contrast, endothelin markedly dilated the systemic vascular bed independently of activation of beta 2-adrenoceptors. The present study provides the first report of the activity of endothelin on pulmonary and systemic hemodynamics in vivo. Moreover, the potent vasodilator activity of endothelin in the systemic vascular bed and its weak effect on pulmonary vessels suggest that endothelin may be more important in the regulation of peripheral vasomotor tone than the pulmonary vascular bed.