Dose-dependent Increases In Cardiac Output Research Articles

Noninvasive Hemodynamic Monitoring of Cocaine-Induced Changes in Cardiac Output and Systemic Vascular Resistance in Subjects With Chronic Cocaine Use Disorder.

Cocaine use disorder (CUD) is a common problem in the United States and worldwide. The mechanisms by which cocaine induces acute cardiovascular toxicity are various. When systemically absorbed through inhaled or intravenous routes, cocaine induces an acute rise in the heart rate (HR) and blood pressure (BP) leading to a significant increase in the cardiac output (CO) and myocardial oxygen demand. Subjects with chronic CUD represent a special population that has experienced long-term cocaine exposure, often without showing signs of cardiovascular disease. We herein present prospectively collected data on the acute hemodynamic effects of intravenous cocaine in a cohort of nontreatment-seeking individuals with CUD without cardiovascular disease. Baseline physiologic data were collected while participants underwent infusion of escalating doses of cocaine (10, 20, and 40 mg administered over 2 minutes) at baseline and after receiving single-blind placebo treatment. Continuous noninvasive hemodynamic monitoring was performed throughout the infusion sessions using the ccNexfin finger cuffs (Edwards Lifesciences Corp, Irvine, CA). The recorded arterial BP tracings allowed for the measurement of beat-to-beat changes in HR, BP, stroke volume, CO, and systemic vascular resistance (SVR). None of the subjects experienced a treatment-related serious adverse event. Cocaine produced significant dose-dependent increases in median HR, BP, CO, and +dP/dt (a measure of cardiac contractility) and a significant dose-dependent reduction in median SVR. Intravenous cocaine in a cohort of otherwise healthy subjects with CUD produced dose-dependent increases in CO, largely explained by an increase in HR, accompanied by a dose-dependent decrease in SVR.

Use of levosimendan in acute heart failure.

As a calcium sensitizer and inodilator that augments cardiac contractility without increasing myocardial oxygen demand or exacerbating ischaemia, levosimendan may be well configured to deliver inotropic support in cases of acute heart failure (AHF). Other factors favouring levosimendan in this setting include its extended duration of action due to the formation of an active metabolite and the lack of any attenuation of effect in patients treated with beta-blockers. Effects of levosimendan on systemic haemodynamics include its significant, dose-dependent increases in cardiac output, stroke volume and heart rate, and decreases in right and left ventricular filling and total peripheral resistance. Rapid and sustained reduction in levels of natriuretic peptides is a consistent effect of levosimendan use and potentially favourable effects on other neurohormonal indicators of cardiac distress are also observed. Levosimendan has repeatedly been shown to be effective in relief of symptoms of AHF, notably dyspnoea and fatigue, while mortality data from clinical trials and registries suggest that levosimendan is markedly less likely than catecholaminergic inotropes to worsen prognosis. The vasodilator pharmacology of levosimendan is also pertinent to the drug’s use in AHF, in which setting organ under-perfusion is often a key pathology. These considerations suggest that levosimendan may have a more favourable impact on the circumstances of the majority of AHF patients than adrenergic agents that act only or primarily as cardiac stimulants. They also suggest that levosimendan may advantageously be integrated into a comprehensive strategy of early intervention designed and intended to prevent cardiac destabilization worsening to the point where hospitalization is necessary. Levosimendan should be used with caution and with tightened haemodynamic monitoring in patients who have low baseline blood pressure (systolic blood pressure <100 mmHg; diastolic blood pressure <60 mmHg), or who are at risk of a hypotensive episode.

Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist.

[Pyr(1)]apelin-13 is an endogenous vasodilator and inotrope but is downregulated in pulmonary hypertension and heart failure, making the apelin receptor an attractive therapeutic target. Agonists acting at the same G-protein-coupled receptor can be engineered to stabilize different conformational states and function as biased ligands, selectively stimulating either G-protein or β-arrestin pathways. We used molecular dynamics simulations of apelin/receptor interactions to design cyclic analogues and identified MM07 as a biased agonist. In β-arrestin and internalization assays (G-protein-independent), MM07 was 2 orders of magnitude less potent than [Pyr(1)]apelin-13. In a G-protein-dependent saphenous vein contraction assay, both peptides had comparable potency (pD2:[Pyr(1)]apelin-13 9.93±0.24; MM07 9.54±0.42) and maximum responses with a resulting bias for MM07 of ≈350- to 1300-fold for the G-protein pathway. In rats, systemic infusions of MM07 (10-100nmol) caused a dose-dependent increase in cardiac output that was significantly greater than the response to [Pyr(1)]apelin-13. Similarly, in human volunteers, MM07 produced a significant dose-dependent increase in forearm blood flow with a maximum dilatation double that is seen with [Pyr(1)]apelin-13. Additionally, repeated doses of MM07 produced reproducible increases in forearm blood flow. These responses are consistent with a more efficacious action of the biased agonist. In human hand vein, both peptides reversed an established norepinephrine constrictor response and significantly increased venous flow. Our results suggest that MM07 acting as a biased agonist at the apelin receptor can preferentially stimulate the G-protein pathway, which could translate to improved efficacy in the clinic by selectively stimulating vasodilatation and inotropic actions but avoiding activating detrimental β-arrestin-dependent pathways.

Hemodynamic Effects of 6% Hydroxyethyl Starch Infusion in Sevoflurane-Anesthetized Thoroughbred Horses

To determine hemodynamic effects of hydroxyethyl starch (HES) infusion during anesthesia in horses, incremental doses of 6% HES were administered to 6 healthy Thoroughbred horses. Anesthesia was induced with xylazine, guaifenesin and thiopental and maintained with sevoflurane at 2.8% of end-tidal concentration in all horses. The horses were positioned in right lateral recumbency and administered 3 intravenous dose of 6% HES (5 ml/kg) over 15 min with 15-min intervals in addition to constant infusion of lactated Ringer's solution at 10 ml/kg/hr. Hemodynamic parameters were measured before and every 15 min until 90 min after the administration of 6% HES. There was no significant change in heart rate and arterial blood pressures throughout the experiment. The HES administration produced significant increases in mean right atrial pressure, stroke volume, cardiac output (CO) and decrease in systemic vascular resistance (SVR) in a dose-dependent manner. There was no significant change in electrolytes (Na(+), K(+), Cl(-)) throughout the experiment, however, packed cell volume, hemoglobin concentration, and total protein and albumin concentrations decreased in a dose-dependent manner following the HES administration. In conclusion, the HES administration provides a dose-dependent increase in CO, but has no impact upon arterial blood pressures due to a simultaneous decrease in SVR.

Effects of Levosimendan on Left Ventricular Relaxation and Early Filling at Maintained Preload and Afterload Conditions After Aortic Valve Replacement for Aortic Stenosis

We determined the effects of levosimendan, a calcium sensitizer, on left ventricular (LV) diastolic function in patients with LV hypertrophy. In this prospective, randomized, blinded study, 23 patients received either levosimendan (0.1 and 0.2 microg x kg(-1) x min(-1); n=12) or placebo (n=11) after aortic valve replacement for aortic stenosis. The effects on LV performance, dimensions, filling patterns, and isovolumic relaxation time, as well as systemic hemodynamics, were assessed by pulmonary artery thermodilution catheterization and transesophageal 2-dimensional Doppler echocardiography. To circumvent the confounding effects of the levosimendan-induced hemodynamic changes on Doppler echocardiographic indexes of LV early relaxation, heart rate and mean arterial and central venous pressures were kept constant during levosimendan/placebo infusion by atrial pacing, vasopressor, and colloid infusions. In the levosimendan group, dose-dependent increases in cardiac output (28%; P<0.001) and stroke volume (26%; P<0.001) and a decrease in systemic vascular resistance (-22%; P<0.001) were observed. There was a trend for an increase in LV ejection fraction (12%; P=0.058) with levosimendan. There were no significant differences in systolic, diastolic arterial, or LV filling pressures or LV end-diastolic area between the 2 groups. Isovolumic relaxation time decreased (-23%; P<0.001), as did the deceleration slope of early diastolic filling (-45%; P<0.01), whereas peak early diastolic filling velocity (16%, P<0.01) and peak late diastolic filling velocity (15%; P<0.001) increased after levosimendan compared with placebo. Levosimendan, in addition to its inotropic effects, exerts a direct positive lusitropic effect in patients with LV hypertrophy as it shortens isovolumic relaxation time and improves LV filling.

Urocortin 3: haemodynamic, hormonal, and renal effects in experimental heart failure

To investigate the haemodynamic, hormonal, and renal effects of peripheral urocortin 3 (Ucn3) administration for the first time in either normal health or heart failure (HF). Eight sheep received incremental intravenous boli of Ucn3 (10, 50, and 100 microg at 2-h intervals) before (normal) and during pacing-induced HF. Compared with controls, Ucn3 induced immediate, dose-dependent increases in cardiac output (normal 4.21+/-0.23 vs. 5.65+/-0.32 L/min, P<0.001; HF 2.20+/-0.14 vs. 4.43+/-0.31 L/min, P < 0.001) and decreases in peripheral resistance (normal 20.8+/-1.0 vs. 16.2+/-0.8 mmHg/L/min, P < 0.01; HF 34.4+/-1.7 vs. 16.2+/-0.5 mmHg/L/min, P < 0.001) and left atrial pressure (normal 4.5+/-0.3 vs. 0.6+/-0.2 mmHg, P < 0.001; HF 23.0+/-0.6 vs. 5.8+/-1.9 mmHg/L/min, P < 0.001). Arterial pressure was minimally elevated in normals (P < 0.001) and reduced in HF (P < 0.05). In HF only, Ucn3 decreased plasma vasopressin (3.33+/-0.36 vs. 1.73+/-0.21 pmol/L, P < 0.05), endothelin-1 (3.56+/-0.28 vs. 2.64+/-0.24 pmol/L, P < 0.001), renin (2.74+/-1.17 vs. 1.04+/-0.22 nmol/L/h, P < 0.001), aldosterone (1494+/-400 vs. 726+/-168 pmol/L, P < 0.05), and epinephrine (1608+/-278 vs. 1039+/-75 pmol/L, P < 0.05), and increased urine output (P < 0.05), sodium excretion (P < 0.01), and creatinine clearance (P < 0.05). Ucn3 has significant cardiovascular effects in normal and HF sheep, supporting a role for this peptide in circulatory regulation. In HF, more prominent haemodynamic changes were associated with beneficial endocrine and renal effects, suggesting Ucn3 has therapeutic potential in this disease.

Integrated Hemodynamic, Hormonal, and Renal Actions of Urocortin 2 in Normal and Paced Sheep

Urocortin 2 (Ucn2) has potent cardiovascular actions and may participate in the pathophysiology of heart failure (HF). The integrated hemodynamic, endocrine, and renal effects of Ucn2 are unknown. Eight sheep received incremental intravenous boluses of murine Ucn2 (10, 50, and 100 microg at 2-hour intervals) before (normal) and during pacing-induced HF. Compared with control data, Ucn2 induced rapid and dose-dependent increases in cardiac output (peak effects: normal 4.3+/-0.2 versus 6.1+/-0.2 L/min, P<0.001; HF 2.3+/-0.1 versus 4.5+/-0.2 L/min, P<0.001) and reductions in peripheral resistance (normal 20.2+/-1.0 versus 15.2+/-0.8 mm Hg/L per minute, P<0.01; HF 32.2+/-1.7 versus 13.6+/-0.5 mm Hg/L per minute, P<0.001) and left atrial pressure (normal 4.3+/-0.3 versus 0.5+/-0.2 mm Hg, P<0.01; HF 22.9+/-0.6 versus 5.1+/-1.8 mm Hg, P<0.001). Mean arterial pressure was minimally elevated in normals and decreased in HF (both P<0.01). In both states, Ucn2 reduced plasma atrial natriuretic peptide levels (normal 13+/-2 versus 10+/-2 pmol/L; HF 200+/-20 versus 72+/-10 pmol/L) and similarly increased corticotropin, cortisol, and Ucn1 (all P<0.001). In HF only, Ucn2 dose dependently decreased plasma vasopressin (3.09+/-0.36 versus 1.62+/-0.12 pmol/L, P<0.01), renin (2.98+/-1.17 versus 0.69+/-0.10 nmol/L per hour, P<0.001), aldosterone (1186+/-303 versus 364+/-122 pmol/L, P<0.001), endothelin-1 (3.39+/-0.23 versus 2.56+/-0.18 pmol/L, P<0.01), epinephrine (1633+/-260 versus 657+/-142 pmol/L, P<0.01), and brain natriuretic peptide (36+/-3 versus 18+/-4 pmol/L, P<0.001) concentrations. Renal effects, including increased urine volume (1.7-fold, P<0.05), sodium excretion (>12-fold, P<0.01), and creatinine excretion (1.3-fold, P<0.001), also occurred only in HF. Ucn2 has marked and beneficial hemodynamic, hormonal, and renal effects in experimental HF. These results support a role for Ucn2 in pressure/volume homeostasis in HF and suggest that the peptide may have therapeutic potential in this disease.

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.

Thyroid hormone supplementation for the prevention of morbidity and mortality in infants undergoing cardiac surgery.

Paediatric studies have demonstrated that cardiopulmonary bypass is associated with a decline in thyroid hormone levels. Adult patients who undergo open heart surgery and receive triiodothyronine supplementation have demonstrated a dose-dependent increase in cardiac output which has been associated with an improved clinical outcome. Thyroid hormone supplementation in infants may also reduce post-operative morbidity and mortality. To determine if peri-operative thyroid hormone supplementation or replacement in infants undergoing cardiac surgery on cardiopulmonary bypass improves post-operative and longer term morbidity and mortality. The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of The Oxford Database of Perinatal Trials, MEDLINE (1966 - December 2003), EMBASE (1980 - December 2003), CINAHL (1982 - December 2003), The Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2003), previous reviews including cross references, abstracts, conferences, symposia proceedings, expert informants and journal handsearching in the English language. All trials using random allocation to peri-operative thyroid hormone therapy (supplementation or replacement) compared to control (placebo or no therapy) in infants (birth to one year of age) undergoing cardiac surgery requiring cardiopulmonary bypass. Thyroid hormone therapy must be tri-iodothyronine. Primary clinical outcomes included measures of post-operative morbidity and mortality. The standard methods of the Cochrane Neonatal Review Group were used in the assessment of trial quality. Treatment effects were expressed using relative risk (RR) and mean difference (MD). Two very small studies were identified that tested peri-operative thyroid hormone supplementation or replacement in infants aged less than one year undergoing cardiac surgery (Chowdhury 2001; Portman 2000). In the Chowdhury 2001 study, a subgroup of nine neonates was eligible for this review. No deaths occurred during either study. Chowdhury 2001 found no significant effect of peri-operative thyroid hormone supplementation in neonates on either length of hospital stay or duration of mechanical ventilation. Portman 2000 found no significant difference in dopamine requirements for the treatment versus control groups for the first 24 hours post operatively, while in the Chowdhury neonatal subgroup, inotrope requirements were significantly lower in the treatment group. Portman 2000 reported significant differences between the two groups at 1 and 24 hours post operatively for free T3 and at 1 hour post operatively for total T3 levels. Total T4 levels showed no significant difference between groups, either pre-cardiopulmonary bypass or up to 72 hours post operatively. At present, there is a lack of evidence concerning the effects of tri-iodothyronine supplementation in infants undergoing cardiac surgery. Further randomised controlled trials which include sufficiently large subject numbers in a variety of different age strata (neonates, infants and older children) need to be undertaken.

Hemodynamic profile of SKP-450, a new potassium-channel activator.

Hemodynamic profiles of SKP-450, a newly synthesized potassium-channel activator, were evaluated in conscious hypertensive rats of several types, and in anesthetized and conscious beagle dogs. In freely moving conscious rats, orally administered SKP-450 (0.03-0.3 mg/kg) dose-dependently decreased arterial pressure in spontaneously hypertensive rats (SHRs), renally hypertensive rats (RHRs), DOCA/salt-induced hypertensive rats (DHRs), and normotensive rats (NRs) with a greater potency than lemakalim except in DHRs (ED20 values: SKP-450, 0.021, 0.013, 0.024, and 0.034 mg/kg; lemakalim, 0.107, 0.018, 0.016, and 0.063 mg/kg, respectively). The blood pressure-reducing effects of SKP-450 reached their maximum within 30 min and lasted for approximately 4 h in all rats, and >6 h, particularly, in SHRs. In NRs, pretreatment with glibenclamide (20 mg/kg, i.v.) antagonized the hypotensive effect of SKP-450, whereas propranolol (2 mg/kg, i.v.) antagonized the tachycardiac response of SKP-450 (0.03 mg/kg, i.v.) without affecting its hypotensive response in NRs. In anesthetized beagle dogs, intraduodenally administered SKP-450 (0.003-0.03 mg/kg) dose-relatedly decreased arterial pressure (ED20 value, 0.007 mg/kg) for > or =3 h with its peak effects reached within 15 min and without significant changes in heart rate (HR). Antihypertensive effects of SKP-450 were accompanied by concurrent reduction in total peripheral resistance and dose-dependent increase in cardiac output. Indirect measures of myocardial oxygen demand such as rate-pressure product, tension-time index, and systolic time interval were dose-dependently decreased by SKP-450 without significant change in left ventricular dP/dt(max). SKP-450 significantly increased coronary blood flow and decreased coronary vascular resistance dose-dependently with a rapid onset of action and long duration of >4 h (maximal changes, 276 and 83.7% at 0.03 mg/kg, respectively). In conscious dogs, orally administered SKP-450 (0.03-0.3 mg/kg) produced a dose-related decrease in arterial pressure for > or =3 h, with its peak effects reached within 20 min (ED20 value, 0.030 mg/kg) accompanied by tachycardia. These results suggest that SKP-450 is a potent, orally active peripheral vasodilator activating ATP-sensitive potassium channels.

Normal changes in left ventricular filling and hemodynamics during dobutamine stress echocardiography

During high-dose dobutamine infusion, there is a dose-dependent increase in cardiac output, a reduction in systemic vascular resistance, a reduction in left ventricular size, an increase in the mitral A wave velocity, a reduction in the E/A velocity ratio, and a reduction in the isovolumic relaxation time, with little change in the rate-corrected isovolumic relaxation time. Left ventricular cavity obliteration is common. This information may be useful in defining the mechanism of hypotension commonly seen during dobutamine stress echocardiography. It is speculated that the diastolic behavior of the left ventricle during dobutamine stress echocardiography, especially the isovolumic relaxation time, may provide an additional indicator of early myocardial ischemia, but this needs to be confirmed by larger independent studies.

Cardiovascular and hormonal effects of calcitonin gene-related peptide in congestive heart failure

The effects of infusing human alpha-calcitonin gene-related peptide were studied in eight patients with congestive heart failure, five normal rabbits and five rabbits with adriamycin-induced cardiomyopathy. In patients with heart failure, calcitonin gene-related peptide caused a dose-dependent increase in cardiac output and decrease in pulmonary and systemic vascular resistance and pulmonary artery pressure. The systemic blood pressure and right atrial and pulmonary wedge pressures decreased only at the highest infusion rate (16 ng/kg per min). Heart rate remained unchanged. Plasma epinephrine increased (p < 0.05), whereas aldosterone, atrial natriuretic peptide and prolactin concentrations decreased (p < 0.05). Plasma norepinephrine, renin activity, cortisol and growth hormone concentrations remained unchanged.In both groups of rabbits, the drug decreased blood pressure and increased cardiac output and heart rate. There was a significant increase in renal blood flow (p < 0.05). The peptide did not affect the contraction amplitude of human and rabbit ventricular myocytes.These findings suggest that calcitonin gene-related peptide is a vasodilator in the rabbit and humans with little direct effect on ventricular myocardium. This peptide may be useful in some forms of heart failure.

Characterization of Acute Hemodynamic Effects of Antidiuretic Agonists in Conscious Dogs

Conscious dogs instrumented for the measurement of arterial pressure and cardiac output (electromagnetic flowmeter) received intravenous injections of 4-valine-8-D-arginine vasopressin (VDAVP) and 1-deamino-8-D-arginine vasopressin (dDAVP), two specific antidiuretic agonists. Both agents led within minutes to dose-dependent increases in cardiac output and heart rate, as well as to decreases of total peripheral resistance and mean arterial pressure. Indomethacin did not affect the hemodynamic responses to VDAVP administration. The analog 8-arginine-9-desglycinamide vasopressin, which retains behavioral effects of vasopressin but is a weak antidiuretic agonist, showed only weak hemodynamic effects that were similar in nature to those of VDAVP and dDAVP. Thus, the capability to increase cardiac output and decrease peripheral resistance appeared to correlate best with the antidiuretic activity of the three vasopressin analogs tested. We also observed that pretreatment of dogs with a combined vasopressor (V1) and antidiuretic (V2) vasopressin antagonist completely prevented the increase in cardiac output that is normally associated with the infusion of arginine-vasopressin, 10 ng kg-1 min-1, after V1 blockade. Our results confirm the existence of powerful, dose-related hemodynamic effects of various antidiuretic agonists in conscious dogs; these effects being opposite to those normally elicited by arginine-vasopressin.

Characterization of Acute Hemodynamic Effects of Antidiuretic Agonists in Conscious Dogs

Conscious dogs instrumented for the measurement of arterial pressure and cardiac output (electromagnetic flowmeter) received intravenous injections of 4-valine-8-D-arginine vasopressin (VDAVP) and 1-deamino-8-D-arginine vasopressin (dDAVP), two specific antidiuretic agonists. Both agents led within minutes to dose-dependent increases in cardiac output and heart rate, as well as to decreases of total peripheral resistance and mean arterial pressure. Indomethacin did not affect the hemodynamic responses to VDAVP administration. The analog 8-arginine-9-desglycinamide vasopressin, which retains behavioral effects of vasopressin but is a weak antidiuretic agonist, showed only weak hemodynamic effects that were similar in nature to those of VDAVP and dDAVP. Thus, the capability to increase cardiac output and decrease peripheral resistance appeared to correlate best with the antidiuretic activity of the three vasopressin analogs tested. We also observed that pretreatment of dogs with a combined vasopressor (V1) and antidiuretic (V2) vasopressin antagonist completely prevented the increase in cardiac output that is normally associated with the infusion of arginine-vasopressin, 10 ng kg-1 min-1, after V1 blockade. Our results confirm the existence of powerful, dose-related hemodynamic effects of various antidiuretic agonists in conscious dogs; these effects being opposite to those normally elicited by arginine-vasopressin.

Dopamine pharmacokinetics in critically ill newborn infants

To compare clinical responses with plasma concentrations of dopamine and to compare dopamine pharmacokinetics in infants of different gestational age or clinical condition, dopamine was administered under carefully controlled conditions of dose and rate of infusion. The dose was increased stepwise from 1 to 2, to 2 to 4, and 4 to 8 micrograms/kg/min. Plasma concentrations of catecholamines, including dopamine, were compared with blood pressure, heart rate, and Doppler cardiac output. The data were analyzed to determine the threshold or minimal plasma concentration of dopamine necessary to produce discernible effects. Plasma clearance rate was calculated from steady-state plasma concentrations. The average threshold for increases in mean arterial pressure was 50% below that for increases in heart rate. Improvements in arterial pressure were noted before and at lower thresholds than for increases in heart rate. Serial echocardiographic data showed dose-dependent increases in cardiac output and stroke volume without significant change in heart rate or systemic vascular resistance. Thresholds and plasma clearance values were similar in infants of gestational age 27 to 42 weeks and birth weights 900 to 4300 g. Administration of dopamine at initial dosages lower than commonly recommended, followed by incremental increase in dose, may be associated with improved left ventricular performance with avoidance of undesirable tachycardia and arrhythmias.

Comparison of the haemodynamic actions of neuropeptide Y, angiotensin II and noradrenaline in anaesthetised cats

Blood pressure, heart rate, cardiac output, renal flow and femoral flow were recorded in open-chested anaesthetised cats. Dose-response curves were constructed for neuropeptide Y, angiotensin II and noradrenaline after pretreatment with atropine sulphate. Neuropeptide Y, on a molar basis, was 7 and 120 times less potent than noradrenaline and angiotensin, respectively, in producing a 50 mm Hg rise in mean arterial blood pressure. The pressor effect of neuropeptide Y was characterised by dose-dependent increases in total peripheral, renal and femoral resistance with little change in cardiac output. Neuropeptide Y had a similar potency to noradrenaline in causing these resistance changes. However, the pressor response to noradrenaline was associated with a dose-dependent increase in cardiac output. The pressor action of neuropeptide Y was not attenuated by adrenoceptor blockade by phenoxybenzamine (5 mg kg -1) and propranolol (1 mg kg -1).

Characterization of the coronary vasodilator and hemodynamic actions of monensin, a carboxylic ionophore.

The effects of monensin on coronary blood flow (CBF) and other hemodynamic parameters were studied in anesthetized dogs. A dose-response relationship was established, and it was found that the lowest doses of monensin (5-25 micrograms/kg) produced a dose-dependent increase (3-5x) in CBF with a concomitant decrease in total peripheral resistance (TPR). Pretreatment with diphenhydramine, atropine, indomethacin, or propranolol resulted in no reduction in peak increase in CBF or in the duration of response to monensin. However, the response was partially blocked by aminophylline. Large doses (100 and 200 micrograms/kg) produced a dose-dependent increase in cardiac output, aortic pressure, and LV dP/dt max. The duration of these effects was dose-dependent, ranging from 60 to 120 min or longer. Heart rate remained unchanged with all doses of monensin. Pretreatment with propranolol, H87/07 (a cardioselective beta-blocker), and D-600 given alone or in combination significantly reduced, but did not completely abolish, the monensin-induced increase in LV dP/dt max and aortic pressure responses. The increase in CBF in the left anterior descending coronary artery was not significantly affected by these drug pretreatments. Thus, our studies indicate that monensin has two distinct pharmacological effects--in the lower dose range (less than 25 micrograms/kg) it produces a direct relaxation of the blood vessels resulting in an increase in CBF and a decrease in TPR; at high doses (greater than 25 micrograms/kg) it increases myocardial contractility and aortic blood pressure.