Neurotransmitter depletion compromises the ability of indirect-acting amines to provide inotropic support in the failing human heart

To test the hypothesis that cardiac norepinephrine depletion related to heart failure alters contractile responses to beta-adrenergic agonists with a component of "indirect" action (acting by release of neuronal norepinephrine), we examined the inotropic potential of several pharmacologically distinct beta-agonists. Contractile responses to the nonselective beta-agonist isoproterenol, the beta 2-selective agonist zinterol, and the direct- and indirect-acting agonists dopamine and dopexamine were compared in isolated right ventricular trabeculae removed from failing, nonfailing innervated, and previously transplanted and, therefore, denervated nonfailing human hearts. In failing hearts, the contractile response to isoproterenol was significantly lower (41%) than that in nonfailing innervated hearts. The responses to the mixed agonists dopamine and dopexamine were even more attenuated in failing hearts, to a level 76-90% lower than those of nonfailing innervated hearts. In denervated, previously transplanted, nonfailing hearts, the contractile responses to the mixed agonists dopamine and dopexamine were 66-72% lower than those in the nonfailing innervated group, but the response to isoproterenol was not significantly different. The response to zinterol was not significantly different among the three groups. In subjects with severe heart failure, in vivo hemodynamic responses to dopexamine were compared with those of the direct-acting beta-agonist dobutamine. Responses to dopexamine and dobutamine were measured before and after prolonged continuous infusions of each drug. The response to dopexamine, but not to dobutamine, diminished over time. We conclude that a large component of the inotropic response to dopamine and dopexamine in human hearts is due to the ability of these agonists to promote the release of neuronal norepinephrine; when neuronal norepinephrine is depleted, indirect-acting agonists are less able to produce an inotropic response.     

Vascular responsiveness in obstructed gut

Multiorgan system failure due to hypotension and sepsis is an important cause of death in patients with bowel obstruction. We have investigated the pathophysiology of this entity in an animal model. After 5 days of bowel obstruction, blood flow in the superior mesenteric artery was measured with and without Pitressin and norepinephrine given in separate experiments. In controls, Pitressin in moderate dosages caused a substantial fall in gut blood flow, which was not seen in obstructed animals (blood flow reduction 52 percent vs. 11 percent in sham and obstructed animals respectively, P less than 0.01). Similarly, norepinephrine infusion had less of an effect on gut blood flow in obstructed animals (blood flow reduction 79 percent vs. 58 percent sham vs. obstructed animals (P less than 0.05). Thus, both agents had dose-related effects on gut blood flow, which was maintained at a higher level throughout the drug infusion periods in the bowel of obstructed animals, demonstrating that splanchnic flow is less responsive to vasoactive drug infusion under these experimental conditions. Because splanchnic vasoconstriction is an important feature of normal hemodynamic homeostasis, we suggest that these results may help explain some aspects of the pathophysiology of multiorgan failure caused or worsened by systemic hypotension seen in bowel obstruction.     

The effects of anisodamine and dobutamine on gur mucosal blood flow during gut ischemia／reperfusion

AIM：To detemine if anisodamine is able to augment mucsal perfusion during gut I/R ischemia-reperfusion METHODS:A jejunal sac was formend in Sperague Dawley rat.A Laser Doppler probe and a tonometer were inserted into the sac thich was filled with saline.The superior mesenteric artery was occluded(SMAO)for 60 minutes followed by 90 minutes of reperfusion.At the end of 60 minutes of SMAO.either 0.2mg/kg of anisodmine or dobutamine was injected into the jejunal sac.Lase Doppler mucosal blood flow and regional PCO2(PrCO2) measurements were made .RESULTS:Mucosal blood flow was significantly increased at 30,60 and 90 minutes of reperfusion(R30,R60,R90)when intraluminal anisodamine or dobutamine was present compared to intraluminal saline only(44±3.3%or 48±4.1%vs 37±2.6%at R30,57±5.0%,57±5.0%or56±4.7%vs45±2.7%at R60,64±3.3%or56±4.2%.vs48±3.4%at R90,respectively P<0.05),Blood flow changes were also reflected by lowering of jejunal PrCO2 measurements after imtraluminal anisodamine or dobutamine compared with that of the saline controls(41±3.1mmHg or 44±3.0mmHg vs49±3.7mmHg at R30,38±3.7mmHg or 40±2.1mmHg vs47±3.8mmHg at R60,34±2.1mmHg or 39±3.0mmHg vs46±3.4mmHg at R90,respectively,P<0.05),Most interesting finding was that there were significantly higher mucosal blood flow and lower jejunal PrCO2 in anisodamine group than those in dobutamine group at 90 minutes of reperfusion(64±3.3%vs56±4.2%for blood flow or 34±2.1mmHg vs39±3.0mmHg for PrCOs,respectively,P<0.05).suggesting that anisodamine had a more lasting effect on mucosal perfusion than dobutamine.CONCLUSION.Intraluminal anisodamine and dobutamine can augment mucosal blood flow during gut I/R and alleviate mucosal acidosis.The results provided benifical effects on the treatment of splanchnic hypoperfusion following traumatic or burn shock.     

Effects of dopexamine on regional blood flow and leukotriene production in multiple splanchnic sites in endotoxemic rats

BACKGROUND/AIMS: This work examines the effects of lipopolysaccharide (LPS) on splanchnic blood flow and tests the potential effect of dopexamine in preventing LPS-induced decrease in splanchnic blood flow, also analyzing its influence on regional leukotriene production. METHODOLOGY: Male Sprague-Dawley rats were grouped and subjected to i.v. administration (time 0) of the lipopolysaccharide (10mg/kg) or vehicles with some rats receiving dopexamine (2microg/kg/min) (times 2 hrs to 6 hrs) infusion and compared. Microdialysis collection for analyzing leukotrienes concentrations and direct splanchnic laser Doppler flowmetry were started at times 0 to 6 hrs. RESULTS: Mean arterial pressure decreased markedly in LPS-injected animals and it decreased further gradually during observation period. A marked increase in mean arterial pressure was noted following concomitant administration of dopexamine with LPS. CONCLUSIONS: Impaired splanchnic blood flow in the stomach, jejunum and ileum after LPS injection has been attenuated following infusion of dopexamine. The changes in regional blood flow in the specific splanchnic area correlate closely with the systemic mean arterial pressure in this early sepsis model. Increased leukotriene production following LPS injection also has been attenuated in the stomach, jejunum and ileum following dopexamine infusion, and the increase of leukotriene production also correlates closely with systemic mean arterial pressure.     

Laser Doppler flowmetry is useful in the clinical management of small bowel transplantation. The Liver Transplant Group

OBJECTIVE: Laser Doppler flowmetry (LDF) has been used as a research tool to measure splanchnic perfusion. In this report, we aim to demonstrate the clinical value of this technique in perioperative monitoring of transplanted small bowel. METHODS: A 24 year old man underwent small bowel transplantation using a previously described technique. Microvascular blood flow in the transplanted bowel was measured using an LDF splanchnic probe. Postoperatively this was applied to the stoma facilitating direct measurements of graft mucosal flow. Measurements (perfusion units (PU)) were documented prior to implantation, post-reperfusion, postoperatively, during graft ischaemia, and in response to therapeutic interventions (dopexamine and phenylephrine infusions). RESULTS: Prior to transplantation, biological zero was established. Flow at five, 15, and 60 minutes after reperfusion was 74 (1.9) PU, 87.5 (3.3) PU, and 141.5 (2.5) PU, respectively. Postoperative mucosal flow was 141.6 (2.9) PU. Subsequent LDF measurement detected absence of flow even though clinical signs suggested only moderate reduction. This was confirmed on surgical re-exploration and facilitated prompt resection of a non-viable segment. Fluid and dopexamine administration resulted in a dose dependent improvement in flow, independent of blood pressure. Addition of phenylephrine increased total mucosal flow and unmasked a cyclical component. CONCLUSION: This case demonstrates the clinical value of LDF as an "alarm" to indicate graft perfusion failure and as a monitor for therapeutic interventions. Phenylephrine and dopexamine may both be of value in improving mucosal flow in the transplanted small bowel.     

Effects of dopamine and dobutamine on skeletal muscle oxygenation in normoxemic rats

The effects of two vasoactive drugs, dopamine and dobutamine, on skeletal muscle tissue oxygenation were studied in a normoxemic rat model. It is usually claimed that drugs may increase or decrease oxygen delivery to tissues. However, this claim is only valid on the global level. Our interest is directed towards individual organs. Two groups of rats (n = 7 each) were studied. One group received dopamine, the other dobutamine. Blood gases, hematocrits, and mean arterial blood pressures were measured in addition to tissue pO2. Infusion of dopamine 2.5 micrograms/kg/min resulted in a statistically significant decrease in skeletal muscle pO2. Higher doses of dopamine, and all doses of dobutamine, did not influence pO2 at all. The results raise the question of whether blood flow to vital organs may be negatively affected by dopamine 2.5 micrograms/kg/min. Direct measurements of tissue oxygenation are warranted in, e.g., the liver and gut.     

Contrasting effects of dopamine and dobutamine on myocardial release of norepinephrine during acute myocardial infarction

The effects of dopamine and dobutamine on release of norepinephrine from normal and ischemic myocardium were compared in 2 groups of open-chest anesthetized dogs. Both agents were infused intravenously at a rate of 10 micrograms/Kg/min for 2 hours, beginning 40 min after snare occlusion of the left anterior descending coronary artery. There were no major differences in hemodynamic responses between the 2 groups. Blood samples were taken simultaneously from the aorta, coronary sinus and the cardiac vein that ran parallel to the left anterior descending coronary artery before and after coronary artery occlusion. Plasma norepinephrine increased 40 min after the occlusion, with a net efflux in both coronary sinus and cardiac venous blood. Dopamine caused further increases in plasma norepinephrine. At 20 min after the beginning of dopamine infusion the coronary sinus concentration (4.09 +/- 1.36 ng/ml) was significantly greater than the arterial concentration (2.84 +/- 0.87 ng/ml). This transcardiac difference disappeared during continuous infusion 2 hours after coronary artery occlusion. Differences in norepinephrine concentration between the arterial and cardiac venous blood, however, were not significant. In contrast, plasma norepinephrine did not increase during dobutamine infusion in either the ischemic or non-ischemic bed. Thus, the results suggest that while these two agents have similar systemic hemodynamic effects, only dopamine increases myocardial release of norepinephrine from either ischemic or normal myocardium during acute myocardial infarction.     

Relative significance of dopamine receptors, beta adrenoceptors and norepinephrine uptake inhibition in the cardiovascular actions of dopexamine hydrochloride

Studies in our laboratory have confirmed that dopexamine hydrochloride is a potent beta 2-adrenoceptor and DA1-dopamine receptor agonist. We examined the effects of dopexamine hydrochloride on both cardiac contractile force, determined by use of a Walton-Brodie strain-gauge arch sutured to the right ventricle, and heart rate in anesthetized dogs. Dopexamine hydrochloride increased cardiac contractile force and heart rate and decreased blood pressure. After administration of the ganglionic blocking agents, hexamethonium and atropine, or the selective beta 1-adrenoceptor antagonist, atenolol, the positive inotropic and chronotropic effects of dopexamine hydrochloride were reduced or eliminated, demonstrating that the drug had little or no direct beta 1-adrenoceptor action and that a myocardial beta 2-adrenoceptor action was not involved in its cardiac effects. During these investigations, dopexamine hydrochloride was found to be an inhibitor of norepinephrine uptake, potentiating the cardiac effects of both exogenously administered norepinephrine and norepinephrine released from sympathetic nerves. These results led to the following conclusions: Dopexamine hydrochloride stimulates the heart by 2 mechanisms--(1) baroreceptor-mediated release of norepinephrine resulting from hypotension produced by beta 2 adrenoceptor and DA1 dopamine receptor-mediated vasodilatation, and (2) potentiation of the released norepinephrine due to prevention of norepinephrine uptake by sympathetic nerves. The latter mechanism may be involved in the cardiac stimulation observed in patients with congestive heart failure and shock, since excessive sympathetic activity and elevated catecholamine levels are present in these conditions.     

Prostaglandin E1 Infusion and Functional Hepatic Flow in Control Subjects and in Patients with Cirrhosis

Metabolic effects of prostaglandin E1 have beenpreviously demonstrated in cirrhosis, apparentlyindependent of changes in large splanchnic vesselhemodynamics. The effects of prostaglandin E₁on functional liver blood flow were tested by measuring theextrarenal clearance of D-sorbitol in six controls andeight patients with cirrhosis during systemicsuperinfusion of saline or prostaglandin E₁(30 g/hr), in random order. Doppler ultrasonog raphy ofsystemic and splanchnic circulation was also performedbefore the test and at the end of the two study periods.Prostaglandin E₁ infusion increased femoralblood flow by nearly 60% in controls and over 30% incirrhosis, without any effect on mean arterial pressureand heart rate. Mesenteric artery and portal blood flowwere unchanged, as were Dopplermeasured resistance indices in the liver, spleen and kidney.Sorbitol-assessed functional hepatic flow was 30% lowerin cirrhosis, and did not change systematically duringprostaglandin E₁ infusion. We conclude thatprostaglandin E₁, at doses able to elicitmetabolic effects and changes in systemic hemodynamics,does not affect splanchnic blood flow and/or hepaticmicrocirculation in normal subjects and inportal-hypertensive patients with cirrhosis.     

The endothelin receptor antagonist bosentan restores gut oxygen delivery and reverses intestinal mucosal acidosis in porcine endotoxin shock

Background—Endothelin-1, the most potentvasoconstrictor known, is produced in septic states and may be involvedin the pathophysiology of the deteriorated splanchnic circulation seenin septic shock.
Aims—To elucidate the capability of bosentan, anon-peptide mixed endothelin receptor antagonist, to attenuatesplanchnic blood flow disturbances and counteract intestinal mucosalacidosis in endotoxic shock.
Methods—In 16 anaesthetised pigs, central andregional haemodynamics were monitored by thermodilution and ultrasonicflow probes, respectively. A tonometer in the ileum was used formeasurement of mucosal pH. Onset of endotoxin challenge was followed bybosentan administration (to eight pigs) two hours later.
Results—Endotoxin infusion reduced cardiac indexand systemic oxygen delivery; bosentan restored these parameters. Thereduced mean arterial blood pressure and renal blood flow remainedunaffected by bosentan. The profound reduction in gut oxygen deliveryin response to endotoxin was completely abolished by bosentan. Bosentan significantly improved the notably deteriorated intestinal mucosal pHand mucosal-arterial PCO₂ gap. Themucosal-portal vein PCO₂ gap, used to monitorthe mucosa in relation to the gut as a whole (including the spleen andpancreas), was also greatly increased by endotoxaemia and significantlyreversed by bosentan.
Conclusion—Bosentan completely restored theprofound endotoxin induced reductions in systemic and gut oxygendelivery with a concomitant reversal of intestinal mucosal acidosis.Results suggest that endothelin is involved in the pronounced perfusion disturbances seen in the gut in endotoxic shock. Bosentan may proveuseful in reducing gut ischaemia in septic shock.

Keywords:splanchnic circulation; septic shock; tonometry; pHi; PCO₂ gap; endothelin-1

     

Comparison of acute haemodynamic effects of dopexamine hydrochloride, dobutamine and sodium nitroprusside in chronic heart failure

Dopexamine hydrochloride (Dopacard®) is a new syntheticcatecholamine compound, which possesses potent ß2-adrenergicand D A 1-dopaminergic agonistic properties. It is free of a-adrenergicactivity, has no ß1-adrenergic activity and is lesspotent at D A2-dopaminergic receptors than dopamine. In thepresent study the acute haemodynamic effects of dopexamine hydrochloridewere compared to those of dobutamine and nitroprusside in 12patients with idiopathic congestive cardiomyopathy in an opencrossover study. With dopexamine hydrochloride, there were dose-dependentincreases from control in cardiac output and stroke volume,decreases in blood pressure, right and left atrial pressure,systemic vascular resistance and pulmonary vascular resistanceand little change in heart rate. Similar effects were seen withnitroprusside, apart from a marked increase in heart rate, andwith dobutamine, except that systolic aortic blood pressureincreased and there was no change in diastolic or mean pressureor pulmonary artery systolic pressure. In general, dopexamine hydrochloride produced effects betweenthose produced by the other two treatments. This suggests thatdopexamine with its combined vasodilator and inotropic actionhas a desirable cardiovascular profile with advantages overthe ß1-receptor aganist dobutamine and the pure vasodilatorsodium nitroprusside.     

Effect of dopexamine hydrochloride in the early stages of experimental myocardial infarction and comparison with dopamine and dobutamine

The effect of dopexamine hydrochloride on myocardial performance, and on the susceptibility of the myocardium to generation of arrhythmias during the development of myocardial infarction has been compared with dopamine and dobutamine in 2 experimental models of myocardial ischemia. All 3 agents improved cardiac function in the presence of a developing infarct. Dopamine and dobutamine increased myocardial contractility (left ventricular dP/dt and left ventricular dP/dt/P), which would be expected to increase oxygen consumption and thus further compromise the ischemic myocardium. Dopexamine hydrochloride, however, improved cardiac function mainly by reducing afterload. The infusion of dopamine and dobutamine resulted in a high (100%) incidence of ventricular arrhythmias compared with only 63% with dopexamine hydrochloride. The effects of these agents on early ischemic arrhythmias after coronary artery ligation in anesthetized rats were also studied. Dopexamine hydrochloride reduced the incidence and severity of arrhythmias in the early stages of ischemia: At a dose of 0.25 micrograms/kg/min, the total number of ectopic beats was reduced to 375 +/- 175, from 1,250 +/- 330 in control rats (p less than 0.05). Dopexamine hydrochloride also significantly reduced mortality from ventricular fibrillation and there was a slight reduction in the incidence and duration of ventricular tachycardia and fibrillation.     

Induction of glycogenolysis in cultured Ewing's sarcoma cells by dopamine and β-adrenergic agonists

Summary This study describes hormonal regulation of glycogen metabolism in Ewing's sarcoma cells. ³H-Glycogen synthesized in cultured Ewing's sarcoma WE-68 cells from ³H-glucose was hydrolyzed in a concentration-dependent manner by various catecholamines. The order of potency for the glycogenolytic effects of catecholamines was isoproterenol dopamine > norepinephrine > epinephrine. The concentrations giving half-maximal effectiveness (EC₅₀) were about 2×10^-8 M, 3×10^-8 M, 8×10^-8 M, and 5×10^-7 M for isoproterenol, dopamine, norepinephrine, and epinephrine, respectively. Higher concentrations of each of the catecholamines were necessary to elicit EC₅₀ stimulation of cyclic AMP production in Ewing's sarcoma cells. Glycogenolysis induced by dopamine was blocked by chlorpromazine, a dopamine D₁-receptor antagonist, but not by haloperidol, a dopamine D₂-receptor antagonist. The glycogenolytic action of norepinephrine was markedly reduced by propranolol, a -adrenoreceptor antagonist, and was not affected by yohimbine, an -adrenoreceptor antagonist. In addition, chlorpromazine also antagonized the glycogenolytic response to norepinephrine. Dibutyryl cyclic AMP, 3-isobutyl-1-methylxanthine, and the diterpene forskolin were also found to induce ³H-glycogen hydrolysis. Our data indicate that cate-cholamines exert their glycogenolytic effects in Ewing's sarcoma cells by stimulation of cyclic AMP formation via -adrenergic recepetors and dopamine D₁-receptors.     

Blood flow and mucoid cap protect against penetration of carcinogens into superficially injured gastric mucosa of rats

In this study we tested the influence of blood flow and the mucoid cap on the penetration of carcinogens to the proliferative cells in the injured rat gastric mucosa. Ten minutes after mucosal exposure to 4.5 mol/liter NaCl,N-[³H]methyl-N-nitro-N-nitrosoguanidine was instilled intragastrically. Hypertonic saline caused superficial mucosal damage, formation of a mucoid cap, high gastric mucosal blood flow, and a large flux of fluid into the gastric lumen. The mean percentage of S-phase cells labeled with carcinogen (the cell population at risk forN-methyl-N-nitro-N-nitrosoguanidine-induced carcinogenesis) in the antrum and corpus was 0.2 and 0.2, respectively, in the injury control group, 10.1 and 2.0 after removal of the mucoid cap, 1.5 and 9.8 after celiac artery ligation, and 28.2 and 21.9 after removal of the mucoid cap and celiac artery ligation. These results show that both the mucoid cap and gastric mucosal blood flow protect against penetration of carcinogens into the superficially injured gastric mucosa.This work was supported by grants from the Norwegian Cancer Society and Helga Sembs fond. Dr Sørbye is a Research Fellow of the Norwegian Cancer Society.     

Dose/response study of the effects of oestrogens on tumour growth and morphology in the Dunning R3327 prostatic adenocarcinoma

Summary The present study was undertaken to investigate to what extent the oestrogen-induced effects on growth and morphology of the Dunning R3327 rat prostatic adenocarcinoma are dose-dependent. Castrated and testosterone-supplemented rats were used in order to study effects of increasing doses of oestrogens on the tumour. It was found that the lowest dose of oestradiol-17 that reduced the overall growth, the volume density of the epithelium and epithelial cell area in Dunning R3327 prostatic tumours is 10 g given as daily injections. Higher oestrogen doses (50 g, 200 g, and 500 g), in addition to reducing the volume of tumour epithelium, also induced an increase of the volume density of tumour stroma. The area of stroma cell nuclei was increased by 50 g and 200 g oestradiol-17. These observation, may indicate that the lowest effective oestrogen dose is different in the epithelium and stroma of Dunning tumours and that large doses of oestrogen stimulate the stromal compartment. This stimulatory effect did not influence the inhibitory effects seen on the overall growth of the tumour and on the tumor epithelium.     

Comparative circulatory effects of isoproterenol, dopamine, and dobutamine in conscious lambs with and without aortopulmonary left-to-right shunts

We studied the effect on the circulation of the catecholamines isoproterenol, dopamine, and dobutamine in chronically instrumented lambs with aortopulmonary left-to-right shunts (ages 11 to 87 days) and without shunts (ages 8 to 97 days). Infusion of 0.1 microgram/kg/min isoproterenol or 10 micrograms/kg/min dobutamine markedly increased heart rate and systemic and pulmonary blood flows, while stroke volume and the left-to-right shunt flow did not change. Since pulmonary blood flow increased and the left-to-right shunt flow did not change, the left-to-right shunt fraction decreased with the infusions of isoproterenol and dobutamine. The hemodynamic changes during the infusion of isoproterenol and dobutamine occurred immediately after the start of infusion and stabilized within a few minutes. The pattern of hemodynamic changes was not influenced by the presence of an aortopulmonary left-to-right shunt or by age. Infusion of 10 micrograms/kg/min dopamine caused only small hemodynamic changes. This study shows that heart rate and systemic blood flow in the lamb are closely related. Furthermore, it demonstrates that despite an increased systemic blood flow, left-to-right shunt flow does not change after infusion of isoproterenol and dobutamine. Any decision as to which positive inotropic agent might be preferred at an early age should await experimental work concerning the effect of these agents on the myocardial oxygen demand and on the distribution of the systemic blood flow.     

Effect of 16, 16-dimethyl PGE2 on resting and histamine-stimulated gastric mucosal blood flow

Using [¹⁴C]aminopyrine clearance as a measure of mucosal blood flow, 16, 16-dimethyl PGE₂ was administered orally as a single bolus and its effects on resting and histamine-stimulated gastric mucosal blood flow assessed in conscious dogs with vagally denervated gastric pouches. No effect on resting mucosal flow was observed with any of the doses (ie, 2, 10, and 50 g/kg) of prostaglandin given. In histamine-stimulated experiments, intravenous infusion of histamine dihydrochloride (1 mg/hr) elicited a significant (P<0.0005) increase from basal in gastric acid production, volume output, and gastric mucosal blood flow which remained unchanged for the duration of the study. Prostaglandin (50 g/kg) significantly decreased (P<0.0005) these secretory responses and markedly inhibited (P<0.005) muscosal blood flow without altering the ratio (R) of flow to the volume rate of secretion. The observation that R was unchanged suggests that this inhibitory action of 16,16-dimethyl PGE₂ on gastric secretion and blood flow was mediated through direct effects on gastric parietal cells rather than any primary alteration in the gastric microcirculation. We conclude that 16,16-dimethyl PGE₂ given orally has no effect on the resting gastric mucosal circulation and that any reduction in mucosal flow during histamine stimulation is secondary to its inhibitory effects on gastric acid secretion.     

Study of ridazolol on isolated canine and human coronary arteries

Summary Experiments were performed on isolated canine and human coronary arteries to study the alpha- and beta-adrenolytic properties of ridazolol. On canine coronary arteries precontracted with prostaglandin F₂ alpha 2 M and pretreated with phentolamine 1 M, ridazolol competitively antagonized the isoproterenol-induced relaxations, with a pA₂ value of 8.5 (7.8–9.1). Thereafter the alpha-adrenolytic activity of ridazolol was assessed on these same canine coronary vessels. Ridazolol activity was compared with that of prazosin on dose-response curves to norepinephrine in the presence of cocaine (30 M) and propranolol (3 M). Schild plots for both drugs gave straight lines, with slopes not different from unity. The pA₂ value was 7.1 (6.8–7.3) for ridazolol and 8.1 (7.9–8.4) for prazosin. In another set of experiments the alpha-adrenolytic activity of ridazolol was compared on canine and human coronary arteries. A submaximal contraction with norepinephrine (10 M) was first assessed in the presence of propranolol 3 M. The addition of ridazolol 3 M significantly decreased the norepinephrine (10 M)-induced contractions of both preparations. However, the inhibition was more pronounced on canine coronary arteries. In conclusion, ridazolol is a potent beta-adrenergic antagonist with moderate alpha-adrenolytic activity. The weaker inhibition of the norepinephrine-induced contraction observed in human preparations suggests the presence of a heteregeneous population of postjunctional alpha adrenoceptors.     

Inotrope/vasopressor support in sepsis-induced organ hypoperfusion

Vasoactive agents are commonly required in the management of septic shock not only to restore a sufficient tissue perfusion pressure but also to increase blood flow and oxygen delivery to the organs. Importantly, vasoactive agents are no substitute for fluid therapy. Defining end points for therapy remains difficult. These should be, above all, clinical. Even though the gut may play an important role in the development of multiple organ failure, the use of gastric tonometry to guide therapy cannot be recommended at this time. Study of the microcirculation at the bedside with orthogonal polarization spectral imaging may be helpful in the future. Adrenergic agents are the preferred agents for hemodynamic stabilization. Dopamine and norepinephrine are the drugs of choice to increase arterial pressure. Dobutamine remains the agent of choice to increase blood flow to the organs, including the gut and the kidneys. Many questions remain unanswered with respect to optimal hemodynamic management of septic shock.     

Dihydroergotamine decreases the blood content in the skeletal musculature but etilefrine hydrochloride in the splanchnic region in man

Summary Dihydroergotamine (DHE, Dihydergot^®) constricts the capacitance vessels of the striated musculature about twice as strong as etilefrine hydrochloride (E, Effortil^®) for the same increment in central venous pressure. This and the additive effects of both agents on central venous pressure suggested that E may constrict primarily splanchnic capacitance vessels, a hypothesis, that was tested here by looking at the regional distribution of⁹⁹Tc-marked erythrocytes in healthy volunteers.With the subjects supine under a gamma camera the radioactivity was recorded along with central venous pressure, heart rate, and arterial pressure and evaluated for various regions. E was infused twice at a rate of 5 g/kg per minute before and after the injection of DHE (7.5 g/kg).E reduced strongly and selectively the radioactivity in the splanchnic area, not however in skeletal muscle. The reverse held for DHE. Both agents increased the counting rates in the thorax and also central venous pressure, effects which were additive when the two drugs acted together.E preferentially expels blood from the splanchnic vasculature, but DHE from skeletal muscle. The effects add and redistribute blood in favour of the intrathoracic circulation so that the combination of the two agents could be used to advantage for the treatment of cardiac filling disturbances.The support of the Deutsche Forschungsgemeinschaft through the Sonderforschungsbereich 30 Kardiologie Düsseldorf is gratefully acknowledged.