Effects of phentolamine on the adrenergic-induced changes in arterial plasma potassium.

Phentolamine was used as a pure alpha-adrenergic blocking agent in the study of the arterial plasma potassium responses to adrenergic stimulation in dogs. Both the hyperkalemia and hypokalemia evoked by the intravenous infusion of noradrenaline, 5 mug/kg-min-1, were reduced by phentolamine (1-3 mg/kg), the response being completely abolished by increasing the dose of this alpha-blocker (9 mg/kg). The decrease of both parts of this dual response was parallel, and it was not possible to abolish the secondary hypokalemia without abolishing the early rise. The secondary decrease in arterial plasma potassium evoked by the intravenous infusion of the same dose of adrenaline was reduced, but not abolished, by the pretreatment with increasing doses of phentolamine, although the initial increase was completely abolished. These results agree with those that attribute an alpha-adrenergic nature to the adrenergic-evoked hyperkalemia, and a complex origin to the secondary hypokalemia. The different interpretations of the results obtained for these kalemotropic adrenergic effects are discussed, in the light of the Ahlquist hypothesis for adrenergic receptors. It is concluded that the alterations in the metabolic state of the effector cells observed during the administration of either adrenergic agonists or antagonists may influence the results obtained and may be considered as one of the factors responsible for interpretative difficulties described.     

Uneven changes in circulating blood cell counts with adrenergic stimulation to the canine spleen

1. Responses of splenic diameter measured by sonomicrometry to alpha- and beta-adrenoceptor stimulants were estimated together with simultaneously measured systemic arterial and splenic venous concentrations of red blood cells (RBC), white blood cells (WBC) and platelets (PLT) in anaesthetized dogs. 2. Intravenous and intrasplenic arterial injections of adrenaline, noradrenaline and phenylephrine all produced profound decreases in splenic diameter. Increases in systemic arterial concentrations of RBC produced by these stimulants were observed immediately following the splenic contraction and marked increases in splenic venous concentration of RBC. 3. Adrenaline and noradrenaline both caused rapid and transient decreases in WBC release from the spleen and these agonists then, in addition to phenylephrine, caused gradual and small increases in systemic arterial WBC concentrations. The increases in arterial RBC and WBC concentrations were abolished by transient isolation of the spleen from the systemic circulation. These three agents did not significantly modify differences between splenic venous and systemic arterial concentrations of PLT. 4. Intra-arterial injections of isoprenaline caused an increase in splenic diameter and a significant decrease in the splenic venous concentration of WBC, but barely influenced the veno-arterial differences in RBC and PLT concentrations across the spleen. 5. The present results indicate that contraction of the spleen through stimulation of splenic alpha1-adrenoceptors contributes to supplying RBC but not PLT into the systemic circulation, whereas splenic beta-adrenoceptor activation leads to splenic dilatation with increased sequestration of WBC to the spleen despite no changes in the release of RBC and PLT from the spleen.     

Faster and more reliable absorption of adrenaline by aerosol inhalation than by subcutaneous injection.

1. The aim of the present study was to compare absorption of adrenaline given by aerosol spray inhalation with absorption after subcutaneous injection. 2. Arterial plasma adrenaline was measured in nine healthy volunteers following adrenaline administration by both methods. 3. Following inhalation of 20 puffs of adrenaline aerosol, 0.15 mg/puff, a peak arterial adrenaline concentration after 1 min and a rapid fall to baseline from this peak occurred. 4. When given by subcutaneous injection absorption was slower with a peak arterial adrenaline concentration after 4 min. The fall in arterial adrenaline from this peak level was not statistically significant within 30 min after injection. 5. There was less intersubject variation of arterial adrenaline concentration following inhalation when compared with injection. 6. Heart rate, blood pressure and finger tremor followed the changes in arterial adrenaline concentrations. 7. These results indicate that absorption is more reliable when adrenaline is given by inhalation. The rapid fall in arterial adrenaline following inhalation, suggests that repeated inhalations are necessary when such adrenaline therapy is required.     

Hypokalemia in cardiac decompensation

Abstract: The problem of hypokalemia in cardiac decompensation is reviewed. Some methodological sources of error in connection with blood sampling is discussed, as is the definition of hypokalemia. “Hypokalemia” may be present with a serum potassium value within the reference range of 3.5–5.0 mmol/l. Although diuretics are the most common cause of hypokalemia in patients with cardiac decompensation, there are other factors at work. One is an increase of the plasma aldosterone concentration and another the increased sympathetic nervous activity–adrenaline administration reduces the plasma potassium concentration. The clinical importance of hypokalemia, especially for cardiac arrhythmias, is discussed.     

Effects of selective and nonselective beta-adrenoceptor antagonism on isoproterenol-stimulated myocardial potassium uptake in the intact dog

In intact anesthetized dogs, we measured myocardial potassium uptake, as calculated from the aortocoronary sinus difference in potassium concentration and myocardial blood flow, before and during beta-adrenergic stimulation with isoproterenol. Isoproterenol (10 and 30 ng/kg/min, n = 16) lowered arterial potassium concentration from 3.48 +/- 0.08 mmol/L by 0.20 +/- 0.07 and 0.32 +/- 0.06 mmol/L, coronary sinus potassium from 3.45 +/- 0.08 mmol/L by 0.20 +/- 0.06 and 0.35 +/- 0.06 mmol/L, increasing/myocardial potassium uptake from 1.94 +/- 0.99 mumol/min to 2.33 +/- 0.97 and 5.36 +/- 1.29 mumol/min. Unselective beta blockade (propranolol 0.1 mg/kg) significantly attenuated the fall in arterial and coronary sinus serum potassium and the increase in myocardial potassium uptake. Selective beta 1 blockade (metoprolol 0.1 mg/kg) did not significantly influence these effects. We conclude that beta-adrenergic stimulation increases myocardial potassium uptake, lowering serum potassium in the coronary bed, in addition to causing a systemic hypokalemia. This effect is mediated predominantly by beta 2 adrenoceptors.     

Effects of a beta 1-adrenoceptor agonist, prenalterol, on renal function and renin secretion rate in anesthetized dogs

Experiments were conducted to examine the effects of prenalterol on renal function and renin secretion in anesthetized dogs. Specifically, we tested whether prenalterol alters renal function directly, or only indirectly as a consequence of a systemic action of the drug. Accordingly, prenalterol was infused into one renal artery for five consecutive 15-min periods, at incremental rates of 0.1, 0.3, 0.9, 2.7, and 8.1 micrograms X kg-1 X min-1. Heart rate and mean arterial blood pressure were recorded, and renal functions and renin secretion rates were measured bilaterally. Direct intrarenal prenalterol infusion caused a 60 bpm increase in heart rate and resulted in marked increases in renin secretion rates from both kidneys. Intrarenal prenalterol infusion also reduced urinary sodium and potassium excretions bilaterally and equally. There were no consistent changes in mean arterial blood pressure, or in glomerular filtration rate or renal blood flow, during prenalterol infusion. We conclude that although prenalterol increases renin secretion rate markedly and may alter renal electrolyte excretion, these effects are not mediated by a direct intrarenal action of the drug.     

PRESSOR EFFECT OF MODERATE ALCOHOL CONSUMPTION IN MAN: A PROPOSED MECHANISM

1. Ingestion of alcohol was associated with a highly significant increase in systolic blood pressure and heart rate which occurred before the blood alcohol reached its peak concentration of 16.9 (s.e.m. = 1.1) mol/1. 2. Drinking non-alcoholic cold liquids caused a marked but transient fall in adrenaline and a rise in noradrenaline concentration. 3. Alcohol prevented this fall in adrenaline and led to a sustained increase in noradrenaline concentration. 4. These changes may be implicated in the elevation of blood pressure associated with alcohol consumption.     

EFFECTS OF HISTAMINE RECEPTOR ANTAGONISM ON ADRENALINE-INDUCED CHANGES IN BLOOD PRESSURE IN INTACT DOGS

This study was designed to test the hypothesis that histamine may contribute to the vasodepressor response which occurs in response to physiologic increments in adrenaline concentration in intact animals. Accordingly, following a control period of 30 min, adrenaline was infused intravenously for 45 min at a rate of 250 ng/kg per min in 14 anaesthetized dogs (Group I). A second group of eight dogs received an identical adrenaline infusion following complete H1- and H2-histamine receptor antagonism with tripelennamine plus cimetidine (Group II). A time control group of experiments, in which no drugs were infused, as well as groups receiving adrenaline plus either tripelennamine or cimetidine, were also performed. In Group I, adrenaline infusion increased heart rate and reduced mean arterial blood pressure by 10 mmHg (P less than 0.01). Following combined H1- and H2-histamine receptor antagonism (Group II), adrenaline infusion failed to reduce mean arterial blood pressure. However, mean arterial blood pressure was reduced significantly in the groups receiving adrenaline plus only one of the histamine receptor blocking agents. Since only the combined histamine receptor blockade completely eliminated the vasodepressor response to adrenaline, the data suggest that histamine may play a physiological role in the vasodepressor response to circulating adrenaline in the intact animal, and that both H1- and H2-histamine receptors may be involved.     

Effects of arterial hypoxemia and splenic nerve stimulation on myocardial adenosine 3',5'-Monophosphate in dogs.

Epinephrine infusion, 5-percent oxygen breathing, and splenic nerve stimulation were employed to increase cardiac output by 50-100% in anesthetized dogs. Epinephrine infusion as expected, increased plasma and myocardial cyclic AMP concentrations. Arterial hypoxemia increased cyclic AMP concentration in plasma but not in the heart. Practolol pretreatment abolished the increase in plasma cyclic AMP concentration and reduced the rise in cardiac output during hypoxemia. Splenic nerve stimulation was not associated with increases in either plasma or myocardial cyclic AMP. Adenylate cyclase activity was increased by addition of plasma into the incubation medium. However, splenic venous plasma obtained during splenic nerve stimulation did not increase adenylate cyclase activity more than control plasma obtained before stimulation. We conclude that the positive inotropic action of arterial hypoxemia and splenic nerve stimulation does not depend on the adenylate cyclase-cyclic AMP system.     

Hydroxychloroquine overdose: toxicokinetics and management

BACKGROUND: The management and toxicokinetics of hydroxychloroquine overdose are poorly described. CASE REPORT: We report a case of an 18-year-old girl who ingested 20 g of hydroxychloroquine. She developed marked hypokalemia, hypotension, and ventricular tachyarrhythmias but survived with treatment including intubation, adrenaline infusion, high-dose diazepam, and aggressive potassium replacement. Plasma hydroxychloroquine level was 29.40 mumol/L (9.87 mg/L) 2 hours after ingestion and the elimination half-life of hydroxychloroquine was 22 hours. CONCLUSIONS: The clinical manifestations of this hydroxychloroquine overdose were similar to those reported for chloroquine overdose and the management principles recommended for chloroquine overdose appeared to be efficacious in this case.     

Human atrial natriuretic peptide: plasma levels, hemodynamic, hormonal, and renal effects in patients with severe congestive heart failure

The effects of human alpha-natriuretic peptide (alpha-ANP) were investigated in seven patients with severe congestive heart failure by incremental bolus injections and by a continuous infusion for 30 min. alpha-ANP was measured in plasma before and after administration. We found a significant inverse correlation between basal levels of alpha-ANP and cardiac output. The administration of alpha-ANP resulted in a fall of peripheral vascular resistance, an increase in cardiac output, a relatively small decrease in blood pressure, and almost no change in pulmonary arterial pressure. alpha-ANP inhibits aldosterone and cortisol secretion and enhances diuresis and urinary sodium and potassium excretion. Plasma adrenocorticotropic hormone was reduced in two of the patients after the continuous infusion. Plasma renin concentration, norepinephrine, vasopressin, and plasma levels of 6-keto prostaglandin F1-alpha and prostaglandin E2 were unchanged. A small but significant decrease of serum potassium was observed.     

RENAL SODIUM EXCRETION FOLLOWING SYSTEMIC INFUSION OF VASOACTIVE INTESTINAL PEPTIDE IN THE RAT

1. The aim of this clearance study was to examine the renal effects of systemic infusion of vasoactive intestinal peptide (VIP) in the intact rat. 2. Mean arterial blood pressure (MAP), plasma electrolytes and haematocrit, glomerular filtration rate (GFR), and urinary sodium and potassium excretion were measured in a baseline period and following VIP infusion (0.1-1.2 nmol/h per 200 g), as well as during a time control study. 3. During infusion of low doses of VIP (0.1 and 0.4 nmol/h per 200 g), a small increase in fractional and absolute excretion of sodium occurred but this did not differ from that occurring in the time control group. In the high dose VIP group (1.2 nmol/h per 200 g), significant falls occurred in MAP and GFR, and absolute sodium excretion fell (though not significantly) from its baseline level. 4. These findings suggest that systemic VIP has no net natriuretic effect in the rat, but produces haemodynamic changes associated with reduced sodium excretion at high doses. This study does not exclude the possibility of direct effects on tubular sodium transport of VIP released from renal nerves.     

Water immersion induced alterations of plasma adrenaline and noradrenaline levels in patients with endstage renal failure (CRF) and in healthy persons

Water immersion (WI) induced alterations of adrenaline and noradrenaline levels were examined in 20 patients with chronic renal failure (CRF) and 15 healthy persons. In patients with CRF a significantly elevated mean arterial blood pressure (MAP), a markedly elevated plasma level of adrenaline but only a slightly elevated concentration of plasma noradrenaline were observed as compared with healthy persons. In all examined groups WI induced significant decrease of mean arterial pressure and plasma adrenaline and noradrenaline levels. In patients with CRF the WI induced a decrease of MAP and of plasma adrenaline was significantly more marked, while that of plasma noradrenaline was significantly less than in healthy persons. Results presented in this study suggest the existence of an impaired function of the sympathetic nervous system, mainly of the beta-adrenergic one in CRF.     

Peripheral vascular effects of mixtures of isoprenaline and noradrenaline in man

Mixtures of isoprenaline (0.05 μg/min) and noradrenaline (0.05, 0.1 and 0.25 μg/min) were infused into the brachial artery of subjects. The response, an initial transient increase in forearm blood flow followed by a decrease to or below the resting level, resembled the response to an intra-arterial infusion of adrenaline (0.05 to 0.5 μg/min). A five-fold increase in the dose of both drugs in the mixture resulted in a response which was matched by that to a five-fold increase in the dose of adrenaline. The intra-arterial infusions of mixtures and of adrenaline both reduced the thermal conductivity of the skin of the forearm. This result suggests that blood vessels in skeletal muscle responded qualitatively in the same manner to these infusions. Mixtures of isoprenaline (2 μg/min) and noradrenaline (10 μg/min) were infused intravenously into the subjects. The response was an initial transient increase followed by a smaller but sustained increase in the flow of blood to the forearm, and a fall in the flow of blood to the hand. These responses resembled those to the intravenous infusion of adrenaline (10 μg/min). We conclude that the action of adrenaline in the human arm can be explained on the basis of the response of two types of catechol amine receptor.     

The role of β-adrenoceptors in the responses of the hepatic arterial vascular bed of the dog to phenylephrine, isoprenaline, noradrenaline and adrenaline

1 The sympathetically-innervated hepatic arterial vascular bed of the dog was perfused from a femoral artery. Hepatic arterial blood flow and perfusion pressure were recorded continuously, and the hepatic arterial vascular resistance (HAVR) calculated from these measurements.

2 Intra-arterial injections of phenylephrine caused dose-dependent rises in HAVR, indicating hepatic arterial vasoconstriction, at all doses above threshold. No secondary reductions in HAVR followed these responses.

3 Intra-arterial injections of isoprenaline caused only dose-dependent reductions in HAVR at doses above threshold.

4 Intra-arterial injections of noradrenaline typically caused an initial increase in HAVR which was followed at all but the highest doses by a secondary, delayed, reduction in HAVR.

5 Intra-arterial injections of adrenaline, like those of noradrenaline, resulted in hepatic arterial vasoconstriction followed by hepatic arterial vasodilatation.

6 On a molar basis, the most potent hepatic arterial vasoconstrictor was noradrenaline, followed by adrenaline and phenylephrine.

7 The maximum reductions in HAVR caused by adrenaline (mean reduction = 21.9%) and noradrenaline (16.9%) were significantly smaller than those due to isoprenaline (_P < 0.001).

8 Propranolol attenuated the hepatic arterial vasodilator responses due to isoprenaline, and the secondary falls in HAVR following intra-arterial adrenaline and noradrenaline.

9 Propranolol did not modify the vasoconstrictor responses to phenylephrine.

10 Both adrenaline and noradrenaline were more potent hepatic arterial vasoconstrictors after propranolol than in the absence of β-adrenoceptor blockade. The potentiation of the vasoconstrictor effects of adrenaline was statistically significant.

11 After propranolol, adrenaline was a more potent hepatic arterial vasoconstrictor than noradrenaline.

12 Since the β-adrenoceptors in the hepatic arterial vasculature were not blocked by atenolol, but were stimulated by salbutamol, it is concluded that they are predominantly of the β₂-type.

13 The vasoconstrictor actions of phenylephrine, noradrenaline and adrenaline were all antagonized by the systemic administration of phentolamine, all three dose-response curves being shifted to the right.

14 The results are discussed with regard to the possible control of the hepatic arterial vasculature by naturally-occurring catecholamines.

     

Myocardial and circulatory effects of E. coli endotoxin; modification of responses to catecholamines

1. The predominant acute effect of E. coli endotoxin in anaesthetized, ventilated cats was pulmonary hypertension resulting from a 8-12 fold increase in pulmonary vascular resistance. This was followed by decreases in left ventricular (LV) and systemic arterial pressures and in LV dP/dt max. Recovery occurred within 2-4 min and was dependent upon increased sympathetic drive; recovery did not occur in cats treated with the beta-adrenoceptor blocking drug alprenolol.2. The pulmonary vasoconstriction was reduced in cats given compound 48/80 and evidence is presented that it results primarily from histamine release.3. Over the 2-3 h period following endotoxin injection, systemic arterial pressure tended to decrease and heart rate and myocardial metabolic heat production to increase. Myocardial blood flow and LV dP/dt remained fairly stable until the terminal stages of shock.4. The predominant delayed effect of E. coli endotoxin in cats were a markedly reduced stroke volume, an increase in peripheral vascular resistance and a severe metabolic acidosis (arterial base excess-20 mEq/litre). Arterial pO(2) and pCO(2) were not significantly affected. It is concluded that myocardial contractility is maintained at this time through the release of catecholamines and that endotoxin itself depresses contractility.5. The effects of adrenaline and noradrenaline infusions on systolic and diastolic blood pressures, heart rate, cardiac output, myocardial blood flow and LV dP/dt max were markedly reduced in the period 2-3 h after endotoxin. In a few animals some recovery of the response to noradrenaline occurred and was associated with a general circulatory improvement and a reduced metabolic acidosis.     

Correlation between the pharmacokinetics and pharmacodynamics of dopamine in healthy subjects

Summary The pharmacokinetics and the pharmacodynamic action of dopamine were investigated in 5 healthy subjects. Dopamine was given in different doses (200, 400 and 800 µg/min) by constant intravenous infusion over 90 min. In order to control the influence of the procedure on the measured parameters the subjects also received a similar infusion of saline. Dopamine, noradrenaline and adrenaline levels in plasma were followed for up to 6 h after the infusion, and arterial pressure and heart rate were monitored. Dopamine reached a steady state level within 15 to 30 min after commencement of the infusion; the steady state levels averaged 36.5 µg/l at 200 µg/min, 73.8 µg/l at 400 µg/min and 207 µg/l at 800 µg/min. The corresponding total clearances were 5.8 l/ min, 5.51/min and 3.9 l/min suggesting non-linear kinetics. The kinetics could not be described by compartmental model. Noradrenaline and adrenaline levels were found to be elevated during infusion of dopamine. Noradrenaline had returned to its pretreatment level within 15 to 30 min after cessation of the infusion, whereas the adrenaline level did not return to the pretreatment value within the observation period. Heart rate was increased by the dose of 400 µg/min, and the systolic and mean arterial pressures were elevated, whereas distolic blood pressure remained unchanged. Elevated systolic blood pressure was better correlated with plasma dopamine than with noradrenaline concentration. This finding, in conjunction with the unchanged diastolic blood pressure, indicates that elevation of the systolic blood pressure is a direct rather than an indirect effect of dopamine. The increased heart rate was not correlated with the dopamine level.     

Modulation of in vivo generation of prostanoids by drugs affecting membrane ion transport

An in vivo animal model was developed in the rabbit for the study of the mechanisms involved in the generation and release of prostanoids. Following heparinization and, if required, further sensitization of the animals by intravenous administration of haemolysed blood, injection of doses of arachidonic acid not exceeding 180 micrograms/kg induced a marked fall in arterial blood pressure on condition that the plasma anti-inflammatory protein levels were within the normal range. Cicletanine, certain diuretics (furosemide and bumetanide), as well as calcium-entry blockers such as verapamil and the association of insulin and potassium ions, all markedly decreased the AA50 value and were accompanied by a significant increase in the plasma levels of 6-oxo-PGF1 alpha, enhancing as such the ratio of 6-oxo-PGF1 alpha versus TXB2 in plasma. The infusion of insulin in association with potassium ions induced a similar but less sustained effect. Drugs which affect membrane ion transport were investigated in relation to an enhancing effect on the generation and release of prostanoids following the administration of arachidonic acid.     

Effects of intravenous infusion of ouabain on respiration

Effect of continuous infusion of ouabain (2 μg/kg/min) on respiration and on pH, pCO₂ and electrolytes in arterial plasma and CSF were investigated in anesthetized dogs. In most experimental animals, hyperventilation developed about 15 min after ouabain infusion, and cardiac arrhythmia was observed 5–10 min later. During the hyperventilatory phase, arterial blood pH was increased and pCO₂ decreased. CSF pH revealed changes paralleling those in arterial blood. However, the pH values of CSF were lower than those of arterial blood. Arterial plasma potassium concentration was increased after ouabain infusion, but CSF potassium concentration was not affected. Concentrations of sodium and chloride in both plasma and CSF did not alter during the experiment. Results of this study suggest that hyperventilation after ouabain infusion is not due to the changes of chemical constituent in CSF.     

Evidence for noradrenaline and adrenaline as sympathetic transmitters in the chicken.

1 The concentrations of noradrenaline and adrenaline in various organs, arterial plasma and venous outflow from isolated hearts of adult chickens have been determined. 2 The relative adrenaline concentrations (percentage of the sum of noradrenaline and adrenaline) in the heart (33%), spleen (16%) and brain (26%) were higher than those found in mammalian organs. Chemical sympathectomy by pretreatment with 6-hydroxydopamine caused a decrease of the noradrenaline and adrenaline concentrations in the heart to 20 and 23% and in the spleen to 16 and 29%, respectively. 3 Stimulation of the right sympathetic nerves, infusion of tyramine or infusion of a modified Tyrode solution containing 108mM K+ and 44 mM Na+ caused an output of both noradrenaline and adrenaline into the perfusate of isolated hearts. The relative adrenaline concentration in the perfusate (20-28%) was not significantly different from the relative adrenaline concentration remaining in these hearts (19-22%). In the individual experiments, the noradrenaline: adrenaline ratios of the stimulation perfusates were positively correlated with the ratios found in the hearts. 4 The effects of noradrenaline and adrenaline on cardiac rate and tension development were studied in spontaneously beating right atria and electrically driven left atria, respectively. In addition, the arterial pressure rise in response to noradrenaline or adrenaline was;measured in chickens. It was found that the cardio-vaseart rate, cardiac tension development and arterial blood pressure, was not significantly different from that of adrenaline. 5 It is concluded that, in the chicken heart and spleen, both noradrenaline and adrenaline act as sympathetic neutrotransmitters.