Despite numerous examples of the effects of the human gastrointestinal microbiome on drug efficacy and toxicity, there is often an incomplete understanding of the underlying mechanisms. Here, we dissect the inactivation of the cardiac drug digoxin by the gut Actinobacterium Eggerthella lenta. Transcriptional profiling, comparative genomics, and culture-based assays revealed a cytochrome-encoding operon up-regulated by digoxin, inhibited by arginine, absent in nonmetabolizing E. lenta strains, and predictive of digoxin inactivation by the human gut microbiome. Pharmacokinetic studies using gnotobiotic mice revealed that dietary protein reduces the in vivo microbial metabolism of digoxin, with significant changes to drug concentration in the serum and urine. These results emphasize the importance of viewing pharmacology from the perspective of both our human and microbial genomes.

https://dash.harvard.edu/bitstream/handle/1/12872195/1235872Revisedtext.pdf?sequence=3

Predicting and Manipulating Cardiac Drug Inactivation by the Human Gut Bacterium Eggerthella lenta

https://www.heartrhythmjournal.com/article/S1547-5271(09)00739-5/pdf

Drugs and Brugada syndrome patients: review of the literature, recommendations and an up-to-date website (www.brugadadrugs.org)

Much evidence has accumulated to justify the classification of pronethalol (Alderlin; I.C.I.) as a sympathetic β-receptor antagonist described in terms of Ahlquist's (1948) dual-receptor hypothesis. There has now been confirmation in animal experiments of antagonism to adrenergically induced vasodilatation (Ahlquist, 1963; Abboud, Eckstein & Zimmerman, 1963), cardiac stimulation (Meester, Hardman & Barboriak, 1963; Kako, Krayenbuhl, Luthy & Hegglin, 1964; Donald, Kvale & Shepherd, 1964), bronchodilatation (Nagasaka, Schaepdryver & Heymans, 1964), uterine relaxation (Levy & Tozzi, 1963) and gut relaxation after block or loss of α-receptors (Lum & Kermani, 1963). In human pharmacological studies antagonism to catecholamine-induced vasodilatation and cardiac stimulation (Dornhorst & Robinson, 1962; Lowe & Robinson, 1964) has been reported. Reduction of exercise tachycardia in man has been described by Bishop & Segel (1963), Chamberlain & Howard (1964), Harrison, Braunwald, Glick, Mason, Chidsey & Ross (1964) and Schroder & Werko (1964).

The effects of pronethalol in experimental cardiac arrhythmias in dogs and guinea-pigs have been investigated. Antagonism of arrhythmias induced by cardiac glycosides has been reported by Erlij & Mendes (1964), Vaughan-Williams & Sekiya (1963) and Somani, Hardman & Lum (1963). Prevention of arrhythmias induced by adrenaline during anaesthesia with a hydrocarbon has been found by Murray, McKnight & Davis (1963) and by Hess & Hampton (1964). Somani et al. (1963) have shown that pronethalol will block ectopic ventricular tachycardia produced by large doses of adrenaline, and Ehringer & Gogel (1963) claim that it reduces the apical myocardial necrosis produced in rats by large doses of isoprenaline.

This interest in the cardiovascular actions of pronethalol is also shown in various clinical reports. Success in the treatment of some cardiac arrhythmias, including digitalis intoxication, has been reported by Stock & Dale (1963) and Grandjean & Rivier (1963). Encouraging results in the treatment of angina have been found in a multicentre double-blind trial (Alleyne, Dickinson, Dornhorst, Fulton, Green, Hill, Hurst, Laurence, Pilkington, Prichard, Robinson & Rosenheim, 1963) and in a small, placebo-controlled, trial of effort tolerance (Apthorp, Chamberlain & Hayward, 1964). Potential therapeutic value of pronethalol in the management of phaeochromocytoma (Dornhorst & Laurence, 1963) and hypertrophic obstructive cardiomyopathy (Harrison et al., 1964; Cohen, Effat, Goodwin, Oakley & Steiner, 1964) has been described. Effective treatment of ventricular arrhythmias occurring during halothane anaesthesia has been reported by Johnstone (1964) and by Payne & Senfield (1964). These reports confirm the suggestions by Black & Stephenson (1962) that sympathetic β-receptor antagonists might be valuable in the study and treatment of certain cardiac disorders.

The overt toxic effects of pronethalol described by Black & Stephenson (1962) were tremors and convulsions. These signs were correlated with the evidence that the brain concentrations of pronethalol were of the order of 100-times the blood concentration. The acute toxic signs appeared at doses seven- to ten-times greater than those needed for effective β-receptor blockade. While tremors and convulsions have not been described in man, effective doses are often associated with unpleasant subjective side-effects. Mild disorientation, slight inco-ordination, nausea and vomiting have been described (Alleyne et al., 1963). Since the toxic signs in animals are seen with the inactive (+)-isomer as as well as with the active (–)-isomers (Howe, 1963), it has been assumed that the effects of pronethalol on the central nervous system are probably not due to β-receptor blockade. A more serious toxic manifestation was found in mice. Studies showed that pronethalol was a moderately potent carcinogen in this species. Malignant tumours, mainly thymic lymphosarcomata, began to appear after 10 weeks continuous dosing (Paget, 1963; Alcock & Bond, 1964).

This combination of nonspecific central actions and carcinogenic potential in a compound of clinical interest put a premium on finding a less toxic compound. A preliminary communication (Black, Crowther, Shanks, Smith & Dornhorst, 1964) on such a compound has been published; this compound is propranolol (Inderal; LCI.). The relationship of propranolol to pronethalol is shown by the structural formulae:

This paper presents details of the comparative activity of these compounds. Detailed studies of their toxicity by our colleagues have shown that daily treatment of mice with propranolol over a period of 18 months did not produce thymic tumours (Alcock, Baker & Tucker, 1965).

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1965.tb01782.x

Comparison of some properties of pronethalol and propranolol

It is widely recognized that calcium is of singular importance in the viability of the myocardial cell, nonetheless little is known concerning the precise nature of the action of calcium in myocardium as to how it maintains the life of the cell and how it may dictate the death of the cell. However, recent advances in research involved with the study of calcium movement in the heart have been highly valuable for the formulation of new concepts with respect to the physiological and pathological aspects of calcium metabolism in the myocardium. It is becoming clear that calcium movements are closely related to cardiac electrophysiological events, contractile function, membrane integrity and energy metabolism. In particular, a novel theory involving phosphatidylinositol turnover and Ca2+-dependent ATPase activation has been advanced regarding the mechanism and control of calcium entry into the cardiac cell upon excitation. Alterations in the regulation of calcium metabolism through the interaction of a number of separate, elements may affect calcium distribution in the cell and thereby may change cardiac function and metabolism. The part calcium plays in the genesis of pathological states in the myocardium is discussed in the light of research employing various experimental protocols. Intracellular calcium overload and deficiency are postulated to contribute to cardiac contractile failure and cell death through a number of distinct mechanisms. It is now a real challenge to understand the precise nature of processes associated with the occurrence of intracellular calcium overload or intracellular calcium deficiency in order to achieve proper management of cardiac disorders.

Calcium movements in relation to heart function.

1. The interaction of insulin and isometric exercise on glucose uptake by skeletal muscle was studied in the isolated perfused rat hindquarter. 2. Insulin, 10 m-i.u./ml, added to the perfusate, increased glucose uptake more than 10-fold, from 0.3-0.5 to 5.2-5.4 mumol/min per 30g of muscle in hindquarters of fed and 48h-starved rats respectively. In contrast, it did not stimulate glucose uptake in hindquarters from rats in diabetic ketoacidosis. 3. In the absence of added insulin, isometric exercise, induced by sciatic-nerve stimulation, increased glucose uptake to 4 and 3.4 mumol/min per 30g of muscle in fed and starved rats respectively. It had a similar effect in rats with moderately severe diabetes, but it did not increase glucose uptake in rats with diabetic ketoacidosis or in hindquarters of fed rats that had been "washed out" with an insulin-free perfusate. Insulin, at concentrations which did not stimulate glucose uptake in resting muscle, restored the stimulatory effect of exercise in these situations. 4. The stimulation of glucose uptake by exercise was independent of blood flow and the degree of tissue hypoxia; also it could not be reproduced by perfusing resting muscle with a medium previously used in an exercise experiment. 5. At rest glucose was not detectable in muscle cell water of fed and starved rats even when perfused with insulin. In the presence of insulin, a small accumulation of glucose, 0.25 mM, was noted in the muscle of ketoacidotic diabetic rats, suggesting inhibition of glucose phosphorylation, as well as of transport. 6. During exercise, the calculated intracellular concentration of glucose in the contracting muscle increased to 1.1-1.6mM in the fed, starved and moderately diabetic groups. Insulin significantly increased the already high rates of glucose uptake by the hindquarters of these animals but it did not alter the elevated intracellular concentration of glucose. 7. In severely diabetic rats, exercise did not cause glucose to accumulate in the cell in the absence of insulin. In the presence of insulin, it increased glucose uptake to 6.1 mumol/min per 30g of muscle and intracellular glucose to 0.72 mM. 8. The data indicate that the stimulatory effect of exercise on glucose uptake requires the presence of insulin. They suggest that in the absence of insulin, glucose uptake is not enhanced by exercise owing to inhibition of glucose transport into the cell.

Glucose metabolism in perfused skeletal muscle. Interaction of insulin and exercise on glucose uptake.

The relationship between cellular calcium (Ca) stores and isometric contractile force was investigated in isolated, gas-perfused cat hearts. The hearts were preperfused for approximately 5 min with substrate-free Krebs solution modified to contain 0, 1.25, 2.5, 5.0 or 10.0 mEq/liter Ca, gas-perfused for up to 120 min, and then perfused with zero-Ca Krebs solution. Contractile force and [Ca] in the effluent fluid were measured. Our results indicate that: (a) The washout of Ca was characteristic of a three compartment system, (b) A Ca compartment directly associated with muscle contraction was identified by correlation of the rate of Ca washout with the rate of decay of contractility (r = 0.79). (c) Ca content in the compartment was correlated with contractile force (r = 0.77). (d) Contractile force and the Ca content of the compartment which was correlated with contractility approached a steady state during 120 min of gas perfusion.

https://rupress.org/jgp/article-pdf/52/6/969/1244479/969.pdf

Correlation of contractile force with a calcium pool in the isolated cat heart.

The functional refractory period of atrioventricular (AV) transmission has been accepted as a measure of AV nodal refractoriness and has been assumed to be determined solely by conduction of interpolated extrasystoles through the AV node when it is partially refractory. In the present study, we found an important effect of the conduction time of the regular beats by measuring AV nodal conduction times of atrial extrasystoles from the His bundle of isolated, blood-perfused dog hearts. We separated three independent components that determine AV nodal conductivity: (1) a "basal conduction time" measured with a "postmature" extrasystole at low heart rates (<120 /min), (2) a rate-dependent increment in conduction time (previously called "fatigue") that affects both normal and premature cycles equally and (3) an exponential change in conduction time that depends entirely on the immediately preceding interval and, therefore, is not further affected by heart rate. The functional refractory period is one point defining this continuous exponential function. We showed that an important cause of the decrease in the functional refractory period that occurs when heart rate is increased is the change in the conduction time of the regular beats.

Relationship of the Functional Refractory Period to Conduction in the Atrioventricular Node

Dichloroisoproterenol (DCI) has been found to produce a competitive blockade of the positive inotropic action of adrenaline on cat papillary muscles. The effect of adrenaline on electrical excitability of this preparation also is blocked. DCI itself has been shown to have considerable adrenaline-like activity, increasing the strength of contraction and decreasing the threshold of electrical excitability. The positive chronotropic and arrhythmia-inducing effects of adrenaline have been shown to be blocked in the whole animal.

Blockade of some cardiac actions of adrenaline by dichloroisoproterenol

The production of acute necrotic lesions of the myocardium and concomitant changes in myocardial and skeletal muscle potassium concentrations were investigated in rats. Lesions were induced by the administration of 2α inethyl-9α-chlorocortisol plus oral Na2SO4 (which caused a profuse catharsis), steroid plus an irritant cathartic (croton oil), steroid plus low-potassium diet, and low-potassium diet alone. Lesions in the various groups were grossly and microscopically indistinguishable. Their incidence and severity were well correlated with the degree of myocardial potassium depletion below a threshold value of approximately 72 mEq./Kg. wet weight. Skeletal muscle potassium was decreased roughly parallel to that of the myocardium, but some what more variably. Other treatments, including steroid or oral Na2SO4 alone and steroid plus subcutaneous Na2SO4 which failed to produce comparable reductions in myocardial potassium, failed to induce morphological lesions. Any specific interaction between steroid and e...

Pathogenesis of "Electrolyte-Steroid-Cardiopathy"

Relative contributions of the atria and the atrioventricular (AV) node to AV conduction were studied in isolated, blood-perfused dog hearts. The functional refractory period of the atria, although shorter than that of the AV node, determined the functional refractory period of the entire transmission system in 50% of the hearts. Slow atrial conduction of early beats greatly influenced the shape of the curve used to determine the functional refractory period of the transmission system. The atrial effective refractory period was also shorter than the effective refractory period of the AV node. However, the effective refractory period of the entire transmission system was equal to that of the atrium when the driving interval was longer than 320 msec, and it decreased as the driving interval was shortened. At driving intervals of 320 msec or less, the effective refractory period of the AV transmission system abruptly increased and became equal to the effective refractory period of the node. Conduction of early premature responses from near the sinoatrial node to the AV node was supernormal in 50% of the hearts. Supernormal conduction of premature atrial responses in the ventricles was also observed. The period of supernormal conduction in both tissues shifted toward greater prematurity as heart rate increased. The importance of the atrium in determining the functional properties of the AV transmission system has been previously underestimated.

Role of the Atrium in Determining the Functional and Effective Refractory Periods and the Conductivity of the Atrioventricular Transmission System

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