Taurine Role in Cardiology and Cardiac Arrhythmias
George Eby, Austin, Texas
Notice: This page is out of date. My current research is a new medical journal paper titled: "Elimination of cardiac arrhythmias using oral taurine with L-arginine: hypothesis for nitric oxide stabilization of the sinus node with case histories". Please access this new page here. Also please consider large doses ofOmega-3 Essential Fatty Acids.
This page was written up in Natural News by Barbara Minton.
This page is about the extraordinary power, actually the extraordinary NATURAL power of an amino acid called taurine to effectively prevent cardiac arrhythmias. In my case, I was having pre atrial contractions (PACs) each five beats, totally 25,000 abnormal pre atrial contraction (PACs) per day. These pre atrial contractions (PACs) started suddenly in 1998 and continued more or less unabated until I started to regularly add taurine to my diet.
Pre atrial contractions (PACs) are nerve racking and lead to poor sleep habits and irritability. As far as I can determine the article below by Chazov et al. is one of the few articles ever published to demonstrate the extraordinary benefit of taurine in preventing and treating cardiac arrhythmias such as pre atrial contractions (PACs) and premature ventricular contractions (PVCs). I knew from experience that magnesium taurate helped reduce my PACs from one premature beat each 5 seconds to one each 8 to 10 seconds. I had attributed this action to magnesium, and not taurate (taurine), but to more completely eliminate pre atrial contractions with much larger doses of taurine than is possible with magnesium taurate was a really significant observation.
What is going on here? Very briefly, in aging, taurine production by the liver can decline resulting in the "little old man / little old lady syndrome" known and clearly evinced by the mental image invoked. Low taurine production problems appear simple to alleviate with supplemental dietary taurine, which is available at nearly all health food stores, pharmacies and grocery stores in the United States and elsewhere. This is why the "energy drink" Red Bull gives people energy (not the caffeine), it restores their taurine levels to youthful levels, consequently they perform youthfully. A very simple solution to curing the "little old man / little old lady syndrome".
The top strip of the following ECG shows the effect of 12 grams taurine daily in eliminating the pre atrial contractions (PACs) shown in the lower strip (before administration of taurine), clearly showing the early beats are no longer a major issue, but they do occur from time to time always in the familiar every fifth to tenth beat pattern.
How did I figure out this mess? In Timothy Birdwell's article, he writes, "Chazov et al. were able to demonstrate that taurine could reverse EKG abnormalities such as S-T segment changes, T-wave inversions, and extra systoles (extra heart beats like PACS and PVCs) in animals with chemically-induced arrhythmias." Who is "Chazov"? I looked up the Chazov article on PubMed to be disappointed since only the title of the article (Taurine and Electrical Activity of the Heart) was presented. I contacted Circulation Research an official journal of the American Heart Association, and they sent me a copy of the issue, and I republished Chazov's article below.
Chazov reported there were no side effects, so I experimented taking taurine to see what would happen. I started out with what I thought would be a high dosage, 2 grams with breakfast. Within a half hour, my PACs, which had been running along about every 5 seconds, were running along at about one every 5 minutes, a sixty-fold improvement. The effect wore off by lunch-time and I repeated the 2 gram dosage. Again, the PACs disappeared. Was taurine a cure for cardiac arrhythmias? It began to look like it for me! I was thrilled out of my mind! No more useless propranolol!!! Hurray! Within a few days, I settled on a 3 gram dosage with each meal and at bedtime. I now have zero PACs per day (unless I eat too much salt and/or my Candida yeast flares up), as long as I take taurine in these doses. What are the side effects? Diarrhea and excessive nasal and throat mucous can develop from too much taurine. The solution? Reduce taurine intake or stop it for a while. I suspect that my PACs are more realistically reduced by one half, with none over long times.
Please understand that there may be multiple causes of cardiac arrhythmias in the same individual, and low taurine may only be one of them, or taurine treatment may mask the effects of the real cause. For example, if cardiac arrhythmias are caused by a cardiovascular toxin or an allergen, one must become a detective and figure our what that toxin or allergen is. One toxin or allergen that can cause irregular cardiac rhythm is acetaldehyde, a toxin released in large amounts from Candida Albicans fungal/yeast intestinal infections and decay of them. People can be highly allergic to candida and its break down products.
A niacin deficiency can cause lone atrial fibrillations, and their treatment with 500 mg of flush free niacin (inositol hexanicotinate) twice a day will totally stop them.
If any of the prescription antifungals, non prescription antifungals and natural antifungals such as coconut oil, garlic, and kefir are beneficial in temporarily terminating cardiac arrhythmias, then one must find a more permanent solution to the candida problem. Antifungals loose their efficacy after about 5 to 6 days due to resistance buildup and mutation of the candida strain. Iodine is more effective against candida because the various mutations are all susceptible to iodine, but iodine (3 mg per meal) will cause hypothyroidism or hyperthyorism in effective anti-candida doses and it should not be used for more than a few days to a week. Spanish Black Radish and cruciform vegetables contain indole-3-carbinol and sulforaphene. These two substances stimulate two of the body's most powerful detoxification mechanisms - the cytochrome P450 and the Phase II enzyme systems - the body's biochemical pathways for converting toxins into harmless or easily excretable substances. Thus Indole-3-Carbinol and foods known to contain it, like cabbage, kale and broccoli, may render acetaldehyde harmless and stop cardiac arrhythmias. Whether or not taurine will also be needed can then be evaluated. I have found that 200 mg of Indole-3-Carbinol with each meal and at bedtime is sufficient to prevent my cardiac arrhythmias when taken with lower doses of taurine. Consequently,a better intestinal immune system (from Indole-3-Carbinol) and a cardioprotective dose of taurine leads to no arrhythmias and a healthier life.
A very important cause of both benign and potentially lethal cardiac arrhythmias is low blood nitric oxide (NO). Nitric oxide production is supposed to be high in the nose. Nasal nitric oxide production by strong humming (the nasal vocalization) can be increased 15 to 20-fold, thus increasing blood nitric oxide. I can stop my arrhthymias simply by humming very strongly for a while. I discovered this conicidentally to learning how to cure fungal (candida albicans)- induced chronic rhinosinusitis (chronic sinusitis). The full report is here. No benefit may occur unless humming is done for at least an hour a day for several days.
Since humming to reduce arrhythmias works most likely by increasing blood nitric oxide, what would happen if the precursor to nitric oxide, the amino acid L-arginine, were used instead? A friend of mine that was having 20,000 atopic beats from pre ventricular contractions (PVCs) found that 1 gram of arginine (in gelatine capsules) with taurine at each meal and at bedtime would eliminate 100% of his arrhythmias. Did L-arginine work for my pre atrial contractions (PACs)? Yes! The same dose of L-arginine when taken with taurine totally stopped my pre atrial contractions (PACs). For many people L-arginine and taurine will stop arrhytmias better than anything else. How does it work? It has something to do with "nitric oxide" production. Try one gram of the amino acid L-arginine with each meal for a few weeks, but only when L-arginine is packaged in gelatine capsules for extremely important reason shown below.
In several people trying this offbeat technique, three grams of L-arginine (in compressed tablet form) per meal caused severe to extremely severe constipation while using magnesium supplementation that previously caused diarrhea. Serious constipation did not seem to occur with one gram of L-arginine per meal, although is could cause mild constipation. On the other hand, the literature says that too much L-arginine will cause diarrhea, not constipation. Who knows!
On the other hand, L-arginine (in large doses) appears dangerous to people who are recovering from heart attacks. Six out of 76 people recovering from heart attacks treated with 9 grams L-arginine/day (in 500 mg gelatine capsules) died compared with zero for placebo according to this NIH supported study. I would not be surprised to learn that L-arginine in these large doses made them so constipated that it killed them. The mechanism of action shown byTomita et al. is due to increased nitric oxide production in the intestines, which mediates nonadrenergic, noncholinergic inhibitory nerves and plays an important role in the dysmotility observed in the colons of patients with slow-transit constipation. This effect is vastly stronger using compressed tablets of L-arginine than when using gelatin capsules of L-arginine, suggesting that hard compressed tablets reach and dissolve in the colon enhancing local nitric oxide production (and do not dissolve in the stomach). This is the Letter to the Editor of JAMA that I submitted today, January 14, 2006: Sir: Concerning the question of why L-arginine seems to have killed patients in the study of Schuleman et al. (JAMA. 2006;295:58-64), it should be noted that L-arginine in the 9 grams per day (3 grams with each meal) doses used by Schuleman et al. causes extreme, highly dangerous constipation in people with slow-transit constipation, perhaps due to the effect of excessive arginine-induced nitric oxide on nonadrenergic, noncholinergic inhibitory nerves of the colon (Tomita R, Fujisaki S, Ikeda T, Fukuzawa M. Role of nitric oxide in the colon of patients with slow-transit constipation. Dis Colon Rectum. 2002 May;45(5):593-600.). In fact, these 9 grams/day doses may be highly constipating in other people too. For that reason alone, L-arginine should not be used in those excessive doses (particularly in the form of hard compressed tablets likely to reach the colon), while one to two grams per day as dietary supplement (prepared in gelatin capsules) seem harmless. -- George Eby, Austin, Texas . In other words, if you have had a heart attack or have a weakened heart, you do not want to become constipated from excessive L-arginine or from excessive calcium or any other way. Remember how Elvis died! Don't strain trying to poop! Stay loose!
I use Cardiovascular Research Magnesium Taurate (a compound of magnesium and taurine) . Arginine is available here. Warning: Use only L-arginine in gelatine capsules to prevent tablets from getting into the colon and inducing severe constipation.
Obviously, salt (sodium chloride) sensitivity is a serious problem which can lead to heart damage (hypertrophy) and hypertension, and a lower sodium chloride and higher potassium chloride diet is both possible and desirable. The saltly taste from sodium chloride that the West has come to love, is nearly identical from potassium chloride (Morton's Salt Substitute). Unfortunately, it does not have supplemental iodine as is mandated for sodium chloride by United States law, which must be added to the diet by other means, such as supplementation. Failure to obtain sufficient iodine (or too much) can can cause hyptothyroidism which can cause lethal heart attacks, particularly in elderly women. Morton's Salt Company should add iodine to its product for maximum cardiac health and our longevity. Lack of iodine in this product is a principal reason Morton's Salt Substitute comes with a warning to consult a physician before use.
Before we revisit Chazov, what are some of the roles for taurine? From the Holistic Health Encyclopedia page we find:
Taurine is a non-essential amino acid which can be derived from your diet or synthesized from the amino acid cysteine, if there is enough cysteine & pyridoxal-5-phosphate (co-enzyme B-6.) Taurine is highly concentrated in animal & fish protein. Taurine is essential to fetal & new born central nervous system development. The infant cannot initially manufacture taurine & must obtain taurine from its mother's milk. Taurine plays a variety of roles in the normal functioning of the brain, heart, gallbladder, eyes, & vascular system. It is the most important & abundant free amino acid in your heart & contributes to your heart muscles' contractility & regulation of its rhythm. Taurine acts as a neurotransmitter in your brain where it is the second most abundant amino acid. It also protects & stabilizes the brain cells' fragile membranes. It is an inhibitory calming neurotransmitter. Taurine acts by regulating the sodium & potassium concentration in the cells & the magnesium level between the cells. This has everything to do with the electrical activity of the cells & subsequent communication between cells. By this mechanism, it has anti-anxiety & anti-convulsant activity Taurine is found in high concentrations in your eyes & is the most abundant amino acid in your retina. Taurine is known to re-invigorate the natural killer cells of your immune system & to stimulate the release of the immune substance, Interleukin-1.
Additional benefits & uses are:
- Plays a role in decreasing the development of cataracts.
- Useful in the management of chemical sensitivities as a powerful sulfur donor which removes foreign material & oxidized chlorine.
- Useful with absorption of fats.
- Important for proper bile production & fat metabolism, thus the ability to reduce body cholesterol.
- For anxiety, agitation, hyperactivity.
- For insomnia.
- High blood pressure.
- Certain heart irregularities.
- Congestive heart failure.
- Diabetes, potentiates & improves the action of insulin.
- Gallbladder disease.
- Macular degeneration/retinitis pigmentosa.
- Immune problems.
More specifically to cardiac issues, the Life Extension foundation reports three-fourth of the way down their page that: "Taurine has hypotensive and diuretic activity, tempers the sympathetic nervous system, is beneficial in CHF and arrhythmias, and has digitalis-like mentality. Taurine is the most important and abundant of the amino acids in the heart, surpassing the combined quantity of all the others. Under high stress conditions -hypertension and many forms of heart disease - the need for taurine increases to compensate for either an accompanying impairment of taurine metabolism or increased requirements. Dr. H. Kohaski and colleagues (Japan) suggest that entry-level taurine may have been low and, as the stress of hypertension progresses, taurine levels drop even lower (Kahashi 1983; Braverman et al.1987). Taurine has a diuretic action that benefits hypertensive individuals, as well as patients with congestive heart failure. Taurine elicits much of its diuretic action by preserving potassium and magnesium and by promoting sodium excretion (Atkins 1996b). Taurine also reduces blood pressure by acting as an antagonist to the blood pressure-increasing effect of angiotensin, a circulating protein that is activated by renin, a hormone secreted by the juxtaglomerular cells in the kidneys in response to a drop in blood pressure (Braverman et al. 1987). When both blood and urine taurine levels decrease, renin is activated and angiotensin is formed. As a result blood vessels vasoconstrict, water and salt are retained, and blood pressure increases. Taurine suppresses renin and breaks the renin-angiotensin feedback loop. Dr. Robert Atkins, a complementary physician with a creditable cardiology background, amplifies the positive results of scientific literature, stating that taurine would be his choice were he selecting a single nutrient to treat hypertension. Dr. Y. Yamori (a Japanese researcher who established an amino acid-stroke association) studied a strain of rats, genetically susceptible to strokes. Yamori found the rats had a much lower incidence of stroke, dropping from 90% to 20%, if their diet was supplemented with methionine, taurine, and lysine (Yamori et al. 1983; Braverman et al. 1987). Japanese researchers found that 3 grams of taurine, administered daily to patients with congestive heart failure, was more effective than 30 mg of CoQ10 (Azuma et al. 1992). The Japanese, who use taurine widely in the treatment of various forms of heart disease, found that 4 grams of taurine, given for 4 weeks, brought relief to 19 of 24 patients with congestive heart failure. Taurine appears to act much like the drug digitalis, increasing the contractility of cardiac muscle and the force of the pumping action. Taurine appears to impact cardiac arrhythmias through various pathways. For example, some forms of cardiac irregularities are helped by taurine because it regulates membrane excitability and scavenges free radicals. In addition, taurine protects potassium levels inside heart cells, which, when imbalanced, can cause electrical instability and cardiac arrhythmias (Braverman 1987; Chahine et al. 1998). Some types of premature ventricular contractions and arrhythmias respond to taurine because the amino acid tends to dampen activity in the sympathetic nervous system (SNS) and the outpouring of epinephrine. As the SNS is quieted, the heart tends to beat less aggressively and the blood pressure is lowered. Lastly, Lebanese researchers showed that the incidence of ventricular fibrillation and ventricular tachycardia were significantly reduced when taurine therapy was utilized (Braverman 1987; Chahine et al. 1998). A suggested dosage range is 1500-4000 mg daily."
Here is a really good article concerning improving the electrical and contractile properties of skeletal muscle fibers with chronic administration of taurine, which means that with daily taurine supplementation one can ensure normal muscle function in the elderly. I have found as an old man that the amount of taurine that I need is higher than previously believed, and I take between 5 and 10 grams a day to retain youthful muscle function, suggesting that my old liver's ability to make taurine in impaired or that my kidney's ability to recycle taurine is impaired. Many old people could have their youth returned with supplemental taurine.
Don't miss my brand new medical journal article on eliminating angina pectoris and Raynaud's disease (discolored gray hands and face) using high-dose zinc. Looks to me that reducing or eliminating arteriosclerosis with zinc (the only way this discovery could work) is vastly more simple than anyone could possibly imagine, and is dirt cheap. See how I discovered it at this background page and see the medical journal article here .
Also, see this page for more information on taurine.
Taurine and Electrical Activity of the Heart
Supplement III to Circulation Research, Vols. 34 and 35. September 1974.
By E. I. Chazov, L. S. Malchikova, N. V. Lipina, G. B. Asafov, and V. N. Smirnov
From the Laboratory of Myocardial metabolism, Myasnikov Institute of Cardiology, Academy of medical Sciences of the U.S.S.R., Moscow, U.S.S.R. ABSTRACT
- The effects of taurine on the electrical activity of the heart were studied in isolated preparations from guinea pigs and in situ hearts of dogs that were administered toxic doses of strophanthin-K. In the first minute after exposure of isolated hearts to taurine (0.05 mg/mv or more), the height of the T wave increased, the S-T interval lengthened, and bradycardia ensued. At high taurine concentrations (10 mg/ml). inversion of the T wave and downward displacement of the S-T segment were observed. Taurine restored abnormal electrocardiograms to normal, including S-T-segment abnormalities, T-wave inversions, and disorders of conduction. On the other hand, taurine aggravated the ECG abnormalities seen in hearts perfused with K+-free buffer, but sustained electrical activity if added early in the period of potassium deficiency. Taurine uptake by the isolated heart was estimated by disappearance from the medium and was found to be intensified by K* depletion. In dogs given toxic doses of strophanthin-K, taurine reversed the ECG abnormalities in the initial 40 to 50 minutes, after which the abnormalities reappeared. If toxic effects were not present, taurine exerted an inotropic effect.
These findings indicate that taurine is able to regulate the excitability of the myocardium, possibly by modifying membrane permeability to potassium. It is suggested that this effect involves penetration of taurine into the cell and its conversion to isethionic acid.
KEYWORDS: strophanthin, T wave arrhythmias, bradycardia, electrocardiogram, potassium deficiency Introduction
Taurine, the product of metabolism of sulfur-containing amino acids, is present in all body tissues of animals and man and has a pharmacological action, but does not exert a toxic effect. (1) Until recently, the sole well-established function of taurine was its participation in taurocholic acid synthesis.(2 - 4) However, the wide distribution of taurine in many biological systems and its high content in certain organs of vertebrates have led to the thought that its physiological role is not restricted to formation of bile acids. (5, 6)
There is special interest in the few observations suggesting that taurine is of importance in regulation of the functional condition of the cardiovascular system. Thus, taurine causes a temporary reduction in blood pressure in rats,(7) exerts a vasodilator effect and increases the heart rate in frogs and rabbits, (8, 9) and leads to an increase in duration of the refractory period of the canine ventricles.(10) Taurine has a positive inotropic effect on the isolated guinea pig heart and a negative inotropic effect on the rat heart. In rat hearts it potentiates the effect of strophanthin-K. (11, 12) Read and Welty have shown that intravenous administration of taurine eliminates extrasystoles caused by epinephrine and the arrhythmia that occurs in chronic digitalis intoxication.(13) Taurine also has a therapeutic effect in angina pectoris and muscular dystrophy. (14 - 16)
These data suggest an important physiological role of taurine in regulation of cardiac activity; however, they do not permit a judgment on its mechanism of action. Proceeding from these observations, we attempted to study the effect of taurine on the electrical activity of the heart and to develop a possible mechanism for the effects of taurine on this important indicator of cardiac function. The nature of the change in electrical activity of the heart when the heart is exposed to buffer-containing taurine was investigated in the isolated hearts of guinea pigs and in the in situ hearts of dogs to which toxic doses of strophanthin-K had been given. Methods
PERFUSION OF THE ISOLATED HEART
Random-bred male guinea pigs weighing 250 to 300 g were used. The hearts were removed from animals anesthetized with pentobarbital and were perfused via the aorta by the Langendorff method. Tyrode solution (131 mM NaCl, 5.6 mM KCl, 2.16 him CaCl< sub="">2, 0.25 mM MgCl2, 5 mM Tris, 11 mM glucose, pH 7.35) was supplied at a pressure of 60 mm Hg. The perfusion solution was oxygenated with a mixture of 95% 02 plus 5% CO2. Tyrode solutions with a low potassium content (2.8 mM KCl), with a high potassium content (11.2 mM KCl), and potassium-free Tyrode were also used. Potassium-free and 2.8 mM KCl Tyrode solutions were prepared by means of equimolar replacement of KCl by sucrose.<>
EXPERIMENTS WITH DOG HEARTS
Male dogs weighing 8 to 10 kg were anesthetized with pentobarbital sodium and vagotomized. Strophanthin-K and taurine were dissolved in 0.9% NaCl and administered intravenously.
RECORDINGS OF HEART ACTIVITY
In the experiments on dog hearts the electrocardiogram and right and left ventricular and arterial pressures were recorded on an M-81 mingograph (Elema, Sweden). Electrical activity of the isolated guinea pig heart was recorded on a one-channel K-061 electrocardiograph (U.S.S.R.) with bipolar leads from nonpolarizable electrodes.
TAURINE AND STROPHANTHIN-K SOLUTIONS
In tests on the isolated guinea pig heart taurine, prepared in Tyrode solution at concentrations of 5.10-4, 5.10-3 and 2.102 g/ml and strophanthin-K at a concentration of 10-5 g/ml were used. In experiments on dog hearts taurine was administered in doses of 4 to 5 mM/kg body weight and strophanthin-K in doses from 0.05 to 0.1 MMg/kg body weight.
TAURINE UPTAKE BY THE ISOLATED HEART
Uptake of taurine by the isolated heart was determined by the change in taurine concentration in the perfusion medium. The taurine content was determined using an M-121 amino acid analyzer (Beckman) by the standard single-column method.(17) The 0.9 by 69 cm column was filled with M-72 resin to a height of 40 cm. Taurine was eluted with lithium citrate buffer, pH 2.8, at a rate of 60 ml/hour and a temperature of 38°C.
The following reagents were used: taurine (Chemapol, Czechoslovakia), sucrose and strophanthin-K (U.S.S.R.), lithium citrate and Ninhydrin (Merck), and M-72 resin (Beckman, U.S.A.). Results
EFFECT OF TAURINE ON ELECTRICAL ACTIVITY Of ISOLATED HEARTS
During perfusion of the heart with Tyrode solution containing taurine, changes in the several parameters of the electrocardiogram were observed. In the firs.t minute after addition of taurine, a significant increase in the height of the T wave and lengthening of the S-T interval took place. After two to three minutes a stable bradycardia developed (Table 1, Fig. IA). An increase in the height of the R wave that was proportional to the time of exposure to taurine was occasionally observed (Fig. IA). Upon removal of the taurine from the perfusate, all ECG parameters of the isolated heart gradually returned to the initial values.
A dependence of the amplitude of the T wave on taurine concentration was noted. Taurine has a detectable effect at a concentration of 5.10-4 g/ml. With an increase in concentration a more pronounced increase in the amplitude of the T wave and S-T segment was noted, and bradycardia began sooner. A high taurine concentration (2.10-2 g/ml) caused an inversion of the T wave and a downward displacement of the S-T segment (Fig. IB).
Electrocardiograms that were initially abnormal were restored to normal by taurine. Taurine eliminated T-wave inversion (Fig. 24) and restored the conduction (Fig. 2B).
TAURINE AND POTASSIUM IONS
Having demonstrated that taurine causes a change in the T wave of the isolated guinea pig heart, and supposing that both the amplitude and polarity of the T wave depend on the concentration of K+ in the plasma,(18 - 20) we attempted to evaluate the role of K+ in the effects of taurine on the heart.
Perfusion of the heart with Tyrode solution containing twice the usual K+ concentration was accompanied by an increase in frequency of the beat and S-T elevation. Upon addition of taurine to the perfusate a negligible bradycardia was observed. With half the usual K+ concentration in the perfusate, the ECG did not change significantly and the effect of taurine was less pronounced.
Complete removal of potassium ions from the medium resulted in ECG changes. In the potassium free medium a significant increase in the S-T interval, a change in the amplitude of the T and R waves, and a decrease in heart rate were observed within one minute (Table 2). After eight to ten minutes of perfusion the normal ventricular rhythm was replaced by an arrhythmia which progressed to fibrillation.
Addition of taurine to the K + -free perfusate (before onset of fibrillation) lengthened the S-T interval and aggravated the bradycardia. However, taurine would sustain the electrical activity which was established before its administration in hearts perfused with K + -free buffer. For example, addition of taurine to the perfusate after a ten-minute perfusion with K+-free Tyrode solution preserved the electrical activity for a period of six minutes, while without taurine irreversible fibrillation developed.
Replacement of a medium devoid of K+ by Tyrode solution of the normal ionic composition resulted in complete restoration of the initial ECG if a severe arrhythmia or fibrillation had not developed. When the medium without potassium ions was replaced by Tyrode solution containing taurine, a tendency toward lengthening of the S-T interval, an increase in the amplitude of the T wave, and maintenance of bradycardia were noted. In the absence of taurine under similar conditions, the initial ECG was restored by the tenth minute. In those cases in which fibrillation had developed in hearts perfused with K + -free buffer, addition of taurine eliminated it (Fig. 3B, 3C). A similar effect was observed when K+-free perfusate was replaced with Tyrode solution containing taurine. However, replacement of the K+-free perfusate by normal Tyrode solution without taurine did not eliminate fibrillation, even after prolonged perfusion (Fig 3A).
TAURINE UPTAKE BY ISOLATED HEART
To determine whether the observed effects of taurine were dependent on its binding to membrane receptors or to penetration of the cell, the following experiments were conducted. Isolated guinea pig hearts were perfused with Tyrode solution containing taurine for a period often minutes. At one-minute intervals samples of the perfusate flowing out of the heart were taken and their taurine content determined. Taurine uptake by the isolated heart was judged by the change in taurine concentration in the perfusate.
Maximal uptake of taurine from the perfusate was observed in the first 30 seconds of perfusion (Fig. 4). Uptake then decreased, and the taurine concentration in the perfusate flowing from the heart approximated the initial concentration by the fifth minute and remained at this level until the end of perfusion. In perfusion of the heart with a K+-free medium containing taurine, taurine uptake proceeded more intensively and continued during the entire perfusion period (Fig. 4).
EFFECT OF TAURINE ON CHANGE IN ELECTRICAL ACTIVITY INDUCED BY STROPHANTHIN-K
Having shown that taurine was capable of converting an arrhythmia to a normal rhythm under certain conditions, we carried out a series of experiments in which we attempted to estimate the effect of taurine on the arrhythmia induced by strophanthin-K.
Strophanthin-K was administered intravenously to dogs. An increase in the P-Q interval, S-T-segment abnormalities, T-wave inversions, extrasystoles, and other arrhythmias developed gradually. Taurine was administered intravenously upon .appearance of the toxic effects of strophanthin-K. Twenty-five to 30 minutes after administration, normal electrical activity of the heart could be observed (Fig. 5).
In the absence of a toxic effect of strophanthin-K, taurine showed a positive inotropic effect, indicated by an increase in developed pressure within both ventricles (Fig. 6). Ten minutes after taurine administration was stopped the pressures in the ventricles returned to the initial levels. Intravenous administration of physiological saline as a control did not modify ventricular pressures.
Correction of disturbances of electrical activity of the heart that were induced by strophanthin-K was observed in the isolated guinea pig heart when exposed to taurine (Fig. 7). Prior perfusion of the heart for four minutes with Tyrode solution containing strophanthin-K led to a change in the rate of repolarization of the ventricles; namely, to an increase in the T-wave amplitude and shortening of the S-T interval. The changes were prevented by taurine. Discussion
The effect of taurine on electrical activity of the heart described in this paper indicated the following:
1. Taurine causes changes in parameters of the ECG that represent the rates of repolarization of the ventricles of the isolated guinea pig heart. This was expressed by the duration of the S-T interval and the amplitude of the T wave.
2. In association with these changes, taurine is taken up from perfusate flowing through the heart.
3. Taurine reverses the arrhythmia induced by toxic doses of strophanthin-K in dog hearts and eliminates the ECG changes caused by strophanthin in isolated guinea pig hearts.
These findings are evidence for the ability of taurine to regulate the excitability of the myocardium and to provide a basis for considering possible mechanisms of this regulation. Experiments conducted on the isolated perfused hearts of guinea pigs showed that addition of taurine to the perfusate led, within one minute, to change in the ECG parameters associated with repolarization of the ventricles. The S-T interval and amplitude of the T wave increased. An increase in amplitude of the T wave without a change in its duration and the increase of S-T interval in hearts exposed to taurine are evidence for an increase in the repolarization period and, consequently, of the relative refractory period, since the durations of the S-T segment and T wave reflect the relative refractory period of the myocardium.(21)
An increase in the refractory period in dog myocardium after taurine administration was also observed by other authors.(10) Thus, the change in the electrophysiological property is a characteristic feature of taurine action on the heart. Considering that an outflux of potassium ions takes place during the repolarization period (22) and that the maximal outflux of potassium ions takes place during the repolarization period (22) and that the maximal outflux corresponds to the T wave, (18, 23) a prolongation of the S-T interval can be interpreted as indicating a slower outflux of potassium ions from myocardial cells in the presence of taurine. In acute experiments on dogs we found that intravenous administration of taurine completely reversed the arrhythmia induced by prior administration of toxic doses of strophanthin-K.
The antiarrhythmic effect of taurine had been noted earlier by other investigators. It was shown that intravenous administration of taurine, at a final dose of 0.5 to 2.5 mM/kg body weight, prevented the extrasystoles induced by epinephrine as well as the arrhythmias and inversion of the T wave induced by chronic administration of toxic doses of digoxin.(13, 14, 23) The protective effect of taurine has also been found in the cat heart.(26) In studying the mechanism of the antiarrhythmic effect of taurine on dog hearts, Read and Welty (13, 25, 27) established two facts: (1) taurine, in eliminating arrhythmia, prevented the loss of K+ by the myocardium; and (2) taurine reversed the effects of potassium loss in sections of dog heart incubated in the presence of epinephrine and of toxic doses of digoxin.
The onset of ventricular extrasystoles in hearts exposed to toxic doses of glycosides is associated with shortening of the absolute refractory period and reduction of K+ concentration in myocardial cells.(21, 28) The decrease in potassium ion concentration in the myocardium is a consequence of the inhibition of active ion transport by the glycosides and, mainly, of inhibition of potassium influx into the cells.(29 - 31) In this connection, the cessation of arrhythmias in hearts exposed to strophanthin-K and digoxin and the cessation of potassium loss from the myocardium indicate that taurine may control the excitability of the myocardium by regulation of permeability of the cell membranes to potassium ions. The site of taurine action, in this case, should be the myocardial cell membrane.
However, this conclusion contradicts the results of experiments we carried out on the isolated heart. In the first 30 seconds of perfusion, taurine absorption was maximal and gradually fell. The physiological effect of taurine in increasing the T-wave amplitude and S-T interval and inducing bradycardia accompanied the uptake. Perfusion of the heart with a solution devoid of potassium ions increased the amount of taurine accumulated by the heart threefold compared with hearts perfused with Tyrode solution. A direct relationship was noted between the amount of taurine accumulated by the heart and maintenance of electrical activity of the isolated heart perfused with K+-free buffer. Thus, the change in electrical activity of the heart induced by taurine is obviously connected with an increase in its intracellular concentration in the myocardium. The speed of absorption of taurine is possibly explained by the ability of taurine to move against the concentration gradient, as has been noted in rabbit ciliary body iris in vitro.(32)
The following facts also favor the suggestion that taurine exerts its effects after entering the myocardial cells. It was shown, in sections of dog heart, that taurine is a precursor of isethionic acid.(33) A positive correlation has been noted between the dose of epinephrine that would induce ventricular extrasystoles in dog hearts and the content of isethionic acid in the myocardium.(13, 27) Since it is a strong anion, isethionic acid itself may control excitability of the cell membrane by affecting the accumulation of cations.(34)
Based on the considerations above, the mechanism of change in electrical activity of the cardiac muscle that is induced by taurine may be the following: After penetrating the myocardial cells, taurine is converted into isethionic acid which, as an anion, may facilitate retention of intracellular potassium ions. The latter leads to stabilization of the membrane potential, since the resting potential of myocardial fibers is determined by the potassium ion concentration gradient.(35 - 37) Stabilization of the membrane potential, in turn, maintains the normal electrical rhythm of the heart.
Considering that the process of excitation of any muscle is closely connected to contraction, the intimate mechanism responsible for the physiological effect of taurine on the work of the heart, under one set of conditions or another, is much more complicated, and is obscure at present. However, a whole series of factors indicate that taurine exerts an effect on excitation-contraction coupling. It is known that a change takes place in intracellular calcium ion concentration when the cells are exposed to glycosides. Some investigators connect this with an increase in the entry of Ca + + into the cells,(38 - 40) and others consider that the glycosides facilitate the release of calcium ions from the sarcoplasmic reticulum.(41 - 43) Potentiation of the inotropic effect of digitalis on isolated rat and guinea pig hearts by taurine (11, 12) and our observations of a positive inotropic effect on the dog heart are convincing indications of the connection of taurine with movements of calcium ions.
All the physiological effects of taurine on the heart, observed by us and by other investigators in animal experiments, as well as the therapeutic effect of taurine noted in patients with ischemic heart disease and cardiomyopathy, indicate that the effect of taurine on the heart is directed toward maintenance of the normal functional state of the organ and that this effect has a regulatory function. Since taurine is present in large quantities in myocardial cells, it may possibly be the substance that is switched into the chain of reactions that are responsible for normalization of functional activity in emergency situations. In this connection, the question of the mechanism of action of taurine on the heart is important and requires further investigation. Acknowledgment
The authors express thanks to V. Bogoslovskii, N. Goldberg, A. Nazaev, V. Kukharchuk, and V. Kravtsov for assistance in conducting the experiments and for fruitful discussion.
Dr. Eugene Braunwald, Boston, Massachusetts: What are the undesirable systemic effects of taurine if administered in low doses to an animal, recognizing that it is a normal substance within the body?
Dr. Chazov: This is very important for future research. If we are to speak about possible implications in the effect of treating arrhythmias, we must always remember the possibility of development of disturbances of conductivity.
Dr. Braunwald: In much larger doses, what are the effects on the electrocardiogram?
Dr. Chazov: With larger doses progressive bradycardia develops.
Dr. G. A. Langer, Los Angeles, California: I take it from the time course of action of taurine that it is probably dependent upon entry into the cell rather than upon an external or superficial membrane effect. It is interesting that effects on potassium conduction by certain tetraethylammonium compounds are internal rather than external. The fact that it is apparently necessary for these compounds to enter the cell and possibly raise the internal concentration may give some clues to the mechanism of action on potassium exchange. Is it correct that entry into the cell is necessary?
Dr. Chazov: Yes, we think the effect of taurine is connected with its entry into the cell. Questions regarding activity of taurine are still in need of further study, particularly the question of the interrelationship of taurine with the movement of calcium ions. Using taurine as an example, we would like to demonstrate that biologically active substances which change the cellular metabolism or composition may affect the electrical activity of the heart. This is a question that seems important for the sake of discussion and for further research.
Dr. Howard E. Morgan, Hershey, Pennsylvania: In heart muscle the intracellular concentration of taurine is very high, as Professor Chazov has indicated, approximately 30 mM. To what extent does this concentration change when taurine is added to the perfusate?
Dr. Chazov: We have given exact figures in our report, but it works in two phases, as it were. During the first period of introduction the absorption of taurine is more significant; afterward, it is decreased. However, I don't think it will lead to overload of the heart with the taurine.
Dr. Braunwald: Do you believe that taurine can reverse the arrhythmic effect of cardiac glycosides without simultaneously reversing the inotropic effect?
Dr. Chazov: We have not studied that particular question.
Supplement III to Circulation Research, Vols. 34 and 35. September 1974.