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Biomedical subjects

R G Merin

Publications and source records attributed to R G Merin.

At least 73 records · Page 4Linked to original sources
PubMed1978

Myocardial metabolism for the toxicologist.

Drug effects on myocardial contractile function are obviously of considerable practical importance for the toxicologist. The basic mechanism of such actions must reside at some point in the metabolism of cardiac muscle. Interference in the liberation of energy from the fuels that the heart uses may be implicated. It is possible that drugs may interfere with the storage (conservation) of that energy as the high energy phosphates (ATP and CP). Finally, the utilization of that stored energy by the contractile proteins themselves may be altered. The latter process is highly dependent on intracellular calcium ion kinetics. Anesthetic drugs, which produce reversible depression of myocardial contractile function is a dose-dependent fashion, have been shown to interfere to some extent with all three processes. However, the most important mechanism probably involves utilization of energy and intracellular calcium ion movement. A basic knowledge of the biochemistry of cardiac muscle is necessary for the understanding of drug action and toxicity at the subcellular level.

Adenosine Triphosphate↗
PubMed1977

Dose-dependent depression of cardiac function and metabolism by halothane in swine (Sus scrofa).

Halothane depresses myocardial blood flow and metabolism in the dog, but no studies in man have been published. However, the coronary circulation of the pig is remarkably similar to that of man. The authors investigated the effects of halothane-nitrous oxide anesthesia on cardiac function and metabolism in piglets. Thermodilution cardiac output, catheter-tip-manometer measurement of left ventricular function, electro-magnetic flowmeter measurement of coronary blood flow, and blood and tissue measurements of gases and metabolites were made during 0.04 (control), 0.46 (low concentration), and 1.04 (high concentration) per cent halothane vaporized in nitrous oxide, 60 per cent: oxygen, 40 per cent. Compared with control, the low concentration decreased cardiac output (CO) by 10 per cent, left ventricular systolic pressure (LVSP) by 30 per cent, peak contractile element velocity (Vmax by 34 percent, coronary blood flow (CBF) by 36 per cent, and cardiac oxygen uptake (V02) by 55 per cent. Compared with control, the high concentration decreased CO by 32 per cent, LVSP and Vmax by 53 per cent, CBF by 63 per cent and V02 by 62 per cent. This indicates that the dose-related depression in left ventricular function produced by halothane was accompanied by equivalent decreases in coronary blood flow and oxygen comsumption. There was minimal evidence of anaerobic metabolism in these depressed ventricles. Tissue levels of the high-energy phosplates, adenosinetriphosphate and creatine phosphate, and glycogen were unchanged. It is concluded that changes in cardiac oxygenation and metabolism in the pig during halothane anesthesia result from the changes in ventricular function.

Animals↗
PubMed1977

Effect of anesthetic drugs on myocardial performance in man.

All potent CNS depressant drugs can depress cardiac function in man in a dose-dependent manner. The dose-effect curve is considerably flatter with several drugs (diethyl ether, cyclopropane, fluroxene, isoflurane, and ketamine), presumably from sympathetic nervous-system activation. Potent analgesics and tranquilizers appear to produce less depression, but have been incompletely studied. Neuromuscular blocking drugs and regional anesthesia produce minimal effects on the heart in healthy people. However, not as much is known about diseased man. For instance, nitrous oxide produces more depression in "muscle" function in IHD patients (43), while diazepam (28) and morphine (44) do not adversely affect pump function in this class of patients. Fluroxene (45) is more depressant in VHD patients, but nitrous oxide (46), morphine (30), fetanyl (46), and droperidol-fentanyl (46) seem to have equivalent effects to those seen in health patients. In any given patient, therefore, accurate prediction of the effect of any anesthetic drug on cardiac performance is not possible. Adequate monitoring and careful titration of drug dose offer the safest method of assuring a satisfactory response.

Analgesics↗
PubMed1977

The role of the canine spleen in cardiovascular homeostasis during halothane anesthesia.

Barbiturate anesthesia is known to increase canine splenic sequestration of red blood cells. In our laboratory, high halothane concentrations have produced a decreased arterial hematocrit in the dog. In order to assess the role of the spleen in this phenomenon, central hematocrit, plasma volume, and ventricular hemodynamics were studied at low and high halothane concentrations before and after splenectomy in the same group of dogs. Although the hematocrit difference was less after splenectomy, it was not abolished. In addition, there was more cardiovascular depression by equivalent or lower halothane doses after splenectomy. It appears that the dog has other areas of red cell sequestration than the spleen accounting for the persistently lower hematocrit with high halothane concentrations after splenectomy. The modifying effect of the canine spleen on the circulatory depression produced by halothane should be taken into account when the drug is used in the dog.

Anesthesia, Inhalation↗
PubMed1976

Toxicity following methoxyflurane anaesthesia. IV. The role of obesity and the effect of low dose anaesthesia on fluoride metabolism and renal function.

Seven obese and five normal weight patients were studied before, during and after one hour of methoxyflurane-nitrous oxide anaesthesia during peripheral surgical operations and compared with eight patients of normal weight anaesthetized with nitrous oxide-meperidine and d-tubocurare. Estimates were made of renal function, including serum and urinary electrolytes, osmolarity, uric acid, urea and creatinine. Renal clearances for the latter three substances were also calculated. Serum and urinary inorganic and organic fluoride concentrations were measured, as were renal clearances. This low dose methoxyflurane anaesthesia resulted only in a decrease in uric acid clearance among all the measures, when compared to the meperidine-nitrous oxide controls. The clearance of uric acid remained depressed for longer in the obese patients, but otherwise they did not differ from the normal weight patients. It is possible but not proven that depressed uric acid clearance may be related to the organic fluoride metabolite and an early indicator of methoxyflurane renal toxicity. The previously documented biotransformation of methoxyflurane was seen in this study. A double peak in serum inorganic fluoride was shown in all patients but one. Rather large differences in peak levels of serum inorganic fluoride occurred. The only significant difference between the obese and normal weight patients as far as fluoride metabolism was concerned was a greater variability in the serum inorganic fluoride levels in the obese patients. It would appear that the obese patient metabolizes methoxyflurane in a quantitatively if not qualitatively different fashion than the normal weight patient, perhaps because of fatty infiltration of the liver. Caution is advised in the use of methoxyflurane for more than 90 minutes of low concentration administration in view of the unpredictability of the biotransformation.

Anesthesia↗
PubMed1976

Myocardial function and metabolism in the conscious dog and during halothane anesthesia.

Chronically catheterized dogs were studied awake and during anesthesia with high and low concentrations of halothane to assess the relationship between cardiac function and metabolism. Low concentrations of halothane (0.79 per cent endtidal) increased heart rate and decreased left ventricular stroke volume, stroke work, and dP/dt without producing other hemodynamic changes. However, similar heart rate increases produced by atrial pacing in awake animals increased aortic pressure and cardiac output and decreased left atrial pressure. Consequently, the halothane-induced tachycardia partially compensated for the negative inotropic effect of the halothane. High concentrations of halothane (1.74 per cent endtidal) further increased heart rate and elevated left atrial pressures. Cardiac output, stroke volume, stroke work, aortic pressure, LV dP/dt, myocardial blood flow and oxygen consumption were markedly decreased. Myocardial glucose extraction was also decreased. Myocardial oxygen extraction was unchanged, and lactate extraction rose with both concentrations of halothane. Consequently, the dose-dependent negative inotropic effect of halothane resulted in a decrease in cardiac oxygen demand which was equal to or greater than the decrease in oxygen delivery. Whether the same relationship would be seen in the ischemic heart is yet to be demonstrated.

Anesthesia, Inhalation↗
PubMed1976

Enflurane depresses myocardial function, perfusion, and metabolism in the dog.

Trained dogs with chronically implanted catheters and left ventricular (LV) pressure transducers were anesthetized with 2.3 per cent (1 + MAC) and 3.6 per cent enflurane. Left ventricular function and metabolism were studied while the dogs were awake and during exposure to the two anesthetic concentrations. Enflurane depressed LV function in a dose-dependent fashion. Myocardial blood flow and oxygenation mirrored the functional changes. Myocardial oxygen extraction decreased and lactate extraction increased to the myocardium. Low concentrations of halothane in the same dogs on different days had similar effects. However, 2 MAC halothane resembled 1.6 MAC enflurane, suggesting that the cardiovascular dose-effect curve for enflurane is steeper than that for halothane. Both anesthetics produce dose-dependent negative inotropic effects in the intact dog, accompanied by equivalent decreases in cardiac oxygen demand. Contrary to previous suggestions, enflurane appears to be at least at depressant to the dog heart as halothane.

Animals↗
PubMed1975

Effect of anesthetics on the heart.

In man, high doses of the "group 1" inhalation anesthetics (diethylether, cyclopropane, and fluroxene) produce relatively minor depression of ventricular function, although it is possible to depress the heart if the dose is great enough. The "group 2" drugs (halothane, methoxyflurane, etc.) produce dose-related depression in cardiac function, but reasonable caridac outputs and blood pressure can be maintained at light anethetic levels. Much the same can also be said for the intravenous barbiturates and other hypnotics. If ventilation is supported and hypovolemia avoided, large doses of the narcotic analgesics appear to produce minimal cardiac effects. The only intravenous drug which stimulates the heart is the dissociative anesthetic ketamine, and this is probably an autonomic, reflex phenomenon (as with group 1 inhalation anesthetics). Regional anesthesia and the neuromuscular blocking drugs appear to have relatively little effect on ventricular function. Most of the work in man on the effect of anesthetics has been in healthy patients or volunteers. The effects on patients with severe heart or other systemic disease may well be different. In fact, low concentrations of fluroxene have been shown to produce significant depression of stroke volume in patients with aortic vavular disease in contrast to the effects on healthy volunteers. All potent central nervous system depressant drugs possess the potential for significant cardiac depression. If such depression is undersirable in a particular patient, the only safe way to administer anesthesia is by careful titration of the dose against the best measurement of cardiac function which is available. At the present time, this would mean measuring at least direct arterial pressure, central venous pressure, and a continuous electrocardiogram. The optimal management would prpbably include recording systolic time intervals, pulmonary capillary wedge pressure, and some measure of cardiac output as well. All the skill and pharmacologic knowledge available connot substitute for vigilant monitoring and carful tiration of drug dose in the clinical situation.

Adrenergic beta-Agonists↗
PubMed1975

Halothane decreases actomyosin ATPase activity: a possible mechanism of the negative inotropic effect.

Like all inhalation anesthetics, halothane (CF3CHBrCl) has a dose-dependent negative inotropic effect on cardiac muscle. The mechanism of the action has not been determined, although effects on glycolysis, mitochondrial respiration and calcium kinetics, and sarcoplasmic reticulum ATPase activity have been suggested. Previous studies of the effect of halothane on the ATPase of contractile protein suffered from design and dosing defects. We have measured ATP splitting by canine cardiac natural actomyosin using extraction and equilibration procedures described previously (Honig, C. R. and Reddy, Y. C. 1973, J. Pharmacol. 184: 330-338). Drug dosing calculations were facilitated by measurement of the partition coefficient of halothane in protein. Halothane shifted the Ca++ concentration effect curve for actomyosin ATPase activity to the right. The maximum depression occurred at pCa 7.0 or 6.5. The effect was dose dependent with less than 10 percent depression at threshold and 50-60 percent depression at peak. Enzyme inhibition was antagonized by high Ca++ concentration, and was reversed by removing halothane from the reaction mixture. We suggest that inhibition of ATP utilization by the contractile system may be a mechanism of the in vivo myocardial depression produced by halothane.

Actomyosin↗
PubMed1975

Effects of inhalation anesthetics on cardiac function and metabolism in the intact dog.

In healthy, closed-chest dogs, dose-dependent depression of ventricular function was produced by the anesthetics halothane, methoxyflurane, and fluroxene, as evidence by decreases in left venticular stroke volume, stroke work, dP/dt, and an increased enddiastolic pressure. Myocardial blood flow and oxygen consumption decreased concomitantly and were correlated with aortic blood pressure decreases. There was no change in myocardial lactate extraction with halothane and methoxyflurane, suggesting that myocardial oxygenation was adequate in spite of the decrease in blood flow. However, even with marked increases in arterial lactate concentration during fluroxene anesthesia, extraction did not chance and, in fact, tended to decrease. The hemodynamic effects of halothane and methoxyflurane are similar to those previously reported in man, but those of fluroxene are different. Consequently, clinical speculation from these results is not justified at this time.

Anesthesia, Inhalation↗