© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Simultaneous measurement of cardiac output and its distribution with microspheres in the rat
Head of Department of Clinical Pharmacology and Therapeutics, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, UK
* Tel.: +44-1382-632180; fax: +44-1382-644972 d.g.mcdevitt{at}dundee.ac.uk
This paper was one of the products of a year which I spent as a Merck International Fellow in Clinical Pharmacology in the Division of Clinical Pharmacology at Vanderbilt University in 1974–75. At that time clinical pharmacology was very much at a developmental stage in the United Kingdom and in Europe, but there were several large centres in the United States, one of which was in Nashville. I already held a senior academic appointment in the Medical School in The Queen's University, Belfast but had little experience of clinical pharmacology outside the cardiovascular area and particularly the autonomic nervous system. Therefore, my aim was to get as broad and varied experience as I could, preferably avoiding the topics in which we had expertise in Belfast.
Because the Division in Vanderbilt was so large there were many different foci. John Oates decided that my primary task would be the clinical evaluation of the new anti-arrhythmic drug, tocainide, which involved me in learning laboratory drug measurement methodology and also in trying to create automated systems for monitoring cardiac arrhythmias. However, one of the other interests of the unit at that time, particularly of Alan Nies, David Shand and Grant Wilkinson, was exploration of the parameters which controlled drug disposition and clearance. Evolving from some pivotal studies on the disposition of propranolol in their laboratory and elsewhere, it had been suggested that drug clearance by an organ such as the liver depended not only on the intrinsic function of the organ, e.g. enzyme activity or biotransformation, but also on the rate of drug delivery to the organ. The study described in this paper was, thus, part of the next phase of examining the relationships between intrinsic hepatic clearance and liver blood flow in drug disposition.
In the early 1970s there were conflicting reports about the effect of drugs which alter hepatic enzyme activity on liver blood flow – for example, in the rat, phenobarbital had been reported both to increase liver blood flow [1] and not to change it [2]. In the rhesus monkey, phenobarbital had been shown to increase liver blood flow by 34% [3]. It seemed likely that the differences described might be accounted for by methodological difficulties in the measurement of liver blood flow, particularly with an experimental animal as small as the rat. Therefore, in order to carry the process further forward, we felt that the key lay in finding a more accurate and reproducible method of measuring hepatic blood flow in the rat. Radioactive microspheres had been used in the rat to determine the distribution of blood flow but not to quantitate cardiac output. However, in large animals the microsphere technique did appear to give an accurate estimate of cardiac output. We decided to investigate whether the technique could be adapted in the laboratory rat to enable the simultaneous determination of cardiac output, fractional distribution of microspheres and hence organ blood flow. The paper described our findings. It appeared that not only was the technique feasible, but it gave us results both for cardiac output and for liver blood flow which were reproducible and compared favourably with figures obtained by a variety of other methods.
During my remaining time in Vanderbilt, we were able to go on to demonstrate the facility of this method by using it firstly to explore the effects of alteration of hepatic microsomal enzyme activity on liver blood flow in the rat [4] and then to evaluate the relative contributions of induction and altered liver blood flow to the hepatic clearance of indocyanine green in the phenobarbital-treated rat [5]. Thus it was demonstrated that, although the enzyme-inducing agents phenobarbital, 3,4-benzpyrene and 3-methyl-cholanthrene all increased the size of the liver, only phenobarbital caused an increase in total liver blood flow. The enzyme-inhibitor SKF-525A affected neither liver blood flow nor liver mass. The increase in liver blood flow with phenobarbital appeared to be related to the increase in liver mass and was due entirely to an increase in flow to the splanchnic organs draining into the portal vein. The mechanisms responsible for the change were at that time unknown. In the second study, the influence of phenobarbital, 3,4-benzpyrene and 3-methylcholanthrene on the clearance of indocyanine green (ICG) in the rat was investigated. Of the 3 inducing agents only phenobarbital increased ICG clearance and that in a dose dependent manner. This change had previously been ascribed to increase in the cytoplasmic anion binding protein ligandin [6] but since 3,4-benzpyrene and 3-methylcholanthrene also increased this protein, this now appeared unlikely. Phenobarbital was again shown to increase both liver mass and liver blood flow. Using a perfusion-limited model of hepatic elimination, it was possible to quantitate the relative contributions of the increases in flow and the liver's intrinsic ability to remove ICG to the changes in ICG clearance at the various doses studied. The influence of the altered flow decreased with increasing ICG dose, but at the lowest dose it was responsible for nearly 50% of the phenobarbital-induced increase in ICG clearance.
Interesting though these studies were, after my return to Belfast, the major need was to generate programmes related to clinical pharmacology. Given the imbalance between the number of pharmacologists and clinical pharmacologists, I have always felt that, if possible, my research focus should be clinical with man as the experimental animal! My research, therefore, returned to cardiovascular and respiratory themes but was greatly enhanced by the knowledge and experience, which I had gained in the United States. I did not seek to set up these animal models in my laboratory and, after a short time, did not actively attempt to keep up with the literature in this area. Thus it came as a great surprise to me to receive the communication from the editors of Cardiovascular Research informing me that the paper was one of their best-cited articles. This may have something to do with it being about methodology. I have had a similar experience with a paper which I published in the cardiovascular field, also in the 1970s [7]. I am sure that knowledge in this field has moved on very considerably over nearly 25 years.
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- Ohnhaus E.E., Thorgeirsson S.S., Davies D.S., Breckenridge A. Changes in liver blood flow during enzyme induction. Biochemical Pharmacology. (1971) 20:2561–2570.[CrossRef][Web of Science][Medline]
- Denis P., Ossenberg F.W., Benhamou J.P. Hepatic blood flow and enzyme induction in the rat. Biochemical Pharmacology. (1975) 24:249–251.[CrossRef][Web of Science][Medline]
- Branch R.A., Shand D.G., Wilkinson G.R., Nies A.S. Increased clearance of antipyrine and d-propranolol after phenobarbital treatment in the monkey. Journal of Clinical Investigation. (1974) 53:1101–1107.[Web of Science][Medline]
- Nies A.S., Wilkinson G.R., Rush B.D., Strother J.T., McDevitt D.G. Effects of alteration of hepatic microsomal activity on liver blood flow in the rat. Biochemical Pharmacology. (1976) 25:1991–1993.[CrossRef][Web of Science][Medline]
- McDevitt D.G., Neis A.S., Wilkinson G.R. Influence of phenobarbital on factors responsible for hepatic clearance of indocyanine green in the rat: relative contributions of induction and altered liver blood flow. Biochemical Pharmacology (1977) 26:1247–1250.[CrossRef][Web of Science][Medline]
- Reyes H., Levi A.J., Gatmaitan Z., Arias I.M. Studies of Y and Z, two hepatic cytoplasmic organic anion-binding proteins: effects of drugs, chemicals, hormones and cholestasis. Journal of Clinical Investigation. (1971) 50:2242–2252.[Web of Science][Medline]
- McDevitt D.G. The assessment of beta-adronoceptor blocking drugs in man. British Journal of Clinical Pharmacology. (1977) 4:413–425.[Web of Science][Medline]
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