Normalization of depressed heart function in rats by ribose.

Severe constriction of the abdominal aorta and simultaneous injection of isoproterenol in rats induced depression in heart function and reductions in cardiac adenosine triphosphate and total adenine nucleotides. When ribose was continuously infused for 24 hours, biosynthesis of cardiac adenine nucleotides was stimulated to such an extent that the reductions in adenosine triphosphate and total adenine nucleotides were prevented and left ventricular hemodynamic parameters were normal. These results support the hypothesis that adenosine triphosphate is primarily responsible for depression in myocardial contractility and that ribose is cardioprotective through its pronounced effects on adenine nucleotide metabolism in heart muscle.

Reduction of the isoproterenol-induced alterations in cardiac adenine nucleotides and morphology by ribose.

Continuous intravenous infusion of ribose (200 milligrams per kilogram per hour) for 24 hours induced a marked stimulation of cardiac adenine nucleotide biosynthesis in unanesthetized and unrestrained rats that had been treated with isoproterenol subcutaneously (25 milligrams per kilogram). The diminution of adenine nucleotides characteristic for the action of high doses of isoproterenol was entirely prevented, and the incidence of the isoproterenol-induced myocardial cell damage was significantly reduced when ribose was administered. These results support the view that depletion of adenine nucleotides is involved in the development of cardiac necrosis.

Ribose intervention in the cardiac pentose phosphate pathway is not species-specific.

Ribose is cardioprotective in the rat in a variety of pathophysiological conditions. The metabolic basis for this effect is the low capacity of the oxidative pentose phosphate pathway in the myocardium. Ribose bypasses this pathway, elevates the available pool of 5-phosphoribosyl-l-pyrophosphate, and thus stimulates the biosynthesis of adenine nucleotides. In this study reported here the activity of glucose-6-phosphate dehydrogenase, the first and rate-limiting enzyme of the oxidative pentose phosphate shunt, was very low in the human heart and was of the same order of magnitude in the myocardium of various animal species. Furthermore, ribose had a similar stimulating effect on myocardial adenine nucleotide biosynthesis in the guinea pig, in which hemodynamic parameters are different from those in the rat. It is concluded that the metabolic basis for the effectiveness of ribose is similar in all species investigated.

Subchronic alpha- and beta-adrenergic regulation of cardiac gap junction protein expression.

Gap junction channels are essential for intercellular electrical communication in the heart. The most important cardiac gap junction proteins are connexin43 (predominantly) (Cx43), connexin40 (Cx40), and in early developmental stages connexin45. Since catecholamines play an important role in cardiac (patho)physiology, we wanted to elucidate whether catecholamines may affect expression of Cx43 and Cx40. Cultured neonatal rat cardiomyocytes were exposed for 24 h to increasing concentrations of noradrenaline (1-10000 nM) (physiological agonist at alpha and beta-adrenoceptors), resulting in significantly increased Cx43-expression, while Cx40 was unaffected. In further experiments cells were incubated with either phenylephrine (alpha-adrenergic agonist) or isoproterenol (beta-adrenergic agonist) (0.1-1000 nM) for 24 h. Both catecholamines lead to a concentration-dependent increase in Cx43 protein and mRNA expression (EC50: 10-20 nM). Inhibition experiments showed that the phenylephrine effect was transduced via PKC, while the isoproterenol effect was mediated by PKA. Dual whole-cell voltage clamp demonstrated that increased Cx43-expression was accompanied by significant increases in gap junction current. In additional in vivo experiments, adult rats were subjected to 24-h infusion of isoproterenol or phenylephrine showing again significant increase in Cx43 but not Cx40. Adrenergic stimulation of cardiomyocytes can enhance Cx43 expression thereby increasing cellular coupling, indicating a possible role for catecholamines in the regulation of cardiac gap junction expression in cardiac disease.

Catecholamine-induced cardiac hypertrophy: significance of proto-oncogene expression.

The effect of beta- and alpha-adrenergic stimulation on cardiovascular function and development of cardiac hypertrophy was studied in rats by measuring the heart weight/body weight and cardiac RNA/DNA ratios. Beta-receptor stimulation with isoproterenol over 3 days induced an increase in the biosynthesis of cardiac adenine nucleotides, myocardial protein synthesis, and the heart weight/body weight ratio. The isoproterenol-induced metabolic effects were prevented by simultaneous beta-adrenergic blockade with propranolol. Alpha-adrenergic stimulation with norfenephrine for 3 days induced an increase in heart rate, total peripheral resistance, the myocardial RNA/DNA, and left ventricular weight/body weight ratio. The calcium antagonist verapamil prevented the hemodynamic changes but did not influence the development of cardiac hypertrophy. The alpha-adrenergic blocker prazosin reversed the norfenephrine-induced functional changes and prevented cardiac hypertrophy. Norepinephrine was infused into isolated perfused working rat hearts to elucidate some molecular biological changes that precede the development of cardiac hypertrophy. It increased transiently and sequentially the mRNA of c-fos and c-myc. This enhancement occurred at about the same time as that induced by elevation of pre- and afterload but was more pronounced. These findings were compared with those obtained in other studies assessing the effects of catecholamines on proto-oncogene expression. Combination of norepinephrine with pre- and afterload elevation induced the c-fos mRNA signal to appear earlier, to be more pronounced, and to persist for a longer period of time. Similar results were obtained in regard to the c-myc mRNA. These findings indicate that the combination of two hypertrophy-inducing stimuli which may cause a higher degree of cardiac hypertrophy in vivo induce an earlier, more pronounced, and longer lasting expression of the proto-oncogenes c-fos and c-myc.

Acute effects of catecholamines on function of the rat right heart.

OBJECTIVE: Although the haemodynamic effects of catecholamines on the rat left ventricle have been investigated extensively, only few systematic in vivo studies have been performed on the right ventricle. The aim was to examine the acute effects of noradrenaline and isoproterenol on rat right ventricular function. METHODS: Haemodynamic variables were measured during acute, 20 minute infusion of noradrenaline (0.1 mg.kg-1 x h-1) or isoproterenol (12 micrograms.kg-1 x h-1) in female Sprague Dawley rats. To estimate the contribution of alpha and beta receptor stimulation to these effects, eight rats each were infused with prazosin (0.1 mg.kg-1 x h-1), metoprolol (1.0 mg.kg-1 x h-1), or the alpha and beta antagonist carvedilol (0.5 and 1.0 mg.kg-1 x h-1) alone and in combination with noradrenaline or isoproterenol. RESULTS: Noradrenaline and isoproterenol increased right ventricular systolic pressure (RVSP) from 30.3 (SEM 0.5) (n = 32) to 72.7(2.7) (n = 24) and 72.3(4.4) (n = 8) mm Hg, right ventricular (RV) dP/dtmax from 1848(70.3) to 4058(301) and 3612(366) mm Hg.s-1, and heart rate from 329(6) to 371(6) and 420(8) beats.min-1, respectively. Metoprolol completely prevented the isoproterenol induced haemodynamic changes, but neither metoprolol nor prazosin was able to significantly affect the pressure effect of noradrenaline (noradrenaline + metoprolol: 67.3(6.9) mm Hg, noradrenaline + prazosin: 67.0(3.8) mm Hg). The combination of both blockers, however, prevented the noradrenaline induced rise in RVSP (noradrenaline + metoprolol + prazosin: 36.5(5.1), and noradrenaline + prazosin + metoprolol: 30.0(1.2) mm Hg). Carvedilol (1.0 mg.kg-1 x h-1) significantly attenuated the noradrenaline induced RVSP increase (39.1(3.0) mm Hg), but not to the control range. Metoprolol or carvedilol completely prevented the noradrenaline elicited increases in heart rate (254(7) and 287(20) min-1) and RVdP/dtmax, but prazosin alone had no effect on the heart rate and RVdP/dtmax increase. Thus beta receptor blockade alone failed to significantly influence the noradrenaline induced increase of RVSP despite prevention of the increase in heart rate and RVdP/dtmax. Prazosin had a significant effect on RVSP only in combination with metoprolol. CONCLUSIONS: The combined effect of both alpha and beta blockade exceeds the pure addition of the single effects in the rat right ventricle. Moreover, we speculate that the failure to reduce the noradrenaline induced increase in RVSP by either alpha or beta blockade alone is due to the stimulation of the receptor that is not affected by the respective blocker.

Functional and metabolic effects of ribose in combination with prazosin, verapamil and metoprolol in rats in vivo.

Ribose improves the function of the rat heart in various pathological conditions through its effects on cardiac energy metabolism, while having no direct haemodynamic actions. We therefore studied its functional and metabolic effects in closed chest rats when given in combination with prazosin, verapamil or metoprolol, all of which have direct effects on the circulation. Ribose administration for 24 h at 200 mg.kg-1.h-1 did not affect heart function but increased the available pool of 5-phosphoribosyl-1-pyrophosphate in heart (four fold) and skeletal muscle (1.7-fold), as assessed by the incorporation of 14C-adenine into the adenine nucleotides. The utilisation of adenine for adenine nucleotide synthesis, expressed as the ratio of adenine nucleotide radioactivity to tissue extract radioactivity, was 70% in heart and 20% in skeletal muscle under control conditions, and 97% and 88% after 24 h of ribose administration. Ribose decreased the 14C-adenine incorporation into the adenine nucleotides in kidney, lungs and liver. After 24 h infusion of prazosin (100 micrograms.kg-1.h-1), heart rate and LVdP/dtmax were not changed, but LVSP (-20%), mean aortic pressure (-16%) and peripheral resistance (-40%) were decreased. Cardiac output was enhanced (+40%). Verapamil (2mg.kg-1.h-1) and metoprolol (2mg.kg-1.h-1) infused for 24 h decreased the pressure-rate and pressure-volume product of the left ventricle to the same extent (-40%). Verapamil had no influence on cardiac output, while metoprolol depressed it (-30%). Simultaneous administration of prazosin, verapamil or metoprolol with ribose did not affect the ribose induced increase in the myocardial 5-phosphoribosyl-1-pyrophosphate pool.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of pressure and volume overload on proto-oncogene expression in the isolated working rat heart.

OBJECTIVE: The aim was to study the effect of pressure and volume overload on the expression of the proto-oncogenes, c-fos and c-myc, in isolated perfused working rat hearts and to compare these results with the known effects of noradrenaline. METHODS: Working rat hearts were obtained by converting the Langendorff preparation into the working mode by perfusion through the left atrium. Using specific cDNA clones, the mRNAs of c-fos and c-myc were measured by northern blots and quantified with densitometry. Total RNA was isolated from hearts after stimulation with noradrenaline (3 x 10(-8) M), after increasing afterload from 80 to 100 cm H2O, and left atrial filling pressure (preload) from 8 to 16 cm H2O for 15, 30, 60, 90, and 120 min, respectively. RESULTS: The mRNAs of c-fos and c-myc were not detectable in freshly excised rat hearts. When the hearts were perfused in the working mode for 15, 30, 60, 90, and 120 min, c-fos and c-myc mRNAs were measurable, and these mRNA levels served as control baseline values that were set at 100%. When noradrenaline was infused, c-fos mRNA was increased fivefold after 30, threefold after 60, and 3.8-fold after 90 min. The mRNA of c-myc was increased 1.8-fold after 60 min and 3.8-fold after 90 min. The increase in afterload induced a threefold increase of c-fos mRNA after 30 min and a threefold increase of c-myc mRNA after 90 min. When preload was increased, c-fos mRNA rose 1.8-fold after 30 min, and c-myc mRNA twofold after 60 min and 2.8-fold after 90 min compared to the controls. CONCLUSIONS: Pressure and volume overload have effects on the expression of c-fos and c-myc mRNA that are similar to those obtained with noradrenaline stimulation which induced the most pronounced signals. Our time course studies showed that c-fos mRNA always rose before c-myc mRNA. This common sequential induction pattern may have important signal function in the processes that trigger the development of cardiac hypertrophy.

Serum depletion induces cell loss of rat cardiac fibroblasts and increased expression of extracellular matrix proteins in surviving cells.

OBJECTIVE: Since reduced nutrient supply is one component of ischemia, we have studied the effect of serum depletion on the survival of fibroblasts isolated from adult rat hearts and on the expression and degradation of extracellular matrix (ECM) proteins. Furthermore, we measured the role of the cAMP-dependent pathway in these processes. METHODS: Isolated cardiac fibroblasts were grown to confluency in 10% serum containing medium. Serum was then removed and cell number was measured by use of a Coulter Counter. The activity of the cAMP response element binding protein (CREB) was investigated by Western blotting and subsequent use of the specific antibody which binds to the active form of the protein. The expression of colligin, collagen I and III, matrix metalloproteinases 2 (MMP-2), and tissue inhibitor of matrix metalloproteinase 2 (TIMP-2) was examined by ribonuclease protection assay (RPA) and Western blotting. Zymographic measurements were done to investigate gelatinase activity of MMP-2. RESULTS: Serum withdrawal caused the death of 36% of the cells during the first 8 h. CREB was strongly phosphorylated 5 min after serum removal. Activation persisted up to 8 h and decreased thereafter. The mRNA abundance of colligin, collagen I and III, MMP-2, and TIMP-2 started to increase after 5 and 10 h, respectively, reaching a maximum after 20-30 h and decreasing thereafter. Protein levels of collagen I, collagen III, colligin and TIMP-2 were higher after 24 h until up to 96 h. MMP-2 zymographic activity was elevated 15-fold after 72 h. Application of the protein kinase A (PKA) blocker RpcAMPS suppressed the increase in phosphorylation of CREB. The increase in collagen III and MMP-2 mRNA abundance and elevation of collagen I and III, and TIMP-2 protein was diminished by RpcAMPS. The rise of colligin protein was completely suppressed. The increase in MMP-2 zymographic activity was also attenuated. RpcAMPS improved survival rate from 56 to 84%. CONCLUSIONS: Serum depletion led to cell death of isolated cardiac fibroblasts. Survival was associated with the increase in the expression of various ECM proteins. The transcription factor CREB was activated after serum removal. Inhibition of PKA improved the serum depletion induced decrease in the survival rate. The increase in collagen I, collagen III, MMP-2, TIMP-2, and colligin evoked by serum depletion was also diminished by PKA inhibition.

Different response of the rat left and right heart to norepinephrine.

The in vivo hemodynamic and morphologic responses of the rat left (LV) and right (RV) ventricle to continuous long-term i.v. infusion of norepinephrine (NE) at different dosages and for different durations of infusion were studied. Female Sprague-Dawley rats received continuous intravenous infusion of norepinephrine from infors syringe pumps for 24, 48 and 72 h at a dose of 200 mu g center dot kg-1 x h-1. Furthermore, NE was infused for 72 h at dosages of 50, 100 and 200 mu g center dot kg-1 x h-1. The beta-adrenergic blocker and vasodilator with alpha1-blocking activity carvedilol (0.5 mg x kg-1 x h-1) was coinfused with NE for 72 h. The hemodynamic effects were measured on intact, anesthetized rats with special Millar ultraminiature pressure tip catheters, and the weights of the left and right ventricles were measured. NE increased heart rate at any time or dose, whereas cardiac output and total peripheral resistance remained unchanged. LV and RV dP/dtmax were nearly doubled as compared to control values and RVSP was elevated by more than 100%. The effect of NE on LVSP was much less pronounced (< 20%) and only significant at 50 mu g x kg-1 x h-1 for 72 h. Neither LV nor RV end-diastolic pressures were elevated, indicating that cardiac failure had not occurred. The LV developed hypertrophy with an increase of the ventricular weight/body weight ratio (LVW/BW) of 22% even after only 2 days of NE (200 mu g x kg-1 center dot h-1). The RV showed no hypertrophy at any time of the experiments. The NE-induced changes in HR, dP/dtmax, RVSP and LVW/BW were completely prevented by the coinfusion of carvedilol. These studies show that the hemodynamic responses to continuous infusion of NE are more pronounced in the RV than in the LV. Conversely, NE induced hypertrophy only in the LV, not in the RV. The hemodynamic effects of chronic NE infusion did not change significantly between 1 and 3 days of infusion. The in vivo responses to exogenous NE therefore were unaffected by adaptive effects such as downregulation of adrenergic receptors.

Cardiac remodeling after long term norepinephrine treatment in rats.

OBJECTIVE: In this study we have tested the hypothesis that degradation of collagen by matrix metalloproteinase 2 (MMP-2) precedes the deposition of extracellular matrix (ECM) after long term norepinephrine (NE) treatment. METHODS: Female Sprague-Dawley rats received continuous i.v. infusion of NE (0.1 mg/kg.h) for 1, 2, 3, 4 and 14 days. Heart function and weight as well as expression of cardiac colligin and of collagen I and III were examined. Furthermore, we have assessed the degradation pathway of collagen by measuring the mRNA and activity of myocardial MMP-2 and tissue inhibitor of metalloproteinase 2 (TIMP-2) as well as the protein level of TIMP-2. RESULTS: NE induced hypertrophy predominantly of the left ventricle (LV) in a time-dependent manner. It increased the mRNAs of colligin, collagen I and III, and of MMP-2 and TIMP-2 as well as MMP-2 activity in two phases: In the initial phase, at 3 and 4 days, the mRNA of colligin and of collagen I and III was elevated predominantly in the LV, MMP-2 and TIMP-2 mRNA, as well as TIMP-2 protein and MMP-activity were increased in both ventricles. The second phase, after 14 days, was characterized by a less pronounced increase in colligin, collagen I and III and in MMP-2 activity which occurred exclusively in the LV. Finally, long-term treatment with NE induced a 37% increase in interstitial fibrosis which was shown to occur exclusively in the LV after 14 days. CONCLUSION: NE treatment induced fibrosis exclusively in the LV which was associated with hypertrophy predominantly of the LV. The elevated MMP-2 activity seems to be necessary for the ECM to adapt to the enlargement of myocytes and to reduce overproduction of collagen.

Functional responses of the left and right heart of diabetic rats to alpha- and beta-adrenergic receptor stimulation.

It was the aim of the present study to examine the influence of alpha-and beta-receptor stimulation on the function of the right (RV) and left (LV) ventricle of streptozotocin-diabetic rats (STZ; 60 mg.kg-1; n = 14). Phenylephrine (PE; 3 mg.kg-1.h-1) or isoproterenol (ISO; 24 micrograms.kg-1.h-1) were infused intravenously for 20 min 4 weeks after STZ injection. The hemodynamic parameters were measured on intact, anaesthetized animals with special Millar ultraminiature tipcatheter manometers. In the non-diabetic animals (n = 15), PE caused a significant elevation of left ventricular systolic pressure (LVSP) from 138.5 +/- 3.2 to 205.4 +/- 7.5 mmHg and raised heart rate (HR) from 362 +/- 12.6 to 399 +/- 17.2 beats.min-1 (mean +/- S.E.M.; P < 0.05). LVSP and HR were significantly lower in the diabetic animals under control conditions (110.5 +/- 6.4 mmHg and 273 +/- 16.0 beats.min-1, respectively) and not affected by PE. ISO induced a significant and comparable decrease in diastolic aortic pressure (DAP) and an increase in HR in both the non-diabetic and diabetic group. The PE-induced enhancements of LV dP/dtmax and RV dP/dtmax from 10533 +/- 805 to 21533 +/- 1386 and from 2044 +/- 262 to 3867 +/- 733 mmHg.s-1 were significant in the control animals. In the diabetic rats, LV dP/dtmax was lower (5971 +/- 901 mmHg.s-1) and was increased by PE to the range of control rats (11171 +/- 1591 mmHg.s-1). The PE-induced elevation of RV dP/dtmax from 2028 +/- 284 to 2771 +/- 391 mmHg.s-1 was less pronounced in the diabetic rats than in the controls. Under the influence of ISO, the increase of dP/dtmax in both ventricles was comparable to the effect of PE and fully preserved in the diabetic animals. Right ventricular systolic pressure (RVSP) was increased under PE and ISO in both groups to comparable values. These results demonstrate that the in vivo response to beta-adrenoceptor stimulation is well preserved in the diabetic rat, while the effects of alpha-stimulation are markedly reduced, especially in the left ventricle and systemic circulation.

Perfusion of isolated organs and the first heart-lung machine.

In 1885, Max von Frey (1852-1932), while working in Carl Ludwig's Physiological Institute in Leipzig, Germany, designed an apparatus that had criteria characteristic of a heart-lung machine. With this device, he perfused the entire lower extremity of dogs, and took measurements of oxygen consumption, and carbon dioxide and lactate production. In 1935, another type of perfusion apparatus was constructed by Charles A Lindbergh (1902-1973). This device was the result of cooperation with Alexis Carrel (1873-1944) who was a pioneer of experimental organ transplantation. Using Lindbergh's pulsating device, organs such as thyroid, ovary, suprarenal gland, spleen, heart and kidney from fowls and cats were perfused with an oxygenated medium, and were maintained under sterile conditions. Beginning in 1934, John H Gibbon (1903-1973) developed and tested a heart-lung machine to institute cardiopulmonary bypass in cats during experimental occlusion of the pulmonary artery. In 1953, he performed the first successful open-heart operation in a patient using a heart-lung machine. This included elements that were similar to those used by von Frey - ie, the oxygenator and the pumps for continuous circulation of blood. A comparison of the three experimental devices revealed the following: the application for experimental purposes preceded clinical use; the development shifted from Europe to the United States, and was achieved by people who were not specialists; and the intention to build such a device was first purely scientific interest, but later shifted to the care for and treatment of patients with heart and circulatory defects by open-heart surgery.

Modifications of the isolated frog heart preparation in Carl Ludwig's Leipzig Physiological Institute: relevance for cardiovascular research.

Carl Ludwig was the first physiologist to systematically study isolated organs (heart, muscle, kidney, liver, lung). In his Leipzig Physiological Institute, the isolated perfused frog heart preparation was established in 1866 by Elias Cyon. This preparation was subsequently subjected to various modifications, and many important observations were made by scientists such as Joseph Coats, Henry Pickering Bowditch, Luigi Luciani, Michael Joseph Rossbach, Hugo Kronecker and Otto Frank. The influence of filling pressure on contraction amplitude, the all-or-none law of the heart, the absolute refractory period, postextrasystolic potentiation, the staircase ('Treppe') phenomenon and the dependence of heart function on oxidative metabolism were discovered. The negative chronotropic and inotropic effects of vagus nerve stimulation were also first documented, and a model to induce arrhythmias was established. The isolated frog heart preparation became a widely used standard model for teaching and for basic cardiovascular research. Sidney Ringer discovered the essential role of calcium ions for heart function. Otto Loewi discovered the chemical transduction mechanism of the vagus with acetylcholine as transmitter. In more recent times, the cyclical changes in cAMP and cGMP that occur during the cardiac cycle were first described in the frog heart by Wollenberger and associates. Thus, the isolated perfused frog heart established and modified in Carl Ludwig's Leipzig Physiological Institute led not only to the discovery of basic phenomena, but also to observations that became the basis for concepts to be developed and elaborated later. Furthermore, the isolated perfused frog heart was the starting point for the development of the isolated mammalian heart in the retrogradely perfused, nonworking mode in the heart-lung modification and in the working heart preparation.

The contributions of Carl Ludwig to cardiology.

The basic instruments for measuring functional cardiovascular parameters and the most important discoveries made by Carl Ludwig and his disciples in cardiovascular physiology are described and put into perspective in regard to the further development of his methods and ideas. The most important apparatus was the kymograph, which, for the first time, made recording and documenting of functional parameters possible. This instrument was also used for the functional evaluation of the isolated perfused frog heart that was developed by Elias Cyon in Ludwig's Leipzig Physiological Institute. In the isolated frog heart, important phenomena were discovered such as the staircase ('Treppe'), the absolute refractory period and the all-or-none law of the heart. The isolated dog heart was used to determine the origin of the first heart sound, which was characterized as a muscle tone. To measure regional blood flow and eventually cardiac output, a flowmeter ('Stromuhr') was designed. Precise measurements of cardiac output became possible only when Adolf Fick had developed his principle, which served as the basis for the modern indicator methods. Cyon and Ludwig also discoverd the depressor nerve, which constitutes the basis of the baroreceptor reflex. Finally, the precise localization of the vasomotor centre in the ventrolateral medulla was achieved in Ludwig's Leipzig Physiological Institute. This was confirmed more than 100 years later with modern neuroanatomical methods making use of retrograde axonal transport. Thus, Ludwig and his scholars made major substantial contributions to cardiovascular knowledge that can be considered to constitute the basis of modern cardiology.

Technology and application of ultraminiature catheter pressure transducers.

After a brief historical account of the methods for pressure measurements in the cardiovascular system, the basic structural elements of a new generation of miniaturized catheter pressure transducers are described. These catheters have an outside diameter at the tip of 0.9 mm (3 French) and have been routinely applied in left and right heart catheterization in intact, anesthetized rats. Together with cardiac output measured by the thermodilution technique, a complete set of basal functional parameters can be obtained in vivo. The method of cardiac catheterization in rats is accurate, reliable and easy to perform. As to left heart function, changes occurring in several models of cardiac hypertrophy and heart failure have been recorded and correlated with morphological and metabolic alterations. In addition, the functional effects of catecholamines and thyroid hormones have been evaluated. In addition to the routine catheterization procedure, a double catheter method has been introduced recently, which allows measurement of left ventricular isovolumetric pressure in intact rats. Catheterization of the right ventricle requires a more refined catheter with a characteristic bend at the tip so that it can be comfortably slid from the right atrium into the right ventricle. With this method it was found that right ventricular systolic pressure was elevated markedly in rats with chronic myocardial infarction induced by ligation of the left anterior descending coronary artery, by pulmonary artery banding, by intermittent chronic hypoxia and by noradrenaline administration. The ultraminiature catheter pressure transducer has also been successfully applied in an isolated working rat heart preparation. Recent modifications of this kind of catheters also enabled the catheterization of the left ventricle in mice. Future applications of ultraminiature catheter pressure transducers may be directed to catheterization of the pulmonary artery in rats and to the in vivo and in vitro assessment of heart function of transgenic mice.

Studies on the regulation of the biosynthesis of myocardial adenine nucleotides.

1) Changes in the rates of biosynthesis of adenine nucleotides in rat hearts under various experimental conditions are paralleled by corresponding alterations in the concentration of cyclic AMP. 2) Pentoses and pentitols cause an acceleration of the de novo synthesis of adenine nucleotides in the normal heart and a further amplification of the increase of adenine nucleotide synthesis in isoproterenol-stimulated hearts. 3) The enhancement of de novo synthesis of adenine and nucleotides induced by isoproterenol as well as by pentoses and pentitols appears to be causally related to a greater availability of 5-phos-phoribosyl-1-pyrophosphate.

Effect of triiodothyronine on the biosynthesis of adenine nucleotides and proteins in the rat heart.

1) During the development of myocardial hypertrophy induced by 3,3',5-triiodo-L-thyronine the enhancement of de novo synthesis of adenine nucleotides occurs very early and precedes the increase of protein synthesis. In this respect there is a striking parallelism with other types of cardiac hypertrophy. 2) The acceleration of adenine nucleotide synthesis under these experimental conditions seems to be due to a greater availability of cardiac 5-phosphoribosyl-1-pyrophosphate. 3) The triiodothyronine-induced enhancement of adenine nucleotide synthesis can be attenuated by beta-receptor-blocking agents.

Long-term effects of ribose on adenine nucleotide metabolism in isoproterenol-stimulated hearts.

1. Among the precursor substances tested 1-14C-glycine is the most suitable for measuring rates of AN biosynthesis in rat hearts in vivo. 2. Continuous i.v. infusion of ribose for 24 hours stimulates AN biosynthesis in normal hearts and amplifies the enhancement of this process in hearts of isoproterenol-treated rats. The isoproterenol-induced decline of myocardial ATP is prevented by long-term application of ribose. 3. Elevation of the available PRPP pool mainly mediated by ribose and release of feedback inhibition of PRPP amidotransferase activity by the isoproterenol-induced ATP decline appear to be the optimal conditions required for maximal stimulation of myocardial AN biosynthesis.

Heart function and morphology in rats with chronic large myocardial infarction.

Large transmural myocardial infarctions were created in rats by occlusion of the descending branch of the left coronary artery. Four weeks after surgery, parameters of left and right ventricular function and of peripheral circulation were measured in the closed-chest, anesthetized animals and compared with those obtained in sham-operated controls. The morphology of the hearts was examined both at the macroscopic and cell size level. Cardiac output, LVSP, and the LV weight/body weight ratio were markedly lower than in sham-operated controls. LVEDP was elevated up to 32 +/- 2 mm Hg. On the other hand, RVSP, RV dp/dtmax, the right ventricular weight/body weight ratio, and the volume of myocytes isolated from the right ventricular free wall were increased. Histological examination of the lungs revealed marked thickening of the tunica media of small pulmonary arteries with narrowing of the lumen. These changes are considered to represent the morpohological basis for the increased pulmonary vascular resistance which was associated with right ventricular pressure overload and hypertrophy.