Ferdinand Urthaler

Analysis of components in a cardiogenic hypertensive chemoreflex.

A cardiogenic hypertensive chemoreflex was studied in 38 anesthetized and three unanesthetized dogs. Serotonin (100 &mgr;g/ml) injected into either the left atrium or small branches of the proximal left coronary artery produced a maximal response, with 96 ± 18 mm Hg increment in mean aortic pressure within 6 ± 2 seconds, lasting about 1 min; a later phase of the same hypertension lasted 9 ± 5 minutes more and could partially be produced with serotonin injected into the thoracic aorta. Injections into the distal left coronary artery produced only the Bezold-Jarisch reflex. Concomitant with the immediate hypertension there were vagal and sympathetic efferent effects in both the sinus node and the atrioventricular (A-V) junction. Either of these effects could be selectively eliminated and the other augmented by direct local perfusion with an appropriate cholinergic (atropine 10 &mgr;g/ml) or adrenergic &bgr;-receptor (propranolol 10 &mgr;g/ml) blocking agent. Bilateral vagotomy markedly attenuated but did not eliminate the acute hypertension, but it abolished both chronotropic and dromotropic effects. Phentolamine (2 mg/min i.v.) markedly diminished the hypertensive response. Guanethidine or reserpine pretreatment markedly diminished the hypertensive response; reserpine eliminated the electrophysiologic effects but guanethidine did not. Infiltration of serotonin around the main left coronary partially reproduced the reflex, but similar infiltration of xylocaine hydrochloride blocked the reflex. Serial section histologic studies of the region around the main left coronary artery in seven dog hearts and nine human hearts demonstrated the presence of a small structure resembling a chemoreceptor; its blood supply originated from the left coronary artery. Some possible clinical implications are discussed.

Peroxynitrite irreversibly decreases diastolic and systolic function in cardiac muscle

Much of the damaging action of nitric oxide in heart may be due to its diffusion-limited reaction with superoxide to form peroxynitrite. Direct infusion of peroxynitrite into isolated perfused hearts fails to model the effects of in situ formation because the bulk of peroxynitrite decomposes before reaching the myocytes. To examine the direct effects of peroxynitrite on the contractile apparatus of the heart, we exposed intact and skinned rat papillary muscles to a steady state concentration of 4-microM peroxynitrite for 5 min, followed by a 30-min recovery period to monitor irreversible effects. In intact muscles developed force fell immediately to 26% of initial force, recovering to 43% by 30 min. Resting tension increased by 600% immediately, and was still elevated 500% by 30 min. Nitrotyrosine immunochemistry showed that peroxynitrite can induce tyrosine nitration at low concentrations and is capable of penetrating 200-380 microm into the papillary muscle after a 5-min infusion. Decomposed peroxynitrite had no effect on either intact or skinned muscle developed force or resting tension. Our results show that peroxynitrite directly damages both developed force and resting tension of isolated heart muscle, which can be extrapolated to systolic and diastolic injury in intact hearts.

MDL-28170, a membrane-permeant calpain inhibitor, attenuates stunning and PKCε proteolysis in reperfused ferret hearts

Objectives : This paper tests the hypothesis that calpains are activated in the ischemic (I)/reperfused (R) heart and contribute to myocardial stunning. Methods : Isolated ferret hearts were Langendorff perfused isovolumically, and subjected to 20 min of global I followed by 30 min of R in the presence or absence of 0.2 μ M MDL-28170, a membrane-permeant calpain inhibitor. Right trabeculae then were isolated from these hearts, skinned chemically, and pCa2+-force curves obtained. Samples of left ventricle were extracted, subjected to SDS-PAGE, and Western analyzed for PKCe and PKMe. Results : Perfused ferret hearts exhibit a 43% decline in left ventricular developed pressure during R. Pre-treatment of hearts with MDL-28170 prior to I significantly improves function during R. Trabecular myofilaments from normal hearts have a KD for Ca2+ of 6.27±0.06; I/R decreased the KD to 6.09±0.04; trabeculae from I/R hearts pre-treated with MDL-28170 have a KD of 6.28±0.04. Western analysis shows ferret hearts to contain a single ≈96 kDa species of PKCe. I/R hearts contain the native PKCe and a ≈25 kDa smaller species of PKCe, which corresponds to PKMe, the calpain proteolyzed form of PKCe. Pre-treatment of I/R hearts with MDL-28170 markedly diminishes PKMe in reperfused hearts. Conclusions : Mechanical stunning during R is sensitive to MDL-28170. Depressed mechanical function is reflected in a hyposensitization of trabecular myofilaments to Ca2+. Western analysis shows that PKMe is present in R hearts.

Comparison of contractile performance of canine atrial and ventricular muscles.

This study compared the contractile performance of a canine right atrial trabecula with that of a macroscopically indistinguishable trabecula isolated from the right ventricular apex. The heart was removed from nine mongrel puppies weighing 6–8 kg and placed in Krebs-Ringers bicarbonate solution. The bathing solution contained only 1.25 mmoles of Ca2+ and was bubbled with a 95% O2–5% CO2 gas mixture. Each atrial trabecula was specially selected from the right atrial appendage. Histologically, these trabeculae showed a remarkable longitudinal orientation of the fibers. At Lmax (the length of the muscle at which developed tension was maximum) under identical conditions of temperature, rate of stimulation, ionic milieu, pH, and O2 and CO2 supply, right atrial trabeculae achieved the same developed and total tensions but in a much shorter time than did ventricular trabeculae. In both muscle groups the maximum developed tension averaged about 2.5 g/mm2. Since Lo (expressed as a fraction of Lmax) was less in atrial muscle than it was in ventricular muscle, we concluded that atrial muscle can be stretched considerably more than can ventricular muscle before optimum length is reached. At any given initial muscle length, the maximum of tension rise for atrial trabeculae amounted to at least twice that for ventricular trabeculae. At any given load up to 1.5 g/mm, the maximum velocity of shortening of an atrial trabecula was about three to four times that of a ventricular trabecula. These results collectively indicate that the contractile performance of the right atrial muscle is in many respects superior to that of the right ventricle, at least under the conditions of these experiments.

Experimental studies on the pathogenesis of asystole after verapamil in the dog.

The effect of verapamil on automaticity and conduction in the atrioventricular (A-V) junctional region was studied in anesthetized dogs. In five normal dogs verapamil, 10 microgram/ml, was selectively perfused into the A-V nodal artery and caused first degree heart block, which progressed to second degree heart block in three of the five. Higher concentrations of verapamil, 25 microgram/ml, caused complete heart block in three of five other dogs, but no episodes of asystole (defined as a ventricular pause of 10 or more seconds). In six other dogs after beta receptor blockade with propranolol, 20 microgram/ml, perfused into the A-V nodal artery, verapamil, 10 microgram/ml, regularly caused second degree heart block; in four of the six dogs there was a transient episode of third degree A-V block, and in two of these there was a period of asystole. In each of the 10 dogs pretreated with reserpine, verapamil, 10 microgram/ml, caused third degree A-V block; in seven of these there was a period of asystole with ventricular standstill up to 30 seconds. Concentrations of verapamil that do not produce high grade heart block in the normal heart thus readily cause both high grade block and prolonged ventricular standstill after elimination of adrenergic influences in the A-V junction.

Electrophysiological effects of magnesium on cells in the canine sinus node and false tendon.

Sinus node cells in the isolated perfused canine right atrium and cells of the right ventricular false tendons were used to assess the effects of extracellular Mg2+ concentration ([Mg2+]o,) on cardiac electrical activity. Removal of Mg2+ from the perfusate into the sinus node led to an increase of 36% in sinus rate that was sustained for as long as Mg2+ was absent; doubling [Mg2+]o to 2 mmol/liter caused the sinus rate to decrease by 19%. During Mg2+-free perfusion, the accelerated sinus rate could be depressed by the addition of certain substances; verapamil and Mn2+ produced the same percent depression regardless of [Mg2+]<» but tetrodotoxin and reduced [Na*] in the solution each brought about significantly greater depression of sinus rate when Mg2+ was absent. No change in maximum diastolic potential was observed in the sinus node cells when Mg2+ was withheld. In false tendon cells, on the other hand, removal of Mg2+ was accompanied by depolarization of the transmembrane potential to a stable level of approximately -40 mV, at which potential action potentials could not be elicited. Increasing [Mg2+]<, to 4 mmol/liter caused slight hyperpolarization of false tendon cells, but maximum upstroke velocity of the action potential and overshoot were reduced in spite of the more negative resting transmembrane potential. In both types of tissue, sinus node and false tendon, all changes clearly began to reverse within 30 minutes after restoration of normal [Mg2+]o, and recovery was complete by 60 minutes. Since neither atropine, 5 /μg/ml, nor propranolol, 15 μg/ml, modified the responses to Mg2+ alteration, these results indicate that Mg2+ has a direct effect on transmembrane electrical processes. The functional response to changes in concentration of this cation depends upon the specific type of cell acted upon. Circ Res 44:182-188, 1979

Anatomic and physiologic considerations of a cardiogenic hypertensive chemoreflex.

Abstract Within both human and canine hearts there is a mass of chemoreceptor tissue lying just between the origins of the aorta and pulmonary artery and receiving its blood supply from the proximal portion of the left coronary artery. In the dog this is considered to be the site of origin for a powerful hypertensive reflex stimulated by serotonin. There is brief generalized arterial vasoconstriction, except for the coronary and pulmonary arteries. The afferent limb of this cardiogenic hypertensive Chemoreflex courses in thoracic branches of the vagus. Autonomic efferent responses are both vagal arid, sympathetic events. These include simultaneous positive and negative inotropic effects on the atria, a positive inotropic effect on both ventricles, positive and negative chronotropic actions and similarly mixed dromotropic effects. Methods for separately identifying and quantifying these responses are discussed and illustrated. Vagotomy eliminates the reflex, as does the administration of cyproheptadine (but not methysergide). Among possible human counterparts for this cardiogenic hypertensive Chemoreflex are the pressor responses associated with angina pectoris, with very early acute myocardial infarction and after certain forms of cardiac surgery such as saphenous vein bypass grafting.

Mathematical relationship between automaticity of the sinus node and the AV junction

Abstract Stable sinus and AV junctional rates (each in the same animal) were obtained in 50 open-chest dogs anesthetized with pentobarbital. After cannulation of both the sinus node and the AV node arteries, the control sinus rate was 135 ± beats per minute (mean ± 1 SD), the range being 84 to 192. Following selective eserinization of the sinus node (10 or 100 μg per milliliter, 2 ml.), which progressively slows the sinus node until a stable AV junctional rhythm emerges, the mean AV junctional rate was 88 ± 19 beats per minute, ranging between 48 and 126. The plot of AV junctional rates (AVJR) versus corresponding sinus rates (SR) from each dog demonstrates a 2:3 ratio between these two variables. On mathematical analysis of these data there is a consistent correlation (r = 0.942; p

A mathematical model of automaticity in the sinus node and AV junction based on weakly coupled relaxation oscillators

Abstract A general mathematical model is proposed for the study of the effects of changes in two interacting pacemaker rates on the nature of cardiac rhythms. The model is based on the weak interaction of two systems of differential equations each of which is capable of self-perpetuating oscillations. Some results of computer experimentation with the model are presented for one simple system of coupling the oscillators. The mathematical model reproduces satisfactorily the physiological results of experiments previously performed on dogs in this laboratory. The model is useful in both the design and analysis of biologic experiments to define most known determinants of either normal or abnormal cardiac rhythm.

Canine atrial and ventricular muscle mechanics studied as a function of age.

Agedependent differences in mechanical performance and morphometric and electron microscopic characteristics of atrial and ventricular trabeculae are described. At 3 months, atrial and ventricular trabeculae develop the same amount of force. At 9 months, the ventricular muscle develops twice as much force as its atrial counterpart, although shortening is almost identical in both muscles. At any age, velocity of shortening of atrial trabeculae is at least twice that of the ventricular muscles. StereologicaJ data indicate that atrial and ventricular working myocytes maintain fixed volume fractions of myofibrils (70%) and mitochondria (25%) between 3 and 9 months of age. A broad frequency distribution of sarcomere lengths was measured at Lmax in muscles of the younger age groups. More than 80% of sarcomeres of adult atrial and ventricular myocytes clustered around 2.05 to 2.25 μm; only 30% of sarcomeres of younger atrial myocytes and 45% of sarcomeres of younger ventricular myocytes were within that length bracket. About 45% of sarcomeres in younger atrial muscles had lengths in excess of 2.35 pm; less than 3% of sarcomeres were longer than 2.35 fun in adult atrial muscles. Sarcomere lengths cluster more and more around the mean with increasing age, suggesting that with maturation there is a more homogeneous recruitment of sarcomeres. At both ages, there is a marked difference between atrial and ventricular myocytes whether examined in terms of morphological development or functional performance. We conclude that any work correlating myocardial structure and function must account for two things: the site from which the muscle was excised and the age of the donor heart.