Correlation of the glycoside response, the force staircase, and the action potential configuration in the neonatal rat heart.

Abstract

The rat heart demonstrates marked alterations in its responses to ouabain and increased frequencies of stimulation and in the duration of its action potential during the initial 21 days of life. At an age of 6.2 days 5 x 10" 5 M ouabain produced a 158.2% increase in dP/dt compared with a 17.2% increase at 21.1 days (P < 0.001). At 6.2 days dP/dt increased by 53.4% when the heart rate was accelerated from 30 to 90 beats/min compared with an increase of 12.2% at 21.1 days (P < 0.005). The positive glycoside and staircase responses at the younger age were virtually eliminated when the hearts were perfused with a solution containing 50% [Na + ] o and 25% [Ca 2+ ]o ([Ca 2+ ] o /[Na + ] 0 2 maintained constant). The duration of the ventricular action potential progressively decreased from 350-400 msec at birth to 100-150 msec at 21 days of life. This decrease was due to a shortening and a decrease in the potential level of the plateau phase. The prominent plateau typical of the early neonatal period was significantly diminished by perfusion with 50% [Na + ] o . The results suggest that Na + flux through a slow membrane channel plays a significant role in the positive staircase and glycoside responses of the early neonatal rat heart. As the heart matures and becomes functionally anomalous relative to other mammalian species, the slow channel progressively closes. KEY WORDSsodium flux calcium excitation-contraction coupling slow sodium channel ouabain dP/dt action potential plateau• The adult rat heart demonstrates a number of unique physiological and pharmacological characteristics. It has an action potential of short duration with little evidence of a plateau (1) and an interval-force relationship (staircase) which is atypical in that it is dominated by a tendency for contractile strength to decrease with increasing frequency (2); moreover, the adult rat heart is particularly resistant to the action of digitalis glycosides (3, 4). The neonatal rat heart however has strikingly different characteristics with respect to all of these phenomena. The purpose of the present study was to document these characteristics over the early neonatal period. If the sequential changes related to age are interrelated, an understanding of them might provide further clues to the ionic mechanisms important in the control of the myocardial contractile response. MethodsSprague-Dawley rats were used for all of these studies. The standard perfusion medium had the following millimolar composition: NaCl 142, KC1 4, MgCl 2 1.0, CaCl 2 1.0, and glucose 5.56. When it was buffered with 3 mM HEPES (N-2-hydroxyethylpiperazine-N'-2-ethane sulfonic acid), the perfusate was equilibrated with 100% O 2 ; when it was buffered with 12 mM NaHC0 3 , the NaCl content was lowered to 130 mM and the perfusate was equilibrated with 98% O 2 -2% CO 2 . The standard solution was modified to give a "low Na + -low Ca 2+ " solution by replacing 71 mmoles NaCl/liter with 71 mmoles choline chloride/liter and decreasing the Ca 2+ concentration to 0.25 mM; th...

Activation of cardiac ryanodine receptors by cardiac glycosides

“…In contrast to the high sensitivity of human heart to glycosides, rat heart is known to be less sensitive to the effects of cardiac glycosides than many other mammalian species, including the dog, cat, guinea pig, and human (2,18). We tested the effects of digoxin on rat RyR2 channel to determine if glycoside effects on single-channel activity were similar to that of the dog and human.…”

“…One of the most striking effects of cardiac glycosides is the species difference in sensitivity to the inotropic and toxic actions of these agents. It is well known that rat heart is generally insensitive to glycoside actions, requiring at least 10-fold and often far greater drug concentrations, depending on experimental conditions (2,18). This was thought to be the result of a selective expression of a glycoside-insensitive isoform of the NKA (␣ 1 ) in the adult rat rather than the more common glycosidesensitive isoform (␣ 3 ) predominantly present in sensitive species (28).…”

Interspecies variation in myocardial physiology: the anomalous rat

“…As with AP and force-frequency the neonatal rat myocardium presents a different response which is much less anomalous (2). Papillary muscle from a rat 5 days old demonstrated an increase of 160o in dPldt upon perfusion with 5 x 10-5M ouabain.…”

“…Diminution in both delayed and anomalous rectification for K would shorten the plateau as would loss of a slow conducting Na channel. There is experimental evidence for the latter (2). If the Na concentration in the per- fusion medium is reduced to one-h (choline chloride substituted to maintair ity) for the 1 day old ventricle the j amplitude and duration decrease marke4 This suggests the presence of a significward Na current during the early neor with progressive closing of the slow-chz rat ages.…”

“…In the area of mammalian myocardial physiology the rat has provided just such an anomalous condition. The rat heart demonstrates anomalies with respect to its action potential (1, 2), forcefrequency response (1-3), ionic exchange parameters (2,(4)(5)(6) and response to digitalis glycosides (2,7,8). Investigation of these characteristics has provided further insight into fundamental properties of myocardial function not only in the rat but in other mammalian species.…”