SUMMARY1. Intracellular Na' activity (aIa) and membrane resting potential were studied in quiescent guinea-pig atrial and papillary muscles by means of Na'-sensitive and conventional microelectrodes. The effects of the cardioactive steroid dihydroouabain (DH11) on aia, force of contraction and sarcolemmal Na', K+-ATPase activity were also investigated.2. In thirty atria and twenty-two papillary muscles, a'a amounted to 8-0 + 0 2 and 4 7 +0 3 mm, respectively (means±+S.E.M.). When both tissues were from the same animal, with the same ion-sensitive microelectrode mean a'a values of 79 + 02 and 541 + 0-5 mm (P < 0 0 1) were obtained from eight atrial and eight papillary muscles, respectively.3. Membrane resting potentials (Em) were significantly (P < 0-001) more negative in the papillary muscles (-83 5 + 0 7 mV; n = 8) than in the atrium (-7841 + 0 5 mV; n = 8). Deviation of Em from EK (determined by K+-sensitive microelectrodes) was 30 + ±0)2 mV in ventricular (P < 0 05) and 641 + 0 3 mV in atrial preparations (/' < 0 05).4. Inhibition of the Na+ pump by DHO increased aia of the atrium within 10 min by 06+01 (n = 7). 13+01 (n = 5) and 32+02 mm (n = 5) at 5,10 and 30jCtM, respectively. In the papillary muscle, 10 yUM DHO was without effect while a'a rose by 1-0+0-1 (n = 5) and 2-9+02 mm (n = 6) at 30 and 120 /aM DHO.5. Consistent with the a'a measurements, the potency of DHO to increase force of the isometric contraction was three times higher in atrium than in papillary muscle (stimulation frequency 0 2 Hz).6. Hydrolytic activity of sarcolemmal Na+,K+-ATPase isolated from atria amounted to only one third of that detected in ventricles (0-07 +001, n = 6, versus 0-2+0±-01 /mol phosphate released min-(g tissue)-', n = 5). The inhibitory potencies of DHO on sarcolemmal Na+,K+-ATPase preparations were found to be identical in the enzymes from either tissue.

Recent studies suggest that inhibition of Na+,K(+)-ATPase may contribute to the positive inotropic action of the imidazopyridine sulmazole. Therefore, we investigated the effect of sulmazole and its stereoisomers and for comparison the effect of the cardioactive steroid dihydroouabain (DHO) on intracellular Na+ activity by means of Na(+)-sensitive microelectrodes. In the resting papillary muscle of the guinea pig, (+/-)-sulmazole increased intracellular Na+ activity (aiNa) within 15-20 minutes by 0.5 +/- 0.1 (n = 3), 1.3 +/- 0.1 (n = 7), 2.7 +/- 0.2 (n = 6), and 4.9 +/- 0.5 (n = 6) mM at 60, 100, 300, and 1,000 microM, respectively. (+)-Sulmazole was more effective than the racemate; aiNa was increased by 1.2 +/- 0.3, 2.1 +/- 0.3, and 4.0 +/- 0.2 mM at 60, 100, and 300 microM, respectively (n = 2 for each concentration). In the contracting papillary muscle (0.2 Hz), (+)- and (+/-)-sulmazole (600 and 1,000 microM) produced a maximum positive inotropic effect that exceeded that of DHO by 11% and 8%, respectively. As an inotropic agent, (+)-sulmazole was almost twice as potent as the racemate. The maximum direct inotropic effect of (-)-sulmazole (1,000 microM) amounted to only 14% of the DHO maximum and was, in contrast to the racemate and (+)-sulmazole, antagonized by 3 microM carbachol. (-)-Sulmazole did not affect aiNa.(ABSTRACT TRUNCATED AT 250 WORDS)

1 The effect of carbachol on force of contraction, contraction duration, intracellular Na+ activity and cyclic AMP content was studied in papillary muscles of the guinea-pig exposed to isoprenaline or the phosphodiesterase inhibitor 3-isobutyl, 1-methyl xanthine (IBMX). The preparations were obtained from reserpine-pretreated animals and were electrically driven at a frequency of 0.2 Hz.2 Isoprenaline (10nM) and IBMX (100pM) produced comparable positive inotropic effects of 9.8 and 9.7 mN, respectively. Carbachol (3 gM) attenuated the inotropic effects by 82% (isoprenaline) and by 79% (IBMX). The shortening of contraction duration which accompanied the positive inotropic effect of isoprenaline (by 14.9%) and of IBMX (by 22.4%) was not significantly affected by 3 gM carbachol. 3 The positive inotropic effect of 10 nm isoprenaline and of 10OMM IBMX was accompanied by an increase in cellular cyclic AMP content of 58 and 114%, respectively. Carbachol (3Mm) failed to reduce significantly the elevated cyclic AMP content of muscles exposed to either isoprenaline or IBMX. 4 In the quiescent papillary muscle, isoprenaline (10 nM) and IBMX (100 Mm) reduced the intracellular Na+ activity by 28 and 17%, respectively. This decline was not influenced by the additional application of 3 JiM carbachol. 5 The results demonstrate that muscarinic antagonism in guinea-pig ventricular myocardium exposed to cyclic AMP-elevating drugs is restricted to force of contraction. The underlying mechanism does not apparently involve the cytosolic signal molecule cyclic AMP.