Independence of the positive inotropic effect of ouabain from the inhibition of the heart Na+/K+ pump.

Isolated left atria from guinea pigs were stimulated at 3.3 Hz and bathed at 30 degrees C in Tyrode's solution containing 6 mM KCl. After equilibration, this solution was replaced by a low-K solution or by Tyrode's solution containing ouabain or dihydroouabain. These treatments evoked an increase in the contractility of the atria. The time to peak increase was about 30 min, and the inotropic effect was sustained for at least 40 min. After 30 min, 42K was added to the bathing solution in order to estimate the activity of the Na+/K+ pump. A linear relationship was observed between the degree of inhibition of the Na+/K+ pump and the increase in systolic tension. The regression line was the same for low-K solutions and dihydroouabain but not for ouabain. For a given degree of inhibition of the pump, ouabain evoked a higher increase in contractility. These findings indicate that inhibition of the Na+/K+ pump can be the only mechanism responsible for the positive inotropic effect of dihydroouabain but cannot be the sole mechanism for that of ouabain

Role of Na-H exchange in the inotropic action of Bay K 8644 and of ouabain in guinea-pig isolated atria.

1. The inotropic effects of two concentrations of ouabain and of Bay K 8644 have been studied in isolated left atria of the guinea-pig in physiological solutions at pH lowered from 7.4 to 6.0 and in the presence of ethylisopropylamiloride (EIPA) an inhibitor of Na+/H+ exchange. The low concentration of ouabain (300 nM) was chosen to saturate the high affinity binding sites (it occupied about 7% of the low affinity sites). The high concentration of ouabain saturated both high and low binding sites. Bay K 8644 evoked a positive inotropic effect of a magnitude similar to ouabain (300 nM). 2. When comparing the positive inotropic effects of equi-effective concentrations of ouabain (300 nM) and of Bay K 8644 (100 nM), it was observed that extracellular acidification specifically depressed the inotropic effect of ouabain 300 nM; the positive inotropic effect of the high concentration of ouabain (3 microM) was barely affected by extracellular acidification. 3. EIPA 10 microM depressed the positive inotropic effect of ouabain 300 nM, but did not affect the peak response to Bay K 8644. The depressant action of EIPA on the positive inotropic effect of ouabain was concentration-dependent and was much more obvious on the effect of ouabain 300 nm than on ouabain 3 microM. 4. An increase in diastolic tension was evoked by 3 microM but not by 300 nM ouabain. This increase in tone was reduced dose-dependently by EIPA (10-30 microM). It was also significantly reduced when the extracellular pH was equal to 6.4 or 6.0. 5. Ouabain (300 nM) evoked a gain in tissue Na and an equivalent loss in tissue K.(ABSTRACT TRUNCATED AT 250 WORDS

Competitive and stereoselective histamine H1 antagonistic effect of cicletanide in guinea-pig isolated ileum.

The histamine H1 antagonistic effects of the racemic form and the enantiomers of cicletanide, a new antihypertensive furopyridine derivative, were investigated in guinea-pig isolated ileum. Both the racemic and the (-) enantiomer behaved as competitive histamine antagonists (pA2 values of 6.8 and 7.2, respectively). The (+) enantiomer was at least 100 times less potent than the (-) enantiomer. The H1-blocking effect of cicletanide is the most potent and is the only stereoselective property so far reported for the drug

1,3-Diacylaminopropan-2-ols and corresponding 2-acyl derivatives as drug carriers: unexpected pharmacological properties.

The design of lipid vectors (pseudotriglycerides, PTGs), achieved by the amide isosteric substitution of the ester moieties of 1,3-diacylglycerols, is based on the structural similarity with natural triglycerides facilitating the passage of pharmacological agents across biological membranes. 2-S-Acetylthiorphan (hemiacetorphan) pseudotriglycerides, Z-glycine pseudotriglycerides and 1,3-diacylaminopropan-2-ols vector molecules differing by the nature of the acid side-chain are examined in acute toxicity, radioligand binding and guinea-pig ileum experiments. These evaluations have led us to distinguish two types of compounds. Linear derivatives, palmitoyl and decanoyl, are devoid of toxicity and intrinsic activity. Cyclic derivatives, which contain in the acyl chain a phenyl, cyclohexyl, cyclopentyl or adamantoyl ring, present additional properties. Cyclic derivatives of hemiacetorphan are lethal after intravenous administration. The mortality is governed by the 2-hemiacetorphan moiety in the cyclic vector molecules. Hemiacetorphan alone is also lethal. Cyclic vector molecules and related compounds inhibit the contractile response of the guinea-pig ileum induced by electrical stimulation, histamine or acetylcholine (noncompetitive antagonism) whereas linear entities and parent compounds are not active. In particular, the 2-hemiacetorphan 1,3-diadamantoylamide PTG presents pD'2 values 7.87 +/- 0.29 (vs histamine) and 7.97 +/- 0.12 (vs acetylcholine)