Acute antihypertensive effects of the new generation calcium antagonist 3-pyridine carboxylic acid 5-[(cyclopropylamino)-carbonyl]-1,4-dihydro-2,6-dimethyl-4-(2-nitrophen yl) octyl ester on conscious spontaneously hypertensive rats and renal hypertensive rats. Droperidol exerts dual effects on repolarization and induces early afterdepolarizations and triggered activity in rabbit Purkinje fibers. Comparison of in vitro effects of cicletanine, its enantiomers and major metabolite on rat thoracic aorta. Rx drugs

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Arzneimittelforschung. 1993 Aug;43(8):847-51.
Acute antihypertensive effects of the new generation calcium antagonist 3-pyridine carboxylic acid 5-[(cyclopropylamino)-carbonyl]-1,4-dihydro-2,6-dimethyl-4-(2-nitrophen yl) octyl ester on conscious spontaneously hypertensive rats and renal hypertensive rats.

Hojo M, Tanaka Y, Katayama O, Teramoto N.

Pharmacological Department, Nippon Shoji Kaisha Ltd., Osaka, Japan.

The acute antihypertensive effects of 3-pyridine carboxylic acid 5-[(cyclo-propylamino)carbonyl]-1,4-dihydro-2,6-dimethyl-4-(2-nitroph eny l) octyl ester (NP-252, CAS 132031-81-3) administered orally to conscious spontaneously hypertensive rats (SHRs) and renal hypertensive rats (RHRs) were evaluated using the impedance plethysmographical technique as a modified tail cuff method, and compared with those of nifedipine (NF). In the fitness test of this indirect method, the average value of blood pressure (BP) measured in 7 conscious SHRs was 201 +/- 6.9 mmHg. This value showed good correlation with that (201 +/- 8.8 mmHg) of systolic BP measured by the direct method in the same animals. In the comparative study of antihypertensive activities of the compounds on both models of hypertension using this method, NP-252 and NF dose-dependently lowered BP having a different peak time and restoration after dosing. Therefore, the antihypertensive activities were compared using a 20% effective dose (ED20) for producing hypotension, and the ED20 values of NP-252 and NF were 2.55 and 2.00 mg/kg in SHRs, and 1.25 and 0.67 mg/kg in RHRs, respectively. Moreover, the duration of actions of the compounds were evaluated by the simulated duration time (SDT) which was calculated from the peak time of BP-fall and the pharmacological half life time for the maximum BP-fall and the SDT values of NP-252 and NF were 1.85-4.70 and 0.90-0.75 h in SHRs, and 3.30-12.80 and 0.57-6.90 h in RHRs, respectively. Also, the BP-falls by the compounds were accompanied by an increase in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

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J Pharmacol Exp Ther. 1993 Aug;266(2):884-93.
Droperidol exerts dual effects on repolarization and induces early afterdepolarizations and triggered activity in rabbit Purkinje fibers.

Adamantidis MM, Kerram P, Caron JF, Dupuis BA.

Laboratoire de Pharmacologie, Institut National de la Sante et de la Recherche Medicale, Faculte de Medecine, Lille, France.

This study was designed to clarify discrepancies concerning the effects of droperidol on cardiac repolarization. Myocardial electrical activity was recorded by using microelectrode technique in rabbit Purkinje fibers and guinea pig ventricular muscle. In Purkinje fibers stimulated at 60 pulses/min, low concentrations (0.01-0.3 microM) of droperidol increased in a dose-dependent fashion action potential duration (APD) without altering the other parameters. At 1 and 3 microM, droperidol led to the reversal of the prolonging effect. The highest concentrations used (10 and 30 microM), produced shortening in APD at 50% repolarization concomitantly with a significant decrease in Vmax, action potential amplitude and resting membrane potential. Inexcitability occurred in 4 of 15 preparations exposed to 30 microM. In 8 of 15 Purkinje fibers, the prolonging effect induced by low concentrations was so important that APD exceeded the 1000-msec period of basal stimulation and early afterdepolarizations (EADs) and triggered activity developed. In guinea pig ventricular muscle, these effects were notably less pronounced. Prolongation of action potential showed a reverse use-dependence (i.e., much greater at the lowest stimulation frequencies), whereas Vmax depression was use-dependent. Decreasing extracellular K concentration from 4.0 to 2.7 mM enhanced the incidence of EADs in Purkinje fibers, whereas elevating the K concentration from 2.7 to 5.4 mM abolished them completely and shortened drastically APD. EADs were also eliminated by increasing magnesium concentration from 1 to 5 mM. Addition of isoproterenol favored EADs, whereas these were suppressed at plateau level by exposure to 0.3 microM nifedipine. The results indicate that in rabbit Purkinje fibers, droperidol exerts a dual effect on repolarization, prolongation with low concentrations with development of EADs and subsequent triggered activity. These abnormalities were suppressed at high concentrations concomitantly with a marked depression of other characteristics. These observations suggest multiple ionic channel activities and further studies are required to precise the underlying mechanisms at channel level.

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Naunyn Schmiedebergs Arch Pharmacol. 1993 May;347(5):548-52.
Comparison of in vitro effects of cicletanine, its enantiomers and major metabolite on rat thoracic aorta.

Mikkelsen EO, Sehested J, Poulsen SH.

Institute of Pharmacology, University of Aarhus, Denmark.

The effects of cicletanine ((+/-)-cic)), its optical isomers (BN-50417,(+)-cic); (BN-50418,(-)-cic) and major metabolite (BN-50699,cic-Met) on active tension were investigated in rat thoracic aortas. (+/-)-cic, (+)-cic, (-)-cic shifted the K(+)-concentration response curve to the right and depressed the maximum contractile response. Cic-Met was devoid of inhibitory effect on K(+)-induced contractions. (-)-Pinacidil had a far more potent inhibitory effect on K(+)-induced contractions than the cicletanine enantiomers and shifted the K(+)-concentration response curve to the right without affecting the maximum contractile response. (+/-)-Cic and nifedipine caused a concentration-related inhibition of Ca(2+)-induced contractions. Nifedipine was far more potent than (+/-)-cic in this respect. The slope of the Schild plot for nifedipine was not different from unity contrary to the significantly different slope for (+/-)-cic. (+/-)-Cic, (+)-cic, (-)-cic and cic-Met (3 x 10(-5) M to 3 x 10(-4) M) caused a concentration-related relaxation of noradrenaline (NA), serotonin (5-HT) and prostaglandin F2 alpha (PGF2 alpha)-induced contractions. In NA-precontracted preparations (-)-cic (10(-4) M-3 x 10(-4) M) had a stronger relaxant effect than (+)-cic. Cic-Met was a weaker antagonist of NA-induced contractions than (+) and (-)-cic. The enantiomers were far less potent relaxing NA-induced contractions than phentolamine. (+)-Cic, (-)-cic and cic-Met had a similar relaxant effect on 5-HT-induced contractions.(ABSTRACT TRUNCATED AT 250 WORDS)

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