The R-(-) and S-(+) enantiomers of 11-hydroxy-N-n-propylnoraporphine, (R)-3 and (S)-3, were synthesized in six steps from 1-(3-methoxy-2-nitrobenzyl)isoquinoline. Neuropharmacological evaluation of the R and S isomers (by affinity to dopamine receptor sites in rat brain tissues, induction of stereotyped behavior, and interaction with motor arousal induced by (R)-apomorphine in the rat) indicated that, similar to the 10,11-dihydroxy congener 2, both enantiomers can bind to dopamine receptors but that only (R)-3 activates them, whereas (S)-3 shows activity as a dopaminergic antagonist.

Animals↗

PubMed1988

Renal disease and the development of hypertension in salt-sensitive Dahl rats.

To elucidate the role of the kidneys in the development of hypertension in Dahl salt-sensitive (S), as compared to resistant (R) rats of the JR strain, we analyzed functional and morphological changes before and after the administration of an 8% NaCl diet and the onset of hypertension. The diet was begun at six weeks of age and was continued until 12 weeks of age. At six weeks, blood pressure was not different between S and R rats. Hypertension occurred in S rats receiving the 8% NaCl diet at week 8, and in S rats receiving 0.9% NaCl at week 10. Albuminuria and proteinuria were found in S rats prior to the 8% NaCl diet and progressed regardless of diet. Electron microscopy of glomeruli revealed segmental loss of epithelial foot processes in S rats at six weeks prior to the 8% NaCl diet. Mesangial widening, arteriolar myo-intimal cell hyperplasia and interstitial fibrosis occurred in all S rats. Inulin and PAH clearances in S rats decreased with time, the changes being accelerated by the 8% NaCl diet. Micropuncture of S and R rats prior to the 8% NaCl diet revealed no glomerular hypertension in S rats. The number of glomeruli in S and R rats were not different. We conclude that prehypertensive S rats of the JR strain already have albuminuric glomerular disease not associated with reduced number of glomeruli or glomerular hypertension. The renal pathology is accelerated once hypertension develops. A lower NaCl intake delays, but does not prevent renal disease in S rats.

Albuminuria↗

PubMed1988

Removal of the epithelium potentiates acetylcholine in depolarizing canine bronchial smooth muscle.

Experiments were designed to determine whether the airway epithelium affects the membrane potential of the underlying smooth muscle. The effect of epithelium removal (by gentle rubbing) on the responsiveness of isolated canine bronchi was studied. Simultaneous recordings of mechanical and electrical activity were made in paired circumferential strips (with and without epithelium) of third-order bronchi. Changes in tension were recorded with a force transducer, and changes in membrane potential were measured with a microelectrode. The cell membrane potential and resting tension of the bronchial smooth muscle were stable over a 150-min period and were not affected by removal of the epithelium. In the presence of antagonists at muscarinic and adrenergic receptors, the resting tension and membrane potential were comparable in preparations with and without epithelium. By contrast, the anticholinesterase, echothiophate, caused depolarization in bronchi without epithelium. Exposure to high potassium induced similar levels of depolarization and contraction in tissues with and without epithelium. No significant differences in threshold for depolarization or for mechanical activation in the membrane potential-tension relationship were noted in the presence or absence of epithelium. In the presence of echothiophate, removal of the epithelium augmented the contraction of the bronchi to acetylcholine; the depolarization of the cell membrane induced by the cholinergic transmitter was significantly larger than in control tissues, even when matched contractions were compared. These observations indicate that the respiratory epithelium generates an inhibitory substance that dampens depolarization and contraction of bronchial smooth muscle caused by acetylcholine.

Acetylcholine↗

PubMed1988