Stereoselective effects of the enantiomers, quinidine and quinine, on depolarization‐ and agonist‐mediated responses in rat isolated aorta

Abstract

1. The effects of the two enantiomers, quinidine and quinine, were studied on depolarization- and agonist-induced isometric contractions in rat isolated thoracic aortic rings. 2. Quinidine or quinine (10(-6)M-3 x 10(-4)M) produced a concentration-dependent relaxation of 80 mM KCl-contracted rings, the pD2 values being 4.89 and 4.23, respectively. Thus, quinidine was about 4-5 times more potent than quinine. 3. The voltage-dependence of quinidine- and quinine-induced inhibition was studied in rings that had been incubated in 5 or 40 mM KCl Ca(2+)-free solution and then contracted by changing the bath solution to 100 mM KCl and 2 mM Ca2+. The inhibitory effects of quinidine were significantly enhanced when the rings were preincubated in 40 mM KCl (depolarizing conditions), when compared to normally polarized rings. In contrast, the effects of quinine were similar in 5 or 40 mM KCl solution. 4. The antagonism of noradrenaline (NA)-induced contractions by low concentrations of quinidine (< 10(-4)M) and quinine (< 3 x 10(-4)M) was competitive, as demonstrated by the concentration-dependent parallel rightward shift of the NA concentration-response curves (pA2 values 6.20 and 5.68, respectively, P < 0.05). 5. At low concentrations (< or = 3 x 10(-5)M), quinidine and quinine did not shift the concentration-response curve to 5-hydroxytryptamine (5-HT) or endothelin-1, whereas at higher concentrations they produced a downward shift of these curves. Quinidine and quinine (> 10(-4)M) inhibited to a similar extent both the phasic (induced in Ca(2+)-free media) and tonic responses (after restoring extracellular Ca2+) induced by 5-HT. 6. In conclusion, quinidine and quinine produced a stereoselective inhibition of depolarization and NA-induced contractions, quinidine being more potent than quinine. The inhibition of KCl-induced contractions could be attributed to inhibition of Ca2+ entry. Both drugs also behaved as competitive antagonists of alpha 1D-adrenoceptors. At high concentrations, quinidine and quinine also decreased the contractions induced by endothelin-1 and 5-HT in a non-stereoselective manner.

Quinine Inhibits Vascular Contraction Independent of Effects on Calcium or Myosin Phosphorylation

“…This finding is consistent with previous reports describing the actions of quinine on rabbit and rat aorta (Cook et al, 1987;Del Pozo et al, 1996). Quinine was earlier identified as a sympatholytic drug (Hiatt, 1950) exhibiting a higher degree of inhibition of the ␣ 1 -adrenoceptor compared with the ␣ 2 -adrenoceptor (Motulsky et al, 1984).…”

“…Quinine has been shown to inhibit calcium release from internal stores of brain microsomes and macrophages (Lee and Go, 1996;Misra et al, 1997). More to the point of this present study, quinine reduced 5-hydroxytryptamine-induced contractions of rat aorta smooth muscle in calcium-free medium (Del Pozo et al, 1996).…”

“…Quinidine and quinine inhibit KCl-induced contractions in rat and rabbit aorta (Cook et al, 1987) and rat rectum (Del Pozo et al, 1996) as well as angiotensin II-stimulated contractions in rabbit aorta (Cook et al, 1987). These compounds also inhibit KCl-induced 45 Ca uptake in A7r5 cells (Cook and Quast, 1990) and shift the CaCl 2 -force response to the right in depolarized guinea pig taenia coli (Spedding and Berg, 1985).…”