Depolarization-dependent effect of flavonoids in rat uterine smooth muscle contraction elicited by CaCl2. Contractile and relaxant effects of tetrapentylammonium ions in rat isolated mesenteric artery. Short- and long-term efficacy of nifedipine in hypertensive patients with impaired renal function, with special reference to influencing factors. Rx drugs

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Gen Pharmacol. 1997 Nov;29(5):847-57.
Depolarization-dependent effect of flavonoids in rat uterine smooth muscle contraction elicited by CaCl2.

Revuelta MP, Cantabrana B, Hidalgo A.

Departamento de Medicina, Facultad de Medicina, Oviedo, Spain.

1. The effects of the flavonoids genistein (3-60 microM), kaempferol (3-60 microM) and quercetin (1-100 microM) on KCl (60 mM)-induced tonic contraction in rat uterus and their modifications with the inhibitor of cAMP-dependent protein kinases (TPCK, 3 microM), the inhibitor of ornithine decarboxylase [alpha-difluoromethyl ornithine (DFMO), 10 mM] and the polyamine spermine (1 mM) have been assayed. The effects of the three flavonoids were also studied on the contraction elicited by CaCl2 (30 microM to 10 mM) on rat uterus incubated in medium lacking calcium and supplemented with 33, 60 or 90 mM of KCl. For comparison, the effects of the calcium channel blockers nifedipine and verapamil and the activator of adenylyl cyclase forskolin were assayed on contractions induced by KCl and CaCl2. 2. Genistein (IC50: 20.2 +/- 1.0 microM, n = 11), kaempferol (IC50: 10.1 +/- 0.8 microM, n = 8) and quercetin (IC50: 13.2 +/- 0.5 microM, n = 8) relaxed the tonic contraction induced by KCl (60 mM) in a concentration-dependent way. Verapamil (IC50: 70.1 +/- 5.8 nM, n = 7), nifedipine (IC50: 8.4 +/- 0.7 nM, n = 6) and forskolin (IC50: 0.62 +/- 0.08 microM, n = 14) also relaxed the KCl-induced contraction. TPCK (3 microM) significantly antagonized the effect of quercetin, kaempferol and forskolin (P < 0.01) but did not modify the effect of genistein. 3. Spermine (1 mM) increased the effects of genistein and verapamil and antagonized the effect of quercetin but did not modify those of kaempferol and forskolin. DFMO (10 mM) did not modify the effect of quercetin but increased that of genistein and antagonized those of kaempferol and forskolin. The addition of spermine (1 mM) plus DFMO (10 mM) antagonized the effect of quercetin. Spermine counteracted the effect of DFMO on forskolin but not on genistein. 4. KCl (33, 60 or 90 mM) did not produce contraction in calcium-free solution, but CaCl2 (30 microM to 10 mM) induced concentration-dependent contraction after depolarizing with KCl. The EC50 values for CaCl2 were: 0.74 +/- 0.08 (n = 12), 0.34 +/- 0.03 (n = 14) and 0.48 +/- 0.02 (n = 12) mM in a medium with 33, 60 or 90 mM of KCl, respectively. 5. Genistein (20 microM), kaempferol (10 microM), quercetin (15 microM), verapamil (70 nM), nifedipine (10 nM) and forskolin (0.5 microM) inhibited the concentration-response curve to CaCl2 in medium supplemented with 33, 60 or 90 mM of KCl. The effect of kaempferol was independent of the concentration of KCl in the incubation medium. However, the inhibitory effect of genistein on CaCl2-induced contraction was inversely related to the concentration of KCl in the medium. On the contrary, the effect of quercetin was directly related to the concentration of KCl in the medium. 6. The antagonism of verapamil, nifedipine and forskolin on CaCl2-induced contraction seems to be related to the degree of depolarization because increasing the KCl in the medium counteracted their effects. 7. Our results suggest that (1) cAMP contributes to the relaxant effects of quercetin and kaempferol on KCl (60 mM)-induced tonic contraction; (2) polyamines are involved in the relaxant effects of forskolin and kaempferol on KCl-induced tonic contraction but not on CaCl2-induced contraction in the depolarized uterus, and (3) the flavonoids assayed also possess a calcium antagonist action but show a different behavior toward the calcium channel blockers and the cAMP enhancer forskolin.

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Pharmacology. 1998 Oct;57(4):188-95.
Contractile and relaxant effects of tetrapentylammonium ions in rat isolated mesenteric artery.

Kwok KH, Chan NW, Lau CW, Huang Y.

Department of Physiology, Faculty of Medicine, Chinese University of Hong Kong, Shatin, NT, Hong Kong.

Both contractile and relaxant responses to tetrapentylammonium ions (TPA+) were studied in rat isolated mesenteric artery. TPA+ (5-10 micromol/l) caused a sustained increase of muscle tension. The contractile effect of TPA+ (10 micromol/l) was dependent upon the presence of extracellular Ca2+ but independent of the presence of endothelium. TPA+ (10-50 micromol/l) induced biphasic contraction, and the amplitude of peak and sustained tension decreased with increasing TPA+ concentration. TPA+ (100-300 micromol/l) only produced monophasic contraction. TPA+ (50 micromol/l) abolished the transient contraction induced by caffeine (10 mmol/l) or phenylephrine (1 micromol/l) in the absence of extracellular Ca2+. Nifedipine and verapamil concentration-dependently reduced the TPA+-induced contraction with respective IC50 values of 1.34 +/- 0. 24 and 9.46 +/- 1.36 nmol/l, these values were similar to 1.35 +/- 0. 21 and 16.07 +/- 1.71 nmol/l, respectively, for the inhibitory effects of nifedipine and verapamil on the high K+ (60 mmol/l)-induced contraction. TPA+ (>10 micromol/l) concentration-dependently reduced the phenylephrine (1 micromol/l)-, U46619 (30 nmol/l)-, endothelin I (10 nmol/l)- and high K+ (60 mmol/l)-induced sustained tension with respective IC50 values of 53. 7 +/- 9.5, 31.9 +/- 5.3, 30.9 +/- 3.4 and 20.9 +/- 2.8 micromol/l. The present results indicate that TPA+ at low concentrations could contract the arterial smooth muscle probably through promoting Ca2+ influx. At higher concentrations (>20 micromol/l), TPA+ relaxes arterial smooth muscle probably through inhibition of both nifedipine-sensitive Ca+ channels and internal Ca2+ release. TPA+, unlike other quaternary ammonium ions, could therefore act at multiple sites in arterial smooth muscle.

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J Clin Hypertens. 1987 Dec;3(4):452-62.
Short- and long-term efficacy of nifedipine in hypertensive patients with impaired renal function, with special reference to influencing factors.

Matsukawa S, Suzuki H, Itaya Y, Nakajima S, Saruta T.

Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.

Both the antihypertensive efficacy and side effects of nifedipine were investigated in hypertensive patients with impaired renal function (n = 44) in short-term (7 days) and long-term (6 months) therapeutic trials. Comparable hypotensive effects were obtained in both the short- and long-term studies (from 184 +/- 4.6/108 +/- 2.8 to 166 +/- 4.6/97 +/- 3.2 mmHg, and from 178 +/- 4.2/108 +/- 2.1 to 157 +/- 4.4/95 +/- 2.4 mmHg, respectively). In the short-term study (n = 20), the antihypertensive effect was significantly related to the pretreatment blood pressure (r = 0.51) and inversely related to the plasma renin activity (PRA) (r = -0.61; p less than 0.05). However, it was not related to age or reciprocal value of the pretreatment serum creatinine. In the long-term study (n = 24), blood-pressure-lowering effects of nifedipine were found to depend on the reciprocal value of the serum creatinine but not on PRA. The blood urea nitrogen and creatinine were not changed significantly during the observation period. Side effects occurred in 8 of the 44 patients, but severe side effects necessitating termination of administration were observed in only 2 patients. These results indicate that nifedipine is effective in both the short- and long-term treatment of hypertensives patients with impaired renal function. Impaired renal function is a key factor in the hypotensive effects of nifedipine in long-term therapy.

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