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Effects of long-term sarpogrelate (5-HT2 antagonist) administration on the systolic blood pressure of Wistar-Kyoto normotensive rats (WKYs) and spontaneously hypertensive rats (SHRs) were studied and compared with those of quinapril (ACE-I). Sarpogrelate and quinapril were administered orally for 12 weeks and body and heart weights, systolic blood pressure and the relationships between heart weight and systolic blood pressure were determined. Although both drug treatments caused decreases in the body weight of WKYs and SHRs, only quinapril induced a decrease in the heart weight of SHRs. In addition, quinapril induced a dose-dependent decrease in systolic blood pressure in WKYs and SHRs while sarpogrelate had no effect on systolic blood pressure. Thus, quinapril showed hemodynamic effects on WKYs and SHRs, but the 5-HT2 antagonists sarpogrelate did not shown such effects, suggesting that 5-HT2 receptor antagonists may not be important for controlling systolic blood pressure.

This study was performed to assess the affinities of propranolol, bopindolol, its two metabolites (18-502, 20-785), pindolol, metoprolol, and atenolol to β1- and β2-adrenoceptor (β1- and β2-AR) subtypes using the membranes of COS-7 cells transiently expressing β1- and β2-AR subtypes. Radioligand-binding assays were performed and the results were compared with those (pKi or pA2 values) obtained from the membrane-enriched fractions from the rat heart, cerebral cortex, bovine heart, tracheal smooth muscle or guinea-pig heart muscle. The pKi values of propranolol, bopindolol, its two metabolites, atenolol, pindolol and metoprolol to β1-AR subtypes obtained from COS-7 cell membranes were 9.02 ± 0.04, 7.44 ± 0.12, 9.38 ± 0.31, 6.65 ± 0.16, 5.55 ± 0.14, 8.17 ± 0.15 and 5.99 ± 0.13, respectively. The rank order of pKi values for these agents to β-2-ARs in COS-7 cell membranes was the same as that of β1-ARs. In addition, good correlations were observed between pKi values of homogenates from various tissues and those of transfected COS-7 cell membranes to β1- and β2-ARs. Although good correlations were also observed between pA2 values obtained from tracheal smooth muscle (β2-ARs) and pKi values obtained from transfected COS-7 cell membranes to β2-ARs, low correlation coefficient values to β1-ARs were observed, however. In conclusion, these results suggested that binding characteristics of 3H-CGP-12177 to β-AR subtypes in these membranes from transfected COS-7 cells are similar to those from membrane fractions of various tissues.

In isolated porcine coronary arteries, concentrations of 5-HT (10–8 to 3 × 10–5 mol/l), α-methylserotonin (α-Me-5-HT, 10–8 to 3 × 10–5 mol/l) and ergonovine (10–9 to 3 × 10–4 mol/l) produced contraction, whereas high concentrations (10–5 to 10–4 mol/l) of these drugs produced relaxation. Both sarpogrelate and ketanserin produced rightward shifts of contraction concentration-response curves induced by 5-HT and α-Me-5-HT at the concentration from 10–9 to 3 × 10–5 mol/l, and only sarpogrelate inhibited the relaxation at high concentrations of 5-HT and displayed 155% of maximal contraction at 10–4 mol/l 5-HT. On the other hand, sarpogrelate and ketanserin did not show any inhibitory effects on the relaxation induced by high concentrations of ergonovine. These results suggested that sarpogrelate and ketanserin show different inhibitory effects on the relaxation induced by high concentrations of 5-HT, indicating that these two drugs may have different affinities to 5-HT receptor subtypes that may be involved in relaxation.

The dissociating and/or residual inhibitory effects of bopindolol from β-adrenoceptors (ARs) of atria strips pretreated with this drug and washed out with buffers on isoprenaline-induced chronotropic actions were determined. The effects of this drug were compared with those of its active metabolite 18-502, propranolol, and pindolol. Our results are as follows: (1) Lower concentrations of bopindolol (10–9 and 10–8 mol/l) and the active metabolite 18-502 (10–9 mol/l), propranolol (10–8 and 10–6 mol/l) and pindolol (10–8 mol/l) produced rightward shifts of concentration-response curves of isoprenaline. (2) Higher concentrations of bopindolol (10–7 mol/l) and 18-502 (10–8 and 10–7 mol/l) produced a reduced maximum response by isoprenaline. (3) Bopindolol (10–9–10–7 mol/l), 18-502 (10–9–10–7 mol/l) and propranolol (10–7 and 10–6 mol/l) did not recover to control levels at 180 min even after washout with buffers. In conclusion, bopindolol and 18-502 may slowly dissociate and act as noncompetitive β-antagonists rather than readily reversible β-AR antagonists. These effects may differ from those of propranolol and pindolol, although propranolol did not recover to control levels after washout with buffer.

This study was designed to examine the importance of interaction in the bindings of nonselective β-blockers to β1-adrenoceptors (β1-ARs) as compared with β2-ARs, using molecular modeling. The β-blockers used in this study were bopindolol [4-(benzoyloxy-3-t- butylaminopropyl)-2-methylindol hydrogen malomate], its two metabolites [18-502 – hydrolyzed bopindolol or 4-(3-t-butylamino-2-hydroxypropoxy)-2-methyl indole – and 20-785 – 4-(3-t-butylaminopropoxy)-2-carboxyl indole], and propranolol. Molecular modeling was performed on an Indigo2 workstation (Silicon Graphic) using Discover/Insight II (Molecular Simulations) software. Through molecular modeling, possible binding sites for these drugs were suggested to lie between helices 3, 4, 5, and 6 of the β1-AR. The amine, benzoic acid, indole methyl, t-butyl, phenyl, and indole functional groups of bopindolol possibly interact with Asp138 (transmembrane – TM – 3), Ser190 (TM 4), Ala343 (TM 6), Val137 (TM 3), Pro339 (TM6), Cys336 (TM 4), Leu237 (TM 5), and Pro236 (TM 5) of β1-AR, respectively, by either hydrogen bonding or hydrophobic interactions. In addition, 18-502, 20-785, and propranolol also interacted with sites at the same positions as those of β2-ARs. Thus, the results of the present study suggested that although Ala343 and Val137 of β1-AR among these amino acids were different from those of β2-AR, the interactions at the same sites between ligands and amino acids of β1-AR as those of β2-ARs may occur because these drugs are nonselective.

This study was performed to assess the affinity of tamsulosin to the α1L- in addition to α1B-adrenoceptor (α1-AR) subtypes coexisting in the canine aorta using the radioligand binding assay. The antagonistic effects of this drug on contraction of the rat aorta were also assessed, and the results were compared with those obtained with prazosin, amosulalol, labetalol, ketanserin, clonidine and propranolol. The pKi value of tamsulosin to the α1L-subtype was lower than those of prazosin and HV-723, but higher than those of amosulalol, ketanserin and labetalol. The pKi value of tamsulosin for the α1B-subtype in the canine aorta was similar to that of prazosin. However, this drug showed a higher pKi value than amosulalol, HV-723, labetalol and ketanserin. On the other hand, the order of inhibition potencies for contraction of the rat aorta by phenylephrine was as follows: prazosin > tamsulosin > amosulalol > HV-723 > labetalol > ketanserin > clonidine > propranolol. Thus, although the affinity of tamsulosin to the α1B-AR subtype in the canine aorta was as high as that in the bovine prostate reported in our previous study, the affinity (pKi 7.87) of this drug to α1L-AR in the canine aorta was lower than that (pKi 8.99) in the bovine prostate. These observations suggested that the pharmacological potencies of tamsulosin in the aorta and prostate may be different.

The dissociating and/or residual inhibitory effects of bopindolol from β-adrenoceptors of atria strips pretreated with this drug which was then washed out with buffers on the responses to isoprenaline were determined and compared with those of propranolol, pindolol, atenolol, and the two active metabolites of bopindolol: 18-502 and 20-785. Low concentrations of bopindolol (10–9 to 10–8 mol/l) and the active metabolite 18-502 (10–9 mol/l) produced rightward shifts of the concentration-response curves. On the other hand, high concentrations of bopindolol (10–7 mol/l) and metabolite 18-502 (10–8 and 10–7 mol/l) produced a reduced maximum response by isoprenaline, suggesting that these nonparallel rightward shifts have pD2 values of 7.57 (bopindolol) and 7.67 (18-502), respectively, at 0 min after washout with buffers. Pindolol (10–7 mol/l) and propranolol (10–7 and 10–8 mol/l) also produced a rightward shift of isoprenaline response curves, and these concentration-response curves in guinea pig atria strips pretreated with pindolol (10–7 mol/l) and propranolol (10–6 mol/l) recovered to control levels. Neither of these drugs, however, reduced the maximum response by isoprenaline. A high concentration (10–5 mol/l) of atenolol was required for a rightward shift of the isoprenaline concentration-response curve, and this drug also did not reduce the maximum response. Thus, we conclude that bopindolol and metabolite 18-502 slowly dissociate and act as noncompetitive β-antagonists rather than easily reversible β-adrenoceptor antagonists.

This study was designed to further discriminate α1-adrenoceptor subtypes in rat aorta and prostate using functional experiments. Responses induced by phenylephrine were equilibrated in both tissues. The pA2 values and slope factors of several α1-antagonists were assessed using concentration-response curves. The antagonists used were prazosin, WB-4101, 5-methylurapidil (5-MU), HV-723, and tamsulosin. In addition, the effects of chloroethylclonidine (CEC) and nifedipine on phenylephrine-induced contractions were investigated. A high pA2 value for prazosin was observed in both tissues (aorta 9.84, prostate 9.19) and the ranking of each drug’s pA2 value is as follows: tamsulosin > prazosin > WB-4101 > HV-723 > 5-MU in the aorta, and tamsulosin > prazosin > 5-MU > WB-4101 = HV-723 in the prostate. A significant difference between the pA2 value of each drug except for tamsulosin in the aorta and in prostate was observed (p < 0.01). Inhibition of contraction by pretreatment with CEC was 83.9 ± 2.42% in the aorta, and 6.17 ± 0.94% in the prostate. On the other hand, inhibition of maximal response by pretreatment with nifedipine (1 µmol/l) was 35.1 ± 2.2% in the aorta and 24.5 ± 3.1% in the prostate. A good correlation between these pA2 values and pKi values for recombinant human α1b-adrenoceptor expressed in CHO cells (aorta) and α1a-subtypes of CEC pretreated rat hippocampus (prostate) were observed. In conclusion, these results suggest that: (1) the contraction of these two tissues is mediated by α1H-adrenoceptor with a high affinity for prazosin; (2) α1H-adrenoceptors correspond to α1b-(aorta) and α1a-subtypes (prostate), and (3) each α1-adrenoceptor subtype in the aorta and prostate may be α1b-(aorta) and α1a-subtypes (prostate), respectively.

On March 7 this year, Prof. Robert J. Domenjoz died at the age of 89 years. Pharmacology is extremely indebted to him. He founded the journal in 1959, which was named Medicina Experimentalis and some years later renamed Medicina et Pharmacologia Experimentalis still in the tradition that Latin was the medical language.