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R Massingham

Publications and source records attributed to R Massingham.

11 recordsLinked to original sources
PubMed1992

Protective effect of bepridil against veratrine-induced contracture in rat atria.

In isolated stimulated rat atria, superfusion with veratrine caused a marked contracture (VIC) which was absent in calcium-free medium and which was inhibited by tetrodotoxin (IC50VIC of 1.38 microM). Lowering the extracellular calcium concentration from 2.5 to 0.5 or 0.1 mM reduced the veratrine-induced contracture and delayed its onset. Superfusion of bepridil (1-10 microM) for 60 min before and during veratrine exposure markedly slowed the onset of contracture, reduced the maximum response (IC50VIC = 2.11 microM) and facilitated recovery upon washout of the alkaloid. The direct negative inotropic effect (NIE) of bepridil (IC50NIE = 10.96 microM) resulted in an VIC/NIE ratio of 5.19 for this drug. The protective effects of bepridil were rate-independent and were not modified by the presence of atropine (1.4 microM) and propranolol (0.3 microM) in the medium. Diltiazem, verapamil and nifedipine only reduced veratrine-induced contracture at concentrations much higher than those producing a negative inotropic effect, giving them negative NIE/VIC ratios of 0.31, 0.08 and 0.08 respectively. Like bepridil, flunarizine had a positive NIE/VIC ratio (15.87, IC50VIC = 3.71 microM). The lack of effect of the quaternary derivative of bepridil CERM 11888 indicated that intracellular sites of action may be involved in the activity of bepridil on veratrine-induced contracture. Given that veratrine-induced changes may mimic some of the pathological changes occurring in ischaemia, the results suggest that bepridil and flunarizine may be more effective than L-type, slow calcium ion-channel blockers in protecting against calcium overload during ischaemia and reperfusion injury.

Animals↗
PubMed1992

Calcium antagonists can be classified using in vitro toxicity and potency indices.

The toxicity of eleven calcium antagonists from different chemical families was determined in rat hepatocyte primary cultures. The calcium antagonist potency of the same compounds was also determined in isolated rabbit aortic rings contracted with high K+. The hepatocytotoxicity of the calcium antagonists was not directly linked to blockade of voltage-operated calcium channels, since there was no correlation between the rank order of hepatotoxicity and that for calcium antagonist potency. The toxicity and calcium antagonist potency of each calcium antagonist examined were used to calculate an in vitro therapeutic index value for each compound. It was observed that therapeutic indices fell into three distinct groups and we therefore propose that the in vitro therapeutic index can be used to subclassify the calcium antagonist group of drugs. The proposed classification corresponds very closely with one already suggested by Spedding on pharmacological grounds. In conclusion, the in vitro therapeutic index may provide a useful tool in the characterization and subclassification of novel calcium antagonist compounds.

Animals↗
PubMed1992

Acetylcholine-induced relaxation of the rabbit aorta is preload-independent but markedly dependent upon the degree of excitatory agonist-induced tone.

1. The aim of the present study was to investigate the relationship between endothelium-dependent relaxation evoked by acetylcholine, tissue preload and the degree of noradrenaline-induced tone in the isolated rabbit aorta. 2. In the aorta preload-response curves were bell-shaped with increasing preload augmenting responses to noradrenaline up to a certain point (optimal value) and then declining. Removal of the endothelium significantly increased responses to low concentrations of noradrenaline (less than 0.1 microM) but did not significantly affect the maximum response of the aorta to this amine or the preload-response curves generated at several concentrations of noradrenaline. 3. The optimal preload value was around 10 g for the aorta and changes in preload did not influence the sensitivity of the tissue to noradrenaline as assessed by pEC50 values to this agonist. 4. Acetylcholine (0.01-10 microM) evoked endothelium-dependent relaxations which in absolute terms increased as the tissue preload was increased. This relationship was much less evident when acetylcholine responses were measured in terms of the percentage inhibition of the respective noradrenaline contraction, when little or no change in the acetylcholine responses was noted. 5. When acetylcholine relaxations were expressed in terms of a percentage of the maximum noradrenaline-induced response evoked at each preload setting, the results confirmed that preload changes had little or no influence upon acetylcholine responses. 6. In contrast, tissue sensitivity to, and the extent of acetylcholine-induced relaxation, were markedly affected by the level of excitatory agonist-induced tone. As noradrenaline-induced tone increased, maximum responses and pIC50 values to acetylcholine were reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1975

A comparsion of the effects of prazosin and hydrallazine on blood pressure, heart rate and plasma renin activity in conscious renal hypertensive dogs.

Prazosin, a novel antihypertensive agent, and hydrallazine have been compared in renal hypertensive dogs. I.v. prazosin (0.1 mg/kg) produced greater falls in blood pressure than hydrallazine (1 mg/kg i.v.) but, in contrast to hydrallazine, did not cause any significant alteration in heart rate or plasma renin activity in these animals. When given orally, prazosin (0.1 mg/kg) produced falls in blood pressure equivalent to those observed with i.v. hydrallazine (1 mg/kg) again without significant tachycardia or plasma renin activation.

Animals↗
PubMedDate not supplied

Comparison of in vivo acute lethal potency and in vitro cytotoxicity of 48 chemicals.

The cytotoxicity of 48 compounds included in the MEIC (Multicenter Evaluation of In Vitro Cytotoxicity) list was determined in cultures of rat hepatocytes, McCoy, and MDBK cells. The average minimum concentration of each compound inducing cytotoxicity was measured in each cell type. The cytotoxicity values were then compared with published oral LD50 values for rats and mice. The logarithmic transformation of in vivo toxic doses and the corresponding in vitro cytotoxic concentrations showed a statistically significant correlation between the in vitro and in vivo values. The results show that an accurate in vivo LD50 dose could be predicted from in vitro data for at least 75% of the selected compounds. It is hoped that this finding will not only stimulate others to pursue in vitro technique but will eventually lead to elimination of the in vivo LD50 test.

Animal Testing Alternatives↗