Low mortality from all causes, including myocardial infarction, in well-controlled hypertensives treated with a beta-blocker plus other antihypertensives.

The aim of the present study was to monitor the efficacy of treatment, morbidity and mortality over a 10-year period in 939 moderate to severe hypertensive patients. All patients were treated in the same hypertension clinic with the beta 1-selective agent atenolol, administered either alone or more usually with a diuretic with or without a vasodilator or other agents. Survival rates were compared with predicted survival rates, had the hypertension not been treated, and also with those of a local reference population matched for age and sex. After a mean follow-up time of 6.1 years, mean blood pressure (BP) was significantly lowered from 183/109 to 145/87 mmHg. Biochemical disturbance was minimal. There were 79 withdrawals from treatment, of whom 37 were lost to follow-up. There were 91 deaths on intention to treat. Systolic blood pressure (SBP) on treatment, and not initial BP, was a powerful predictor of mortality. Patients of all age groups with well-controlled SBP were less likely to die, particularly from myocardial infarction, than those with less well controlled SBP (P less than 0.001). However, due to possible J-curve relationships between treated BP and outcome, lowering SBP below 140-150 mmHg in the elderly, and the diastolic blood pressure (DBP) below about 85 mmHg, may not be beneficial. Total mortality and mortality due to myocardial infarction was about 60% [corrected], of predicted level, had a high BP not been treated, being similar to that in a local reference control population (age- and sex-matched). The death rate from stroke was reduced to about 50% of that predicted. Patients who died showed a mean fall in mean serum triglyceride concentration in contrast to the mean increase that occurred in survivors. It is concluded that patients with moderate to severe hypertension who obtain a high level of general health care and optimal control of BP for up to 10 years, experience a significant decrease in total mortality rate and death from myocardial infarction and stroke.

Dynamics of xenobiotic metabolism by isolated rat hepatocytes using a multichannel perifusion system.

The multichannel perifusion system in recirculating and non-recirculating (single-pass) mode has been used to monitor the rate of oxidative metabolism of three model substrates--7-ethoxycoumarin, dichloronitroanisole and aldrin. With control hepatocytes, the rate of de-ethylation of 7-ethoxycoumarin derived from recirculating mode was essentially similar to the rate obtained with conventional flask-incubated cell suspensions. The formation of 7-hydroxycoumarin glucuronide and sulphate by hepatocytes exposed to 7-ethoxycoumarin demonstrated the retention of conjugative ability of cells in the perifusion system. The rate of demethylation of dichloronitroanisole to dichloronitrophenol was low whilst aldrin epoxidation to dieldrin was rapid using control hepatocytes in recirculating mode. The inductive effect of phenobarbitone on hepatic mixed-function oxidases was demonstrated by a marked increase in the rate of 7-ethoxycoumarin (nine-fold) and dichloronitroanisole (64-fold) dealkylation by hepatocytes from phenobarbitone-treated animals in recirculating mode. The rate of substrate oxidation by hepatocytes perifused in the recirculating and the single-pass mode were the same. With dichloronitroanisole as substrate and a single-pass mode, the rate of dichloronitrophenol formation declined rapidly on perifusion with substrate-free medium and rapidly re-attained steady state on re-introduction of the substrate; the presence of metyrapone effectively inhibited dichloronitroanisole metabolism. The perifusion system is recommended for the study of the dynamics of xenobiotic metabolism by isolated mammalian hepatocytes.

Metabolic capability of rat hepatocytes isolated by perfusion and tissue slice techniques.

The metabolic capability of hepatocytes prepared by the perfusion method (P cells) and the tissue slice method (S cells) has been compared using standardised procedures. Yields of P cells were four times greater than for S cells. Trypan blue exclusion viability and oxygen utilization were similar although the viability of S cells deteriorated faster with time. P cells had a lower endogenous rate of glycogenolysis and showed better glucagon stimulation than S cells. Similarly, P cells performed gluconeogenesis at a higher rate. However, there was no significant differences in the metabolism of the xenobiotic ethoxycoumarin. It is concluded that while S cells are probably satisfactory for studies of drug metabolism their use for work involving surface receptor binding and energy demanding processes should be questioned.

A multichannel perifusion system for the continuous monitoring of glycogenolysis and gluconeogenesis in isolated rat hepatocytes.

A multichannel perifusion system for isolated rat hepatocytes entrapped in a Sephadex matrix is described and criteria for the choice of matrices are discussed. This system overcomes the usual problem of clogged filters and impaired flow rates encountered in suspension perifusion systems, and is assembled from standard widely available components. Gluconeogenic capability and mitochondrial respiratory control ratios were unaltered. Decreases in trypan blue viability index and respiration rate were small when compared with flask-incubated hepatocytes. The endogenous rate of glycogenolysis was slightly higher in perifused hepatocytes but hormone response, as judged by glucagon stimulation of glycogenolysis, was unimpaired. The potential of this system is indicated by experiments monitoring glycogenolysis and gluconeogenesis in recycling and non-recycling modes.