Austin E. Doyle

The Australian Therapeutic Trial in Mild Hypertension.

In the Australian Therapeutic Trial in Mild Hypertension treated patients had significantly lower cardiovascular mortality and a significantly lower incidence of cerebrovascular complications than patients given placebos. There was, however, no difference in the incidence of nonfatal myocardial infarction or other new manifestations of ischaemic heart disease. Although the evidence of benefit from treatment was clear-cut, the number of cardiovascular complications in the control group was small. This was due to several factors. Patients admitted to the trial had no preceding evidence of cardiovascular complications, the blood pressure fell spontaneously to below 95 mm Hg in almost half the control group, and patients whose blood pressures rose to levels above 110 mm Hg were given treatment, but remained in the placebo group for analysis. In both treated and placebo groups, trial end-points occurred more frequently in persons whose average diastolic blood pressure during the study remained raised. Ischaemic heart disease and many cases of stroke are due to atherosclerotic arterial disease. This appears not to be favourably influenced by antihypertensive drug therapy.

Plasma Norepinephrine Levels in Essential Hypertension

Abstract In 31 patients with essential hypertension there was a close relation between resting diastolic blood pressure and basal plasma norepinephrine concentrations (r = 0.741, p < 0.001). After ...

Effects of genetic hypertension on diabetic nephropathy in the rat: functional and structural characteristics

Streptozotocin (STZ) diabetes was induced in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. Body weight, blood pressure, renal function, glycaemic control and proteinuria were assessed monthly for 32 weeks. At 32 weeks, the animals were killed and glomerular basement membrane (GBM) thickness and fractional mesangial volume were measured. There was no significant difference in renal function between diabetic SHR and diabetic WKY. Diabetic SHR showed an earlier and larger rise in total proteinuria and urinary albumin excretion than diabetic WKY. Urinary albumin excretion was increased more than tenfold in diabetic SHR compared to diabetic WKY after 32 weeks of diabetes. GBM thickness was significantly increased in diabetic SHR compared with diabetic WKY. Both diabetic WKY and diabetic SHR showed mesangial expansion when compared to their nondiabetic counterparts. On the other hand, both hypertensive models showed increased glomerular volume, which was not influenced by the presence of diabetes. The diabetic SHR model has features of accelerated nephropathy, as evidenced by increased albuminuria and GBM thickness. This suggests that pre-existing hypertension may play an important role in the progression of diabetic renal disease.

Persistent effects on blood pressure and renal haemodynamics following chronic angiotensin converting enzyme inhibition with perindopril.

1. Spontaneously hypertensive rats (SHR) and Wistar‐Kyoto (WKY) rats aged 4 and 16 weeks were given an acute oral dose of either Perindopril (3 mg/kg) or vehicle. Direct blood pressure (BP), glomerular filtration rate (GFR) and renal blood flow (RBF) were measured, and renal vascular resistance (RVR) calculated. GFR and RBF were lower in vehicle‐treated SHR than WKY at 4 weeks of age, but were not different at 16 weeks. Acute Perindopril increased GFR and RBF and reduced RVR in both strains at both 4 and 16 weeks.

Blood pressure responses of conscious normotensive and spontaneously hypertensive rats to intracerebroventricular and peripheral administration of captopril.

SUMMARY In conscious spontaneously hypertensive rats, intracerebroTentricular injection of captopril (2 rag/kg) resulted in a rapid hypotenshe response that lasted several hours. The same dose given by Intracerebroventricular injection had no significant effect on blood pressure (BP) of normotensive Wistar-Kyoto (WK) rats over 7 hours. There was no significant change in BP of conscious spontaneously hypertensive rats (SHR) in response to Intracerebroventricular injection of vehicle and only a transitory fall in BP in response to intravenous injection of captopril (2 mg/kg). There was no significant differences between plasma renin activity (PRA) of conscious norrootenslve WKY rats and the PRA of SHR. These results suggest biochemical differences between the brains of SHR and normotensive WKY control rats. These differences could involve the brain renin-angiotensin system or other iteuropeptides.

Verapamil in the treatment of hypertension.

Summary A randomized, double-blind, crossover trial was carried out in 17 hypertensive patients to evaluate the hypotensive efficacy and safety of verapamil. Verapamil in doses of 120 mg thrice daily was compared with pindolol in doses of 7.5 mg twice daily. A thiazide diuretic was given with both drugs. Blood pressure fell about 14/11 mm Hg during treatment with either drug compared to the placebo period, and neither drug caused significant side effects. Verapamil did not affect plasma renin concentration.

Plasma Renin Levels and Vascular Complications in Hypertension

Plasma renin levels, measured in 39 untreated patients in 1967, under conditions of sodium loading and sodium depletion have been related to the incidence of stroke and myocardial infarction. Renin levels were not significantly different in patients with or without vascular complications. Out of 13 patients with persistently low renin levels 6 had suffered either a stroke or a myocardial infarction and 7 had not. Plasma renin levels were also measured in 116 treated hypertensive patients. There was no relation between plasma renin level and vascular complications. It is concluded that levels of plasma renin are not a reliable index of the probability of hypertensive patients suffering a stroke or myocardial infarction.

The relationship of plasma levels of pindolol in hypertensive patients to effects on blood pressure, plasma renin and plasma noradrenaline levels

1 Fifteen, previously untreated, hypertensive patients were given 20 mg of pindolol, orally. The systolic and diastolic blood pressures fell significantly in 1 h; the effect was maximal 4 h after pindolol, and persisted for at least 8 h. 2 After oral administration of 20 mg of pindolol, its concentration in the plasma reached a peak in 2–3 h. At the end of 8 h, pindolol was not detectable in the plasma. 3 There was a significant relationship between the peak concentration of pindolol in plasma and the maximal change in blood pressure in fifteen previously untreated hypertensive patients. In a separate study of ninety‐nine hypertensive outpatients taking 15–80 mg of pindolol daily, the blood pressure responses corresponded generally to the concentration of pindolol in plasma 2–3 h after the morning dose. 4 There were no significant changes in plasma renin activity, plasma renin concentration or plasma noradrenaline concentration in the previously untreated patients taking 20 mg of pindolol. There was no relationship between initial plasma renin or noradrenaline levels and blood pressure responses to pindolol. Nor was there any significant relationship between the changes in plasma renin or noradrenaline levels and the changes in blood pressure.

Nephropathy in model combining genetic hypertension with experimental diabetes. Enalapril versus hydralazine and metoprolol therapy.

We compared the effects of the angiotensin-converting enzyme inhibitor enalapril and a conventional antihypertensive regimen (hydralazine and metoprolol) on kidney function, albuminuria, and glomerular ultrastructure in hypertensive diabetic and nondiabetic rats. Diabetes was induced with streptozocin at 8 wk of age in spontaneously hypertensive (SHR) rats. Antihypertensive drugs were administered in drinking water from the time of induction of diabetes in all groups. Blood pressure reduction was equal in the diabetic and nondiabetic SHR rats receiving either enalapril or hydralazine plus metoprolol. In diabetic SHR rats, there was a rise in serum creatinine after 32 wk, which did not occur in diabetic rats treated with either antihypertensive regimen or in nondiabetic rats. Both drug regimens reduced albuminuria in diabetic and nondiabetic SHR rats to a similar degree. Enalapril and the combination of hydralazine and metoprolol were associated with decreased glomerular basement membrane thickness and glomerular volume in diabetic and nondiabetic SHR rats without significant effect on fractional mesangial volume. Thus, antihypertensive therapy retards the development of albuminuria, glomerular basement membrane thickening, and glomerular hypertrophy in the rat in the presence or absence of diabetes. No specific benefit of angiotensin-converting enzyme inhibition was observed in these hypertensive models of nephropathy. Human studies comparing the effects of different classes of antihypertensive drugs on kidney function, proteinuria, and glomerular morphology are warranted

INCREASED SODIUM PERMEABILITY OF ERYTHROCYTES IN SPONTANEOUSLY HYPERTENSIVE RATS

1. The Na permeability of red cells from spontaneously hypertensive rats (SHR) has been studied. In the Japanese Wistar‐Kyoto strain, a significant increase of 30% in 22Na influx for male SHR was found compared with normotensive male controls. In contrast the Na influx for genetically hypertensive and normotensive New Zealand rats did not differ. Normotensive Wistar‐Kyoto rats rendered hypertensive by unilateral renal artery clipping, did not show any difference in Na influx from control animals.