Objectives. To study the prognosis in therapy-resistant hypertension (RH).Design. Patients with RH and age- and sex-matched responding hypertensives, were followed-up for a period of 7 years.Setting. All subjects were outpatients at a secondary referral centre for hypertension.Subjects. (i) Age less than or equal to 65 years; (ii) no prior diagnosis of secondary hypertension; (iii) on antihypertensive triple-drug therapy of optimal dosage; (iv) diastolic blood pressure remaining 5 mmHg above their (age-related) target pressure; (v) no history of renal failure, heart failure, stroke or myocardial infarction; and (vi) no record of noncompliance. A total of 800 patients were screened. Thirty-six were finally included. For each study patient, two control patients were randomly selected. Interventions. Continuous efforts to optimize blood pressure control were made in all patients.Main outcome measures. Transient ischaemic attack or stroke, myocardial infarction, congestive heart failure, renal failure, and death. Development of noninsulin-dependent diabetes mellitus (NIDDM).Results. At the end of the follow-up period, RH had a casual functional blood pressure 21/6 mmHg higher than the control hypertensives. RH exhibited an increased incidence of stroke (P < 0.05), renal insufficiency (P < 0.05) and NIDDM (P < 0.05). RH patients had an increased risk of suffering an event during the 7 years [odds ratio (OR) 2.71; P < 0.05].Conclusions. Resistance to antihypertensive therapy may persist even when therapy is aggressively applied in compliant patients. RH is associated to an increased risk of stroke and of target organ damage, foremost renal insufficiency. The apparent association between RH, obesity and NIDDM may imply that hyperinsulinaemia is involved in therapy resistance.

We investigated whether short-term changes in serum insulin would effect a reduction of arterial pressure in subjects with therapy-resistant essential hypertension. Six patients were examined twice with a 3 week's interval in a single-blind cross-over design with euglycemic insulin clamps (A and B). A reduction of endogenous serum insulin was achieved by continuous infusion of 50 microgram octreoid (a somatostatin analogue) per hour. During clamp A low dose insulin infusion (5 mU/m2/min) was given, whereas during clamp B insulin was infused at a rate of 60 mU/m2/min. Preceding each clamp a standard drug therapy was given for one week (50 mg atenolol+ 30 mg furosemide per day). During clamp A plasma insulin was reduced from 21.4 +/- 7.5 to 10.8 +/- 1.2 mU/l (p < 0.01) whereas plasma insulin rose during clamp B from 20.0 +/- 7.5 to 99.0 +/- 17.2 mU/l (p < 0.001). The mean arterial blood pressure did not decrease during clamp A (low dose insulin infusion). There was an increased natriuresis during the high-insulin clamp (70 vs. 38 mmol, p = 0.13), but no difference in arterial pressure between the clamps. The results do not support the notion that high insulin levels contribute to hypertension in therapy resistant hypertensive patients by any direct and immediate mechanism.

Obesity and an enhanced insulin response to oral glucose tolerance test are associated with therapy resistance in hypertension. In order to explore this association further we studied the insulin sensitivity of subjects with essential hypertension resistant to triple drug therapy (RH), with the euglycemic insulin clamp technique. Well controlled hypertensives, matched for age, gender and body mass index (BMI) served as controls. Male subjects (7 RH and 7 controls) were further investigated by biopsies of Musculus Vastus lateralis since structural conditions in skeletal muscles might have a role in the above association. Irrespective of pre-study drug therapy, therapy-resistant hypertensives had a lower insulin sensitivity index than controls (p < 0.05). In spite of the BMI-match waist/hip ratio (WHR) in the RH males tended to be higher (p < 0.07). Insulin clearance tended to be lower in RH subjects (p = 0.09). BMI correlated with a reduced muscular capillary density (r = -0.77, p < 0.01). The average cross-sectional muscle fibre area was larger in RH subjects (p < 0.05). The mean muscle fibre area correlated with basal serum insulin (r = 0.63; p < 0.05). Rarefaction of the muscular capillary bed appears to be related to obesity. Larger muscle fibres might be an effect of the growth factor properties of insulin and could possibly correspond to hypertrophy of smooth muscle in the resistance vessels. This factor might contribute to the association of hyperinsulinemia and hypertension and attenuate the response to antihypertensive therapy.