Reflex sympathetic activation induces acute insulin resistance in the human forearm.

Inferences about the association between sympathetic overactivity and insulin resistance have been drawn from the infusion of sympathomimetic amines in supraphysiological doses. We used the isolated perfused human forearm to investigate the effect of reflex-induced sympathetic nervous system activation on the peripheral utilization of glucose in the skeletal muscles of 14 healthy men. Local hyperinsulinemia in the forearm (132 +/- 25 microunits/mL for 90 minutes) induced a significant increase in the utilization of glucose from baseline (16.4 +/- 3.1 mg.dL-1.min-1 per 100 mL forearm volume) to a plateau (85.7 +/- 15.1 mg.dL-1.min-1 per 100 mL forearm volume) between 40 and 60 minutes of insulin infusion but did not alter the utilization of oxygen. Reflex sympathetic nervous system activation was elicited by unloading of cardiopulmonary receptors with bilateral thigh cuff inflation to 40 mm Hg between 60 and 90 minutes of insulin infusion. Blood flow in the forearm was significantly decreased with inflation of thigh cuffs (average decrease of 19%, p < 0.0001). As a result of thigh cuff inflation, there was a reduction in the utilization of glucose (a decrease of 23%, p < 0.02), whereas oxygen utilization was unchanged. We find that an increase in sympathetic nervous system activation (within the normal range of physiological responses) can cause acute insulin resistance in the forearm of healthy volunteers. The reflex caused no change in oxygen utilization, but the same stimulus elicited a decrease in the utilization of glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

[Hypertension in the elderly - changing attitudes toward treatment].

Raised blood pressure in the elderly is a frequent finding and is not a benign occurence. It should not be viewed as a normal or inevitable consequence of aging. Recent major intervention trials against hypertension in the elderly have showed clear benefits from actively lowering elevated arterial pressure in this group of patients and also in those with isolated systolic hypertension. This review emphasises the importance of antihypertensive treatment in the elderley and underlines the strategies and problems in the care of elderly patients with hypertension.

Early association of sympathetic overactivity, hypertension, insulin resistance, and coronary risk.

Whereas this review is based on the available evidence, interpretation of the data is entirely hypothetical and subjective. To a large degree the review reflects our long-standing fascination with the role of the sympathetic overactivity in hypertension. The basic tenet is that sympathetic overactivity in hypertension may lead to a number of secondary changes, all of which are conductive to coronary heart disease. We also propose that insulin resistance and hypertension are associated through an underlying hemodynamic abnormality and again find good evidence for a possible role of sympathetics in the genesis of such hemodynamic changes. Future research in our laboratory will be oriented toward experimental testing of various aspects of the proposed sympathetic overactivity/hypertension/insulin resistance hypothesis.

Severe arterial hypertension (grade III and IV).

The aim of this study was to evaluate the number, outcome, survival time, and causes of death of patients with severe arterial hypertension who were admitted to the Department of Medicine at Landspitalinn (National Hospital) in Reykjavik during the years 1957 to 1971. During this period 117 patients were found to have severe arterial hypertension (12.6% of all cases of hypertension diagnosed) according to the grading of Keith and Wagener, 20 patients with grade IV retinopathy and 97 patients with grade III. The case histories were analysed according to age and sex distribution, blood urea, electrocardiographic changes, heart size by X-ray at the time of diagnosis and final outcome. The survival calculations were done by the decrement method (life tables) and aim taken from patient age 65 years and less. Relatively fewer patients with severe arterial hypertension were admitted during the last five year period (1967-1971) than during the two previous five year periods. The main causes of death were cerebrovascular accidents (26.6%), myocardial infarctions (22.8%), and renal failure (22.8%). Approximately 50% of the men and 60% of the women survived five years. Elevated blood urea values and signs of left ventricular hypertrophy on ECG at the time of diagnosis carried a more sinister prognosis.

Renal function as an indicator of prognosis in malignant essential hypertension.

Renal function was evaluated in a group of 24 patients (21 men and 3 women, mean age 47 years) who had survived the malignant phase of hypertension during the period of 1969-1979. Five had grade III retinopathy (haemorrhages and exudates) and 19 had grade IV changes (papilloedema, FH IV) at diagnosis. Highest recorded blood pressure was 248 +/- 4/152 +/- 3 mmHg (mean +/- S.E.M.). Renal function rapidly deteriorated in 7 cases with progression to terminal uraemia. All patients in this group had a marked elevation in serum creatinine at diagnosis (448 +/- 105 mumol/l) and inadequate blood pressure control. Two of these 7 patients died and 5 underwent renal transplantation. The other 17 patients initially had serum creatinine less than or equal to 250 mumol/l (169 +/- 19 mumol/l-glomerular filtration rate (GFR) 51 +/- 7 ml/min). All except one were reinvestigated after a mean time of 6 years (range 6 months-11 years) with evaluation of blood pressure and determination of GFR by 51Cr-EDTA clearance. At follow-up their blood pressure was fairly well controlled (153 +/- 3/99 +/- 2 mmHg). Their GFR was 62 +/- 6 ml/min. Of the 11 patients in whom two GFR determinations were available (one initially and one at follow-up), six patients showed a marked increase in GFR while 5 patients showed only slight or no improvement in spite of fairly good blood pressure control. In malignant hypertension adequate antihypertensive treatment can lead to a pronounced improvement in GFR unless renal function has deteriorated gravely.

Metabolic adverse effects of thiazide diuretics: the importance of normokalaemia.

It has been suggested that the failure of thiazide therapy, administered to treat high blood pressure, to prevent coronary heart disease is related to the metabolic adverse effects of these drugs. The almost consistent observation of reduced serum potassium and total body potassium associated with diuretics appears to be of clinical importance. It may cause not only an increased risk of cardiac arrhythmias but also impaired glucose tolerance and abnormal lipid metabolism, while replacement of potassium has been shown to eliminate the risk of arrhythmias as well as thiazide-induced hyperglycaemia. The effect of the thiazide-induced short-term changes in serum lipids is unclear. Present experience suggests that thiazide-induced impairment of glucose tolerance is due to both reduced glucose-stimulated insulin release and increased peripheral resistance to the action of insulin. The blunted initial response of the pancreatic beta-cells to glucose is clearly dependent on serum potassium, and may cause postprandial hyperglycaemia during most of the day and night. This hypothesis is supported by the observation of enhanced glucose and insulin levels after an overnight fast, as well as 60-120 min after glucose challenges. Increased average levels of insulin may eventually cause down-regulation of cellular insulin receptors, i.e. insulin resistance. It is also conceivable that elevated insulin levels may cause hypertriglyceridaemia and possibly other abnormalities of lipid metabolism. Some recent observations indicate that the prognosis in treated hypertensive patients improves if both blood pressure and cholesterol levels are successfully controlled. We therefore emphasize the importance of normalizing serum potassium when using diuretic-based therapies in the treatment of hypertension.

White coat hypertension: a follow-up.

Home blood pressure readings by self-monitoring (14 readings in 7 days) have been compared to readings taken in the clinic in 937 participants of the Tecumseh Blood Pressure Study. In the absence of firm criteria "hypertension at home" was defined as having home readings in the upper decile of the whole population. If a clinic reading exceeded 140 and/or 90 mmHg a subject was categorized as having clinic "hypertension". Two hypertensive groups emerged; one with both clinic and home hypertension ("sustained" N = 47) and one with high clinic but normal home blood pressure ("white coat" N = 50). Groups with "white coat" and "sustained" hypertension were very similar. Both groups were overweight, had faster heart rates, elevated cholesterol, insulin, triglyceride and decreased HDL levels. Blood pressure readings at previous exams (age 5, 8, 21 and 22) were elevated in both the "sustained" and white coat hypertension group compared to the normotensive controls. Subjects with white coat hypertension were not hyperresponders to the stress of mental arrythmetrics or to isometric exercise. The white coat hypertensives did not show abnormal anger, excessive submissiveness, or anxiety. The pathophysiology of the reproducible elevation of the clinic blood pressure in the white coat hypertensives remains unclear. Because of a higher risk of coronary heart disease and a risk for late development of sustained hypertension, subjects with white coat hypertension should be counselled on nonpharmacologic methods to control the blood pressure elevation and to ameliorate coronary risk factors.

The interconnection between sympathetics, microcirculation, and insulin resistance in hypertension.

The pathophysiology of the frequent association of insulin resistance and hypertension has not been elucidated. The skeletal muscle is the major site of insulin resistance; when stimulated with insulin, the hypertensive skeletal muscles extract less glucose than the normotensive. We postulate that hypertension-related changes in the skeletal muscle microcirculation contribute to the impaired glucose uptake in hypertension. Vascular rarefaction in hypertension impairs the delivery of insulin and glucose to muscle cells. Insulin resistance has been described both in human and experimental hypertension and both conditions are associated with vascular rarefaction. Functional studies (response to whole body or forearm exercise) and anatomic investigations (conjunctival photography, mesenteric and muscle biopsies) show vascular rarefaction in human hypertension. In addition, patients with hypertension are known to have a larger proportion of insulin resistant, poorly vascularized fast twitch muscle fibers. A few interventions can increase or decrease insulin resistance and these effects can be explained on hemodynamic grounds. Beta adrenergic blocking agents aggravate insulin resistance, and their main hemodynamic effect is a decrease of cardiac output. Converting enzyme inhibitors, alpha adrenergic blocking agents and possibly calcium antagonists decrease the insulin resistance, and their major hemodynamic effect is vasodilation. Physical training decreases insulin resistance; a higher capillary density in skeletal muscles is the hallmark of physical training. A hypothesis ought to rest on sufficient supporting data and its validity ought to lend itself to experimental verification. We believe our hypothesis meets both criteria. After outlining the supporting evidence we propose a number of tests to prove or disprove the hypothesis. In addition to the testable hypothesis we also speculate on the possible cause of the frequent association between hypertension and insulin resistance. We propose that both insulin resistance and blood pressure elevation represent a facet of the "defense reaction" which might have offered an early survival advantage and may, over evolutionary times, have fostered natural selection of subjects with both conditions.

Malignant hypertension--improving prognosis in a rare disease.

A follow-up was made of 69 patients diagnosed as having malignant hypertension during 1969--76, essential in 26, secondary in 39 and unclassified in 4. A clear male dominance was seen (41 men, 28 women), particularly in the group with essential hypertension (18 men, 8 women). The mortality in this series was less than in previously published series. Thus, the 5-year survival rate was 75% in the patients with essential and 72% in those with secondary hypertension. In part this was due to haemodialysis and renal transplantation. The importance of renal function at the time of diagnosis was evident in this study. In most patients with essential hypertension and serum creatinine levels below 300 mumol/l, renal function could be maintained or improved when antihypertensive treatment was instituted, whereas progression of the renal damage was seen in those with serum creatinine levels above 300 mumol/l in spite of antihypertensive treatment with 3 or more drugs. The incidence of new cases of malignant hypertension tended to decrease during the observation period, particularly as regards essential hypertension.

Treatment of hypertension with beta-blockers with and without intrinsic sympathomimetic activity.

In a randomized double-blind trial 36 patients with essential hypertension were treated with either metoprolol or pindolol for 6 months following a 6-week placebo period. At the end of the placebo period and after 6 weeks and 6 months of active therapy peripheral hemodynamics at rest and during maximal vasodilatation were studied. Exercise heart rate was reduced to the same extent with both metoprolol and pindolol, indicating that the doses used (metoprolol average 179 mg/day; pindolol average 12 mg/day) were equipotent as regards beta-adrenoceptor blocking effect. The antihypertensive effect was identical with both compounds. However, metoprolol caused a significant reduction of heart rate at rest both at 6 weeks and 6 months. With pindolol the reduction in heart rate was not significant at 6 weeks, and it was clearly much less than with metoprolol. On the other hand, no change in calf vascular resistance was seen during metoprolol therapy, whereas a marked and statistically significant reduction was caused by pindolol. Resistance at maximal dilatation in the forearm did not change with metoprolol, but tended to fall with pindolol after 6 weeks and was significantly reduced after 6 months. This indicates that although metoprolol and pindolol have the same antihypertensive potency, the two agents appear to reduce blood pressure through different mechanisms. Thus, cardiac mechanisms seem to play the most important role with metoprolol, whereas pindolol mainly acts by a reduction in vascular resistance. It also seems that treatment with pindolol normalizes the structural arteriolar abnormality present in hypertension as indicated by the reduction in resistance at maximal vasodilation.

Haemodynamic effects of metoprolol and pindolol: a comparison in hypertensive patients.

1 In a double-blind study, 36 patients with essential hypertension were randomly allocated to treatment with either metoprolol, 100--300 mg/day, or pindolol, 5--15 mg/day for 6 months. Haemodynamic investigations were made on three separate occasions. Blood flow in the calves and in the forearm was determined by venous occlusion plethysmography after 6 weeks of placebo, after 6 weeks and again after 6 months of active therapy. 2 Both drugs reduced blood pressure significantly, by 17.1/11.8 mm Hg with metoprolol and 21.9/10.9 mm Hg with pindolol after 6 weeks (P less than 0.005). No further changes were seen after 6 months. 3 Heart rate after 6 weeks was significantly reduced by metoprolol (10.7 +/- 2.4 beats/min, P less than 0.001) but not by pindolol (4.4 +/- 2.3 beats/min, NS). After 6 months a significant reduction was seen also in the pindolol group (5.2 +/- 2.1 beats/min, P less than 0.05). 4 The vascular resistance in the calves at rest was reduced by pindolol (P less than 0.05), whereas resistance tended to increase with metoprolol. 5 Resting vascular resistance in the forearm after 6 months was significantly reduced in the metoprolol group (P less than 0.001) as well as in the pindolol group (P less than 0.02). The increase in forearm vascular resistance seen during leg exercise was not influenced by either drug. 6 Vascular resistance at maximal vasodilatation was unchanged in the calves, but a significant reduction (-17.4 +/- 5.7%, P less than 0.01) in the forearm vascular bed was seen after 6 months of pindolol. No change was observed with metoprolol. 7 It is concluded that pindolol reduces elevated blood pressure partly through peripheral vascular mechanism. Metoprolol, on the other hand, probably acts mainly via central cardiac mechanisms.

A hemodynamic study of arteriolar changes in patients with previous malignant hypertension.

Blood flow resistance was studied in two peripheral vascular beds in 15 patients with previous malignant hypertension and in matched groups of patients with "benign" hypertension and control subjects. Both hypertensive groups had significantly higher resistance in the hands (skin vessel bed) at maximal dilatation (2.5 and 2.5 U, respectively) than the normotensive group (1.9 U) (p less than 0.01). This increase indicates structural changes in the arteriolar wall in both hypertensive groups. It indicates a similar degree of adaptation of the vascular changes to the present blood pressure level in both hypertensive groups, although the initial blood pressure had been much higher in the group with previous malignant hypertension than in the group with "benign" hypertension. Different findings were made in the calves (muscle vessel bed), and the most severe changes were found in patients with previous malignant hypertension. Resistance at maximal dilatation was 2.4 U compared to 1.9 U in the group with "benign" hypertension (p less than 0.05) and 1.6 U in the control group (p less than 0.001 and p less than 0.05, respectively).

Mode of action of beta-adrenoceptor blocking agents in hypertension. A comparison between metoprolol and pindolol with special reference to peripheral vascular effects.

beta-Adrenoceptor blocking drugs are generally recognized as being effective in the treatment of hypertension. The mechanisms whereby these drugs reduce blood pressure are, however, not fully understood. In a double-blind, randomized study either metoprolol, 100--300 mg/day, or pindolol, 5--15 mg/day, was given for 6 months and the effects on blood pressure, heart rate and vascular resistance in the calf and forearm were investigated. Measurements were made at rest, during and after physical exercise, and during postischaemic hyperaemia. Both drugs reduced blood pressure to the same extent both at rest and during and after exercise. Metoprolol reduced heart rate to a greater extent than pindolol at rest and after exercise, whereas no difference was seen during physical exercise. Pindolol reduced the vascular resistance in the calf at rest by 14% (p less than 0.05), whereas metoprolol tended to increase vascular resistance, the difference in effect being highly significant (p less than 0.005). During and after leg exercise, there was no difference in forearm vascular resistance between the two drugs. It may be concluded that pindolol reduced resting blood pressure partly through peripheral vasodilatation. This was probably an effect of beta 2-adrenoceptor stimulation linked to the pronounced intrinsic sympathomimetic activity (ISA) of pindolol. Metoprolol on the other hand, acted mainly through cardiac mechanisms, as suggested by its pronounced reduction of heart rate.

Human leucocyte antigens in patients with previous essential malignant hypertension.

1. Human leucocyte ABC antigens were determined by means of a lymphocytotoxicity test in 27 patients with previous essential malignant hypertension and in 500 blood donors. 2. In 18 patients with grade IV retinopathy human leucocyte antigen B15 (HLA B15) was found in 44%, as compared with 23% in the control subjects (P = 0.888). 3. All patients with HLA B15 had a positive family history for hypertension. 4. In 18 patients with grade IV retinopathy HLA B15 was found in eight whereas none of the nine patients with grade III retinopathy had this antigen (P = 0.039). 5. Of the 27 patients, 19 had a positive family history of hypertension and of these eight had HLA B15, whereas none of the eight patients with a negative family history had this antigen (P = 0.068). 6. The findings do not rule out that HLA B15 may be associated with the development of the malignant phase in patients with essential hypertension, but a statistically significant relationship could not be established.

Metoprolol and pindolol in hypertension: different effects on peripheral haemodynamics.

1. Thirty-six patients with essential hypertension, were randomly allocated to double-blind treatment with either metoprolol (100--200 mg/day) or pindolol (5--10 mg/day). The effects upon blood pressure and peripheral blood flow were determined. Both drugs reduced blood pressure significantly. 2. Heart rate was significantly reduced by metoprolol but not by pindolol. 3. Vascular resistance at maximal dilatation was not changed by either pindolol. 4. At rest, pindolol reduced vascular resistance in the calf by 14% (P less than 0.05) but metoprolol tended to increase the resistance slightly. The difference in effect was also significant (P less than 0.005). 5. During leg muscle work there were no changes in vascular resistance in the forearm with either compound. 6. We conclude that pindolol appears to reduce blood pressure at least partly through vascular mechanisms, in contrast to metoprolol. The response to sympathetic stimulation induced by physical exercise does not differ between metoprolol- and pindolol-treated patients.

Recreational exercise and cardiovascular status in the rural community of Tecumseh, Michigan.

BACKGROUND: Because of population stability, Tecumseh, a rural community in Michigan, was the site of health surveys over a period of three decades. METHODS: In the recent survey anthropometrics, blood pressure (BP), blood chemistry, echo/Doppler cardiac exam, personality and exercise questionnaires were collected on site. RESULTS: In this rural community 70% of subjects (447 men, 410 women, average age 30 years) do not engage in recreational exercise. Sedentary subjects were heavier (4 kg), had higher BP (2.3/2 mm Hg), faster heart rate (4 beats/min), and lower stroke volume (2 ml/m2) than physically more active subjects (p = 0.02 to 0.00001). Measures of cardiac structure and function were more favorable in exercising subjects. Cholesterol (+8 mg/dl), triglycerides (+15 mg/dl) and insulin (+2.4 microU/ml) were higher and HDL cholesterol was lower (-2 mg/dl) in the sedentary group (p = 0.04 to 0.003). Being sedentary was associated with more anxiety, anger and feeling time pressure (p = 0.001 to 0.00001). Exercise demands at work had no effect while even once a week recreational exercise was associated with a more favorable cardiovascular risk status. A difference in cardiovascular status between the sedentary and exercising subjects was not apparent throughout childhood, adolescence or early adult life, suggesting that subjects who exercise presently were not a priori healthier than presently sedentary subjects. CONCLUSIONS: Seventy percent of the residents studied in Tecumseh are physically inactive and have a less favorable cardiac risk profile. Enhancement of exercise habits may beneficially affect cardiovascular status and, presumably, the prognosis.