Ivar K. Eide

Low-renin status in therapy-resistant hypertension: a clue to efficient treatment.

Objective Therapy resistance is an enduring problem in clinical hypertension. Our aims were to estimate: (1) the contribution of a low-renin status in therapy resistance; (2) whether such status could give a clue to more successful treatment; and (3) the contribution by adrenal cortical adenomas and by primary aldosteronism. Setting Patients were referred from general and internal medicine practices following written invitations and included consecutively. Participants were examined and followed-up on an outpatient basis. Design and interventions Patients were divided according to renin status. Low-renin patients were treated with an aldosterone inhibitor in a prospective, randomized, placebo-controlled, double-blind, cross-over study. Main outcome measures Prevalence of low-renin status in therapy resistance. Blood pressure and hormonal responses to specific treatment. Numbers of adrenocortical adenomas and primary aldosteronism. Results In 90 treatment-resistant hypertensive, 67% had plasma renin activity (PRA) below 0.5 nmol/l per hour. Of the 60 low-renin patients, 38 were studied on a fixed combination of amiloride and hydrochlorothiazide. Three weeks’ treatment reduced blood pressure by 31/15 mmHg compared to placebo (P ⩽ 0.0001). Serum aldosterone and plasma renin activity increased substantially during active treatment. Through the subsequent 6–12 months of open treatment, seven patients (18%) showing an escape phenomenon had their high blood pressure effectively treated by extra amiloride. Of the 60 low-renin patients, eight had adrenal adenoma. Conclusion A low-renin status characterized two-thirds of patients with treatment-resistant hypertension, who could be treated efficiently by aldosterone inhibition. Patients with an escape phenomenon (18%) could effectively be treated by increasing the aldosterone inhibitor. Low-renin hypertensives had high prevalence of adrenocortical adenomas and primary aldosteronism.

Sympathoadrenal Stress Reactivity Is a Predictor of Future Blood Pressure: An 18-Year Follow-Up Study

In the present study we hypothesized that arterial catecholamine concentrations during rest and 2 laboratory stress tests were independent predictors of blood pressure at an 18-year follow-up. At entry, blood pressure, heart rate, and arterial plasma epinephrine and norepinephrine concentrations were measured in 99 healthy men (age: 19.3±0.4 years, mean±SD) at rest, during a mental arithmetic test, and during a cold pressor test. After 18.0±0.9 years of follow-up, resting blood pressure was measured. The norepinephrine and epinephrine concentrations during the mental arithmetic explained 12.7% of the variation of future systolic blood pressure after adjusting for initial resting blood pressure, family history, body mass index, and systolic blood pressure during the stress test in a multiple regression analysis (adjusted R2=0.651; P<0.001). To conclude, the present study shows that sympathetic nervous activity during mental arithmetic predicts future blood pressure, indicating a possible causal factor in the development of essential hypertension independent of the initial blood pressure.

Awareness of high blood pressure increases arterial plasma catecholamines, platelet noradrenaline and adrenergic responses to mental stress

Thirty-six, 19-year-old men within the 95th percentile of mean blood pressure (110 mmHg) at a routine medical screening were randomized into two groups and requested to return for a follow-up visit in 2 weeks. One group was sent a neutral letter, while the other was sent a letter conveying the information that their blood pressures were elevated. After 15 min sitting in the laboratory, there was a significantly higher heart rate (P less than 0.05) in the informed group. Thirteen informed and 13 uninformed subjects were examined further by intra-arterial blood pressure recording and serial sampling of arterial catecholamines during cold pressor and mental stress tests. The study was undertaken examiner-blind. Informing the subjects of high blood pressure increased both baseline plasma noradrenaline (P less than 0.01) and adrenaline (P less than 0.05) and intraplatelet noradrenaline (P less than 0.05). Blood pressure (P less than 0.05) and heart rate (P less than 0.05) increased significantly more in the informed group when the subjects were told of the cold pressor test. In addition, there were exaggerated adrenaline (P less than 0.05) and diastolic blood pressure (P less than 0.05) responses to mental stress in the informed group. Thus, awareness of high blood pressure in young men may increase sympathetic tone and responses as measured in the laboratory. Conclusions from studies on early pathogenesis of essential hypertension should therefore be drawn with more caution when patients are aware of their high blood pressure.

Antihypertensive Drugs and Blood Lipids: The Oslo Study

The effects on blood lipids and uric acid of six different antihypertensive drugs used alone, and of five different combinations of two antihypertensive drugs, are reported here. Prazosin significantly lowered serum low density lipoprotein and very low density lipoprotein (LDL + VLDL) cholesterol and total triglycerides while maintaining high density lipoprotein (HDL) levels. Atenolol lowered LDL + VLDL cholesterol slightly. Both pindolol and hydrochlorothiazide (HCTZ) were neutral, while oxprenolol increased total triglycerides. Propranolol lowered HDL cholesterol and increased total triglycerides and uric acid. The combination of prazosin plus pindolol has a direct favorable lipid profile, while the combination of propranolol plus HCTZ lowered HDL cholesterol and increased total triglycerides. The combination of propranolol plus prazosin lowered HDL cholesterol. but to a lesser degree than propranolol alone, which suggests that prazosin was not able to completely counteract the negative effects of propranolol on HDL. Methyldopa plus HCTZ. and HCTZ plus amiloride were neutral with regard to effects on blood lipids. It is suggested that the metabolic effects of antihypertensive drugs could be of special importance in the long-term treatment of mild hypertension

The sympathetic nervous system may modulate the metabolic cardiovascular syndrome in essential hypertension

Summary: The association between blood pressure and coronary artery disease may be caused by a concurrence of atherogenic biochemical abnormalities in hypertensive patients, i.e., the metabolic cardiovascular syndrome (increased total cholesterol, triglycerides, and insulin; decreased high-density lipoprotein (HDL) cholesterol; and insulin resistance, glucose intolerance, and blood platelet dysfunction). There are numerous reports of sympathetic nervous system overactivity in hypertensive subjects that could be of importance for the pathophysiology of the high blood pressure. Plasma catecholamines have metabolic hormonal effects at concentrations slightly above low normal resting levels. Even transiently and certainly chronically raised plasma catecholamine levels may cause biochemical abnormalities. Catecholamines may raise total cholesterol, triglycerides, and insulin, decrease HDL cholesterol, and cause insulin resistance and glucose intolerance, and recent evidence supports an in vivo influence of epinephrine on blood platelets, causing dysfunction in hypertensive subjects. Thus, the sympathetic nervous system may modulate the metabolic cardiovascular syndrome in essential hypertension. Hypertensive subjects may respond to environmental stimuli with larger sympathoadrenal responses than normal subjects. Furthermore, emotional stress has been associated with coronary artery disease. Thus, the metabolic hormonal effects of catecholamines, by causing the metabolic cardiovascular syndrome, may be the crucial link between “stress” and cardiovascular disease.

Increased Arterial Catecholamines in Pre-Eclampsia

Arterial and venous plasma catecholamines were measured in 13 pre‐eclamptic and 13 normotensive pregnant women. in the pre‐eclamptic group, arterial concentrations were higher for adrenalin (p<0.001), noradrenalin (p<0.05) and dopamine (p<0.01) than in the normotensive group, whereas in venous plasma only adrenalin (p<0.01) and dopamine levels were higher (p<0.05). Arterial adrenalin concentrations in the pre‐eclamptic group were, on average, three times as high as normotensive arterial adrenalin. the arterial‐venous (a‐v) differences were higher for adrenalin (p<0.001) and dopamine (p<0.05) in the preeclamptic than in the normotensive group. in the preeclamptic group, arterial adrenalin was correlated with mean arterial blood pressure (r=0.89, p<0.001) and with increased heart rate (r=0.78, p<0.01). According to these results, both sympathetic nervous and sympathetic adrenal activities are increased in patients with pre‐eclampsia.

Gender specific sympathetic and hemorrheological responses to mental stress in healthy young subjects

Objective - Activation of the sympathetic nervous system may increase hematocrit (Hct), whole blood viscosity (WBV), and possibly cardiovascular risk. The aim was to study gender specific differences of mental stress on sympathetic reactivity and blood rheology. Methods - Responses in blood pressure, heart rate (HR), Hct, WBV (Bohlin rotational viscosimeter), and plasma catecholamines to a mental arithmetic stress test (MST) were measured in male ( n = 10, 23 - 3 years, BMI 23 - 2 kg/m2) and female ( n = 10, 21 - 4 years, BMI 24 - 2 kg/m2) students. Results - Systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR increased during MST in men and women, and declined to baseline levels after 15 min of recovery. In men, plasma adrenaline increased by 217% during MST ( p < 0.01, ANOVA), and plasma noradrenaline increased by 68% ( p < 0.05). Hct and WBV at low shear rates (0.5 and 1.1 l/s) increased as well ( p < 0.01, p < 0.05, and p < 0.05, respectively). In women, the increase in plasma adrenaline averaged 118% during MST ( p < 0.05) while plasma noradrenaline (-3%, p = 0.38), Hct, and WBV at all shear rates remained unchanged. Men and women differed in j adrenaline ( p < 0.05), j noradrenaline ( p = 0.01), j Hct ( p < 0.05), and j WBV ( p < 0.05). j Hct tended to correlate with j SBP ( r = 0.60, p = 0.07), j DBP ( r = 0.57, p = 0.09), and j HR ( r = 0.50, p = 0.14), and correlated significantly with j noradrenaline ( r = 0.66, p < 0.05) in men only. Multiple regression analysis showed that gender independently explained 22% of the change in Hct during mental stress. Conclusion - Data suggest gender specific differences in sympathetic and hemorrheological responses to mental stress in healthy young subjects. In men, sympathetic responses were related to hemorrheological responses, but not in women. It may be speculated whether such differences in stress responses may contribute to lower cardiovascular risk in premenopausal women than in men.OBJECTIVEnActivation of the sympathetic nervous system may increase hematocrit (Hct), whole blood viscosity (WBV), and possibly cardiovascular risk. The aim was to study gender specific differences of mental stress on sympathetic reactivity and blood rheology.nnnMETHODSnResponses in blood pressure, heart rate (HR), Hct, WBV (Bohlin rotational viscosimeter), and plasma catecholamines to a mental arithmetic stress test (MST) were measured in male (n = 10, 23 +/- 3 years, BMI 23 +/- 2 kg/m2) and female (n = 10, 21 +/- 4 years, BMI 24 +/- 2 kg/m2) students.nnnRESULTSnSystolic blood pressure (SBP), diastolic blood pressure (DBP), and HR increased during MST in men and women, and declined to baseline levels after 15 min of recovery. In men, plasma adrenaline increased by 217% during MST (p < 0.01, ANOVA). and plasma noradrenaline increased by 68% (p < 0.05). Hct and WBV at low shear rates (0.5 and 1.1 l/s) increased as well (p < 0.001, p < 0.05, and p < 0.05, respectively). In women, the increase in plasma adrenaline averaged 118% during MST (p < 0.05) while plasma noradrenaline (-3%, p = 0.38), Hct, and WBV at all shear rates remained unchanged. Men and women differed in A adrenaline (p < 0.05), A noradrenaline (p = 0.01), delta Hct (p < 0.05), and delta WBV (p < 0.05). A Hct tended to correlate with delta SBP (r= 0.60, p = 0.07), A DBP (r = 0.57. p = 0.09). and delta HR (r = 0.50, p = 0.14), and correlated significantly with A noradrenaline (r = 0.66, p < 0.05) in men only. Multiple regression analysis showed that gender independently explained 22% of the change in Hct during mental stress.nnnCONCLUSIONnData suggest gender specific differences in sympathetic and hemorrheological responses to mental stress in healthy young subjects. In men, sympathetic responses were related to hemorrheological responses, but not in women. It may be speculated whether such differences in stress responses may contribute to lower cardiovascular risk in premenopausal women than in men.

Adrenaline during mental stress in relation to fitness, metabolic risk factors and cardiovascular responses in young men

We studied plasma adrenaline (A) in relation to physical fitness, metabolic cardiovascular risk factors and cardiovascular responses. Men (age 21–24 years) with high and normal (both nu200a=u200a19) screening blood pressure (BP) were studied cross‐sectionally. We measured peak oxygen uptake (VO2peak) (treadmill exercise), and plasma catecholamines, heart rate (HR), finger systolic (SBP) and diastolic (DBP) BP, and insulin‐adjusted glucose disposal rate (GDR/I) during a hyperinsulinaemic glucose clamp (rest) and mental arithmetic stress test (MST). By multiple regression, A at rest (Arest) (βu200a=u200a0.37, p<0.05) and during MST (Amst) (βu200a=u200a0.40, p<0.01) were associated with high screening BP. In the respective models, Arest was negatively related to body mass index (BMI) (βu200a=u200a−0.56, p<0.001) and Amst positively to VO2peak (βu200a=u200a0.54, p<0.001). BP and HR responses correlated positively with VO2peak, but were determined by Amst in multiple regression models. Independently of BMI and VO2peak, serum high‐density lipoprotein cholesterol was positively related to A levels, whereas GDR/I was independently related only to VO2peak. Increased adrenaline secretion may be related to high BP, but may at the same time be associated with a beneficial metabolic profile.

Enhanced platelet release reaction related to arterial plasma adrenaline and blood pressure in pre-eclampsia

Summary. The platelet release product β‐thromboglobulin (BTG) in venous plasma, and arterial and venous catecholamines were measured in 13 severe pre‐eclamptic and 13 normotensive pregnant women. In the pre‐eclamptic group, BTG was significantly higher and the platelet count significantly lower than in the normotensive pregnant group. In the pre‐eclamptic group, arterial concentrations were significantly higher for adrenaline, noradrenaline and dopamine, whereas in venous plasma only adrenaline and dopamine were higher. Significant positive correlations appeared in the pre‐eclamptic patients between venous BTG and arterial adrenaline (r= 0·82), arterial noradrenaline (r= 0·76) and venous adrenaline (r= 0·55). In the pre‐eclamptic group, BTG also highly correlated with systolic (r= 0·84) and diastolic blood pressure (r= 0·77) and heart rate (r= 0·67). These findings indicate that sympathetic nervous tone, as measured by arterial and venous plasma catecholamines, is a good predictor of in‐vivo blood platelet activation. In pre‐eclampsia, increased sympathetic tone may play a key role in platelet activation and consumption and thus in the activation of the coagulation system.

Effects of β1- and β2-blockade on blood pressure and sympathetic responses to flight phobia stress

Cardiovascular and sympathoadrenal effects of short‐term oral treatment with β1‐blockade (atenolol, 50 mg, administered two times) and β2‐blockade (ICI 118,551, 50 mg, administered three times) were compared with placebo during actual flying in subjects with flight phobia (n = 34). β1‐Blockade lowered resting blood pressure and heart rate and prevented a heart rate response but not a blood pressure response to this psychologic stress. β2‐Blockade minimally lowered resting heart rate and prevented a heart rate response, but it failed to lower resting blood pressure or blood pressure response to the stress. Plasma epinephrine increased with all three treatments and more with β1‐blockade than with placebo. Plasma norepinephrine decreased with administration of β2‐blockade. Thus neither β1‐ nor β2‐blockade prevents an increase in blood pressure during acute flight phobia stress. Increased plasma epinephrine seems to be the sympathetic variable that is closest related to this increase in blood pressure. Norepinephrine may be less consistently related to the blood pressure rise during flight phobia stress as shown by the decrease in plasma norepinephrine with administration of β2‐blockade.