Markers of collagen synthesis is related to blood pressure and vascular hypertrophy: a LIFE substudy.

Cardiac fibrosis and high levels of circulating collagen markers has been associated with left ventricular (LV) hypertrophy. However, the relationship to vascular hypertrophy and blood pressure (BP) load is unclear. In 204 patients with essential hypertension and electrocardiographic LV hypertrophy, we measured sitting BP, serum collagen type I carboxy-terminal telopeptide (ICTP) reflecting degradation, procollagen type I carboxy-terminal propeptide (PICP) reflecting synthesis and LV mass by echocardiography after 2 weeks of placebo treatment and after 1 year of antihypertensive treatment with a losartan- or an atenolol-based regimen. Furthermore, we measured intima-media thickness of the common carotid arteries (IMT), minimal forearm vascular resistance (MFVR) by plethysmography and ambulatory 24-h BP in around half of the patients. At baseline, PICP/ICTP was positively related to IMT (r=0.24, P<0.05), MFVR(men) (r=0.35, P<0.01), 24-h systolic BP (r=0.24, P<0.05) and 24-h diastolic BP (r=0.22, P<0.05), but not to LV mass. After 1 year of treatment with reduction in systolic BP (175+/-15 vs 151+/-17 mmHg, P<0.001) and diastolic BP (99+/-8 vs 88+/-9 mmHg, P<0.001), ICTP was unchanged (3.7+/-1.4 vs 3.8+/-1.4 microg/l, NS) while PICP (121+/-39 vs 102+/-29 microg/l, P<0.001) decreased. The reduction in PICP/ICTP was related to the reduction in sitting diastolic BP (r=0.31, P<0.01) and regression of IMT (r=0.37, P<0.05) in patients receiving atenolol and to reduction in heart rate in patients receiving losartan (r=0.30, P<0.01). In conclusion, collagen markers reflecting net synthesis of type I collagen were positively related to vascular hypertrophy and BP load, suggesting that collagen synthesis in the vascular wall is increased in relation to high haemodynamic load in a reversible manner.

Is inappropriate left ventricular mass related to neurohormonal factors and/or arterial changes in hypertension? A LIFE substudy.

We investigated whether inappropriately high left ventricular (LV) mass, defined as observed LV mass exceeding the level of individual LV mass predicted from gender, height, and stroke work, may be associated with an imbalance between growth-promoting and growth-inhibitory factors and/or structural vascular changes. In 53 patients with hypertension and electrocardiographic LV hypertrophy, 24-h ambulatory blood pressure (BP); echocardiographic LV mass, stroke volume and stroke work; minimal forearm vascular resistance (MFVR); and intima-media cross-sectional area in common carotid arteries (IMA) were evaluated after 2 weeks of placebo treatment. Serum insulin, plasma epinephrine, norepinephrine, endothelin, angiotensin II, aldosterone, and brain natriuretic peptide (BNP) were also measured. High observed LV mass was related to high IMA (r=0.46, P<0.001), MFVR (in men: r=0.36, P<0.05), 24-h ambulatory systolic BP (r=0.30, P=0.06), and lower plasma angiotensin II (r=-0.33, P<0.05), but not to other circulating growth factors. Stroke work was similarly related to IMA (r=0.42, P<0.01), MFVR (in men: r=0.41, P<0.05), and plasma angiotensin II (r=-0.32, P<0.05). Inappropriate LV mass, identified by the ratio between observed LV mass and the value predicted for gender, height, and stroke work, was not significantly related to any of the arterial or neurohormonal variables. In this small series of older hypertensive patients, inappropriate LV mass was not significantly related to arterial changes or to measured circulating growth factors, although weak relations cannot be excluded. Alternatively, inappropriately high LV mass might be related to unmeasured factors such as local myocardial alterations in growth factors and/or genetic predisposition to develop excessive LV hypertrophy.

Association between vascular dysfunction and reduced myocardial flow reserve in patients with hypertension: a LIFE substudy.

Impaired myocardial flow reserve (MFR) has been demonstrated in hypertension, and has been associated with peripheral vascular changes. We investigated whether MFR was impaired and associated with structural and/or functional vascular changes in hypertensive patients without evidence of coronary artery disease (CAD). We measured left ventricular (LV) mass index by echocardiography and MFR by positron emission tomography in 33 unmedicated, hypertensive patients with electrocardiographic LV hypertrophy without CAD, and 15 age- and gender-matched normotensive subjects. We also measured 24-h ambulatory blood pressure, minimal forearm vascular resistance (MFVR) by plethysmography, media:lumen ratio in isolated, subcutaneous resistance arteries by myography, intima-media cross-sectional area of the common carotid artery, and flow-mediated (FMD) and nitroglycerin-induced dilatation (NID) of the brachial artery by ultrasound. Compared to the controls, the patients had impaired MFR (2.4 (95% CI 1.95-2.8) vs 3.4 (2.7-4.2), P<0.01) due to increased resting myocardial blood flow (MBF) (0.82 (0.73-0.91) vs 0.65 (0.56-0.75) ml/g min), and decreased dipyridamole-stimulated MBF (1.80 (1.55-2.1) vs 2.3 (1.80-2.8) ml/g min, both P<0.05). The difference in resting MBF disappeared (80 (74-87) vs 86 (74-97) microl/kg mmHg, NS) when normalized for blood pressure and heart rate. MFR correlated negatively to median 24-h systolic blood pressure (r=-0.50, P<0.01) as well as to LV mass index (r=-0.45, P<0.05) and MFVR in men (r=-0.47, P<0.05), and positively to FMD (r=0.44, P<0.05) and NID (r=0.40, P<0.05). Hypertensive patients with electrocardiographic LV hypertrophy without CAD had impaired MFR associated with cardiovascular hypertrophy and vasodilatory dysfunction. This suggests that MFR is impaired by LV hypertrophy and structural/functional vascular damage in the coronary and noncoronary circulation.

Cushing's syndrome due to pharmacological interaction in a cystic fibrosis patient.

UNLABELLED: Treatment of allergic bronchopulmonary aspergillosis with itraconazole is becoming more widespread in chronic lung diseases. A considerable number of patients is concomitantly treated with topical or systemic glucocorticoids for anti-inflammatory effect. As azole compounds inhibit cytochrome P450 enzymes such as CYP3A isoforms, they may compromise the metabolic clearance of glucocorticoids, thereby causing serious adverse effects. A patient with cystic fibrosis is reported who developed iatrogenic Cushing's syndrome after long-term treatment with daily doses of 800 mg itraconazole and 1,600 microg budesonide. The patient experienced symptoms of striae, moon-face, increased facial hair growth, mood swings, headaches, weight gain, irregular menstruation despite oral contraceptives and increasing insulin requirement for diabetes mellitus. Endocrine investigations revealed total suppression of spontaneous and stimulated plasma cortisol and adrenocorticotropin. Discontinuation of both drugs led to an improvement in clinical symptoms and recovery of the pituitary-adrenal axis after 3 mo. CONCLUSION: This observation suggests that the metabolic clearance of buDesonide was compromised by itraconazole's inhibition of cytochrome P450 enzymes, especially the CYP3A isoforms, causing an elevation in systemic budesonide concentration. This provoked a complete suppression of the endogenous adrenal function, as well as iatrogenic Cushing's syndrome. Patients on combination therapy of itraconazole and budesonide inhalation should be monitored regularly for adrenal insufficiency. This may be the first indicator of increased systemic exogenous steroid concentration, before clinical signs of Cushing's syndrome emerge.

Endothelial dysfunction in resistance arteries is related to high blood pressure and circulating low density lipoproteins in previously treated hypertension.

BACKGROUND: Peripheral endothelial dysfunction has been demonstrated in hypertension. However, its relationship to blood pressure (BP) load, vascular structure, and metabolic disturbances in patients with long-standing, previously treated hypertension is unclear. METHODS: A total of 41 patients with stage I to III essential hypertension and electrocardiographic left ventricular hypertrophy were studied. After 2 to 3 weeks of placebo treatment we measured nitroprusside-induced relaxation (NIR), acetylcholine-induced relaxation (AIR), and media:lumen ratio in isolated, subcutaneous resistance arteries by myography, as well as 24-h ambulatory BP, and serum lipids. RESULTS: Maximal AIR correlated negatively with median 24-h diastolic BP (r=-0.42, P=.01), and sensitivity to AIR correlated negatively with serum low density lipoprotein (LDL) (r =-0.36, P < .05). In multiple regression analyses, sensitivity to AIR correlated negatively with serum LDL (beta=-0.33) independently of maximal NIR (beta=0.41) (adjusted R2 =0.26, P < .01). Maximal acetylcholine-induced relaxation correlated negatively with median 24-h diastolic BP (beta=-0.38) independently of maximal NIR (beta=0.45) (adjusted R2= 0.32, P < .001). Acetylcholine-induced relaxation was not significantly related to diabetes or to media:lumen ratio (r = -0.26, NS). CONCLUSIONS: High diastolic BP and high serum LDL were associated with impaired maximal AIR and reduced sensitivity to AIR, respectively, independently of smooth muscle cell responsiveness to nitroprusside. This indicated decreasing endothelial function in small resistance arteries with increasing BP and increasing LDL in hypertension. Endothelial function was not significantly related to vascular structure of the resistance arteries or to diabetes in these patients with long-standing hypertension.

Neuroendocrine and renal effects of intravascular volume expansion in compensated heart failure.

To examine if the neuroendocrine link between volume sensing and renal function is preserved in compensated chronic heart failure [HF, ejection fraction 0.29 +/- 0.03 (mean +/- SE)] we tested the hypothesis that intravascular and central blood volume expansion by 3 h of water immersion (WI) elicits a natriuresis. In HF, WI suppressed ANG II and aldosterone (Aldo) concentrations, increased the release of atrial natriuretic peptide (ANP), and elicited a natriuresis (P < 0.05 for all) compared with seated control. Compared with control subjects (n = 9), ANG II, Aldo, and ANP concentrations were increased (P < 0.05) in HF, whereas absolute and fractional sodium excretion rates were attenuated [47 +/- 16 vs. 88 +/- 15 micromol/min and 0.42 +/- 0.18 vs. 0.68 +/- 0.12% (mean +/- SE), respectively, both P < 0.05]. When ANG II and Aldo concentrations were further suppressed (P < 0.05) during WI in HF (by sustained angiotensin-converting enzyme inhibitor therapy, n = 9) absolute and fractional sodium excretion increased (P < 0.05) to the level of control subjects (108 +/- 34 micromol/min and 0.70 +/- 0.23%, respectively). Renal free water clearance increased during WI in control subjects but not in HF, albeit plasma vasopressin concentrations were similar in the two groups. In conclusion, the neuroendocrine link between volume sensing and renal sodium excretion is preserved in compensated HF. The natriuresis of WI is, however, modulated by the prevailing ANG II and Aldo concentrations. In contrast, renal free water clearance is attenuated in response to volume expansion in compensated HF despite normalized plasma AVP concentrations.

Maximal exercise capacity is related to cardiovascular structure in patients with longstanding hypertension. A LIFE substudy. Losartan Intervention For Endpoint-Reduction in Hypertension.

BACKGROUND: Cardiovascular hypertrophy and remodeling in patients with never-treated hypertension has been associated with impaired exercise capacity, but whether this relationship remains in patients with longstanding hypertension and target organ damage is less elucidated. METHODS: In 43 unmedicated patients with essential hypertension and electrocardiographic left ventricular (LV) hypertrophy, we measured maximal workload and oxygen reserve by bicycle test, 24-h ambulatory blood pressure (BP), LV mass index by magnetic resonance imaging (LVMI(MRI), n = 31), LVMI(echo) and systemic vascular compliance by echocardiography, minimal forearm vascular resistance (MFVR) by plethysmography, and intima media thickness and distensibility in the common carotid arteries by ultrasound. RESULTS: The patients did not achieve the maximal workload as predicted by age, gender and body composition (146[129-163] v 162[146-179] Watt, P = .01). This impaired exercise capacity, calculated as the ratio between achieved and predicted maximal workload, was in simple regression analyses related to lower distensibility of the common carotid artery (r = 0.38, P = .01) and lower oxygen reserve (r = 0.68, P < .001). In multiple regression analyses, lower oxygen reserve was related to higher LVMI(MRI) (beta = -0.44), lower systemic vascular compliance (beta = -0.36), and higher MFVR (beta = -0.52) (adjusted R2 = 0.53, P < .001). CONCLUSIONS: Patients with longstanding hypertension and target organ damage cannot achieve the predicted maximal workload. This impaired exercise capacity was associated with lower common carotid distensibility and lower oxygen reserve. The latter was independently related to LV hypertrophy, low systemic vascular compliance and peripheral vascular remodeling, suggesting that cardiovascular hypertrophy and remodeling may reduce exercise capacity by itself.

Left ventricular structure and diastolic function in subjects with two hypertensive parents.

PURPOSE: To examine the influence of (i) strong predisposition to essential hypertension and (ii) insulin sensitivity and plasma levels of cardiomyotrophic hormones on echocardiographic parameters of left ventricular structure and function. METHODS: 26 normotensive subjects (age 18-35) with bi-parental hypertension and 26 matched controls with normotensive parents. Families with non-insulin-dependent diabetes or morbid obesity were excluded. (i) Echocardiography; (ii) plasma concentrations of renin, angiotensin-II, aldosterone, epinephrine and norepinephrine; (iii) euglycaemic, hyperinsulinemic clamp study. RESULTS (means +/- SD): Hypertension-prone subjects vs controls had (i) higher resting systolic (117.0 +/- 14.0 vs 107.1 +/- 11.9 mmHg), and 24-h diastolic blood pressure (77.9 +/- 7.1 vs 72.9 +/- 7.2 mmHg), (ii) higher relative wall thickness (RWT) (0.39 +/- 0.09 vs 0.34 +/- 0.06). They had similar left vetricular mass index, diastolic function parameters, insulin sensitivity and plasma concentrations of cardiomyotrophic hormones. The increased RWT was not attributable to any other factor than the systolic blood pressure. CONCLUSION: In a carefully selected group of subjects with two hypertensive parents compared to a control group, the only echocardiographic change demonstrated was an increased RWT. This remodelling was attributable to a higher systolic blood pressure in the hypertension-prone subjects, but not to insulin sensitivity or a selection of cardiomyotrophic hormones.

Dipyridamole dilates large cerebral arteries concomitant to headache induction in healthy subjects.

Dipyridamole is used for secondary prophylaxis in ischemic stroke and as a vasodilator agent in myocardial scintigraphy. An important side effect to administering dipyridamole is headache. The aim of the current study was to investigate the effects of dipyridamole on cerebral blood flow, large artery diameter, and headache induction. Twelve healthy subjects were included in this single-blind placebo-controlled study in which placebo (0.9% NaCl) and dipyridamole 0.142 mg/kg x min were administered intravenously over 4 minutes 1 hour apart. Blood flow velocity in the middle cerebral artery (Vmax) was recorded by transcranial Doppler and regional cerebral blood flow in the middle cerebral artery (rCBFmca) was measured using single photon emission computed tomography and 133Xenon-inhalation. Blood pressure, heart rate, and pCO2 were measured repeatedly. Headache response was scored every 10 minutes on a verbal scale from 0 to 10 (10 = worst). Dipyridamole caused a decrease in pCO2 (P < 0.001). pCO2 corrected rCBFmca was 41.7 +/- 6.9 mL/100 g x min after placebo versus 41.2 +/- 6.9 after dipyridamole (P > or = 0.05). pCO2 corrected Vmca decreased 8.4% +/- 11.7 (P < 0.001) after dipyridamole, indicating a mean 5.6% +/- 6.7 (P = 0.005) relative increase of the arterial diameter. After dipyridamole the median peak headache score was 2 (range 0 to 7) compared with 0 (range 0 to 3) after placebo (P = 0.02). Dilatation of the middle cerebral artery outlasted the headache response. In conclusion, dipyridamole causes a modest pCO2 independent dilatation of the MCA, which is time-linked to the onset, but not to the cessation, of headache.

A possible link between endothelial dysfunction and insulin resistance in hypertension. A LIFE substudy. Losartan Intervention For Endpoint-Reduction in Hypertension.

BACKGROUND: We wanted to investigate whether insulin resistance and time to steady state during isoglycemic clamp were associated with endothelial dysfunction, peripheral vascular remodeling and forearm blood flow (FBF) in patients with longstanding hypertension. METHODS: In 43 unmedicated, hypertensive patients with electrocardiographic-defined left ventricular hypertrophy we performed a 2-h oral glucose tolerance test and a 3-h isoglycemic hyperinsulinemic clamp with measurements of circulating plasma epinephrine and FBF by plethysmography. Delayed steady state was assessed by measuring the increase in insulin sensitivity from the second to the third hour of clamping. We measured 24-h ambulatory blood pressure, minimal forearm vascular resistance (MFVR) by plethysmography, media:lumen ratio (MLR) and acetylcholine-induced relaxation (AIR) in isolated, subcutaneous resistance arteries by myography. RESULTS: Insulin sensitivity after 2 and 3 h of clamping was not related to maximal AIR, MLR, MFVR or FBF. The increase in insulin sensitivity in men was negatively correlated to maximal AIR (r = -0.36, p < 0.05), and was independently correlated to relative changes in FBF (beta = 0.46) and in circulating epinephrine (beta = 0.33; adj. R = 0.33, p < 0.001). CONCLUSIONS: Insulin sensitivity was not correlated to parameters of peripheral vascular remodeling, endothelial function or microvascular rarefaction in patients with longstanding hypertension and left ventricular hypertrophy. However, the action of insulin on peripheral glucose uptake was influenced by endothelial dysfunction (delayed transcapillary insulin transport) and by changes in and/or redistribution of blood flow suggesting a link between vascular function and insulin sensitivity.

Thyroid structure and size and two-year follow-up of solitary cold thyroid nodules in an unselected population with borderline iodine deficiency.

OBJECTIVE: Multinodular goitre has been found with a high prevalence in iodine-deficient areas, but less frequently in iodine-replete areas; the iodine intake sufficient to prevent goitre has not been established, however. METHODS: We report data from an ultrasonic investigation of the thyroid glands of 2656 randomly selected subjects aged 41 to 71 years in an area with borderline iodine deficiency. RESULTS: Median iodine concentration in spot urine samples was 70microg/l. Multinodular thyroid structure was found in 23% of the population, increasing in women from 20 to 46% with increasing age, and in men from 7 to 23%. Solitary, scintigraphically cold, thyroid nodules >10mm were found in 2.4% of the population with the same prevalence in the different age and sex groups. Two years of follow-up of these cold nodules revealed no signs of malignancies. Median thyroid volume was 11.0ml. Thyroid enlargement (>18ml for women and >25ml for men) was found among 13. 1% of the women and 6.2% of the men, and the prevalence increased with age. The presence of thyroid nodules was related to positive anti-thyroperoxidase antibody (TPO Ab) titres, whereas thyroid enlargement was associated with iodine excretion <50microg/day. CONCLUSIONS: Thyroid enlargement was associated with low iodine excretion and median thyroid volume was slightly increased compared with iodine-replete areas. Multinodular thyroid structure was found with a high prevalence and was associated with TPO Ab >200kU/l. Cold thyroid nodules were moderately prevalent, with no cases of detected malignancies during 2 years of follow-up.

Effects of the non-selective phosphodiesterase inhibitor pentoxifylline on regional cerebral blood flow and large arteries in healthy subjects.

The vasodilating properties of the non-selective phosphodiesterase (PDE) inhibitor pentoxifylline were evaluated. Pentoxifylline has been reported to increase cerebral blood flow (CBF) and improve recovery rate of stroke patients. Whether these results are due to a dilating effect on arteries or to other mechanisms is not clear. In the present double-blind crossover study, 10 healthy subjects received pentoxifylline 300 mg or placebo intravenously on separate days. Blood flow velocity in the middle cerebral artery (V(mca)) was recorded by transcranial Doppler and rCBF was measured using (133)Xenon-inhalation SPECT. High-frequency ultrasound was used for measurements of temporal and radial artery diameter. Cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) concentrations were assessed in plasma. Except for increased heart rate (P < 0.05), systolic blood pressure (P < 0.05) and plasma cAMP (P < 0.001), no significant differences in CBF, rCBF(mca) or plasma cGMP were seen between placebo and pentoxifylline infusion. During pentoxifylline infusion, V(mca) decreased 7.2% (SD 12.0; P < 0.05) and temporal artery diameter increased 9.0% (SD 7.0; P < 0.001), suggesting minor dilatation of the large arteries. However, this change was not significantly different from placebo. In conclusion, pentoxifylline 300 mg had no effect on rCBF. A possible minor dilatation of the middle cerebral artery and the temporal artery cannot be excluded. Any potential clinical effect of pentoxifylline is most likely mediated through non-vascular mechanisms.

Renal effects of hyperinsulinaemia in subjects with two hypertensive parents.

The aim of this investigation was to study the effects of isoglycaemic hyperinsulinaemia on the renal metabolism of electrolytes and water in subjects with a strong genetic predisposition to essential hypertension, compared with that in non-predisposed subjects. We studied 25 normotensive subjects aged 18-35 years whose parents both had essential hypertension, and 22 age- and sex-matched subjects whose parents were both normotensive. Diabetes or morbid obesity in any subject or parent excluded the family. The 24-h blood pressure was measured. The subjects received an isocaloric diet with a fixed content of sodium and potassium for 4 days before the study. An isoglycaemic, hyperinsulinaemic clamp with infusion of insulin (40 munits.min(-1).m(-2)) was performed. We measured the renal clearance of diethylenetriaminepenta-acetic acid, sodium, potassium and lithium both under basal conditions and during hyperinsulinaemia. In response to hyperinsulinaemia, renal sodium clearance decreased to a significantly greater extent in the hypertension-prone subjects [0.57 (0.74, 0.36) ml.min(-1).1.73 m(2) (median and quartiles)] than in the controls [0.34 (0.56, 0.18) ml. min(-1).1.73 m(2)] (P=0.04). Compared with the controls, the subjects predisposed to hypertension had a higher 24-h diastolic blood pressure [78 (70, 82) mmHg, compared with 73 (68, 77) mmHg], but a similar insulin sensitivity index ¿10(7)x[313 (225, 427)] compared with 10(7)x[354 (218, 435)] l(2).min(-1).pmol(-1).kg(-1)¿. Thus the sodium-retaining effect of insulin was more pronounced in subjects with a strong genetic predisposition to essential hypertension than in subjects with normotensive parents. This effect may contribute to the development of hypertension in subjects with a genetic predisposition to hypertension.

Insulin resistance, exercise capacity and body composition in subjects with two hypertensive parents.

OBJECTIVE: To study insulin resistance in subjects with strong genetic predisposition to essential hypertension, compared with non-disposed subjects. SUBJECTS: Thirty normotensive subjects aged 18-35 years whose parents both had essential hypertension, and 30 age- and sex matched subjects whose parents were both normotensive, were studied. Subjects or parents with diabetes and morbid obesity were excluded. METHODS: The study comprised (1) a frequent sampling oral glucose tolerance test; (2) an isoglycemic hyperinsulinemic clamp study; (3) an analysis of body composition by dual-energy X-ray absorptiometry; (4) an exercise test with gas exchange analysis; and (5) investigation of composition of usual diet by diet registration for 5 days. RESULTS: The 24-h diastolic blood pressure was higher in subjects predisposed to hypertension compared with the controls: 78.1 versus 74.0 mmHg (confidence interval for the difference between the means; -0.5; -7.9), but the insulin sensitivity index was similar: 312 versus 362 I(2) min(-1) pmol(-1) kg(-1) (28; -129). The two groups were similar in terms of body composition, exercise capacity and composition of usual diet. Resting and 24-h diastolic blood pressures were correlated to abdominal fat mass but not to insulin sensitivity. CONCLUSION: Subjects with a strong genetic predisposition to essential hypertension had increased diastolic blood pressure compared with subjects with normotensive parents, but they were not insulin resistant. This may be due to the subjects being highly selected as to confounding factors. The increased blood pressure in the hypertension prone subjects could not be attributed to differences in body composition, exercise capacity or dietary habits.

Hemodynamic and renal effects of indomethacin in losartan-treated hypertensive individuals.

This study was undertaken to examine whether prostaglandin (PG) inhibition with indomethacin interferes with angiotensin II receptor blockade (losartan) during treatment for arterial hypertension. In a double-blind crossover design 10 patients with essential arterial hypertension and treated with losartan were randomized to supplementary treatment with indomethacin or placebo for 1 week, with a 2-week washout period interposed. At the end of each treatment period the following examinations were performed, preceded by 4 days on sodium-fixed diet: 24-h blood pressure (BP), 24-h sodium excretion (UNaV), supine BP, glomerular filtration rate (GFR), renal resistive index (RRI), extracellular fluid volume (ECV), sodium clearance (Cl(Na)), body weight, peripheral blood flow (PBF), and plasma concentrations of aldosterone, renin (PRC), and atrial natriuretic peptide (ANP). Indomethacin did not change BP. Indomethacin increased weight (P < .05) and ECV (P < .05). A nonsignificant decrease in UNaV was seen after indomethacin, as in 24-h Cl(Na). Conversely, in the laboratory in the supine position Cl(Na) increased after indomethacin (P = .05). Indomethacin increased plasma ANP (P < .01). No changes were observed in GFR, RRI, PBF, PRC, or plasma aldosterone. Thus indomethacin did not attenuate the antihypertensive effect of losartan, neither was peripheral blood flow affected. Indomethacin caused sodium retention in the nonresting situation, which was not counterbalanced by the increased Cl(Na) in the resting supine position. The observed changes during prostaglandin (PG) inhibition seem most likely due to lack of PG "protection" of renal function, when the sympathetic nervous system is activated throughout the day.

Influence of non-steady state during isoglycemic hyperinsulinemic clamp in hypertension. A LIFE substudy.

We wanted to investigate whether time to steady state was reached within 2 h of insulin infusion during isoglycemic hyperinsulinemic clamp, comparing the glucose uptake index (M/IG) with Bergman's insulin sensitivity index (Sip). We performed a 2-h oral glucose tolerance test and a 3-h isoglycemic hyperinsulinemic clamp in 26 young, healthy subjects and 43 elderly patients with unmedicated essential hypertension and left ventricular hypertrophy. The 3-h Sip correlated strongly with the 2-h M/IG in the patients (r = 0.88, p < 0.001) as well as in the healthy subjects (r = 0.96, p < 0.001) with relatively narrow limits of agreement in the patients. However, during the third hour of insulin infusion, M/IG (10.0 vs 12.21(2) x kg(-1) x min(-1) x mmol(-1), p < 0.001) as well as Sip (7.1 vs 9.41(2) x kg(-1) x min(-1) x mmol(-1), p < 0.001) increased significantly in the patients, but not in the healthy subjects. Because the 2-h M/IG correlated strongly with the 3-h Sip with relatively narrow limits of agreement, it is a good measure of insulin sensitivity. However, a 2-h clamp results in lower insulin sensitivity values in elderly, hypertensive patients due to the fact that steady state is not reached, demonstrating a higher prevalence of insulin resistance in such a population.

Serial changes in atrial natriuretic peptide and endothelin-1 concentrations. Their relationships to the cardiac performance of patients hospitalized for acute myocardial infarction.

AIM: The study was designed to assess temporal changes in atrial natriuretic peptide (ANP) and endothelin-1 (ET) concentrations in patients hospitalized for acute myocardial infarction (AMI) and their relationships to cardiac performance determined by radionuclide ventriculography. PATIENTS AND METHODS: 20 patients with first AMI were studied. Blood samples were drawn within the first 4-18 h, after 18-24 h, and on days 2, 3 and 6. Plasma concentrations of ANP and ET were measured in blood samples taken simultaneously. Radionuclide ventriculography was performed on the day of discharge to determine left-ventricular ejection fraction (LVEF), left-ventricular end-diastolic volume index, end-systolic volume index and left-ventricular stroke volume index. RESULTS: Median concentrations of ET decreased from 2.15 pmol/l on admission to 1.45 pmol/l at discharge (32%, p < 0.001). Median ANP rose from 29 to 79 pg/ml (172%, p < 0.001). The increment in ANP and the decrease in ET concentrations from admission to discharge was inversely correlated (r = -0.81, p < 0.005). ANP was inversely correlated to LVEF (r = -0.82, p < 0.001) and to the end-systolic volume index at discharge (r = -0.73, p < 0.003). CONCLUSION: Dynamic and inverse fluctuations in ET and ANP occur within the 1st week of AMI. The magnitude of endocrine activation in the ANP-ET system seems to reflect an impairment in the left-ventricular systolic performance.

Basal insulin-level oscillations in normotensive individuals with genetic predisposition to essential hypertension exhibit an irregular pattern.

BACKGROUND: Insulin is secreted in regular pulses at intervals of 12-14 min in normal fasting subjects. An abnormal pattern has been found in subjects with non-insulin-dependent diabetes mellitus (NIDDM) and in young individuals predisposed to NIDDM. It has been suggested that there might be a causal relationship between insulin-secretion abnormalities and insulin resistance. OBJECTIVE: To examine whether insulin-secretion abnormalities are also present in offspring of patients with essential hypertension. METHODS: Eleven young (aged 18-35 years) normotensive individuals each of whom had two parents with essential hypertension were compared with 10 age- and sex-matched controls each of whom had two normotensive parents. We verified that diabetes and morbid obesity were absent among the subjects and their parents. We studied basal insulin-secretion patterns during a 60 min period, glucose tolerance by administering an oral glucose-tolerance test, insulin resistance by using an isoglycaemic hyperinsulinaemic clamp and basal plasma catecholamine levels. RESULTS: Autocorrelation analysis of insulin concentrations showed that the hypertension-prone subjects had a significantly reduced or irregular oscillatory pattern compared with the regular insulin-level oscillations with a period of 12-14 min in control subjects. The hypertension-prone subjects had significantly higher systolic blood pressures and tended to be insulin-resistant. CONCLUSION: This is the first evidence of early insulin-secretion abnormalities in young normotensive individuals with a genetic predisposition to essential hypertension, but with a normal glucose tolerance and without a genetic predisposition to NIDDM. Early insulin-secretion abnormalities may be the very first step towards the development of insulin resistance and an important factor initiating the hypertension in hypertension-prone individuals.

AT1 receptor blockade and the sympathoadrenal response to insulin-induced hypoglycemia in humans.

An important facilitating effect of angiotensin II on adrenal catecholamine release has been demonstrated in several species. To determine whether specific AT1 receptor blockade affects medullary epinephrine secretion and musculocutaneous norepinephrine release during insulin-induced hypoglycemia, 16 healthy volunteers received losartan vs. placebo followed by an intravenous insulin bolus and measurement of effect variables at short intervals for 150 min. AT1 receptor blockade was effective, as evidenced by substantially increased circulating renin and angiotensin II levels, a 60% inhibition of circulating aldosterone, and an 8.5% decrease of mean arterial pressure over time compared with placebo. Arterial glucose concentration fell to a nadir of 1.9 mM, arterial epinephrine concentration increased 23-fold, forearm musculocutaneous norepinephrine release increased 4-fold, heart rate increased 40%, and forearm blood flow increased 3-fold. All absolute values and the time course of these changes were independent of AT1 receptor blockade. It is concluded that a putative interaction between angiotensin II and the sympathoadrenal axis may not be mediated by AT1 receptors in humans.