Harriet Dige-Petersen

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·min were administered intravenously over 4 minutes 1 hour apart. Blood flow velocity in the middle cerebral artery (Vmca) 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 ·min after placebo versus 41.2 ± 6.9 after dipyridamole (P ≥ 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.

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 (Vmca) was recorded by transcranial Doppler and rCBF was measured using 133Xenon‐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, rCBFmca or plasma cGMP were seen between placebo and pentoxifylline infusion. During pentoxifylline infusion, Vmca 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.

Radioimmunoassay of Endothelin in Human Plasma

A specific and sensitive radioimmunoassay (RIA) for determination of endothelin-1 (ET-1) in human plasma has been developed. Antibodies were raised in rabbits using synthetic ET-1 conjugated to thyroglobulin as immunogen. The antibodies obtained were used at a final dilution of 1:300,000 yielding maximum binding of 61.7 +/- 3.0% (mean +/- 1 SD, n = 20) of 125I-ET-1. The ID50 (inhibitory dose 50%) was 4.5 +/- 0.6 fmol/100 microliters (mean +/- 1 SD, n = 20). The sensitivity of the RIA was 0.33 fmol/100 microliters standard solution. No cross reactivity was observed with endothelin-3, big-endothelin-1, atrial natriuretic factor, angiotensin I or angiotensin II. The cross-reactivity with endothelin-2 was 100%. Endothelin was extracted from acidified plasma with Sep-pak C18 cartridges and recovery of ET-1 added to normal plasma was 70.9 +/- 10.3% (mean +/- 1 SD, n = 12). The concentration of ET-1 in plasma from normal subjects was 1.5 +/- 0.4 pmol/l (mean +/- 1 SD, n = 11) ranging from 1.0 to 2.2 pmol/1. Extracts of normal human plasma subjected to high performance liquid chromatography on a reverse phase C18 column showed one peak of immunoreactivity co-eluting with the standard for ET-1. From these data it is concluded that the immunoreactive material measured in normal plasma with the present RIA is identical to ET-1.

Maximal exercise capacity is related to cardiovascular structure in patients with longstanding hypertension. a LIFE substudy

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.

Endothelin release and enhanced regional myocardial ischemia induced by cold-air inhalation in patients with stable angina.

This study was designed to determine the influence of cold-air inhalation on regional myocardial perfusion in patients with ischemic heart disease. A selected group of vasoactive hormones was measured to investigate their possible roles as ischemic agents. Ten men who had recently had a myocardial infarction and anginal symptoms and with verified pathologic ST deviations during a preceding exercise test volunteered to participate in this randomized cross-over study. Two identical exercise tests were performed on different days; one with inhalation of cold (-22 degrees C) air and the other one with inhalation of thermoneutral air (22 degrees C). Scintigraphic imaging (single-photon emission computed tomography) of regional myocardial blood flow was performed with technetium 99m isonitrile flowtracer and a Bulls eye visual display with calculation of the scintigraphic ischemic severity score. The score was significantly higher during exercise with inhalation of cold air as compared to exercise with inhalation of thermoneutral air. Furthermore, only with cold-air inhalation did arterial plasma endothelin concentration increase significantly from rest to exercise and correlate with the change of ischemic severity score. In contrast, no change was observed under thermoneutral conditions. There was no significant difference between peak values of heart rate, systolic blood pressure, adrenaline, and noradrenaline concentrations in the two situations. We conclude that inhalation of cold air during exercise increases the degree of regional myocardial ischemia and that this is not caused by an increased myocardial oxygen demand. We suggest that cold air directly influences the vasomotor tone of the myocardial resistance vessels and that endothelin may be involved in the ischemic response.

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 insulinresistant. 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.

Left Ventricular Hypertrophy is Associated with Reduced Vasodilatory Capacity in the Brachial Artery in Patients with Longstanding Hypertension. A LIFE Substudy

Background: Left ventricular (LV) hypertrophy has been found to be associated with endothelial dysfunction in untreated patients with mild, uncomplicated hypertension. Whether similar relations exist in patients with longstanding hypertension and target organ damage remain to be elucidated. Methods: In 40 unmedicated, hypertensive patients with electrocardiographic LV hypertrophy we measured 24-h ambulatory blood pressure ( n = 37), LV mass index by echocardiography (LVMI echo ) and magnetic resonance imaging (LVMI MRI, n = 31), flow-mediated (FMD) and nitroglycerin-induced dilatation (NID) in the brachial artery by ultrasound, acetylcholine- (AIR) and nitroprusside-induced relaxation (NIR) in isolated resistance arteries by wire-myography. Results: LVMI MRI correlated negatively to NID ( r =-0.60, p < 0.001, n = 30) and to FMD ( r =-0.53, p < 0.01, n = 31), but were not significantly correlated to maximal AIR nor NIR. NID ( r =-0.53, p < 0.001, n = 36), FMD ( r =-0.43, p <0.01, n = 37), LVMI MRI ( r = 0.60, p < 0.001, n = 29) and LVMI echo ( r = 0.39, p < 0.05, n = 37) were all significantly correlated to 24-h systolic blood pressure, whereas maximal AIR and NIR were not. Conclusions: LV mass was related to NID and FMD, but not to AIR. The relationship to FMD was not independent of NID indicating that LV hypertrophy in patients with longstanding hypertension is more closely related to reduced overall vasodilatory capacity in the brachial artery than to endothelial dysfunction in conduit or subcutaneous resistance arteries. High LV mass and low NID were both related to high blood pressure, suggesting that vasodilatory capacity in conduit arteries is modified parallel to LV geometry by elevated blood pressure.

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.

The effect of selenium supplementation on skeletal and cardiac muscle in selenium-depleted patients.

BACKGROUND The purpose of the present study was to evaluate the effect of sodium selenite on skeletal and cardiac muscular function in patients with severe Se deficiency. METHODS Skeletal and cardiac muscular function was investigated in 10 selenium depleted patients on long-term home parenteral nutrition because of short bowel syndrome. The following examinations were applied: Skeletal muscle biopsy, muscular force test (Kin-Com dynamometer test), electromyography (EMG) and radionuclide ventriculography. The patients were blindly randomized to intravenous supplementation with selenium 200 micrograms 5 to 7 times per week or placebo for 4 months. Hereafter the examinations were repeated. The patients randomized to placebo received selenium in an open study for a further 4 months and hereafter their skeletal and cardiac function was reevaluated. RESULTS Plasma selenium increased to normal levels from median .21 mumol/l (range 0-.69) to 1.25 mumol/l (range .9-2.27) following selenium repletion. The muscle biopsies showed only minor abnormalities. The only change after selenium supplementation was a small but statistically significant increase of the mean diameter of fiber type 1. The muscle strength of the quadriceps muscle was unchanged after selenium substitution. EMG did not reveal signs of myopathy. The cardiac function was normal and remained unchanged. CONCLUSION Despite severe selenium depletion ten patients on long term home parenteral nutrition had normal cardiac function, and no clinically significant signs of skeletal myopathy. The only change after selenium supplementation was a small but statistically significant increase of the mean diameter of muscle fiber type 1.

Vasodilatory capacity and vascular structure in long-standing hypertension: a LIFE substudy☆

BACKGROUND Flow-mediated dilatation (FMD), which is considered a measure of endothelial function, has been found impaired in hypertension. However, it is unclear whether this impairment is explained solely by endothelial dysfunction, or whether it is associated with structural vascular changes and reduced vasodilatory capacity. METHODS In 42 unmedicated patients with hypertension and electrocardiographic left ventricular hypertrophy, we measured the following: 24-h ambulatory blood pressure (BP), minimal forearm vascular resistance (MFVR) by plethysmography, intima-media cross-sectional area of the common carotid arteries (IMA), FMD, and nitroglycerin-induced dilatation (NID) in the brachial artery by ultrasound. RESULTS We found that FMD was correlated positively with NID (r = 0.38, P < .05). However, FMD as well as NID correlated negatively to 24-h systolic BP (r = -0.41, P = .01 and r = -0.52, P = .001), IMA/height (r = -0.41, P < .01 and r = -0.53, P < .001) and MFVR(men) (r = -0.44, P < .05 and r = -0.42, P < .05). CONCLUSIONS Low FMD as well as low NID were related in parallel to high systolic BP and to the severity of vascular changes in different vascular beds, suggesting that elevated BP load in hypertension induces parallel abnormalities in conduit artery structure and overall vasodilatory capacity. Therefore, the decrease in FMD observed in severe hypertension may be caused by endothelial dysfunction as well as by structural vascular changes, suggesting difficulties in interpreting FMD solely as a measure of endothelial dysfunction in hypertensive patients with left ventricular hypertrophy.