Hans P. Schobel

Preeclampsia -- a state of sympathetic overactivity.

BACKGROUND Preeclampsia is characterized by a marked increase in peripheral vascular resistance leading to an increase in blood pressure, but the triggering mechanisms are unclear. METHODS To determine whether augmented sympathetic vasoconstrictor activity may be an important mechanism in mediating the increase in vasomotor tone, we measured postganglionic sympathetic-nerve activity in the blood vessels of skeletal muscle by means of intraneural microelectrodes in nine women with preeclampsia, eight normotensive pregnant women, six normotensive nonpregnant women, and seven nonpregnant women with hypertension, both at rest and during noninvasive cardiovascular-reflex testing (with the Valsalva maneuver and the cold pressor test). RESULTS The mean (+/-SE) rate of sympathetic-nerve activity in the normotensive pregnant women (10+/-1 bursts per minute) was not significantly different from that in normotensive nonpregnant women (12+/-2 bursts per minute) or hypertensive nonpregnant women (15+/-3 bursts per minute). In contrast, the rate of sympathetic-nerve activity in the patients with preeclampsia (33+/-3 bursts per minute) was more than three times as high as that in the normotensive pregnant women (P<0.05) and more than twice as high as in the group of nonpregnant women with hypertension (P<0.05). Hemodynamic and sympathetic-nerve responses to both reflex tests did not differ significantly among the four groups. Six patients with preeclampsia were studied again after delivery; mean sympathetic-nerve activity at that time had decreased significantly from the value during pregnancy (from 36+/-4 to 13+/-2 bursts per minute, P<0.01), as had mean arterial pressure (from 118+/-3 to 96+/-1 mm Hg, P<0.01). CONCLUSIONS Preeclampsia is a state of sympathetic overactivity, which reverts to normal after delivery. Our data indicate that the increases in peripheral vascular resistance and blood pressure that characterize this disorder are mediated, at least in part, by a substantial increase in sympathetic vasoconstrictor activity.

Decrease of blood pressure by ventrolateral medullary decompression in essential hypertension

BACKGROUND About 20% of adults worldwide will develop hypertension. Studies and clinical observations suggest an association between hypertension and pulsatile compression of the ventrolateral medulla oblongata by a looping artery. We investigated whether neurosurgical microvascular decompression substantially decreases blood pressure long-term in patients with severe essential hypertension. METHODS We included eight patients who had received three or more antihypertensive drugs without adequate control of blood pressure, intolerable side-effects, or both. All patients underwent microvascular decompression at the root-entry zone of cranial nerves IX and X after neurovascular compression of the ventrolateral medulla oblongata was seen on magnetic-resonance angiography. FINDINGS 3 months after surgery, blood pressure and antihypertensive regimens had decreased substantially in three patients. Four patients who were followed up for more than 1 year became normotensive, but their antihypertensive regimens remained the same as those at 3 months. One patient did not improve. No complications associated with decompression occurred. One patient experienced a transient vocal-cord paresis after the laryngeal part of the vagus nerve was manoeuvered during surgery. INTERPRETATION We showed a direct causal relation between raised blood pressure and irritation of cranial nerves IX and X. A subgroup of patients with essential hypertension may exist who have secondary forms of hypertension related to neurovascular compression at the ventrolateral medulla and who may be successfully treated with decompression.

Pregnancy‐induced sympathetic overactivity: a precursor of preeclampsia*

Background  Preeclampsia has been shown to constitute a state of sympathetic overactivity. However, it remains unclear if the sympathetic activity precedes preeclampsia or represents only a secondary phenomenon. To further investigate this issue, we performed a prospective study in pregnant women considered to be at increased risk for preeclampsia owing to preeclampsia during a preceding pregnancy.

Severely Impaired Baroreflex-Buffering in Patients With Monogenic Hypertension and Neurovascular Contact

Background—We identified a family with a monogenic syndrome of hypertension, brachydactyly, and neurovascular contact of the brain stem. Neurovascular contact of the ventrolateral medulla may lead to arterial hypertension by interfering with baroreflex function. Methods and Results—In 5 patients with monogenic hypertension (18 to 34 years old), we conducted detailed autonomic function tests. Blood pressure during complete ganglionic blockade was 134±4.9/82±4.1 mm Hg and 90±6/49±2.4 mm Hg in patients and in control subjects, respectively. During ganglionic blockade, plasma vasopressin concentration increased 24-fold in control subjects and <2-fold in patients. In patients, cold pressor testing, hand-grip testing, and upright posture all increased blood pressure excessively. In contrast, muscle sympathetic nerve activity was not increased at rest or during cold pressor testing. The phenylephrine dose that increased systolic blood pressure 12.5 mm Hg was 8.0±2.0 &mgr;g in patients and 135±35 &mgr;g in control subjects before ganglionic blockade and 5.4±0.4 &mgr;g in patients and 13±4.8 &mgr;g in control subjects during ganglionic blockade. Conclusions—In patients with monogenic hypertension and neurovascular contact, basal blood pressure was increased even during sympathetic and parasympathetic nerve traffic interruption. However, sympathetic stimuli caused an excessive increase in blood pressure. This excessive response cannot be explained by increased sympathetic nerve traffic or increased vascular sensitivity. Instead, we suggest that baroreflex buffering and baroreflex-mediated vasopressin release are severely impaired.

Normalization of circadian blood pressure profiles after renal transplantation.

Most patients with secondary hypertension due to renal disease or on maintenance hemodialysis have lost the physiologic fall of blood pressure during sleep. To test the notion that kidney transplantation normalizes the blood pressure profile, we monitored ambulatory blood pressure over 24 hr in 45 patients (29 males and 16 females) after successful renal transplantation. The longer the time after renal transplantation, the more marked was the decrease of blood pressure during sleep (r=0.38, P<0.01). This effect of time after renal transplantation on the fall of blood pressure during sleep was independent of the prevailing level of 24-hr ambulatory blood pressure. The prevalence of dippers (defined by a fall in mean blood pressure during sleep of 10% or more of the awake mean) increased from 27% in the early phase (< 7 months) to 73% in the late phase (≥ 1 year) after renal transplantation (P<0.01). Again, this effect was not attributable to the level of 24-hr ambulatory blood pressure and concomitant antihypertensive or immunosuppressive medication. We conclude that renal transplantation leads to a normalization of the circadian blood pressure profile with a marked decrease of blood pressure during sleep. As a consequence, the lower hemodynamic load imposed on the cardiovascular system may in turn lead to a reduction of cardiovascular morbidity and mortality.

Impact of Aldosterone on Left Ventricular Structure and Function in Young Normotensive and Mildly Hypertensive Subjects

Left ventricular (LV) hypertrophy is an independent risk factor for cardiovascular morbidity and mortality. Experimental data revealed that elevated circulating aldosterone is associated with increased collagen accumulation resulting in myocardial fibrosis. To analyze whether aldosterone is also associated with cardiac structural and functional changes in humans, we examined the effects of aldosterone on LV structure and function before and after suppression of aldosterone by increasing oral salt intake. The study group comprised 26 normotensive male white healthy control subjects (age 26 +/- 3 years) and 31 male white subjects (age 25 +/- 3 years) with mild essential hypertension (World Health Organization stages I to II). Two-dimensional-guided M-mode echocardiography and 24-hour ambulatory blood pressure (BP) monitoring was performed in each subject. Simultaneously, we measured 24-hour urinary sodium excretion, 24-hour urinary aldosterone, and serum aldosterone concentration at baseline and after increasing oral salt intake to suppress aldosterone secretion. In all subjects LV mass correlated with body mass index (r = 0.42, p <0.001) and both 24-hour ambulatory systolic (r = 0.28, p <0.05) and diastolic (r = 0.25, p <0.05) BP. Changes in urinary sodium excretion correlated inversely with changes in serum aldosterone concentration (r = -0.28; p <0.05). Urinary aldosterone concentration after salt loading decreased in normotensive (10.98 vs 7.44 microg/24 hours; p <0.02) but not in hypertensive (9.34 vs 10.51 microg/24 hours; p = NS) subjects. Serum and urinary aldosterone levels at baseline were not related to LV structure or function. In contrast, after increasing oral salt intake, urinary aldosterone concentration was related to LV mass (r = 0.43; p <0.01) and impaired midwall fractional fiber shortening (r = -0.33; p <0.02) in all subjects, independent of 24-hour ambulatory BP. Subgroup analysis revealed that this was significant only in hypertensive (r = 0.46; p <0.01 and r = -0.44; p <0.02, respectively) but not in normotensive (r = 0.28 and -0.16; p = NS for both, respectively) subjects. Consistently, the greater serum aldosterone remained after increasing oral salt intake, the greater was LV mass (r = 0.35; p <0.01). The latter was found in hypertensive subjects (r = 0.44; p <0.02), independent of 24-hour ambulatory BP, but not in normotensive subjects (r = 0.025; p = NS). Inadequate suppression of aldosterone in response to an increase in oral salt intake is related to LV structural and functional changes in hypertensive subjects. Thus, our results support experimental data indicating that aldosterone affects LV structure and function in humans and that this effect is BP independent.

Hemodynamic and sympathetic nerve responses to painful stimuli in normotensive and borderline hypertensive subjects

&NA; Observations in animals and humans show that pain sensitivity might be lower (and pain tolerance higher) in hypertensive as compared to normotensive subjects. One hypothesis, derived from experimental studies, assumes that enhanced activation of baroreceptors leads to an enhanced central inhibition. A central hypothesis assumes changes in the central (endogenous) control of the nociceptive system. To investigate these two hypotheses we quantitatively assessed the minute‐by‐minute changes in mean arterial pressure (MAP), central venous pressure (CVP) heart rate (HR), muscle sympathetic nerve activity (MSNA), and individual pain ratings during noxious mechanostimulation in 10 normotensive (NT) and 13 borderline hypertensive (BH) subjects. Linear regression analysis indicated a close negative correlation for the overall data between resting levels of MAP and pain ratings (r = −0.57, P < 0.0001). The BH group exhibited a lower pain sensitivity compared to the NT group (P < 0.001). The extent of baroreceptor activation during the application of pain was not different between the two groups (P = NS) as assessed by almost identical increases in MAP (+8 ± 1 vs. +9 ± 1 mmHg NT vs. BH group), CVP (+0.7 ± 0.1 vs. +0.5 ± 0.1 mmHg), HR (+2 ± 1 vs. +2 ± 1 beats/min), and MSNA (+5 ± 1 vs. +4 ± 1 bursts/min). The NT subjects exhibited significant correlations between the pain ratings and the increases in MAP (r = +0.52; P < 0.05) and MSNA (r = +0.49; P < 0.05) whereas the BH subjects did not show such a relationship. Thus, the increased pain tolerance in human hypertension cannot be explained by hemodynamically mediated differences in the activation of baroreceptors or by an altered baroreflex sensitivity during the application of pain. We conclude, that the reduced pain sensitivity in hypertensive humans is more likely related to central changes.

Effects of naloxone on hemodynamic and sympathetic nerve responses to pain in normotensive vs. borderline hypertensive men

Pain sensitivity decreases with increasing resting blood pressure. This blood pressure-pain interaction may be mediated by endogenous opioids which have been shown to affect both blood pressure and nociception. To test this hypothesis, we measured mean arterial blood pressure (MAP), central venous pressure (CVP), heart rate (HR), muscle sympathetic nerve activity (MSNA), serum catecholamines, and individual pain rating scales during 2 min periods of noxious mechanostimulation (skin fold pinching) in nine young (26 +/- 2 year), male normotensive (NT) subjects and in 12 age and weight matched males with borderline hypertension (BHT). Measurements were performed before and after the i.v. administration of naloxone (0.15 mg/kg) and placebo in a randomized double-blind cross-over trial. In the pre-naloxone trials, pain led to similar changes in MAP, CVP, MSNA and plasma catecholamines in the two groups except for a higher increase in HR in the BHT group as compared to the NT group (3 +/- 1 vs. 1 +/- 1 bpm; P < 0.005). Opioid blockade with naloxone increased MSNA responses to pain in the NT group (from 5 +/- 1 to 9 +/- 1 bursts/min, and, from 100 +/- 23 to 204 +/- 36 units/min, respectively; P < 0.05) but did not significantly affect the MSNA response to pain in the BHT group. Pain induced responses of MAP, CVP, and catecholamines were not altered by naloxone in either group. Overall, there was a highly significant inverse correlation between pain perception and resting blood pressure which was not significantly affected by naloxone. The BHT subjects exhibited a lower pain perception compared to the NT subjects (P < 0.005). Naloxone increased pain rating in the NT group (from 194 +/- 9 to 218 +/- 13; P < 0.005) but not in the borderline hypertensive group (160 +/- 8 vs. 168 +/- 10; P = 0.36). Except for a decreased HR response in the BHT group, placebo had no effect on the responses to pain. Our data do not indicate a major role of the endogenous opioid system for the blood pressure-pain interaction in man. Endogenous opioids affect pain perception and sympathetic nerve activity responses to pain in normotensive men but their activity seems to be attenuated in borderline hypertensive subjects. Therefore, the lower pain sensitivity in human essential hypertension is probably mediated by non-opioid mechanisms.

Effect of Pregnancy on Long‐Term Kidney Function in Renal Transplant Recipients Treated with Cyclosporine and with Azathioprine

In order to investigate the effect of different immunosuppressive regimens and the time interval between transplantation and pregnancy on long‐term outcome, we performed a case‐control study in pregnant renal allograft recipients. Eighty‐one pregnancies of kidney transplanted recipients were identified [cyclosporine (CYA): n = 40; azathioprine (AZA): n = 41]. Controls were matched with respect to important prognostic factors. Posttransplant follow‐up was 91.3 ± 5 months. Graft and patient survival were similar in both groups and there was no apparent effect of immunosuppression. A total of 28 recipients (33%) delivered within 2 years and 6 (8%) subjects within 1 year after transplantation, but these short transplantation‐to‐pregnancy intervals had no apparent adverse effect on long‐term outcome. In contrast to AZA‐treated patients, CYA‐treated patients experienced an increase in serum creatinine postpartum (1.15 ± 0.2 mg/dL vs. 1.61 ± 0.1 mg/dL; p < 0.05). Whole blood CYA levels decreased transiently during pregnancy from 115.9 ± 8 ng/mL to 80.7 ± 7 ng/mL leading to a gradual increase in drug dose from 240 ± 14 mg/day to 324 ± 21 mg/day (p < 0.05). Following delivery, there was an increase in CYA concentrations to 173 ± 5.4 ng/mL, requiring rapid dose tapering to baseline of 246 ± 15 mg/day. Pregnancies in renal recipients do not affect long‐term patient and graft survival, independent of the immunosuppression. No detrimental effect of short transplantation‐to‐pregnancy intervals on long‐term graft function was detected.

Obesity as a determinant for response to antihypertensive treatment.

OBJECTIVE--To test the hypothesis that beta blockers lower blood pressure more effectively than calcium entry blockers in obese hypertensive patients and that calcium entry blockers are more effective in lean patients. DESIGN--Double blind, randomised controlled trial of treatment over six weeks. SETTING--Tertiary referral centre. SUBJECTS--42 white men with uncomplicated mild to moderate essential hypertension (World Health Organisation stage I or II); 36 completed the study. INTERVENTION--Patients were randomised to metoprolol 50-100 mg twice daily or isradipine 2.5-5.0 mg twice daily for six weeks after a two week run in phase. MAIN OUTCOME MEASURE--Blood pressure after six weeks of treatment. RESULTS--When stratified according to treatment and presence of obesity (body mass index < or = 27 kg/m2), the mean (SD) fall in blood pressure in the beta blocker group was 24 (13)/18 (10) mm Hg in obese patients and 18 (19)/12 (13) mm Hg in lean patients. In the calcium entry blocker group, the fall in blood pressure was 21 (15)/17 (6) mm Hg in lean patients and 18 (11)/8 (10) mm Hg in obese patients. After taking age and blood pressure before treatment into account there was a significant interaction between obesity and drug therapy (p = 0.019) with a better diastolic blood pressure response to calcium entry blockers in lean patients and to beta blockers in obese hypertensive patients. CONCLUSION--Obesity affects the efficacy of metoprolol and isradipine in reducing blood pressure.