of the Max - MDC

Cardiovascular and Metabolic
Regulation
Jens Jordan
The main interest of the group is basic (mechanism-oriented) patient-oriented research in the field of clinical
autonomic disorders, arterial hypertension, obesity, and the metabolic syndrome. We run the Clinical Research
Center (CRC) at the Experimental and Clinical Research Center. The CRC provides the infrastructure for state-of-theart
patient oriented research. One intention of our group is to combine patient-oriented research with basic science
and genetics in the field of cardiovascular and metabolic diseases. The purpose of our research is to develop new
treatment strategies for patients with obesity, the metabolic syndrome, arterial hypertension, orthostatic intolerance,
and autonomic failure based on a better understanding of the pathophysiology of these conditions. We believe
that studies on rare human diseases that are associated with low blood pressure may also give important insight
in the mechanisms of essential and obesity associated hypertension. We are involved in currently ongoing projects
on the International Space Station (ISS). To elucidate the potential influence of candidate genes we participate in
twin studies together with HealthTwist. We have a close collaboration with other groups at the MDC to confirm
hypothesis that are generated in humans in already available or in newly created animal models.
Figure 1. Individual differences
in tolerated time during head-up
tilt testing between NET inhibition
and placebo treatment. In
subjects who tolerated the full
duration of the tilt study, both,
on placebo and during NET inhibition,
the difference is 0. The
solid vertical lines indicate the
mean value and the boundaries
of the 95% confidence interval.
Norepinephrine transporter function and human
cardiovascular regulation
In the last years, we established an internationally leading
center on disorders of the autonomic nervous system. We
are studying mechanisms of autonomic failure, the postural
tachycardia syndrome (POTS), neurally mediated syncope,
and baroreflex failure. The program has a strong focus on
clinical pharmacology. Many cardiovascular autonomic disorders
result from changes in norepinephrine turnover
either in the brain or in peripheral tissues. The norepinephrine
transporter (NET) reclaims norepinephrine that is
released from adrenergic neurons. We showed earlier that
functional NET gene mutations are a cause of POTS. POTS
features excessive cardiac sympathetic activation. In contrast,
neurally mediated syncope results from acute withdrawal
of sympathetic activity. We therefore tested the
hypothesis that pharmacological NET inhibition may be beneficial
in neurally mediated syncope. In the event, NET inhibition
improved orthostatic tolerance on a head-up tilt
table (Figure 1). We also showed that NET inhibition causes
a redistribution of sympathetic activity from kidneys and
vasculature towards the heart. Finally, we showed that the
weight loss drug sibutramine inhibits sympathetic activity
through central nervous mechanisms. The finding is clinically
important given the widespread use of the drug.
Adipose tissue as an endocrine organ in human
subjects
Adipose tissue secretes a large number of products that
have been implicated in the pathogenesis of cardiovascular
disease. We are particularly interested in adipose tissuederived
angiotensin II, leptin, and endocannabinoids. The
renin-angiotensin-aldosterone system has been causally
implicated in obesity-associated hypertension. We previously
showed that the expression of the adipose tissue reninangiotensin
system is altered in obese women, particularly
in those with arterial hypertension. We now tested the
hypothesis that the adipose renin angiotensin system
responds to changes in sodium intake. We obtained subcutaneous
adipose tissue biopsies at the end of low sodium
period (0.7 mmol Na/kg*d) and at the end of the high sodium
period (7.7 mmol Na/kg*d). High sodium intake profoundly
suppressed the activity of the systemic reninangiotensin
system while circulating atrial natriuretic peptide
increased. In contrast, the expression of adipose reninangiotensin
system components or of natriuretic peptide
20 Cardiovascular and Metabolic Desease Research