Is it possible to develop drugs that act more selectively on large arteries?
BACKGROUND
Patients with high pulse pressures have an increased risk for cardiovascular events. Drugs that selectively decrease high pulse pressure may be of interest for these patients. Such drugs have a more pronounced effect on large arteries than on resistance vessels.


OBJECTIVE
To compare the selectivity to large arteries of the new nitric oxide donor sinitrodil with the classic nitrate isosorbide dinitrate in healthy young men in order to investigate whether it is possible to develop drugs that act more selectively on large arteries.


METHODS
The study had a double-blind, 5-way cross-over design. In randomized order, subjects received a single oral dose of 10 mg sinitrodil, 20 mg sinitrodil, 40 mg sinitrodil, isosorbide dinitrate and placebo. Measurements were performed before and 45 min after administration of the drugs. Between each drug administration, at least 3 days of wash-out was allowed.


METHODS
The effects of the drugs on large arteries and resistance vessels were assessed by their effects on brachial artery compliance and total peripheral resistance, respectively.


RESULTS
Brachial artery compliance increased gradually with increasing doses of sinitrodil (by 10, 20 and 27% with 10, 20 and 40 mg sinitrodil, respectively). Total peripheral resistance index decreased with isosorbide dinitrate (by 11%) and 40 mg sinitrodil (by 7%), while it remained unchanged with 10 mg and 20 mg sinitrodil.


CONCLUSIONS
The results of this study show that it may be possible to develop drugs with a higher selectivity for large arteries. Such drugs may be good candidates to decrease high pulse pressure without substantially decreasing mean and diastolic blood pressures.
Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands. I.vanbortel@farmaco.unimaas.nl
L M
LM
Van Bortel
J J
JJ
Spek
E J
EJ
Balkestein
M
M
Sardina
H A
HA
Struijker Boudier
D000328:Adult; D001158:Arteries / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D048588:Benzoxazines; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D015195:Drug Design; D006801:Humans; D007548:Isosorbide Dinitrate / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D009566:Nitrates / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000009:adverse effects / Q000494:pharmacology*; D010078:Oxazines / Q000494:pharmacology*; D011674:Pulse; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000009:adverse effects / Q000494:pharmacology
D048588:Benzoxazines; D009566:Nitrates; D020030:Nitric Oxide Donors; D010078:Oxazines; D014665:Vasodilator Agents; D007548:Isosorbide Dinitrate; C091726:sinitrodil