Abnormal vasoconstrictor responses to angiotensin II and noradrenaline in isolated small arteries from patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
OBJECTIVE
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by ultrastructural abnormalities in small cerebral and systemic vessels. We assessed vasomotor function in systemic small arteries in CADASIL.


METHODS
We studied 10 CADASIL patients and 10 control subjects. Resistance arteries isolated from gluteal biopsies were mounted on small-vessel myographs, and concentration responses were determined for vasoconstrictors (noradrenaline, angiotensin II, and endothelin-I) and vasodilators (acetylcholine, bradykinin, spermine-NONOate, and nifedipine). Maximum data are shown as percent potassium contraction.


RESULTS
There was reduced potency for noradrenaline in CADASIL (CADASIL [38 arteries]: EC50, 240 nmol/L; control subjects [27 arteries]: EC50, 100 nmol/L; 2-way analysis of variance, F=9.76, P=0.002). Maximum response to angiotensin II was greater in CADASIL (120+/-8% versus 97+/-5% in control subjects; F=4.28, P=0.043). Tachyphylaxis to angiotensin II occurred in all control subjects studied but in only 3 of 9 CADASIL subjects (P=0.011, Fisher's exact test). Vasodilation was similar in CADASIL patients compared with control subjects for endothelium-dependent dilators (acetylcholine and bradykinin) and endothelium-independent dilators (spermine-NONOate and nifedipine).


CONCLUSIONS
These results suggest a selective systemic microvascular vasoconstrictor abnormality in CADASIL in noradrenaline and angiotensin II pathways that is not explained by vasodilator impairment in endothelium or vascular smooth muscle. This could have important implications for prophylaxis and treatment of CADASIL.
Hussain
Monira B
MB
Pharmacology and Clinical Pharmacology, St George's Hospital Medical School, London, UK.
Singhal
Sumeet
S
Markus
Hugh S
HS
Singer
Donald R J
DR
D000804:Angiotensin II / Q000494:pharmacology*; D001158:Arteries / Q000033:anatomy & histology / Q000187:drug effects / Q000503:physiopathology*; D046508:Culture Techniques; D015161:Dementia, Multi-Infarct / Q000175:diagnosis / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000503:physiopathology; D008875:Middle Aged; D009638:Norepinephrine / Q000494:pharmacology*; D012307:Risk Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000804:Angiotensin II; D009638:Norepinephrine