(1) Increased vascular resistance in chronic heart failure (CHF) has been attributed
to stimulated neurohumoral systems. However, local mechanisms may also importantly
contribute to set arterial tone. Our aim, therefore, was to test whether pressure-induced
myogenic constriction of resistance arteries in vitro--devoid of acute effects of
circulating factors--is increased in CHF and to explore underlying mechanisms. (2)
At 12 weeks after coronary ligation-induced myocardial infarction or SHAM-operations
in rats, we studied isolated mesenteric arteries for myogenic constriction, determined
as the active constriction (% of passive diameter) in response to stepwise increase
in intraluminal pressure (20 - 160 mmHg), in the absence and presence of inhibitors
of potentially involved modulators of myogenic constriction. (3) We found that myogenic
constriction in mesenteric arteries from CHF rats was markedly increased compared
to SHAM over the whole pressure range, the difference being most pronounced at 60
mmHg (24+/-2 versus 4+/-3%, respectively, P<0.001). (4) Both removal of the endothelium
as well as inhibition of NO production (L-N(G)-monomethylarginine, 100 micro M) significantly
increased myogenic constriction (+16 and +25%, respectively), the increase being similar
in CHF- and SHAM-arteries (P=NS). Neither endothelin type A (ET(A))-receptor blockade
(BQ123, 1 micro M) nor inhibition of perivascular (sympathetic) nerve conduction (tetrodotoxin,
100 nM) affected the myogenic response in either group. (5) Interestingly, increased
myogenic constriction in CHF was fully reversed after angiotensin II type I (AT(1))-receptor
blockade (candesartan, 100 nM; losartan, 10 micro M), which was without effect in
SHAM. In contrast, neither angiotensin-converting enzyme (ACE) inhibition (lisinopril,
1 micro M; captopril, 10 micro M) or AT(2)-receptor blockade (PD123319, 1 micro M),
nor inhibition of superoxide production (superoxide dismutase, 50 U ml(-1)), TXA(2)-receptor
blockade (SQ29,548, 1 micro M) or inhibition of cyclooxygenase-derived prostaglandins
(indomethacin, 10 micro M) affected myogenic constriction. (6) Sensitivity of mesenteric
arteries to angiotensin II (10 nM - 100 micro M) was increased (P<0.05) in CHF (pD(2)
7.1+/-0.4) compared to SHAM (pD(2) 6.2+/-0.3), while the sensitivity to KCl and phenylephrine
was not different. (7) Our results demonstrate increased myogenic constriction in
small mesenteric arteries of rats with CHF, potentially making it an important target
for therapy in counteracting increased vascular resistance in CHF. Our results further
suggest active and instantaneous participation of AT(1)-receptors in increased myogenic
constriction in CHF, involving increased sensitivity of AT(1)-receptors rather than
apparent ACE-mediated local angiotensin II production.