Myogenic constriction is increased in mesenteric resistance arteries from rats with chronic heart failure: instantaneous counteraction by acute AT1 receptor blockade

Abstract

(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.

Figure 1

(a) Pressure – diameter curves of mesenteric arteries from CHF rats (n=9) and SHAM-operated rats (n=9) determined in calcium-free Krebs solution (passive diameter) and calcium-containing Krebs solution (active diameter), respectively. (b) Myogenic constriction of mesenteric arteries from CHF rats (n=9) and SHAM-operated rats (n=9) determined as the degree of active constriction (i.e. decrease in lumen diameter) comparing arteries in calcium-free (passive diameter) and calcium-containing Krebs solution (active diameter) and expressed in per cent constriction compared to passive lumen diameter. (c) Myogenic constriction of mesenteric arteries from CHF rats in the absence of any drug (CHF vehicle, n=9) and in the presence of the AT₁ receptor blocker candesartan, 100 nmol l⁻¹ (CHF candesartan, n=5), losartan, 10 μmol l⁻¹ (CHF losartan, n=5), or the ACE inhibitor lisinopril, 1 μmol l⁻¹ (CHF lisinopril, n=4). *P<0.05.

Figure 2

(a) Myogenic constriction of mesenteric arteries from SHAM-operated rats in the presence of the endothelium (SHAM +endothelium, n=5) or in the absence of the endothelium (SHAM -endothelium, n=5). (b) Myogenic constriction of mesenteric arteries from CHF rats in the presence of the endothelium (CHF +endothelium, n=5) or in the absence of the endothelium (CHF -endothelium, n=5). *P<0.05.

Figure 3

Concentration-dependent constriction to (a) Ang II, (b) phenylephrine (PE) and (c) KCl for mesenteric arteries of CHF rats (n=6 for each) and SHAM-operated rats (n=6 for each) determined at an intraluminal pressure of 60 mmHg and expressed in per cent constriction compared to the maximally dilated (passive) diameter of the same vessel at the same pressure. *P<0.05 for pD₂ values.