C-Type Natriuretic Peptide–Induced Vasodilation Is Dependent On Hyperpolarization in Human Forearm Resistance Vessels

Abstract

Abstract-Animal studies have demonstrated that CNP causes endothelium-independent vasodilation, which is limited by neutral endopeptidase (NEP) activity. However, the vasodilating mechanism of CNP in humans is still unknown. Therefore, we investigated the vasodilator actions of CNP in human forearm resistance vessels before and after inhibition of nitric oxide (NO) and then prostacyclin production and after inhibition of Ca 2ϩ -dependent potassium channel activation and NEP activity. Three separate studies were performed. In each study, forearm blood flow was recorded by venous occlusion plethysmography in 8 healthy nonsmoking subjects. Brachial artery infusion of CNP (70, 140, 280, and 560 ng per 100 mL forearm volume per minute) caused significant forearm vasodilation in all studies (forearm blood flow from 3.94 to 8.50 mL per 100 mL forearm volume per minute). Inhibition of the endogenous generation of NO by L-N G -monomethyl arginine (by use of the NO-clamp technique) did not block the maximal vasodilating effects of CNP (forearm blood flow from 3.69 to 6.93). In addition, when the cyclooxygenase system was inhibited by 600 mg of acetylsalicylic acid (aspirin) administered orally 30 minutes before start of measurements, the rise in forearm blood flow remained intact (forearm blood flow from 3.31 to 8.27 mL per 100 mL forearm volume per minute). However, inhibition of Ca 2ϩ -dependent potassium channels with tetraethylammonium chloride (0.1 mg per 100 mL forearm volume per minute) significantly attenuated vasodilation caused by CNP (forearm blood flow from 2.28 to 3.06 mL per 100 mL forearm volume per minute), which suggests that CNP opens vascular potassium channels. Vasodilation to all doses of CNP was significantly increased when activity of NEP was blocked with thiorphan (30 nmol/min), which suggests that NEP activity limits vasodilation of CNP. CNP is a dilator of human resistance vessels that mediates its effects through hyperpolarization of the vessel wall independent of the NO and prostaglandin system. Inhibition of local NEP activity increases CNP bioavailability. This may be of relevance to cardiovascular disease, given that vascular tone is well balanced between NO and an endothelium-derived hyperpolarizing factor, which suggests that in pathological situations, impaired NO activity can be compensated for by enhanced endothelium-derived hyperpolarizing factor release to maintain vascular homeostasis. (Hypertension. 2001;37:1179-1183.)

CNP, but not ANP or BNP, Relax Human Isolated Subcutaneous Resistance Arteries by an Action Involving Cyclic GMP and BKCa Channels

“…The direct effects of CNP on human arteries have not been examined previously and these observations extend previous findings by demonstrating that ANP does not relax subcutaneous resistance arteries, although it did relax human renal and skeletal muscle resistance arteries. 15 In humans the effect of CNP in vivo has been shown to be blocked by tetraethylammonium, an inhibitor of K Ca channels 16 and CNP has recently been proposed to act as an endothelium-dependent hyperpolarising factor (EDHF) in rat arteries. 17 Our observation of blockade of CNP responses by Ibx, a selective inhibitor of BK Ca channels, is broadly consistent with these observations, although membrane potential was not measured in our study.…”

ATP‐induced vasodilation in human skeletal muscle

“…Previously, in our laboratory, Pickkers & de Hoon showed that indomethacin at a concentration of 5 mg dl À1 FAV min À1 was able to inhibit cyclooxygenase: in a set of experiments, they confirmed (Honing et al, 2000), which acts via EDHFs. TEA was also able to inhibit the CNP-induced vasodilation (Honing et al, 2001) and the vasodilation induced by acetazolamide (Pickkers et al, 2001) in the human forearm; both openers of K Ca channels. The infused concentration of 2.0 mg glibenclamide min dl À1 FAV min À1 was based on a study previously performed in our laboratory, which showed that a concentration seven times lower was capable of effectively blocking K ATP channels (Bijlstra et al, 1996).…”

“…Pickkers et al (2001) also found that TEA had no significant effect on baseline vascular tone after SNP infusion. TEA also had no influence on baseline vascular tone after infusion of hydrochlorothiazide (Pickkers et al, 1998) and C-type natriuretic peptide (CNP) (Honing et al, 2001). FVR at recontrol, just before start of TEA infusion, did not differ from baseline values, which makes it unlikely that the observed vasoconstrictor action of TEA is due to vanishing ATP-induced vasodilation by a carry-over effect, but cannot be excluded.…”

Treatment of Streptozotocin-Induced Diabetic Rats With AVE7688, a Vasopeptidase Inhibitor

“…CNP was found to be released from endothelial cells of the perfused rat mesenteric bed in response to endotheliumdependent vasodilators such as acetylcholine (5,6). CNP induced hyperpolarization and relaxation of mesenteric artery vascular smooth muscle through activation of natriuretic peptide receptor subtype B and the same potassium channels that are activated by EDHF (5)(6)(7)(8). In this study, we provide evidence that epineurial arterioles of the sciatic nerve contain CNP, predominantly in endothelial cells, and that exogenous CNP causes vascular relaxation that can be prevented by potassium channel blockers that we have previously shown inhibit the EDHF component of acetylcholine-mediated vascular relaxation (9).…”