Endothelium‐dependent relaxations in sheep pulmonary arteries and veins: resistance to block by N^G‐nitro‐L‐arginine in pulmonary hypertension

Abstract

1 The effect of the nitric oxide synthase inhibitor, NG-nitro-L-arginine (L-NOARG), on endotheliumdependent relaxation to a receptor-independent agent, ionomycin, was examined in isolated pulmonary arteries and veins from control, short-term and chronic pulmonary hypertensive sheep. All vessel segments were contracted to optimal levels of active force with endothelin-I to record endotheliumdependent relaxation. 2 Pulmonary hypertension was induced by continuous pulmonary artery air embolization for 1 day (short-term) and 14 days (chronic) and was associated with a 2 and 3 fold increase in pulmonary vascular resistance respectively.3 L-NOARG (0.1 mM) reduced the maximum relaxation (Rm,) to ionomycin in large and mediumsized pulmonary arteries from control sheep by approximately 70%. By contrast, L-NOARG (0.1 mM) did not inhibit the Rmax to ionomycin in matched vessels from short-term and chronic pulmonary hypertensive sheep. 4 Resistance of ionomycin-induced relaxations to inhibition by L-NOARG, was confined to the arterial vasculature in chronic pulmonary hypertensive animals, as relaxations to ionomycin in large and medium-sized chronic pulmonary hypertensive veins were, like those in control veins, abolished by L-NOARG. Both large and medium-sized pulmonary veins from short-term pulmonary hypertensive sheep, however, were resistant to block by L-NOARG.5 Neither sensitivity (pEC5o) nor RmS, to ionomycin in large, short-term pulmonary hypertensive arteries was affected when the extracellular concentration of K+ was increased isotonically to 30 mm. Nifedipine (0.3 gM) was present throughout to prevent high K+-induced smooth muscle contraction. In the presence of this high extracellular K+, however, L-NOARG (0.1 mM) caused complete inhibition of the relaxation to ionomycin, whereas in normal extracellular K+ (4.7 mM), L-NOARG only weakly inhibited ionomycin relaxations. 6 In conclusion, the onset of pulmonary hypertension in sheep following air embolization, is associated with the development of resistance of endothelium-dependent relaxations to block by L-NOARG. The mechanism of L-NOARG resistance appears to be due to the up-regulation of a K+ channel-mediated backup vasodilator mechanism which can compensate for the loss of nitric oxide (NO)-mediated relaxation. Although this mechanism remains functionally 'silent' in the presence of NO it is able to maintain adequate endothelium-dependent vasodilatation during pulmonary hypertension if NO synthesis is compromised.

Pharmacological characterisation of endothelium-dependent relaxation in human radial artery: comparison with internal thoracic artery

“…from any one patient. As the initial relaxation varied Maximal contractile responses to phenylephrine were There were marked differences between patients with greater in RA than ITA 3.0660.38g compared to respect to age, plasma cholesterol levels, drug treatment 1.6460.17 g. Similarly overall the PE values used to 50 and underlying disease which could all influence relaxation study relaxation to carbachol were higher in RA than ITA, to carbachol resulting in marked differences between 1.6260.08 in RA and 1.0360.08 in ITA. However, within responses in rings from different patients.…”

“…Fifteen minutes later the rings were again conby a no-touch technique leaving the vessels surrounded by stricted to the EC for phenylephrine. If necessary, the 50 internal thoracic fascia. The discarded distal end (1-2 cm) dose of phenylephrine was adjusted so that the tone was was placed in physiological salt solution.…”

Evidence for mediation by endothelium‐derived hyperpolarizing factor of relaxation to bradykinin in the bovine isolated coronary artery independently of voltage‐operated Ca2+ channels

“…Furthermore, the L-NOARG-resistant response to BK was not mediated by prostanoids since all experiments were carried out in the presence of the cyclo-oxygenase inhibitor, indomethacin. The L-NOARG-resistant response was, however, significantly blocked by approximately 70% by high extracellular KCl, a treatment both known to inhibit K+ channel activity (Chen & Suzuki, 1989) and used widely to inhibit the effects of EDHF (Nagao & Vanhoutte, 1992;Adeagbo & Triggle, 1993;Cowan et al, 1993;Kilpatrick & Cocks, 1994;Waldron & Garland, 1994; Kemp et al, 1995;Kuhberger et al, 1995). Thus, it is likely that L-NOARG-resistant relaxations in the bovine coronary artery are at least partially mediated by EDHF (see Holzmann et al, 1994).…”

Obesity Up-Regulates Intermediate Conductance Calcium-Activated Potassium Channels and Myoendothelial Gap Junctions to Maintain Endothelial Vasodilator Function

“…Altered endothelial function is associated with animal models of type I diabetes (Shi et al, 2006), type II diabetes (Park et al, 2008), pulmonary hypertension (Kemp et al, 1995), hypercholesterolemia (Brandes et al, 1997), heart failure (Katz and Krum, 2001), and aging (Gaubert et al, 2007), where NO activity is reduced, and K Ca -mediated EDH is preserved or up-regulated to maintain overall vasodilation. The disease-related effects of endothelium-dependent vasodilation in diet-induced obesity are unknown.…”