Gamma irradiation induces acetylcholine-evoked, endothelium-independent relaxation and activates K-channels of isolated pulmonary artery of rats.

PURPOSE: To test the effects of irradiation (R*) on the pulmonary artery (PA). METHODS AND MATERIALS: Isolated PA rings were submitted to gamma irradiation (cesium, 8 Gy/min(-1)) at doses of 20 Gy-140 Gy. Rings were placed in an organ chamber, contracted with serotonin (10(-4) M 5-hydroxytryptamine [5-HT]), then exposed to acetylcholine (ACh) in incremental concentrations. Smooth muscle cell (SMC) membrane potential was measured with microelectrodes. RESULTS: A high dose of irradiation (60 Gy) increased 5HT contraction by 20%, whereas lower (20 Gy) doses slightly decreased it compared with control. In the absence of the endothelium, 5-HT precontracted rings exposed to 20 Gy irradiation developed a dose-dependent relaxation induced by acetylcholine (EI-ACh) with maximal relaxation of 60 +/- 17% (n = 13). This was totally blocked by L-NAME (10(-4) M), partly by 7-nitro indazole; it was abolished by hypoxia and iberiotoxin, decreased by tetra-ethyl-ammonium, and not affected by free radical scavengers. In irradiated rings, hypoxia induced a slight contraction which was never observed in control rings. No differences in SMC membrane potential were observed between irradiated and nonirradiated PA rings. CONCLUSION: Irradiation mediates endothelium independent relaxation by a mechanism involving the nitric oxide pathway and K-channels.

Chronic carbon monoxide exposure of hypoxic rats increases in vitro sensitivity of pulmonary artery smooth muscle.

Exogenous carbon monoxide (CO) induces pulmonary vasodilation by acting directly on pulmonary artery (PA) smooth muscle cells. We investigated the contribution of K+ channels and soluble guanylyl cyclase to the regulation of PA tone by acute CO in chronic hypoxic rats (3 weeks at 0.5 atm (1 atm = 101.325 kPa); hypoxic) and in chronic hypoxic rats exposed to exogenous CO (3 weeks at 0.5 atm + 50 ppm CO; hypoxic-CO). Acute CO induced relaxation in PA rings from all animals. However, the amplitude of CO relaxation was significantly decreased in hypoxic rings and increased in hypoxic-CO rings. This different effect occurred with a decrease and an increase of pD2, respectively, in hypoxic and hypoxic-CO rings. We showed a positive relation between the percentage of inhibition of CO relaxation by a blocker of K+ channels and the increase of CO sensitivity. Thus, we showed for the first time that chronic hypoxia decreases acute CO sensitivity, which in contrast, increases in the presence of chronic CO. The present study provides initial evidence of a link between increased K(+)-channel activity and CO sensitivity.

Cardiac morphology and function following long-term exposure to carbon monoxide at high altitude in rats.

Although chronic exposure to high altitude or carbon monoxide (CO) induces several cardiovascular adaptations in mammals, very little information is available on the cardiovascular effects due to exposure to these concomitant stresses. In particular, cardiac functional responses to chronic CO inhalation at high altitude has never been investigated. Thirty-two male Dark Agouti rats were exposed for 10 wk in steel chambers to (1) normoxic conditions (N rats), (2) 4000 m simulated high altitude (chronic hypobaric hypoxia, CH rats), (3) 50 ppm CO (CO rats), or (4) 50 ppm CO at 4000 m simulated high altitude (CH + CO rats). Left ventricular (LV) morphology and function were evaluated in normoxic conditions (1) using transthoracic Doppler echocardiography, just before as well as after exposure to environments, and (2) using transparietal intraventricular catheterisms following a short ventilatory-controlled thoracotomy (10 ml/kg volume inflow, pO2 ~159 torr) after exposure. Right ventricular (RV) function was evaluated using the same catheterism process after exposure. Body weight increased in all groups during exposure, but to a lesser extent in CH and CH + CO than in N and CO rats. At the end of exposure, hematocrit ratio was higher in CH than in CO rats, and in CH + CO than in CH rats. Carboxyhemoglobin levels were higher in CH + CO than in CO, CH, or N rats. Although neither a simulated high altitude nor CO alone had an effect on LV morphology and function, combined environments increased LV + septum weight, interventricular and posterior wall thicknesses, relative wall thickness, and LV systolic function. LV diastolic function was not altered by environmental conditions in the four groups. CO intensified the altitude-induced RV hypertrophy as well as the altitude-induced decrease in RV diastolic function. RV systolic function increased in CH rats, but adding CO did not amplify this adaptation process. Moreover, significant polynomial relationships were obtained between hematocrit ratio and LV + septum weight or left ventricular systolic pressure. Our results indicate that CO at high altitude induced severe hematological responses that could be involved in morphological and functional cardiac adaptations of both ventricles. Data indicate that CO at high altitude may be more detrimental to cardiac function than CO inhaled at sea level.

Chronic carbon monoxide enhanced IbTx-sensitive currents in rat resistance pulmonary artery smooth muscle cells.

Exogenous carbon monoxide (CO) can induce pulmonary vasodilation by acting directly on pulmonary artery (PA) smooth muscle cells. We investigated the contribution of K+ channels to the regulation of resistance PA resting membrane potential on control (PAC) rats and rats exposed to CO for 3 wk at 530 parts/million, labeled as PACO rats. Whole cell patch-clamp experiments revealed that the resting membrane potential of PACO cells was more negative than that of PAC cells. This was associated with a decrease of membrane resistance in PACO cells. Additional analysis showed that outward current density in PACO cells was higher (50% at +60 mV) than in PAC cells. This was linked to an increase of iberiotoxin (IbTx)-sensitive current. Chronic CO hyperpolarized membrane of pressurized PA from -46.9 +/- 1.2 to -56.4 +/- 2.6 mV. Additionally, IbTx significantly depolarized membrane of smooth muscle cells from PACO arteries but not from PAC arteries. The present study provides initial evidence of an increase of Ca2+-activated K+ current in smooth muscle cells from PA of rats exposed to chronic CO.