The cellular mechanisms that determine differences in reactivity of arteries of varying size and origin are unknown. We evaluated the hypothesis that there is diversity in the distribution of K+ channels between vascular smooth muscle (VSM) cells within a single segment of the pulmonary arteries (PAs) and that there are differences in the prevalence of these cell types between conduit and resistance arteries, which contribute to segmental differences in the vascular response to NO and hypoxia. Three types of VSM cells can be identified in rat PAs on the basis of their whole-cell electrophysiological properties- current density and the pharmacological dissection of whole-cell K+ current(I(K))-and morphology. Cells are referred to as "K(Ca), K(Dr), or mixed," acknowledging the type of K+ channel that dominates the IK: the Ca2+-sensitive (K(Ca)) channel, delayed rectifier (K(Dr)) channel, or a mixture of both. The three cell types were identified by light and electron microscopy. K(Ca) cells are large and elongated, and they have low current density and currents that are inhibited by tetraethylammonium (5 mmol/L) or charybdotoxin (100 nmol/L). K(Dr) cells are smaller, with a perinuclear bulge, but have high current density and currents that are inhibited by 4-aminopyridine (5 mmol/L). Conduit arteries contain significant numbers of K(Ca) cells, whereas resistance arteries have a majority of K(Dr) cells and few K(Ca) cells. NO rapidly and reversibly increases I(K) and hyperpolarizes K(Ca) cells because of an increase in open probability of a 170-pS K(Ca) channel. Hypoxia depolarizes K(Dr) cells by rapidly and reversibly inhibiting one or more of the tonically active K(Dr) channels (including a 37-pS channel) that control resting membrane potential. The effects of both hypoxia and NO on K+ channels are evident at negative membrane potentials, supporting their physiological relevance. The functional correlate of this electrophysiological diversity is that K(Dr)-enriched resistance vessels constrict to hypoxia, whereas conduit arteries have a biphasic response predominated by relaxation. Although effective in both segments, NO relaxes conduit more than resistance rings, in both cases by a cGMP-dependent mechanism. We conclude that regional electrophysiological diversity among smooth muscle cells is a major determinant of segmental differences in vascular reactivity.

Chronic pulmonary hypertension is a serious complication of a number of chronic lung and heart diseases. In addition to vasoconstriction, its pathogenesis includes injury to the peripheral pulmonary arteries leading to their structural remodeling. Increased pulmonary vascular synthesis of an endogenous vasodilator, nitric oxide (NO), opposes excessive increases of intravascular pressure during acute pulmonary vasoconstriction and chronic pulmonary hypertension, although evidence for reduced NO activity in pulmonary hypertension has also been presented. NO can modulate the degree of vascular injury and subsequent fibroproduction, which both underlie the development of chronic pulmonary hypertension. On one hand, NO can interrupt vascular wall injury by oxygen radicals produced in increased amounts in pulmonary hypertension. NO can also inhibit pulmonary vascular smooth muscle and fibroblast proliferative response to the injury. On the other hand, NO may combine with oxygen radicals to yield peroxynitrite and other related, highly reactive compounds. The oxidants formed in this manner may exert cytotoxic and collagenolytic effects and, therefore, promote the process of reparative vascular remodeling. The balance between the protective and adverse effects of NO is determined by the relative amounts of NO and reactive oxygen species. We speculate that this balance may be shifted toward more severe injury especially during exacerbations of chronic diseases associated with pulmonary hypertension. Targeting these adverse effects of NO-derived radicals on vascular structure represents a potential novel therapeutic approach to pulmonary hypertension in chronic lung diseases.

These observations indicate that anorexic agents, like hypoxia, can inhibit potassium current, cause membrane depolarization, and stimulate pulmonary vasoconstriction. They suggest one mechanism that could be responsible for initiating pulmonary hypertension in susceptible individuals. It is possible that susceptibility is the result of the reduced production of an endogenous vasodilator, such as NO, but this remains speculative.

The hypothesis that the endothelium-derived relaxing factor/nitric oxide (EDNO) activity is elevated in chronic hypoxic pulmonary hypertension (CH-PHT) was tested using isolated Krebs-albumin-perfused rat lungs. Concentration of the EDNO decomposition products (NOx) in the lungs' effluent was measured by a modified chemiluminescence assay. The functional significance of basal EDNO production was studied by measuring the vasoconstrictor response to an EDNO synthesis inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME). Reactivity to the endothelium-dependent vasodilator substance P and to exogenous NO was also studied. More NOx was found in effluent from CH-PHT (22.3 +/- 9.8 nM) than control (0.4 +/- 3.9 nM) lungs. The L-NAME-induced vasoconstriction was greater in CH-PHT than in control rats. The sensitivity, but not the maximal vasodilation, to exogenous NO was elevated in CH-PHT. The substance P-induced vasodilation was potentiated in CH-PHT compared with control rats and blocked by L-NAME in both groups. We conclude that basal and agonist-stimulated pulmonary EDNO activity is enhanced in this model of CH-PHT. The EDNO synthesis may play a counterregulatory role in CH-PHT.