Vasodilator Action Of Nitric Oxide Research Articles

Kv7 Channels in Cyclic-Nucleotide Dependent Relaxation of Rat Intra-Pulmonary Artery.

Pulmonary hypertension is treated with drugs that stimulate cGMP or cAMP signalling. Both nucleotides can activate Kv7 channels, leading to smooth muscle hyperpolarisation, reduced Ca2+ influx and relaxation. Kv7 activation by cGMP contributes to the pulmonary vasodilator action of nitric oxide, but its contribution when dilation is evoked by the atrial natriuretic peptide (ANP) sensitive guanylate cyclase, or cAMP, is unknown. Small vessel myography was used to investigate the ability of Kv7 channel blockers to interfere with pulmonary artery relaxation when cyclic nucleotide pathways were stimulated in different ways. The pan-Kv7 blockers, linopirdine and XE991, caused substantial inhibition of relaxation evoked by NO donors and ANP, as well as endothelium-dependent dilators, the guanylate cyclase stimulator, riociguat, and the phosphodiesterase-5 inhibitor, sildenafil. Maximum relaxation was reduced without a change in sensitivity. The blockers had relatively little effect on cAMP-mediated relaxation evoked by forskolin, isoprenaline or treprostinil. The Kv7.1-selective blocker, HMR1556, had no effect on cGMP or cAMP-dependent relaxation. Western blot analysis demonstrated the presence of Kv7.1 and Kv7.4 proteins, while selective activators of Kv7.1 and Kv7.4 homomeric channels, but not Kv7.5, caused pulmonary artery relaxation. It is concluded that Kv7.4 channels contribute to endothelium-dependent dilation and the effects of drugs that act by stimulating cGMP, but not cAMP, signalling.

Preventive dietary potassium supplementation in young salt-sensitive Dahl rats attenuates development of salt hypertension by decreasing sympathetic vasoconstriction

Increased potassium intake attenuates the development of salt-dependent hypertension, but the detailed mechanisms of blood pressure (BP) reduction are still unclear. The aims of our study were (i) to elucidate these mechanisms, (ii) to compare preventive potassium effects in immature and adult animals and (iii) to evaluate the therapeutic effects of dietary potassium supplementation in rats with established salt hypertension. Young (4-week-old) and adult (24-week-old) female salt-sensitive Dahl rats were fed a high-salt diet (5% NaCl) or a high-salt diet supplemented with 3% KCl for 5 weeks. The participation of vasoconstrictor (renin-angiotensin and sympathetic nervous systems) and vasodilator systems [prostanoids, Ca(2+) -activated K(+) channels, nitric oxide (NO)] was evaluated using a sequential blockade of these systems. Preventive potassium supplementation attenuated the development of severe salt hypertension in young rats, whereas it had no effects on BP in adult rats with moderate hypertension. Enhanced sympathetic vasoconstriction was responsible for salt hypertension in young rats and its attenuation for potassium-induced BP reduction. Conversely, neither salt hypertension nor its potassium-induced attenuation were associated with significant changes of the vasodilator systems studied. The relative deficiency of vasodilator action of NO and Ca(2+) -activated K(+) channels in salt hypertensive Dahl rats was not improved by potassium supplementation. The attenuation of enhanced sympathetic vasoconstriction is the principal mechanism of antihypertensive action exerted by preventive potassium supplementation in immature Dahl rats. Dietary potassium supplementation has no preventive effects on BP in adult salt-loaded animals or no therapeutic effects on established salt hypertension in young rats.

Effect of Moderate-Intensity Exercise, Whole-Body Periodic Acceleration, and Passive Cycling on Nitric Oxide Release Into Circulation

To determine if a 3-min bout of moderately intensive supine bicycle exercise, whole-body periodic acceleration (pGz), and passive motorized cycling cause nitric oxide (NO) release into the circulation, as detected by dicrotic notch descent on the diastolic limb of a finger pulse wave. Fourteen healthy adults underwent two levels of supine bicycle ergometry that caused heart rate to rise to 56% (light moderate exercise) and 67% (heavy moderate exercise) of maximum predicted heart rate, and a single bout of pGz. Several months later, 9 of the 14 subjects underwent passive motorized cycling. The ECG and finger pulse wave were recorded. The dicrotic notch position was computed from the amplitude of the digital pulse wave (a) divided by the height of the dicrotic notch above the end-diastolic level (b) and designated the a/b ratio. Increase of the a/b ratio due to dicrotic notch descent reflects the vasodilator action of NO on resistance vessels. The last 30 s of baseline, exercise or pGz, and recovery periods were analyzed. Compared to baseline, light moderate exercise produced a nonsignificant rise of the a/b ratio. Both heavy moderate exercise and pGz produced statistically significant rises of peak and mean a/b ratios over baseline. Heavy moderate exercise produced a greater mean a/b ratio than pGz, but the peak a/b ratio did not differ between the two. Episodic rises and falls of a/b ratios were more common during pGz than exercise. Passive motorized cycling did not alter the a/b ratio. Dicrotic notch descent occurs during a brief bout of moderate cycling exercise, consistent with NO release into circulation. pGz produces comparable descent, but passive motorized cycling does not. In terms of the beneficial effects of NO, this suggests that pGz might serve as a substitute in subjects who are physically incapable of exercising.

Nitric Oxide Is Released Into Circulation With Whole-Body, Periodic Acceleration

To determine if comfortably applied, whole-body, periodic acceleration releases significant amounts of nitric oxide (NO) into the circulation of healthy subjects and patients with inflammatory diseases. Fourteen healthy adults and 40 adult patients with inflammatory diseases underwent single 45-min trials of whole-body, periodic acceleration with a new "passive exercise" device, while an ECG and a digital pulse wave were obtained with a photoelectric-plethysmograph sensor. The position of the dicrotic notch from the pulse waveform was computed from the amplitude of the pulse divided by the height of the dicrotic notch above the end-diastolic level (a/b ratio). Increase of the a/b ratio reflects the vasodilator action of NO that causes downward movement of the dicrotic notch in the diastolic limb of the digital pulse, thereby elevating the a/b ratio. Application of whole-body, periodic acceleration was well tolerated in all participants, and all completed the 45-min treatment. The peak value of the a/b ratio markedly rose during periodic acceleration and returned to baseline during a 5-min recovery period in all healthy subjects and patients with inflammatory diseases. Whole-body, periodic acceleration increased pulsatile shear stress to the endothelium leading to vasodilatation and a fall in the dicrotic notch, consistent with increased NO bioactivity in every healthy adult and adult patient with inflammatory disease so treated. Therefore, passive exercise using whole-body, periodic acceleration produces an important benefit that occurs with active exercise.

Cyclic GMP-dependent Protein Kinase Signaling Pathway Inhibits RhoA-induced Ca2+ Sensitization of Contraction in Vascular Smooth Muscle

The potent vasodilator action of cyclic GMP-dependent protein kinase (cGK) involves decreasing the Ca(2+) sensitivity of contraction of smooth muscle via stimulation of myosin light chain phosphatase through unknown mechanisms (Wu, X., Somlyo, A. V., and Somlyo, A. P. (1996) Biochem. Biophys. Res. Commun. 220, 658-663). Myosin light chain phosphatase activity is controlled by the small GTPase RhoA and its target Rho kinase. Here we demonstrate cGMP effects mediated by cGK that inhibit RhoA-dependent Ca(2+) sensitization of contraction of blood vessels and actin cytoskeleton organization in cultured vascular myocytes. Ca(2+) sensitization and actin organization were inhibited by both 8-bromo-cGMP and sodium nitroprusside (SNP). SNP also caused translocation of activated RhoA from the membrane to the cytosol. SNP-induced actin disassembly was lost in vascular myocytes in culture after successive passages but was restored by transfection of cells with cGK I. Furthermore, cGK phosphorylated RhoA in vitro, and addition of cGK I inhibited RhoA-induced Ca(2+) sensitization in permeabilized smooth muscle. 8-Bromo-cGMP-induced actin disassembly was inhibited in vascular myocytes expressing RhoA(Ala-188), a mutant that could not be phosphorylated. Collectively, these results indicate that cGK phosphorylates and inhibits RhoA and suggest that the consequent inhibition of RhoA-induced Ca(2+) sensitization and actin cytoskeleton organization contributes to the vasodilator action of nitric oxide.

Essential Role for Nitric Oxide in Neurogenic Inflammation in Rat Cutaneous Microcirculation

The possible modulatory role of nitric oxide (NO) in neurogenic edema formation in rat paw skin, induced by electrical stimulation of the saphenous nerve, was investigated by using two NO synthase inhibitors, NG-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI). Both L-NAME (100 mg/kg IV, P < .05) and 7-NI (10 mg/kg IV, P < .05) caused an L-arginine (100 mg/kg IV, P < .01)-reversible inhibition of neurogenic edema as measured by 125I-albumin accumulation, whereas D-NAME (inactive enantiomer of L-NAME) and 6-aminoindazole (structurally similar to 7-NI) were without inhibitory effect. L-NAME produced the predicted vasopressor effect (before, 115 +/- 18 mm Hg; 5 minutes after, 174 +/- 18 mm Hg; n = 6; P < .05), whereas 7-NI showed no significant increase in blood pressure (before, 96 +/- 9 mm Hg; 5 minutes after, 102 +/- 10 mm Hg; n = 6), and neither L-NAME nor 7-NI had any effect on basal or vasodilator calcitonin gene-related peptide (CGRP, 10 pmol per site)-stimulated local blood flow in rat skin, as measured by laser Doppler flowmetry. Furthermore, systemic and local 7-NI had no effect on edema formation induced by local administration of substance P (with or without CGRP) and histamine (with or without CGRP) in rat skin. Since 7-NI blocks edema produced by stimulation of the saphenous nerve, it is suggested that release of NO is involved in neurogenic edema formation, but the vasodilator action of NO is unimportant in this context.(ABSTRACT TRUNCATED AT 250 WORDS)