Potassium-induced intermittent vasomotion in rat isolated pulmonary artery.

A novel intermittent vasomotion induced by potassium in rat pulmonary artery was investigated with a view to characterize the ion channel mechanisms governing such secondary oscillatory activity. Isometric force was recorded from ring preparations of rat isolated pulmonary arteries incubated in a modified Krebs buffer containing K⁺ 15-18 mM and nitro-L-arginine methyl ester (10 µM). Tissues exhibited a stable pattern of on-off vasomotion consisting of intermittent contractile wave (ICW) activity with a periodicity of 7-8/hr and a rising phase of oscillatory ramping-up of contractile tone at 7 cycles/min. L-channel antagonists arrested (nicardipine; 3 nM) or retarded (verapamil, 30 nM) ICW activity with a concomitant wave asynchronization or decrease in amplitude. Mibefradil (30-100 nM) inhibited ICW ramping-up without affecting ICW period. Niflumic acid (1.0-3.0 µM) exerted dual actions on ICW amplitude but arrested ICW cycling at 10 µM. K⁺-channel blockers produced shortening of ICW period (4-aminopyridine, Ba²âº 30 µM; Cs⁺ 3.0-6.0 mM) and increase (tetraethylammonium; 1.0 mM) or decrease (Ba²âº, 100 µM) in amplitude. Cyclopiazonic acid caused ICW asynchronization (0.3 µM) or cessation (1.0 µM) of ICW cycling. Fasudil retarded ramping-up contractile oscillations without changing ICW period. The inhibitory effects of nicardipine, niflumic acid and cyclopiazonic acid were partially surmounted by small additional increments in [K⁺](e). Our findings support the concept that a secondary vasomotive oscillator operates in rat pulmonary artery which enables the activity of the primary oscillator to be regulated in a cyclic manner via sarcolemmal L-type Ca²âº channels and an array of K conductances.

Young adult outcomes of children growing up with chronic illness: an analysis of the National Longitudinal Study of Adolescent Health.

OBJECTIVE: To examine young adult outcomes in a nationally representative US cohort of young adults growing up with a chronic illness. DESIGN: Secondary analysis of nationally representative data from wave III (in 2001) of the National Longitudinal Study of Adolescent Health. SETTING: United States. PARTICIPANTS: The analytic sample comprised 13 236 young adults aged 18 to 28 years at wave III. MAIN EXPOSURE: Self-report of a chronic physical illness (asthma, cancer, diabetes mellitus, or epilepsy) in adolescence. Respondents with asthma or nonasthmatic chronic illness (cancer, diabetes mellitus, or epilepsy) were compared with individuals without these conditions. MAIN OUTCOME MEASURES: Self-report of high school graduation, ever having employment, currently having employment, living with a parent/guardian, and ever receiving public assistance. RESULTS: Three percent of young adults had nonasthmatic chronic illness (cancer, diabetes, or epilepsy), and 16.0% had asthma. Most young adults with chronic illness graduated high school (81.3%) and currently had employment (60.4%). However, compared with healthy young adults, those with nonasthmatic chronic illness were significantly less likely to graduate high school, ever have had employment, or currently have employment and were more likely to receive public assistance. Compared with young adults with asthma, those with nonasthmatic chronic illness again had significantly worse young adult outcomes on all measures. CONCLUSIONS: Most young adults growing up with a chronic illness graduate high school and have employment. However, these young adults are significantly less likely than their healthy peers to achieve these important educational and vocational milestones.

Alteration in hemodynamic effects of interleukin 2 after treatment with indomethacin in anesthetized rats.

The cardiovascular effects of interleukin 2 (IL2), were investigated in animals pretreated with indomethacin. Bolus intravenous administration of IL2 alone caused a significant reduction in cardiac output over time. Pretreatment with indomethacin significantly accentuated the reduction in cardiac output produced by IL2. The administration of IL2 or indomethacin alone or combined had no significant effects on dP/dt, heart rate or plasma troponin levels. As well, administration of either compound alone or combined had limited effects on mean circulatory filling pressure and arterial blood pressure. Injection of IL2 alone significantly increased resistance to venous return and arterial resistance at 3h post injections. Pretreatment with indomethacin caused IL2 to produce a significantly greater increase in arterial resistance and resistance to venous return. Administration of IL2 and indomethacin combined also produced significant reduction in stroke volume than IL2 or indomethacin alone. The injection of IL2 or indomethacin alone or combined had no significant impact on blood volume. Acute administration of IL2 appears to have no negative inotropic or chronotropic effects and its impact in reducing cardiac output is the result of an increase in vascular resistance. It seems that activation of prostanoids, possibly prostacyclin, has an acute beneficial effect in attenuating the initial negative effects of IL2 on cardiac output.

Transmural pressure and membrane potential in human saphenous vein.

OBJECTIVE: An increase in transmural pressure reportedly depolarizes myocytes in various arterial blood vessels. We have examined the relationship between transmural pressure and membrane potential (E(m)) in human saphenous veins with a view to determine whether contractile force generation, hence spasmogenesis in vein grafts, involves a similar process of mechanoelectrical excitation. METHODS: Intracellular recordings were made by sharp glass microelectrodes in human isolated saphenous veins and parallel measurements were performed in ring preparations. RESULTS: E(m) values obtained in pressurized vessels at four different pressure levels were (mean+/-SD): -74.4+/-5.5 mV (0-6 cm H(2)O; n=10), -72.6+/-6.5 mV (11-14 cm H(2)O; n=27), -72.1+/-6.5 mV (26-27 cm H(2)O; n=30), and -72.9+/-4.0 mV (50-54 cm H(2)O; n=38), demonstrating the lack of an overt pressure-dependence. Except at the lowest transmural pressure tested, these values were significantly different from E(m) obtained in ring preparations (-77.8+/-4.0 mV; n=30). Raising extracellular K(+) to 80 mM produced a comparable depolarization in tissues either pressurized to 50-54 cm H(2)O (-64.9+/-4.3 mV; n=27) or set up as ring preparations (-64.06+/-6.9 mV; n=35). CONCLUSIONS: Human saphenous veins respond to transmural pressure with a limited depolarization that lacks correlation with pressure. The absence of a pressure-induced graded depolarization suggests that pressure-dependent vasoconstriction does not play a primary role in blood flow regulation in lower limb large veins. Moreover, this raises doubts that mechanical stimuli per se would lead to development of vasospasm in the early stages of saphenous vein grafting into arterial vascular beds.

Influence of tangential stress on mechanical responses to vasoactive agents in human saphenous vein with and without perivascular adipose tissue.

AIM: Improvement in short-term patency of vein grafts harvested with the surrounding tissue and no distention has been noted. The influence of transient tangential stress on mechanical function to vasoactive agents in isolated human saphenous veins stripped or with attached perivascular adipose tissue was assessed. METHODS: Concentration-response curves to noradrenaline, 5-hydroxytryptamine, methylcholine, sodium nitroprusside and nicardipine were constructed for veins exposed to no, low (approximately 120 mmHg) or high (approximately 240 mmHg) tangential stress. RESULTS: Tangential stress did not affect contractile effects of noradrenaline or relaxant effects of methylcholine and sodium nitroprusside. Regression analysis of the concentration-response curve to 5-hydroxytryptamine revealed a significant (P=0.042) increase in sensitivity in saphenous veins without perivascular adipose tissue exposed to no tangential stress, compared with veins with attached adipose tissue. Exposure to high stress significantly (P=0.024) increased the potency of 5-hydroxytryptamine in blood vessels without perivascular adipose tissue, as opposed to veins with adipose tissue. Relaxant responses to nicardipine in veins with perivascular adipose tissue were significantly (P=0.001) affected by exposure to low tangential stress compared with no or high tangential stress. A parallel comparison revealed that intact veins compared with those without perivascular adipose tissue exposed to low stress were significantly (P=0.020) more resistant to the relaxant effects of nicardipine. CONCLUSION: The findings of the present report support the view that tangential stress has an impact on the actions of vasoactive agents, but this influence is variable and factor(s) released from perivascular adipose tissue may have a bearing on the observed effect.

beta-adrenoceptor mediated responses in rat pulmonary artery: putative role of TASK-1 related K channels.

The effect of isoprenaline on tone, cyclic adenosine 3':5' monophosphate (cAMP), and smooth muscle membrane potential (E ( m )) were assessed in rat isolated pulmonary arteries. N(omega)-nitro-L-arginine methyl ester (10.0 microM) or removal of endothelium partially inhibited relaxant responses to isoprenaline, but glibenclamide (10.0 microM) and indomethacin (10.0 microM) did not. While Rp-8-Br-cAMP (30.0 microM), tetraethylammonium (0.3 & 1.0 mM), 4-aminopyridine (100 microM), anandamide (10.0 microM), charybdotoxin (0.1 microM), ouabain (100 microM), and barium chloride (100 microM), incompletely blocked relaxation to isoprenaline, cyclopiazonic acid (1.0 microM), apamin (3.0 microM) and zinc acetate (300 microM) were without effect. Increasing extracellular K(+) ([K(+)](e)) inhibited relaxant responses to isoprenaline, completely abolishing the response at 30 mM [K+](e). Vasorelaxant effects of isoprenaline were significantly attenuated in buffer pH 6.4, and concomitant presence of Rp-8-Br-cAMP (30.0 microM) in pH 6.4 produced significant additive inhibition when compared to pH 6.4 without Rp-8-Br-cAMP. Isoprenaline increased cAMP turnover (1.55+/-0.24 fold; mean +/- SEM), which was inhibited by propranolol (1.0 microM). Resting E ( m ) of smooth muscle cells was -63.0+/-0.50 mV, and isoprenaline (1.0 microM) produced hyperpolarisation (-73.3+/-0.80 mV). While glibenclamide failed to affect isoprenaline-induced hyperpolarisation, ICI 118,551 (1.0 microM), anandamide or buffer pH 6.4 prevented it, and barium chloride and oubain combined caused partial inhibition. Isoprenaline-mediated relaxation seems to arise from several processes, including the generation of nitric oxide, the cAMP-cascade and, more importantly, a hyperpolarisation that is not due to activation of ATP-sensitive K channels but possibly of two-pore domain K channels of the TASK family.

A comparison between haemodynamic effects of vasopressin analogues.

Some analogues of arginine vasopressin (AVP) reportedly possess hypotensive properties, and two such peptides are Cys(1)-Tyr(2)-Phe(3)-Val(4)-Asn(5)-Cys(6)-Pro(7)- d-Arg(8)-Gly(9)-NH(2) (VD-AVP) and d(CH(2))(5)-Cys(1)- d-Tyr(Et)(2)-Arg(3)-Val(4)-Asn(5)-Cys(6)-Lys(7)-Lys(8)-ethylenediamine(9) (TA-LVP). In the present investigation we examined the effects of TA-LVP (0.3, 1.0 and 3.0 microg/kg/min), VD-AVP (0.3, 1.0 and 3.0 microg/kg/min) and AVP (1.0, 3.0, 10 ng/kg/min) on haemodynamics, blood volume (BV) and plasma troponin levels in anaesthetised rats. Infusion of TA-LVP significantly ( P<0.05) reduced blood pressure (-45+/-3%; n=8; mean +/- SEM), mean circulatory filling pressure ( P(mcf); -41+/-3%), and cardiac output (CO; -59+/-4%). The reduction in CO at a lower dose of TA-LVP was due to reduced venous tone, while at higher doses the reduction was predominantly the result of reduced BV (-35+/-4%). The large decrease in BV during the infusion of TA-LVP, substantially increased resistance to venous return (50+/-11%), which was the main contributor in reducing CO. Administration of AVP significantly increased blood pressure (41+/-4%) and arterial resistance (98+/-16%) without any impact on P(mcf) and BV, while significantly reducing CO (-26+/-5%). Infusion of VD-AVP did not produce hypotension, but produced a modest but significant reduction in CO (-18+/-5%) and insignificant but moderate increases in peripheral resistance (30+/-12%) and resistance to venous return (28+/-8%). Plasma troponin levels were not affected by any of the peptides. The hypotensive action of TA-LVP was due to a reduction in CO as a result of a reduced pre-load, while the pressor effect of AVP increased after-load sufficiently to impede flow, reducing CO. VD-AVP was devoid of any hypotensive effects, suggesting that V(2)-vasopressin receptors are most likely to play a limited role in the control of cardiac and vascular function in these animals.

Haemodynamic effects of endothelin receptor antagonist, tezosentan, in tumour necrosis factor-alpha treated anaesthetized rats.

Administration of tumour necrosis factor-alpha (TNF-alpha) produces progressive reduction in cardiac output (CO) by affecting preload, afterload and cardiac contractility. We have examined the effect of an endothelin receptor antagonist, tezosentan (1, 3 or 10 mg/kg), on CO, heart rate (HR), blood pressure (BP), mean circulatory filling pressure (P(mcf)), resistance to venous return (RVR), arterial resistance (AR), dP/dt, stroke volume (SV), plasma levels of NO(2)(-)/NO(3)(-), and inducible nitric oxide synthase (iNOS) activity in lungs, ex vivo, following treatment with TNF-alpha (30 microg/kg) in anaesthetized rats. Treatment with TNF-alpha alone resulted in significant reduction in CO (40+/-4%), dP/dt (24+/-2%), P(mcf) (24+/-2%), BP (21+/-3%) and SV (38+/-5%) ( n=6; mean +/- SEM), and significant increases in RVR (38+/-9%) and AR (45+/-6%). There were no significant changes in HR or in plasma levels of NO(2)(-)/NO(3)(-) in animals treated with TNF-alpha but there was a modest but significant increase in iNOS activity. Tezosentan alone did not have any effect on haemodynamics, plasma levels of NO(2)(-)/NO(3)(-) or iNOS activity. Tezosentan at the highest dose abolished the effects of TNF-alpha on dP/dt, AR, and RVR. In animals treated with a combination of TNF-alpha and highest dose of tezosentan CO, P(mcf), BP, and SV were reduced by 28+/-5%, 16+/-3%, 21+/-4%, and 27+/-5%, respectively. Tezosentan was able to inhibit the negative impact of TNF-alpha on AR and dP/dt but not on P(mcf). It is likely that the negative impact of TNF-alpha on CO in tezosentan-treated animals could be entirely attributed to reduction in preload.