Direct and sympathetically mediated venoconstriction in essential hypertension. Enhanced responses to endothelin-1.

Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide. Although circulating concentrations are not increased in essential hypertension, enhanced sensitivity to endothelin-1 has been observed in animal models of hypertension. We investigated dorsal hand vein responses to local infusion of endothelin-1 and norepinephrine in 12 patients with essential hypertension who had never received treatment and in 12 age and sex matched normotensive control subjects. The maximal venoconstriction and the geometric mean of the dose of norepinephrine that caused 50% of maximal venoconstriction were similar in hypertensive (mean +/- SE; 80 +/- 4%; 31 +/- 8 pmol/min) and normotensive subjects (87 +/- 5%, 22 +/- 9 pmol/min). In contrast, mean venoconstriction to endothelin-1 was significantly greater in hypertensive (49 +/- 5%) than in normotensive subjects (27 +/- 2%; P = 0.004). Sympathetically mediated venoconstriction elicited by deep breath was substantially potentiated by endothelin-1 in hypertensive (67 +/- 7% at 90 min) but not normotensive subjects (11 +/- 3% at 90 min; P = 0.001). Venoconstriction to endothelin-1 correlated positively with mean arterial pressure in the hypertensive subjects (r = 0.82; p = 0.001) but negatively in the normotensive subjects (r = -0.58; p = 0.047). Endothelin-1 may contribute to the reduction of venous compliance occurring in the early stages of essential hypertension and to the altered systemic hemodynamics in this condition.     

The effect of sildenafil on nitric oxide-mediated vasodilation in healthy men

BACKGROUND: Sildenafil, a treatment for erectile dysfunction, is a specific phosphodiesterase type 5 (PDE 5) inhibitor that enhances nitric oxide (NO)-mediated vasodilation in the corpus cavernosum by inhibiting cyclic guanosine monophosphate breakdown. Since PDE 5 is widely expressed in the vasculature, we examined the hypothesis that sildenafil could enhance NO-mediated vasodilation in other vascular beds and improve endothelial function. METHODS: NO-mediated responses to acetylcholine (endothelium-dependent) and nitroglycerin (endothelium-independent) were measured in healthy men in the dorsal hand vein (n = 13), after the administration of either sildenafil 50 mg or placebo. Flow-mediated dilation of the brachial artery and forearm postischemic reactive hyperemia were measured before and after sildenafil 50 mg, isosorbide dinitrate 5 mg, and placebo in a double-blind, randomized, crossover study (n = 11). RESULTS: In the hand vein, sildenafil administration increased sensitivity to local nitroglycerin. The 50% effective dose decreased approximately 4-fold from 13.5 ng/min (range, 6.9-26.6 ng/min) to 2.7 ng/min (range, 1.1-6.4 ng/min) (P =.025). Sildenafil decreased the maximum venoconstriction induced by phenylephrine from 81% +/- 3% to 74% +/- 3% (P =.025). Sildenafil did not significantly affect the maximal venodilatory response to acetylcholine (35% +/- 7% after placebo versus 32% +/- 8% after sildenafil) (P =.7). In the arterial vasculature, flow-mediated dilation before (2.4% +/- 1%) and after (2.8% +/- 1.4%) sildenafil (P =.8) and postischemic reactive hyperemia area under the curve before (1807 +/- 393 mL. min. s/100 mL) and after (1467 +/- 257 mL. min. s/100 mL) sildenafil were not different (P =.8). Resting heart rate, blood pressure, and resting brachial artery diameter were unchanged after sildenafil administration. Isosorbide dinitrate, an endothelium-independent vasodilator, caused a significant increase in resting brachial artery diameter from 0.53 +/- 0.01 cm to 0.56 +/- 0.02 cm (P =.005), without altering flow-mediated dilation. CONCLUSIONS: In healthy men sildenafil increased sensitivity to nitroglycerin, an exogenous NO donor, approximately 4-fold but did not affect endothelium-dependent, NO-mediated responses in either the hand vein or forearm vasculature. Differential vascular responses to sildenafil may localize its enhancement of endogenous NO-mediated vasodilation to vascular beds such as the corpus cavernosum.     

Effects of systemic endothelin A receptor antagonism in various vascular beds in men: in vivo interactions of the major blood pressure-regulating systems and associations with the GNB3 C825T polymorphism

OBJECTIVE: We used the orally available endothelin A (ETA) receptor antagonist darusentan to characterize interactions between the major blood pressure-regulating systems in healthy men. Mediators of the endothelin system, the sympathetic nervous system, and the renin-angiotensin system act via G protein-coupled receptors with a possible involvement of the G-protein beta3 subunit (GNB3) C825T polymorphism. We studied the influence of this polymorphism on the responses to ETA antagonism in the presence of endothelin 1 (ET-1), norepinephrine (NA), and angiotensin II (ANGII). METHODS: Thirty-seven individuals were included in a randomized, double-blind, placebo-controlled, crossover trial with 100 mg darusentan. Systemic hemodynamics and plasma ET-1, NA, and ANGII concentrations were assessed. Local studies were performed in the dorsal hand veins (n=18) and skin microcirculation (n=12), respectively. RESULTS: Darusentan lowered systolic and diastolic blood pressure ( P <.001 versus placebo) without any differences according to genotype (mean maximum Delta systolic blood pressure, -7 +/- 2 mmHg for CT/TT versus -5 +/- 3 mmHg for CC, P=.37; mean maximum Delta diastolic blood pressure, -3 +/- 2 mmHg for CT/TT versus -4 +/- 2 mmHg for CC, P=.96). Venoconstriction to ET-1 and NA was not affected by ET A blockade in either group; however, carriers of the 825T allele demonstrated a markedly enhanced venoconstriction to ET-1 and NA (median effective concentration [ED50] for ET-1 after darusentan [placebo]: 2.5 +/- 0.2 pmol/min for CT/TT [2.7 +/- 0.3 pmol/min], P=.42; 3.9 +/- 0.6 pmol/min for CC [4.6 +/- 0.3 pmol/min], P=.42; P=.046 [P=.0005] for CT/TT versus CC) (ED50 for NA after darusentan [placebo]: 5.2 +/- 1.2 ng/min for CT/TT [7.3 +/- 1.2 ng/min], P=.20; 32.9 +/- 7.1 ng/min for CC [19.7 +/- 5.5 ng/min], P=.75; P=.0008 [P=.026] for CT/TT versus CC). Darusentan dilated veins at baseline in CC homozygous subjects (+0.21 +/- 0.05 mm, P=.004 versus placebo). Systemic ET A antagonism inhibited constriction to ET-1 and also to NA and ANGII in the skin microcirculation without differences according to genotype (ET-1, P=.017 for all individuals versus placebo; NA, P=.0005; and ANGII, P=.002). CONCLUSION: GNB3 C825T allele carrier status did not influence systemic hemodynamic or local vascular responses to ET A blockade with darusentan in young, healthy men. However, it determined venoconstriction to exogenous ET-1 and NA. Darusentan markedly inhibited not only ET-1-induced but also NA-induced and ANGII-induced vasoconstriction in the skin microcirculation. In contrast, it had no effects on either ET-1-mediated or NA-mediated venoconstriction, indicating that, in the presence of high local ET-1 concentrations, constrictive endothelin B receptors may be of greater importance in the venous vasculature than has been recognized so far.     

In vitro prostacyclin production by ovine uterine and systemic arteries. Effects of angiotensin II.

Normal pregnancy is associated with reduced systemic pressor responses to infused angiotensin II (ANG II); furthermore, the uterine vascular bed is even less responsive to vasoconstriction by ANG II than the systemic vasculature overall. The mechanism(s) for this refractoriness remains unknown. To determine if vessel production of prostacyclin may be responsible, uterine and omental artery segments were obtained from four groups of sheep, nonpregnant (NP), pregnant (P; 131 +/- 4 d), early postpartum (2.2 +/- 0.4 d), and late postpartum (16 +/- 2 d), and incubated in Krebs-Henseleit alone or with ANG II in the absence or presence of Saralasin. Prostacyclin was measured as 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). Synthesis of 6-keto-PGF1 alpha was de novo, since aspirin inhibited its formation. P and early uterine arteries produced more 6-keto-PGF1 alpha than NP and late vessels (P less than 0.05): 386 +/- 60 (X +/- SE) and 175 +/- 23 vs. 32 +/- 5 and 18 +/- 4 pg/mg X h, respectively. A similar relationship was observed for omental arteries: 101 +/- 14 and 74 +/- 14 vs. 36 +/- 10 and 22 +/- 4 pg/mg X h, respectively. Furthermore, synthesis by arteries from P and early animals was greater in uterine than omental vessels (P less than 0.05); this was not observed in NP or late vessels. ANG II increased 6-keto-PGF1 alpha production 107 +/- 20% and 92 +/- 16% in P and early uterine arteries only; the threshold dose was between 5 X 10(-11) and 5 X 10(-9) M ANG II. This ANG II-induced increase in 6-keto-PGF1 alpha by uterine arteries was inhibited by Saralasin, which by itself had no effect. During pregnancy, the reduced systemic pressor response to ANG II and the even greater refractoriness of the uterine vascular bed may be reflective of vessel production of the potent vasodilator, prostacyclin. Furthermore, in the uterine vasculature, this antagonism may be potentiated by specific ANG II receptor-mediated increases in prostacyclin.     

Cardiovascular and endocrine responses during the cold pressor test in subjects with cervical spinal cord injuries

OBJECTIVE: To investigate cardiovascular regulation and endocrine responses during the cold pressor test in patients with chronic spinal cord injury (SCI). DESIGN: Experimental and control study. SETTING: University laboratory, department of rehabilitation medicine, in Japan. PARTICIPANTS: Eight quadriplegic subjects with complete spinal cord transection at the C6 to C8 level and 6 age-matched healthy subjects. INTERVENTIONS: Cardiovascular and endocrine responses were examined during 2 minutes of control, 3 minutes of ice-water immersion of the foot, followed by a 3-minute recovery. MAIN OUTCOME MEASURES: Blood pressure, heart rate, the Borg 15-point Rating of Perceived Pain Scale, and blood samples for measurement of plasma norepinephrine, epinephrine, plasma renin activity, plasma aldosterone, and arginine vasopressin. RESULTS: The rise in the mean arterial blood pressure during the cold pressor test in patients with SCI (baseline, 81.6+/-3.7mmHg; increased by 30%+/-6.1%) was significantly (P<.05) higher than that in healthy subjects (baseline, 101.2+/-4.5mmHg; increased by 20%+/-4.5%). The SCI subjects had no change in heart rate throughout the test, in contrast to the tachycardia noted in normal subjects. Baseline plasma norepinephrine in SCI subjects (63.0+/-18.3pg/mL) was significantly lower than in normal subjects (162.3+/-19.6pg/mL) and plasma norepinephrine increased significantly during the cold pressor test in both groups. CONCLUSIONS: In the SCI subjects, a reflex sympathetic discharge through the isolated spinal cord results in a more profound rise in mean blood pressure during ice-water immersion. This response was free of inhibitory impulses from supraspinal center and baroreceptor reflexes, either of which might restrain the increase in blood pressure.     

Influence of sibutramine treatment on sympathetic vasomotor tone in obese subjects

BACKGROUND: Sibutramine, a serotonin and norepinephrine transporter blocker, is used as adjunctive obesity treatment. Studies in healthy subjects suggested that sibutramine might have opposing effects on peripheral and central sympathetic activity; an increase in blood pressure has been claimed. Direct measurements of muscle sympathetic nerve activity (MSNA) in sibutramine-treated patients have not been conducted. METHODS AND RESULTS: Twenty nondiabetic obese men and women completed the study (mean body mass index, 35 +/- 3 kg/m2; mean age, 42 +/- 8 years). They were treated for 5 days with 15 mg sibutramine per day or matching placebo in a randomized, double-blind, crossover fashion. At the end of each intervention, heart rate, blood pressure, and MSNA were recorded. Patients underwent cold pressor testing and phenylephrine and nitroprusside infusions. RESULTS: The mean blood pressure (systolic/diastolic) was 118 +/- 13 mm Hg/70 +/- 9 mm Hg with placebo and 120 +/- 13 mm Hg/69 +/- 8 mm Hg with sibutramine (P = .29). The mean resting MSNA was 28 +/- 14 bursts/min with placebo and 12 +/- 10 bursts/min with sibutramine (P < .0001). Sibutramine attenuated the rise in blood pressure (25 +/- 9 mm Hg/9 +/- 9 mm Hg versus 31 +/- 12 mm Hg/14 +/- 9 mm Hg, P < .01) and MSNA (0.3 +/- 0.5 arbitrary units/min versus 1.0 +/- 1.1 arbitrary units/min, P = .01) in response to cold pressor testing. Baroreflex heart rate control was similar with sibutramine and with placebo. The sympathetic baroreflex was shifted such that at a given blood pressure, MSNA was substantially decreased (top, 44 +/- 1.23 bursts/min versus 58 +/- 2.99 bursts/min [P < .001]; center point, 65 +/- 0.32 mm Hg versus 67 +/- 0.81 mm Hg [P < .05]). CONCLUSIONS: Sibutramine treatment profoundly and selectively reduces sympathetic nerve traffic at rest and attenuates the responsiveness to sympathetic stimuli. Our data support the idea that sibutramine's peripheral sympathomimetic effect is counteracted by a central sympatholytic mechanism.     

Inhibition of prostaglandin synthesis does not alter the decrease in pre-capillary resistance in the human calf in response to small cumulative increases in venous congestion

The decrease in pre-capillary resistance in the human calf during gradual cumulative increases in venous congestion pressure has been proposed to represent vasodilator signalling between the venous and arterial microcirculations. The present study investigated whether prostaglandins are involved in this local flow regulation by measuring calf blood flow and microvascular filtration capacity using strain gauge plethysmography in young male subjects before (baseline) and after taking either ibuprofen, an inhibitor of prostaglandin synthesis (1600 mg over 2 days), or placebo. At baseline, inflation of a thigh cuff to 50 mmHg in steps of 10 mmHg, each held for 5 min, did not decrease arterial inflow, confirming a reduction of pre-capillary resistance. Ibuprofen reduced resting calf blood flow by 35% (P<0.001), but flow at a Pcuff (cuff pressure) of 50 mmHg was 97% of this value, i.e. pre-capillary resistance had decreased to the same extent as before inhibition of prostaglandin synthesis. Ibuprofen also reduced microvascular filtration capacity (2.98+/-1.20 compared with 3.71+/-0.89 ml.min-1.100 ml-1.mmHg-1x10(-3); P<0.05), probably due to a combination of reduced arterial inflow and lower venous pressure (8.5+/-5.2 compared with 12.6+/-2.8 mmHg; P<0.05) that moderated capillary hydrostatic pressure to override direct effects of inhibition of prostaglandin synthesis on permeability. Placebo was without effect on any measurement. It is unlikely therefore that prostaglandin-mediated vasodilator signals, which have been demonstrated between paired veins and arteries, are important in local vasodilation in response to venous congestion.     

Influence of St John's wort on catecholamine turnover and cardiovascular regulation in humans

BACKGROUND: St John's wort (Hypericum perforatum) is a popular over-the-counter antidepressant. Its antidepressive effect has been attributed in part to inhibition of monoamine transporters and monoamine oxidase, on the basis of in vitro studies. METHODS: In a double-blind, randomized, placebo-controlled, crossover study, 16 healthy subjects (11 men and 5 women; mean age, 31 +/- 5 years) ingested either St John's wort (300 mg three times daily) or placebo for 7 days. Imipramine treatment (50 mg three times daily) in 7 subjects served as a positive control. After treatment, physiologic and biochemical tests included cardiovascular reflex testing, graded head-up tilt testing, and plasma catecholamine determinations. RESULTS: St John's wort had no effect on blood pressure, heart rate, heart rate variability, or blood pressure variability, regardless of the test condition. St John's wort had no effect on plasma concentrations of norepinephrine and its main metabolite, dihydroxyphenylglycol, whereas plasma dihydroxyphenylacetic acid (DOPAC; the main metabolite of dopamine) concentrations increased in every subject (1661 +/- 924 pg/mL versus 1110 +/- 322 pg/mL with placebo, P=.04). In contrast, imipramine increased resting blood pressure (124 +/- 10 mmHg/71 +/- 5 mmHg versus 110 +/- 8 mmHg/61 +/- 6 mmHg with placebo, P=.005 for systolic values and P=.003 for diastolic values) and heart rate (74 +/- 7 beats/min versus 62 +/- 6 beats/min with placebo, P=.005) and elicited a marked orthostatic tachycardia (increase in heart rate of 43 +/- 17 beats/min versus 26 +/- 8 beats/min with placebo, P=.006). CONCLUSIONS: Our findings challenge the concept that St John's wort elicits a major change in norepinephrine uptake or monoamine oxidase activity in vivo. The consistent increase in plasma DOPAC concentrations might suggest a novel mode of action or an inhibitory effect on dopamine beta-hydroxylase that should be followed up. We propose that a combination of physiologic and biochemical profiling may help better define the mode of action and potential side effects of herbal remedies.     

A new method for measuring inhibition of platelet function by nonsteroidal antiinflammatory drugs

Aspirin is widely used to help prevent vascular occlusion caused by atherosclerotic vascular disease. We used a platelet-aggregation assay (PAA) to evaluate the reliability of a proprietary platelet agonist, platelet prostaglandin agonist (PPA), to detect the amount of platelet inhibition induced by four different classes of nonsteroidal antiinflammatory drugs (NSAIDs) with antiplatelet effects. Twenty normal donors were evaluated before and 24 hours after ingestion of 325 mg of aspirin. With 125 micromol/L PPA, the slope of the PPA-PAA curve completely differentiated aspirin-treated from normal platelets. The aspirin platelet slope, 27.9 +/- 2.0 (range 5.5-47), was significantly decreased (P <.001) compared with the findings before administration of aspirin, 75 +/- 3.1 (range 50-125). Additionally, the time elapsed before 50% platelet aggregation (T(50)) with aspirin, 10.1 +/- 0.7 minutes (range 4.7-17), was significantly prolonged (P <.05) compared with the mean time before administration of aspirin (4.2 +/- 0.2 minutes, range 1.7-6.4). Aspirin in a daily dosage of 325 mg for 14 days produced significantly greater inhibition of PPA-PAA than that induced by a single 325-mg dose (P <.001). The long-term platelet-inhibitory effects of aspirin in 9 normal volunteers were evaluated with PPA-PAA 2, 8, 24, 48, 72, and 96 hours after a single dose of aspirin, 81 or 325 mg. Compared with the preaspirin slope, 79.6 +/- 1.9, the maximal decrease in slope occurred after 2 hours for both 81 mg (61.3 +/- 6.7) and 325 mg (12.1 +/- 1.8). The decreased slopes and increased T(50) observed at 2, 8, and 24 hours (P <.001) reflected the greater degree of platelet inhibition with 325 mg than with 81 mg aspirin. Inhibition of PPA-PAA was observed with nonaspirin nonsteroidal antiinflammatory drugs (NNSAIDs), but, compared with aspirin, the inhibition was minimal. PPA-PAA may be used to help measure the magnitude of NSAID-induced inhibition of platelets.     

Use of alpha 2 adrenoreceptor agonists and antagonists in the functional assessment of the sympathetic nervous system.

We studied the effects of clonidine, an alpha 2-adrenoreceptor agonist, and yohimbine, an alpha 2-adrenoreceptor antagonist, on blood pressure, heart rate, and plasma catecholamines in 12 patients with autonomic dysfunction. Clonidine (0.1 mg, orally) lowered blood pressure 18 +/- 3 torr in six subjects and raised it 5 +/- 1 torr in six. The change in blood pressure in response to this dose of clonidine was inversely proportional to the supine level of norepinephrine (P less than 0.05). Yohimbine (4-64 micrograms/kg) raised plasma norepinephrine and blood pressure in six patients with degenerative autonomic dysfunction. Yohimbine also attenuated by 50% (P less than 0.05) the hypotensive response to head-up tilt of patients with degenerative autonomic dysfunction. Clonidine depends upon postjunctional hypersensitivity and the degree of autonomic insufficiency to elicit its pressor response. In contrast, the pressor response to yohimbine is related to the capacity of the sympathetic nervous system to be activated and release norepinephrine. If plasma norepinephrine levels following yohimbine administration are monitored, the biochemical and hemodynamic response to the drug may provide a sensitive indication of the capacity of the sympathetic nervous system to be activated in patients with autonomic dysfunction.     

The angiotensin II receptor antagonist valsartan inhibits endothelin 1-induced vasoconstriction in the skin microcirculation in humans in vivo: influence of the G-protein beta3 subunit (GNB3) C825T polymorphism

OBJECTIVE: We investigated the influence of angiotensin II receptor blockade on angiotensin II-induced, endothelin 1 (ET-1)-induced, and norepinephrine-induced vasoconstriction to further characterize interactions of the 3 major pressor systems. ET-1, angiotensin II, and norepinephrine act via G protein-coupled receptors with a possible involvement of the G-protein beta3 subunit (GNB3) C825T polymorphism. We studied the influence of this polymorphism on the responses to angiotensin II antagonism in the presence of ET-1, norepinephrine, and angiotensin II. METHODS: Twenty-five healthy men (mean age, 28.6 +/- 4 years; n = 14 CC, n = 9 CT, and n = 2 TT) were included in a double-blind, randomized, placebo-controlled crossover study. We used a laser Doppler imager to evaluate skin perfusion changes after injection of ET-1, angiotensin II, and norepinephrine (10(-18), 10(-16), and 10(-14) mol) after oral intake of the angiotensin II receptor antagonist valsartan (80 mg) or placebo. Data were analyzed with ANOVA or t test and are expressed as arbitrary perfusion units (PU) (mean +/- SEM). RESULTS: Valsartan abolished angiotensin II-induced vasoconstriction and, more importantly, also ET-1-induced vasoconstriction in the skin microcirculation (ET-1 placebo versus valsartan, - 33 +/- 10 PU versus +33 +/- 21 PU for CC [P = .02] and -71 +/- 25 PU versus +108 +/- 21 PU for CT/TT [P < .001]). For both ET-1 and angiotensin II, valsartan effects were greater in GNB3 835T-allele carriers (P = .007 and P = .03 for ET-1 and angiotensin II, respectively, for CC versus CT/TT). Norepinephrine-mediated constriction was not influenced by valsartan. These effects were independent of blood pressure. CONCLUSION: Our results indicate that the renin-angiotensin system may significantly contribute to ET-1-mediated microvascular responses. Valsartan inhibited local vasoconstriction to angiotensin II and ET-1 to a greater degree in carriers of the GNB3 825T allele, which adds to data from earlier studies implicating the C825T polymorphism as a pharmacogenetic marker for drug effects.     

Hemodynamic and neurohumoral effects of various grades of selective adenosine transport inhibition in humans. Implications for its future role in cardioprotection.

In 12 healthy male volunteers (27-53 yr), a placebo-controlled randomized double blind cross-over trial was performed to study the effect of the intravenous injection of 0.25, 0.5, 1, 2, 4, and 6 mg draflazine (a selective nucleoside transport inhibitor) on hemodynamic and neurohumoral parameters and ex vivo nucleoside transport inhibition. We hypothesized that an intravenous draflazine dosage without effect on hemodynamic and neurohumoral parameters would still be able to augment the forearm vasodilator response to intraarterially infused adenosine. Heart rate (electrocardiography), systolic blood pressure (Dinamap 1846 SX; Critikon, Portanje Electronica BV, Utrecht, The Netherlands) plasma norepinephrine and epinephrine increased dose-dependently and could almost totally be abolished by caffeine pretreatment indicating the involvement of adenosine receptors. Draflazine did not affect forearm blood flow (venous occlusion plethysmography). Intravenous injection of 0.5 mg draflazine did not affect any of the measured hemodynamic parameters but still induced a significant ex vivo nucleoside-transport inhibition of 31.5 +/- 4.1% (P < 0.05 vs placebo). In a subgroup of 10 subjects the brachial artery was cannulated to infuse adenosine (0.15, 0.5, 1.5, 5, 15, and 50 micrograms/100 ml forearm per min) before and after intravenous injection of 0.5 mg draflazine. Forearm blood flow amounted 1.9 +/- 0.3 ml/100 ml forearm per min for placebo and 1.8 +/- 0.2, 2.0 +/- 0.3, 3.8 +/- 0.9, 6.3 +/- 1.2, 11.3 +/- 2.2, and 19.3 +/- 3.9 ml/100 ml forearm per min for the six incremental adenosine dosages, respectively. After the intravenous draflazine infusion, these values were 1.6 +/- 0.2 ml/100 ml forearm per min for placebo and 2.1 +/- 0.3, 3.3 +/- 0.6, 5.8 +/- 1.1, 6.9 +/- 1.4, 14.4 +/- 2.9, and 23.5 +/- 4.0 ml/100 ml forearm per min, respectively (Friedman ANOVA: P < 0.05 before vs after draflazine infusion). In conclusion, a 30-50% inhibition of adenosine transport significantly augments the forearm vasodilator response to adenosine without significant systemic effects. These results suggest that draflazine is a feasible tool to potentiate adenosine-mediated cardioprotection in man.     

Vasopressin pressor effects in critically ill children during evaluation for brain death and organ recovery

BACKGROUND: Vasopressin (VP) shows promise as a pressor agent in animals and adult human cardiac arrest and resuscitation, but has not been studied for pressor effect in critically ill or arrested children. VP infusion is routine treatment for diabetes insipidus during brain death evaluation and organ recovery. We hypothesized that low dose VP infusion during organ recovery in critically ill children exerts a pressor effect, without major organ toxicity. METHODS: 34 VP-treated and 29 age-matched critically ill controls (C) < or =18 years were retrospectively reviewed during brain death evaluation and organ recovery. VP infusion protocol titrated VP dose clinically to urine output, with high variability. Pressor and inotrope management was titrated clinically to BP, cerebral perfusion and central venous pressures (when available) and peripheral perfusion with similar protocol targets for pre-load in VP and C groups. Outcome measures include dose, type and number of pressors and inotropes. Organ function was assessed at recovery and 48 h post-transplant by independent surgeon and transplant program organ function criteria. Analysis by Odds Ratio (OR), and chi-square. RESULTS: VP dose averaged 0.041+/-0.069 U/kg/h. Average baseline mean arterial pressure (MAP) before VP infusion was 79+/-17 mmHg VP and 76+/-14 mm Hg C (P=0.6). Subsequent average MAP were: 82+/-21 mmHgVP after VP infusion versus 71+/-16 mmHg C (P=0.01) and 80+/-14 mmHg VP versus 68+/-22 mmHg C (P=0.01). Ability to wean/stop pressors and inotropes was: dopamine (14/23) 42% VP versus (10/26) 38% C (P=0.75), dobutamine (4/7) 57% VP versus (0/6) 0% C (P=0.026), epinephrine (4/5) 80% VP versus (0/6) 0% C (P=0.006), norepinephrine/phenylephrine (4/4) 100% VP versus (2/5) 40% C (P=0. 057). Alpha agonist pressor dependence was successfully weaned from 7/9 (78%) VP versus 0/9 (0%) C: odds ratio=7.3, (P<0.01). There was no VP induced dysrhythmia, hypertension, anuria or toxicity reported. Good organ recovery function was not significantly different at recovery or 48 h post-transplant for kidney (79% VP versus 69% C, P=0.068), liver (87% VP versus 95% C, P=0.533), or heart (90% VP versus 71% C, P=0.11). CONCLUSIONS: Low dose vasopressin infusion exerts a pressor effect in critically ill children treated for diabetes insipidus during brain death and organ recovery. VP treated patients were 7.3 times more likely to wean from alpha agonists than comparably managed age matched controls, without adverse affect on transplant organ function. We speculate that further prospective assessment of VP safety and efficacy as a pressor adjunct for resuscitation of critically ill children is warranted.     

Altered pressor responses in long-term nitrendipine treatment

The effect of long-term treatment with nitrendipine on systemic pressor responses to norepinephrine (NE) and angiotensin II (AII) was evaluated in 11 subjects with mild, uncomplicated hypertension. Pressor responses to NE and AII were measured at the end of a 4-wk placebo period and after 5 wk treatment with nitrendipine (final dose 16 mg twice daily; range 5 to 20 mg/day) or placebo. In subjects who received nitrendipine, clinic supine blood pressure was reduced from 152 +/- 12/96 +/- 4 mm Hg to 134 +/- 11/84 +/- 5 mm Hg and pressor responses to NE but not to AII were attenuated. Endogenous plasma levels of NE and renin activity were not changed by nitrendipine. Data suggest that noradrenergic blood pressure control mechanisms depend more on cellular calcium transport than do AII-mediated ones and may help explain the greater effectiveness of calcium entry blockers in the treatment of low-renin hypertension.     

Differential effects of vasopressin and norepinephrine on vascular reactivity in a long-term rodent model of sepsis

OBJECTIVE: There is escalating interest in the therapeutic use of vasopressin in septic shock. However, little attention has focused on mechanisms underlying its pressor hypersensitivity, which contrasts with the vascular hyporesponsiveness to catecholamines. We investigated whether a long-term rodent model of sepsis would produce changes in endogenous levels and pressor reactivity to exogenous norepinephrine and vasopressin comparable with those seen in septic patients. DESIGN: In vivo and ex vivo animal study. SETTING: University research laboratory. SUBJECTS: Male adult Wistar rats. INTERVENTIONS AND MEASUREMENTS: Fecal peritonitis was induced in conscious, fluid-resuscitated rats. Biochemical and hormonal profiles were measured at time points up to 48 hrs. Pressor responses to intravenous norepinephrine, vasopressin, and F-180, a selective V1 receptor agonist, were measured at 24 hrs. Contractile responses to these drugs were assessed in mesenteric arteries taken from animals at 24 hrs using wire myography. Comparisons were made against sham operation controls. MAIN RESULTS: Septic rats became unwell and hypotensive, with a mortality of 64% at 48 hrs (0% in controls). Plasma norepinephrine levels were elevated in septic animals at 24 hrs (1968 +/- 490 vs. 492 +/- 90 pg/mL in controls, p = .003), whereas vasopressin levels were similar in the two groups (4.5 +/- 0.8 vs. 3.0 +/- 0.5 pg/mL, p = not significant). In vivo, the pressor response to norepinephrine was markedly reduced in the septic animals, but responses to vasopressin and F-180 were relatively preserved. In arteries from septic animals, norepinephrine contractions were decreased (efficacy as measured by maximum contractile response, Emax: 3.0 +/- 0.3 vs. 4.7 +/- 0.2 mN, p < .001). In contrast, the potency of vasopressin (expressed as the negative log of the concentration required to produce 50% of the maximum tension, pD2: 9.1 +/- 0.04 vs. 8.7 +/- 0.05, p < .001) and F-180 (pD2 8.2 +/- 0.04 vs. 7.6 +/- 0.02, p < .001) was enhanced (n > or = 6 for all groups). CONCLUSIONS: This long-term animal model demonstrates changes in circulating vasoactive hormones similar to prolonged human sepsis, and decreased pressor sensitivity to norepinephrine. Ex vivo sensitivity to vasopressin agonists was heightened. This model is therefore appropriate for the further investigation of mechanisms underlying vasopressin hypersensitivity, which may include receptor or calcium-handling alterations within the vasculature.     

Oxygen consumption, assessed with the oxygen absorption spectrophotometer, decreases independently of venoconstriction during hepatic anaphylaxis in perfused rat liver

Anaphylactic shock is accompanied by a decrease in oxygen consumption. However, it is not well known whether oxygen consumption decreases during local anaphylactic reaction in liver. We determined the effects of anaphylaxis and norepinephrine on oxygen consumption in isolated rat livers perfused portally and recirculatingly at constant flow with blood (hematocrit, 12%). Oxygen consumption was continuously measured by monitoring the portal-hepatic venous oxygen saturation differences using the absorption spectrophotometer, the probes of which were built in perfusion lines. Hepatic anaphylaxis was induced by an injection of ovalbumin (0.01 or 0.1 mg) into the perfusate of the isolated liver of the rat sensitized with subcutaneous ovalbumin (1 mg). Hepatic venoconstriction and liver weight loss were similarly observed in response to norepinephrine (0.01-10 micromol L(-1)) and anaphylaxis. However, hepatic anaphylaxis reduced oxygen consumption, whereas norepinephrine increased it. There was a possibility that anaphylactic venoconstriction could reduce the perfused surface area, resulting in decreased oxygen consumption. However, pretreatment with a vasodilator of sodium nitroprusside substantially attenuated venoconstriction but not the decrease in oxygen consumption during anaphylaxis. Thus, we conclude that local hepatic anaphylaxis decreases oxygen consumption independently of venoconstriction in isolated blood-perfused rat livers.     

Role of adenosine in the sympathetic activation produced by isometric exercise in humans.

Isometric exercise increases sympathetic nerve activity and blood pressure. This exercise pressor reflex is partly mediated by metabolic products activating muscle afferents (metaboreceptors). Whereas adenosine is a known inhibitory neuromodulator, there is increasing evidence that it activates afferent nerves. We, therefore, examined the hypothesis that adenosine stimulates muscle afferents and participates in the exercise pressor reflex in healthy volunteers. Intraarterial administration of adenosine into the forearm, during venous occlusion to prevent systemic effects, mimicked the response to exercise, increasing muscle sympathetic nerve activity (MSNA, lower limb microneurography) and mean arterial blood pressure (MABP) at all doses studied (2, 3, and 4 mg). Heart rate increased only with the highest dose. Intrabrachial adenosine (4 mg) increased MSNA by 96 +/- 25% (n = 6, P < 0.01) and MABP by 12 +/- 3 mmHg (P < 0.01). Adenosine produced forearm discomfort, but equivalent painful stimuli (forearm ischemia and cold exposure) increased MSNA significantly less than adenosine. Furthermore, adenosine receptor antagonism with intrabrachial theophylline (1 microgram/ml forearm per min) blocked the increase in MSNA (92 +/- 15% vs. 28 +/- 6%, n = 7, P < 0.01) and MABP (38 +/- 6 vs. 27 +/- 4 mmHg, P = 0.01) produced by isometric handgrip (30% of maximal voluntary contraction) in the infused arm, but not the contralateral arm. Theophylline did not prevent the increase in heart rate produced by handgrip, a response mediated more by central command than muscle afferent activation. We propose that endogenous adenosine contributes to the activation of muscle afferents involved in the exercise pressor reflex in humans.     

Natriuretic effect of caffeine: assessment of segmental sodium reabsorption in humans

In order to assess the intrarenal mechanisms responsible for the natriuretic action of caffeine, the renal clearances of (51)Cr-EDTA [used as a measure of glomerular filtration rate (GFR)] and lithium (used as an index of end-proximal fluid delivery) were measured in eight healthy males before (control period) and immediately after (experimental period) a 400 mg oral dose of caffeine (given over 90 min) or placebo. In caffeine-treated subjects, the fractional excretion of sodium rose from 1.00+/-0.25% in the control period to 1.47+/-0.18% in the experimental period, while corresponding values on the placebo day were 1.04+/-0.16% and 0.70+/-0.07% respectively. GFR was unchanged following either caffeine or placebo. When compared with the placebo day, caffeine caused increases in lithium clearance (experimental period values: caffeine, 37+/-1 ml/min; placebo, 28+/-2 ml/min; P <0.001), the fractional excretion of lithium (caffeine, 34+/-1%; placebo, 26+/-2%; P <0.001) and the sodium/lithium clearance ratio (used as an index of the fraction of sodium delivered to the distal nephron that escapes reabsorption therein: caffeine, 4.4+/-0.3%; placebo, 2.8+/-0.2%; P <0.001). These results suggest that reduced fractional sodium reabsorption in both the proximal tubule and the distal nephron contributes to the acute natriuretic effect of caffeine. The data also confirm the importance of controlling caffeine intake when investigating renal function using lithium clearance.     

The influence of age on dorsal hand vein responsiveness to norepinephrine

The influence of age on the responsiveness of dorsal hand vein alpha-receptors to local infusions of norepinephrine was investigated by the use of a novel technique, the linear variable differential transformer. Studies were conducted in two groups of healthy subjects, 26 elderly individuals (14 men and 12 women) 60 to 78 years old and 32 young individuals (24 men and eight women) 16 to 29 years old. There was wide interindividual variation in responsiveness to norepinephrine within both groups of subjects. The dose of norepinephrine required to produce 50% venoconstriction in the elderly ranged from 1.5 to 300 ng/min (geometric mean 24.0 ng/min). The dose required to produce 50% venoconstriction in younger individuals ranged from 1.6 to 360 ng/min (geometric mean 23.8 ng/min). These results suggest that there is no systematic influence of age on dorsal hand vein alpha-receptor responsiveness. A power calculation demonstrates a very small likelihood of a type II error.     

Acetaminophen has greater antipyretic efficacy than aspirin in endotoxemia: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To compare the antipyretic efficacy of aspirin and acetaminophen (INN, paracetamol) in 30 male volunteers with the use of endotoxin (lipopolysaccharide) to elicit a standardized febrile response. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in parallel groups. Subjects received an intravenous endotoxin bolus of 4 ng/kg after premedication with either placebo, 1000 mg aspirin, or 1000 mg acetaminophen by mouth. RESULTS: Peak body temperatures were 38.5 degrees C +/- 0.2 degrees C in the placebo group, 37.6 degrees C +/- 0.2 degrees C in the acetaminophen group (P = .001 versus placebo), and 38.6 degrees C +/- 0.2 degrees C in the subjects treated with aspirin (P = .001 versus acetaminophen; P = .570 versus placebo) at 4 hours after lipopolysaccharide infusion. Subjective symptom scores for chills and perception of fever were higher in the placebo group than in the acetaminophen group (chills, 2.5 +/- 0.3 versus 1.0 +/- 0.2, P = .009 and fever, 2.5 +/- 0.2 versus 2.0 +/- 0.2, P = .021). Tumor necrosis factor-alpha, interleukin-6, and interleukin-8 levels rose by several orders of magnitude (P < .001 versus baseline in all groups), without significant intergroup differences. CONCLUSIONS: Acetaminophen was the superior antipyretic drug in endotoxemia compared with aspirin. Treatment with acetaminophen ameliorates subjective symptoms induced by endotoxemia without compromising the humoral response of a subject to endotoxin. This observation has clinical interest and may also help to improve the lipopolysaccharide model, which can be used to test anti-inflammatory and anticoagulatory drugs.