Plasma nociceptin/orphanin FQ levels in response to the hyperventilation test in healthy subjects.

In vitro and in vivo studies demonstrated that nociceptin/orphanin FQ inhibits norepinephrine release, while the effects of norepinephrine on nociceptin/orphanin FQ release remain unknown. Previous studies in healthy and hypertensive subjects showed that prolonged and forced hyperventilation induces different blood pressure (BP) responses depending on changes in plasma catecholamine levels. We investigated whether the effects of hyperventilation on the sympatho-adrenergic system involve nociceptin/orphanin FQ release. Fifty-six healthy subjects (26 females, mean age 63+/-2 and 30 males, mean age 63+/-3) underwent the hyperventilation test. A hierarchical cluster analysis based on BP response to hyperventilation identified three groups of subjects: group 1 (n=20) with a decrease in BP, norepinephrine (1311.1+/-45.5 fmol/ml versus 900.0+/-55.3 fmol/ml, P<0.01) and nociceptin/orphanin FQ (13.0+/-0.7 pg/ml versus 7.9+/-0.8 pg/ml, P<0.01), group 2 (n=18) without any change in BP and norepinephrine (1133.0+/-31.5 fmol/ml versus 1176.0+/-44.6 fmol/ml), with a decrease in nociceptin/orphanin FQ (12.5+/-3.2 pg/ml versus 7.4+/-0.6 pg/ml, P<0.01) and group 3 (n=18) with an increase in BP, norepinephrine (1216.7+/-50.9 fmol/ml versus 1666.7+/-44.9 fmol/ml, P<0.01) and nociceptin/orphanin FQ values (11.5+/-1.6 pg/ml versus 19.9+/-1.5 pg/ml, P<0.01). Norepinephrine changes in response to hyperventilation in groups 1 and 3 were directly (P<0.01) correlated with those of nociceptin/orphanin FQ. Our results showed that vigorous and prolonged hyperventilation changes plasma nociceptin/orphanin FQ levels due to the direct effects of hypocapnic alkalosis or to different sympatho-adrenergic system responses.

Plasma nociceptin/orphanin FQ levels rise after spontaneous episodes of angina, but not during induced myocardial ischemia.

The aim of our study was to evaluate the effects of repeated episodes of angina and induced myocardial ischemia on plasma nociceptin/orphanin FQ (N/OFQ) levels. Patients with unstable angina (23 with new onset severe angina or accelerated angina and 18 with subacute angina at rest) who had had repeated spontaneous episodes of chest pain in the last week before the study underwent myocardial perfusion single-photon emission computed tomography using adenosine infusion. Twenty subjects without clinical symptoms of angina matched for age, sex and cardiac risk factors served as a control group. N/OFQ levels were significantly (P<0.01) higher in the patients (15.2+/-2.1 pg/ml) than in the control group (8.5+/-2.6 pg/ml). Blood pressure and heart rate did not significantly differ. All patients showed transient adenosine infusion myocardial ischemia that did not induce chest pain or significantly modify plasma N/OFQ levels or hemodynamic parameters. Our findings show that unstable angina is associated with a significant increase in circulating N/OFQ levels unrelated to intervening transient myocardial ischemia or hemodynamic changes. This increase is probably related to the chest pain repeatedly occurring in the course of coronary artery disease, but absent during transient adenosine-induced myocardial ischemia.

Plasma brain natriuretic peptide at rest and after adenosine-induced myocardial ischemia in normotensive and essential hypertensive patients with suspected coronary artery disease.

This study investigated plasma brain natriuretic peptide (BNP) levels in normotensive and hypertensive patients with suspected coronary artery disease during radionuclide pharmacological stress testing. Twenty-seven normotensive patients (15 males, aged 63.0+/-4.5 years and 12 females, aged 63.0+/-4.1 years) and 38 essential hypertensive patients (25 males, aged 63.3+/-3.3 years and 13 females, aged 64.6+/-2.6 years) with chest pain and exercise stress testing inconclusive for coronary artery disease underwent myocardial perfusion single-photon emission computed tomography (SPECT) using adenosine infusion. SPECT identified patients without (16 normotensive and 22 hypertensive) and patients with (11 normotensive and 16 hypertensive) transient perfusion defects. Basal BNP levels in normotensive patients without transient myocardial ischemia (3.1+/-1.2 fmol/ml) were significantly (P<0.01) lower than those observed in normotensive patients with transient ischemia (8.2+/-1.2 fmol/ml), whereas BNP levels in hypertensive patients without transient ischemia (8.2+/-1.0 fmol/ml) did not significantly differ from those in hypertensive patients with transient ischemia (8.1+/-2.0 fmol/ml). No significant difference was found in BNP levels between males or females either in normotensive or hypertensive patients without or with ischemia. Adenosine infusion did not significantly change BNP levels in any subject group without or with myocardial perfusion defects. Our findings show that increases in BNP allow early detection of myocardial ischemia in normotensive patients, but not in hypertensive patients with suspected coronary artery disease. Adenosine-induced myocardial ischemia does not affect BNP production already activated by coronary artery disease in normotensive patients and by hemodynamic changes in hypertensive patients.

Endothelin-1 response to mental stress in early ischemic lesions of the extremities due to systemic sclerosis.

We studied circulating levels of endothelin-1, catecholamines and nitric oxide after a mental arithmetic test in 14 patients with early ischemic lesions of the extremities due to systemic sclerosis and slightly impaired peripheral vascular flow. The test induced an increase (P<0.01) in blood pressure, heart rate, endothelin-1 and catecholamine levels, whereas it did not change the low basal levels of nitric oxide. In healthy subjects (n=20) the test significantly (P<0.01) decreased endothelin-1 without affecting nitric oxide. The low basal levels of nitric oxide and the high plasma concentration of endothelin-1 after psychological stress cannot be explained by an impaired release from the limited ischemic lesions alone. This suggests a diffuse microvascular derangement that aggravates the course of peripheral microvascular ischemic lesions.

Opioid peptide response to spinal cord stimulation in chronic critical limb ischemia.

Twelve patients with chronic critical limb ischemia in whom a spinal cord stimulation (SCS) system had been implanted for at least one year had increased microvascular flow and achieved healing of trophic acral lesions. After switching off the system, the clinical improvement persisted for 10 days and the neurohormonal pattern showed high plasma values of beta-endorphin and Met-enkephalin, normal dynorphin B, endothelin-1 and catecholamines, and low nitric oxide. Met-enkephalin levels were further increased (P < 0.01) immediately after switching on the electrical stimulation again. The persistence of high plasma opioid levels after switching off the spinal cord stimulation explains the absence of subjective complaints and suggests an involvement of opioids in the regulation and improvement of the microcirculation.

Blood pressure response to hyperventilation test reflects daytime pressor profile.

Recent studies show that healthy subjects and patients with moderate hypertension have different pressor responses to hyperventilation, depending on their sympathoadrenergic reactivity. In the present study, we investigated whether a different response to the hyperventilation test is related to differences in the daily blood pressure profiles recorded with noninvasive ambulatory monitoring. Forty-five healthy subjects and 67 patients with essential hypertension of grades 1 and 2 (Joint National Committee VI and World Health Organization) were investigated. Healthy subjects and hypertensive patients responding to hyperventilation with an increase in systolic blood pressure had, during daytime ambulatory blood pressure assessment, peak systolic blood pressure values (146.0+/-5.0 mm Hg, 182.2+/-9.0 mm Hg, respectively) similar to the hyperventilation peak systolic blood pressure values (147.2+/-3.5 mm Hg, 183.0+/-4.7 mm Hg, respectively). Hypertensive patients responding to hyperventilation with a decrease in blood pressure showed clinic systolic blood pressure values (178.4+/-3.2 mm Hg) higher than daytime average ambulatory systolic blood pressure (155.2+/-7.1 mm Hg; P<0.01). Our results indicate that a hyperventilation test yields information on daily peak blood pressure values in healthy subjects and hypertensive patients when it induces a pressor increase and can identify hypertensive patients with the so-called "white coat effect" when it induces a pressor decrease.

beta-Endorphin modulation of pressor response to hyperventilation in hypertensive patients.

After hyperventilation, systolic and diastolic blood pressure (BP) significantly decreased in 14 hypertensive patients (group 1), did not change in 9 (group 2) and increased in 8 (group 3). Basal BP, norepinephrine and dynorphin B levels were higher in group 1 than in groups 2 and 3. The decrease in BP after hyperventilation was associated with a decrease in plasma norepinephrine, Met-enkephalin and dynorphin B and an increase in beta-endorphin. Naloxone abolished the hyperventilation-induced BP and norepinephrine decreases. Our findings indicate that hyperventilation may select hypertensive patients with different sympatho-adrenergic activity and that the increase in beta-endorphin reduces BP response to hyperventilation in patients with high sympatho-adrenergic tone.