Jan Aldershvile

Autoregulation of Cerebral Blood Flow in Patients Resuscitated From Cardiac Arrest

Background and Purpose— Under normal circumstances, autoregulation maintains cerebral blood flow (CBF) constant within a wide range of mean arterial pressure (MAP). It remains unknown whether patients resuscitated from cardiac arrest have preserved CBF autoregulation. In this study, CBF autoregulation was investigated within the first 24 hours after resuscitation from cardiac arrest. Methods— Eighteen patients and 6 healthy volunteers had relative changes in CBF determined by transcranial Doppler mean flow velocity (Vmean) in the middle cerebral artery during a stepwise rise in MAP by use of norepinephrine infusion. Vmean was plotted against MAP, and a lower limit of autoregulation was identified by double regression analysis based on the least-squares method. Results— In patients, Vmean increased from a median of 33 (range 19 to 73) to 37 (22 to 100) cm/s (P <0.001) during a norepinephrine-induced rise in MAP from 78 (46 to 118) to 106 (60 to 149) mm Hg. Eight of 18 patients had impaired CBF autoregulation, and in 5 of the 10 patients with preserved CBF autoregulation, the lower limit of autoregulation could be identified. The lower limit of CBF autoregulation was 76 mm Hg (41 to 105 mm Hg) in the volunteers and 114 mm Hg (80 to 120 mm Hg) in the 5 patients with preserved autoregulation (P <0.01). Conclusions— We conclude that in a majority of patients in the acute phase after cardiac arrest, cerebral autoregulation is either absent or right-shifted. These results indicate that MAP should be kept at a higher level than commonly accepted to secure cerebral perfusion. We recommend, however, that further randomized clinical trials are performed to determine whether sympathomimetic drugs improve neurological outcome.

Coronary vasorelaxant effect of levosimendan, a new inodilator with calcium-sensitizing properties.

We examined the action of levosimendan, a new Ca2+-sensitizing inodilator, on isolated porcine coronary arteries. Vessel rings were studied in isometric myographs. Arterial cyclic adenosine monophosphate (cAMP) levels were determined by radioimmunoassay. Levosimendan (10(-7)-10(-3) M) completely relaxed arteries preconstricted by prostaglandin F2alpha (PGF2alpha) with a pD2 (-logEC50) value of 3.99 +/- 0.05 (n = 6-9 in all experiments). Pretreatment with levosimendan also prevented contraction induced by PGF2alpha. The vasorelaxation produced by levosimendan (10(-7)-10(-3) M) was not attenuated by removal of the endothelium. Levosimendan (10(-7)-10(-3) M) relaxed contractions induced by 30 mM K+ as well as 80 mM K+, whereas the K+ channel opener levcromakalim selectively relaxed contraction induced by 30 mM K+. Neither the cyclooxygenase inhibitor indomethacin nor the beta-adrenoceptor blocker propranolol influenced levosimendan-induced vasorelaxation. The Ca2+-entry blocker isradipine failed to relax arteries precontracted by endothelin-1 in Ca2+-free/EGTA medium. However, levosimendan (10(-7)-3 x 10(-3) M) completely relaxed endothelin-1-induced contractions in this medium. Levosimendan potentiated the relaxant effect of a cAMP-stimulating drug, isoprenaline, but also that of nitroglycerin and isradipine. At a maximal effective concentration, it increased arterial tissue contents of cAMP twofold. In conclusion, levosimendan produces coronary vasorelaxation by a mechanism that seems to be endothelium independent and not mediated by K+ channel opening, Ca2+-entry blockade, release of cyclooxygenase products, or beta-adrenoceptor stimulation. Accumulation of cAMP may possibly participate in vasorelaxation at high concentrations of levosimendan, but a cAMP-independent mechanism seems to be involved at lower concentrations.

In Vivo Nitrate Tolerance Is Not Associated With Reduced Bioconversion of Nitroglycerin to Nitric Oxide

BACKGROUND In vitro data suggest that reduced bioconversion of nitroglycerin (NTG) to nitric oxide (NO) contributes to the development of vascular and hemodynamic tolerance to NTG. We examined the in vivo validity of this hypothesis by measuring NTG-derived NO formation by in vivo spin-trapping of NO in vascular tissues from nitrate-tolerant and -nontolerant rats. METHODS AND RESULTS Five groups (n = 6 to 8 each) of conscious chronically catheterized rats received NTG (0.2 or 1 mg/h IV) for 72 hours (nitrate-tolerant groups). Four other groups received either NTG vehicle (placebo, for 72 hours) or were left untreated (control). Nitrate tolerance was substantiated by a reduced (55% to 85%) hypotensive response to NTG in vivo and a reduced relaxation to NTG in isolated aortic rings. NTG-derived NO formation in aorta, vena cava, heart, and liver was measured as NOFe(DETC)2 and NO-heme complexes formed in vivo during 35 minutes combined with ex vivo cryogenic electron spin resonance spectroscopy. NO formation was significantly (P < .05) increased in all tissues in nitrate-tolerant rats in an NTG dose-dependent manner. Furthermore, the amount of NO formed from a bolus dose of NTG (6.5 mg/kg over 20 minutes) was similar in nitrate-tolerant and -nontolerant rats. CONCLUSIONS The results suggest that vascular and hemodynamic NTG tolerance occurs despite high and similar rates of NO formation by NTG in tolerant and nontolerant target tissues. This finding is compatible with the assumption that reduced biological activity of NO, rather than reduced bioconversion of NTG to NO, contributes to in vivo development of nitrate tolerance.

Effects of High Thoracic Epidural Analgesia on Myocardial Blood Flow in Patients With Ischemic Heart Disease

Background—In patients with ischemic heart disease, high thoracic epidural analgesia (TEA) has been proposed to improve abnormalities of coronary function by inhibiting cardiac sympathetic tone. We evaluated the effect of TEA on myocardial blood flow in patients with ischemic heart disease. Methods and Results—Twenty male patients with multivessel ischemic heart disease were studied. An epidural catheter was inserted between the second and third thoracic vertebral interspace (Th2 to Th3). Analgesia was induced by epidural injection of bupivacaine 0.5%, and a sensory block from the sixth cervical (C6 to C7) to Th10 (Th8 to Th11) vertebral interspace was achieved. Myocardial blood flow was measured with dynamic 13N-ammonia PET with and without TEA at rest, during pharmacological vasodilation with dipyridamole, and during sympathetic stimulation with the cold pressor test. Myocardial blood flow during dipyridamole increased similarly, regardless of TEA, in all regions except in myocardium subtended by collateral arteries in which blood flow increased more with than without TEA (P<0.05). Without TEA, myocardial blood flow during the cold pressor test remained unchanged compared with myocardial blood flow at rest. In contrast, with TEA, myocardial blood flow increased in all vascular territories. Coronary vascular resistance increased during the cold pressor test without TEA, whereas with TEA, coronary resistance decreased in myocardium subtended by nonstenotic and stenotic coronary vessels and remained unchanged in myocardium subtended by occluded vessels. Conclusions—In patients with multivessel ischemic heart disease, TEA partly normalizes the myocardial blood flow response to sympathetic stimulation.

Tetrahydrobiopterin improves endothelium-dependent vasodilation in nitroglycerin-tolerant rats.

Tolerance to nitroglycerin is caused by a nitroglycerin-mediated increase in vascular superoxide anion production. Administration of tetrahydrobiopterin (co-factor for endogenous nitric oxide (NO) formation) may potentially influence nitroglycerin tolerance in at least two different ways. Firstly, tetrahydrobiopterin may act as a scavenger of the nitroglycerin-mediated production of superoxide anions. Secondly, tetrahydrobiopterin may protect endothelial NO synthesis from the deleterious effects of increased oxidative stress. This study investigates whether in vivo nitroglycerin tolerance is affected by tetrahydrobiopterin supplementation and assesses the in vivo role of tetrahydrobiopterin in endogenous NO-mediated vasodilation in normal and nitroglycerin-tolerant rats. The results show that tetrahydrobiopterin does not affect nitroglycerin-derived, NO-mediated vasodilation, but reduces baseline mean arterial blood pressure (by 8 mm Hg, P<0.05) and normalizes endothelium-dependent responses to N(G)-monomethyl-L-arginine (L-NMMA) (from 7+/-1 to 22+/-4 mm Hg, P<0.05) in nitroglycerin-tolerant rats. It is concluded that altered bioavailability of tetrahydrobiopterin is involved in the pathophysiology of endothelial dysfunction seen in nitroglycerin tolerance.

Independent effects of liver disease and chronic alcoholism on thyroid function and size: The possibility of a toxic effect of alcohol on the thyroid gland

In an autopsy study we found thyroid volume significantly decreased in alcoholics with liver cirrhosis as compared to matched controls: 15 mL (range, 7 to 37 mL) v 25 mL (range, 13 to 90 mL) (P less than .01). At the same time the amount of fibrosis of the thyroid glands was higher in the alcoholics as compared to the matched controls: 20% (range, 6% to 40%) v 12% (range, 6% to 23%) (P less than .01). In order to evaluate the relative importance of alcohol consumption and liver disease on thyroid function and ultrasonically determined size, three groups of patients and matched controls (sex, age, weight, and smoking habits) were investigated: group 1, 18 patients with nonalcoholic liver cirrhosis; group 2, 21 consecutive chronic alcoholics (greater than 100 g of alcohol daily for greater than 5 years) without liver cirrhosis (all had biopsy proven fatty change or normal liver); group 3, 31 nonalcoholic patients with chronic nonhepatic, nonrenal disease. In group 1 median thyroid volume and serum FT4I, FT3I, and TSH levels were unchanged compared with the controls. In group 2 median thyroid volume was 13 mL (range, 9 to 32 mL) compared with 27 mL (range, 12 to 44 mL) in the controls (P less than .005). Serum T3 and FT3I levels were reduced, while T4, FT4I, and TSH levels were unaltered. In group 3 serum T3 and FT3I levels were reduced while serum FT4I and TSH levels and thyroid volume were unaltered compared with the controls. It is suggested that alcohol may have a toxic effect on the thyroid gland independent of the degree of liver damage.

Nitrate tolerance impairs nitric oxide-mediated vasodilation in vivo

OBJECTIVES Nitroglycerin (NTG) is metabolized to nitric oxide (NO) in vascular smooth muscle cells. It is currently not clear whether prolonged exposure to NTG and tolerance development directly affects endogenous NO-mediated vasodilation in vivo. This study investigates NO-mediated vasodilation in conscious chronically catheterized rats before and after development of nitrate tolerance. The effect of the thiol compound N-acetylcysteine (NAC), which may affect NTG responsiveness, was also studied. METHODS Nitrate tolerance was induced by a 72-h intravenous infusion of NTG and confirmed by a 65-68% reduction in the hypotensive response to NTG (P < 0.05). The hypotensive effects of acetylcholine (ACh) and sodium nitroprusside, (SNP) and possible NAC-mediated changes in the responses to these compounds were examined in nontolerant and nitrate-tolerant rats. Furthermore, the hypertensive response to the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) was measured. RESULTS Nitrate tolerance was associated with a significantly attenuated hypotensive response to ACh (before 24 +/- 1 mmHg; after 17 +/- 2 mmHg, n = 7, P < 0.05). Similarly, the response to SNP was reduced from 32 +/- 1 mmHg to 26 +/- 3 mmHg (n = 7, P < 0.05). NTG-vehicle (placebo) did not affect the response to ACh and SNP (P > 0.05). NAC augmented the effect of NTG, ACh and SNP in both nontolerant and nitrate-tolerant animals (P < 0.05). The hypertensive response to L-NAME (n = 8), was reduced by 67% (from 34 +/- 6 mmHg to 11 +/- 1 mmHg, P < 0.05) after induction of nitrate tolerance. CONCLUSIONS The results suggest (1) that nitrate tolerance in vivo is associated with cross tolerance to NO-mediated vasodilation produced by both exogenous and endogenous nitrovasodilators and (2) that also responses to nitrovasodilator agents other than NTG are improved by the addition of NAC.

Effect of Ramipril on mitral regurgitation secondary to mitral valve prolapse

Ramipril 10 mg/day reduced regurgitation in chronic mitral regurgitation secondary to mitral valve prolapse in patients with sinus rhythm.

Endothelium-dependent vasorelaxation is inhibited by in vivo depletion of vascular thiol levels: Role of endothelial nitric oxide synthase

Thiols like glutathione may serve as reducing co-factors in the production of nitric oxide (NO) and protect NO from inactivation by radical oxygen species. Depletion of thiol compounds reduces NO-mediated vascular effects in vitro and in vivo. The mechanisms underlying these actions are not clear, but may involve decreased synthesis of NO and/or increased degradation of NO. This study investigates the effect of glutathione depletion on the response to NO-mediated vasodilation induced by acetylcholine (Ach, 10 μg/kg), endothelial NO synthase (eNOS) activity and potential markers of vascular superoxide anion (O·-2) production in conscious chronically catheterized rats. Thiol depletion induced by buthionine sulfoximine (BSO, 1 g ip within 24 h) decreased the hypotensive effect of Ach by 30% (MAP reduction before BSO 27 ± 3 mmHg, 19 ± 3 mmHg after BSO, (mean ± SEM), p < .05n = 8). The impaired effect of Ach was associated with a significant reduction in eNOS activity (control: 7.7 ± 0.8, BSO: 3.9 ± 0.4 pmol/min/mg protein (p < .05), n = 6). In contrast, neither NADH/NADPH driven membrane-associated oxidases nor lucigenin reductase activity were significantly (p < .05) affected by BSO (BSO: 4415 ± 123, control: 4105 ± 455 counts/mg, n = 6) in rat aorta. It is concluded that in vivo thiol depletion results in endothelial dysfunction and a reduced receptor-mediated vascular relaxation. This effect is caused by reduced endothelial NO formation.

Pro-brain natriuretic peptide as marker of cardiovascular or pulmonary causes of dyspnea in patients with terminal parenchymal lung disease

BACKGROUND Increased plasma concentrations of pro-atrial natriuretic peptide (proANP) and pro-brain natriuretic peptide (proBNP) are features of left ventricular impairment. However, concentrations of proANP and proBNP in patients with isolated terminal parenchymal lung disease are not known. Therefore, we measured the plasma concentrations of natriuretic precursor peptides in patients with terminal parenchymal lung disease who had normal left ventricular function and who were referred for evaluation for lung transplantation. METHODS We measured plasma N-terminal proANP and proBNP in patients undergoing right heart catheterization (n = 50) and related results to hemodynamic variables obtained during catheterization. RESULTS Plasma proBNP concentrations were unaffected in patients with terminal parenchymal lung disease and normal left ventricular function (median, 2.5 pmol/liter; range, 0-22; upper reference limit, 15 pmol/liter). In contrast, patients with primary pulmonary hypertension displayed more than a 40-fold increase in plasma proBNP concentrations (median, 107 pmol/liter vs 2.5 pmol/liter, p < 0.0001). Plasma N-terminal proANP increased moderately (median, 664 pmol/liter; range, 36-1620; upper reference limit, 600 pmol/liter) but correlated to plasma proBNP concentrations (r = 0.47, p < 0.0001). Finally, regional vascular proBNP concentrations revealed the heart as the secretory site. CONCLUSIONS Our findings strongly support the contention that natriuretic peptide measurements are efficient markers for cardiovascular causes of dyspnea. Moreover, our results eliminate natriuretic peptides as markers of moderate pulmonary hypertension in patients with terminal parenchymal lung disease.