血管内皮依赖性超极化因子的研究进展

内皮依赖性超极化因子（endothelium-dependent hyperpolarizing factor，EDHF）是血管平滑肌内皮源性舒张反应中通过非环氧合酶、非一氧化氮合酶途径的舒张因子。在不同物种、不同血管，EDHF反应都得到了确认。其在心血管生理学和药理学方面有着重要的作用。     

Noninvasive Study of Vasodilatory Activity of Albino Rat Cerebral Arteries

Vasodilating activity of rat cerebral vessels was studied. Methodological peculiarities and chronotropic limits of vasomotor testing were determined. Qualitative and quantitative parameters of dilatation of vessels were determined and similarity of rat dilatation responses and human vasodilatory activity was described. __________ Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 140, No. 11, pp. 587–590, November, 2005     

Coronary dilatation reserve in experimental hypertension and chronic heart failure: effects of blockade of the renin-angiotensin system

1. The aim of the present study was to investigate left and right ventricular (LV and RV, respectively) coronary vasodilatation reserve (CVR; fluorescent microsphere technique) in rats with hypertension (spontaneously hypertensive rats (SHR)) or congestive heart failure (CHF) and the effects of early and chronic renin-angiotensin system (RAS) blockade thereupon. 2. In adult SHR, both LV and RV CVR were impaired, especially in the non-hypertrophied RV, the main factor involved being coronary vascular remodelling. Blockade of the RAS normalized both LV and RV CVR, mainly through the prevention of hypertension and suppression of the resulting pericoronary fibrosis. 3. In postischaemic CHF rats, there was an early and severe degradation of LV and RV CVR that developed before any significant vascular remodelling and appeared to be linked to the deterioration of cardiac hypertrophy and haemodynamics. This degradation in CVR further worsened over the longer term due to late-developing pericoronary fibrosis and endothelial dysfunction. Blockade of the RAS had no early effects on LV and RV CVR, but improved RV CVR over the long term, mainly by limiting RV hypertrophy and by preventing the development of pericoronary fibrosis and coronary endothelial dysfunction. 4. In kallikrein-kinin system-deficient mice, CVR was not different from that of wild-type mice, suggesting that this system is not implicated in normal CVR regulation.     

Nitric oxide and vascular responses in Type I diabetes

Vascular complications are major causes of morbidity and mortality in patients with diabetes mellitus. The mechanisms underlying the development of microvascular and macrovascular angiopathy in Type I (insulin-dependent) diabetes mellitus are complex and incompletely understood. The discovery of endothelium-derived nitric oxide has greatly improved our understanding of vascular biology. Nitric oxide has an important role in the regulation of vascular tone and impaired nitric oxide activity could be implicated in the development of diabetic vasculopathy. Vascular studies of endothelial function in Type I diabetes have produced conflicting results. The role of nitric oxide in diabetic vasculopathy is still not clear. [Diabetologia (2000) 43: 137–147]     

Cerebral vascular effects of reactive oxygen species: recent evidence for a role of NADPH-oxidase

1. Reactive oxygen species (ROS) are a diverse family of molecules that are produced throughout the vascular wall. Many ROS, such as the superoxide anion (*O2-) and hydrogen peroxide (H2O2), are now known to act as cellular signalling molecules within blood vessels. In particular, these molecules can exert powerful effects on vascular tone. 2. Cerebral arteries are relatively unusual in their responsiveness to ROS. Unlike in many systemic vessels, both *O2- and H2O2 can cause vasodilatation in the cerebral microcirculation. 3. Reactive oxygen species can be produced in the vasculature via a variety of mechanisms; however, it appears that the primary source of *O2- within blood vessels is the enzyme NADPH-oxidase. 4. In cerebral vessels, activation of NADPH-oxidase causes both *O2- production and vasodilatation, indicating that NADPH-oxidase-derived ROS may have a functional role in the regulation of cerebral vascular tone. 5. Elevated levels of NADPH-oxidase activity and expression occur in cardiovascular disease states such as hypertension, atherosclerosis and subarachnoid haemorrhage. 6. Thus, ROS may contribute to the regulation of cerebral vascular tone during both physiological and pathological conditions.     

Effects of felodipine on systemic and coronary haemodynamics in patients with angina pectoris

In order to study the systemic and coronary haemodynamic effectsof felodipine, a new dihydropyridine derivative, 10 patientswith coronary artery disease were studied during cardiac catheterizalion.Measurements were performed at rest and during pacing-inducedangina pectoris. At rest, the heart rate rose from 70±20to 78±20 (P<0.05), the systemic arterial pressuredecreased by about 20% (P<0–01) and the cardiac indexrose from 2.9±l.2 to 4.0±l.0 (P<0.05). Thecoronary sinus flow (CSF) increased about 50% (P<001). Duringpacing to the same heart rate as in the control measurements,felodipine induced similar changes in systemic haemodynamicvalues as in the resting position. Myocardial lactate extractionand ST segment depressipn were not significantly altered. Afterfelodipine, the pacing rate could be further increased in 7patients as compared with the control value. Both systemic andcoronary effects were then very similar compared with thoseduring the lower pacing rale. In conclusion, felodipine is avery potent systemic and coronary vasodilator with potentialvalue in the treatment of hypertension and cardiac failure.The drug may also be of value in the treatment of ischaemicheart disease, but further studies with titratjon of optimaldoses are needed in that respect.     

ACTH-Suppressive and Vasodilator Actions of Adrenomedullin in Conscious Sheep

Adrenomedullin (ADM) is a 52 amino-acid peptide which is a potent vasodilator in rats, and suppresses basal and CRF-induced ACTH release from cultured pituitary cells. The present study examines the hemodynamic and hormonal actions of human ADM (1–52) infusion in conscious, chronically instrumented sheep. Five sheep were infused intravenously (IV) or intracerebroventricularly (ICV) with ADM at 100 pg/h for 60 min, and mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), total peripheral conductance (TPC), coronary blood flow (CF), coronary conductance (CC), peak aortic flow (Fmax), and left ventricular dF/dt were monitored by a computer-based data collection system every 2 min. Plasma concentrations of adrenocorticotropin (ACTH), arginine vasopressin (AVP) and renin were measured after 60 min of infusion. IV ADM produced a small fall in MAP of 3 ± 1 mmHg, associated with a reflex increase in HR of 14 ± 3 b/min. CO increased by 1.3 ± 0.3 1/min, whereas SV remained unchanged. TPC was markedly increased by 20 ± 3 ml/min/mmHg. Changes in CF were also seen with an increase of 10 ± 2ml/min, and CC increased in parallel by 0.15 ± 0.02 ml/min/mmHg. Fmax and dF/dt showed small increases of 2.1 ± 0.5 Vmin and 85 ± 20 1/min/sec respectively. Plasma concentrations of ACTH and cortisol were reduced by 58% and 55% respectively, whereas plasma renin concentration increased by 106%. There was no change in plasma levels of AVP. ICV infusion of ADM had no effect on any parameter measured. These data suggest that systemic ADM produces a sustained vasodilator action to lower blood pressure in sheep, and this is the first study to report the ACTH-suppressor action of ADM in conscious animals. ADM may therefore be an important hormone involved in the regulation of pituitary/adrenal function, in addition to its cardiovascular and fluid regulatory actions in mammals.     

Acute haemodynamic effects of felodipine in congestive heart failure

Summary The haemodynamic effects of felodipine 0.1 mg/kg p.o., a new arteriolar dilator, were studied in 7 patients with severe congestive heart failure of NYHA Class IV (Group A) and in 3 patients in Class II–III (Group B). In Group A, measurements were made before and 1 and 4 h after felodipine administration. There was a substantial fall in systemic arterial pressure, which was not associated with a compensatory tachycardia. In fact, there was a fall in heart rate from 92 to 82 beats/min 1 h after drug administration. The pulmonary capillary wedge pressure was reduced from 22 to 14 mm Hg and the cardiac index and stroke volume index rose significantly. Consequently, there was a marked reduction in systemic vascular resistance. In Group B measurements were performed at rest and during exercise before and 1 h after felodipine. The pulmonary wedge capillary pressure during exercise was lower than in the control situation. Coronary sinus flow was increased and there was a pronounced fall in coronary vascular resistance. The results would suggest that felodipine, by virtue of its ventricular unloading potency, might be a valuable drug in the treatment of congestive heart failure.     

Clinical significance of bradykinin liberation during cardiopulmonary bypass and its prevention by a kallikrein inhibitor

Activation of the kinin system and effects of Trasylol (Bayer, A.G. Lebukusen, West Germany), a kallikrein inhibitor, were investigated on 52 patients during hemodilutional cardiopulmonary bypass (CPB). Immediately after the start of CPB, neither elevation of bradykinin nor reduction of plasma kininogen (KGN: a precursor of bradykinin) were observed. During CPB, bradykinin level in the blood was markedly elevated, correlating with the significant decrease of kininogen (p<0.001). The longer the CPB time, the more marked the reduction of KGN. In the cases requiring over 60 minutes of CPB, the amounts of bradykinin released (4.6–18.0ng/ml) were sufficient to increase capillary permeability as well as peripheral vasodilatation. As shown by the significant increase of hematocrit (p<0.005) and the extreme reduction of vascular resistance found at the end of CPB in the prolonged cases. Infusion of Trasylol into the extracorporeal circuit actually prevented the reduction of kininogen and the increase of hematocrit as well as the extreme decrease of vascular resistance in the cases of over 60 minutes CPB. These results clearly point out that Trasylol is beneficial for the prevention of bradykinin liberation and capillary permeability increase and for the maintenance of optimum peripheral vascular tone during CPB. Furthermore, the significance of these findings with regards to complications during and after prolonged CPB was discussed.     

EFFECTS OF ARACHIDONATE DEFICIENCY ON ENDOTHELIUM- DEPENDENT VASCULAR REACTIONS

1. The release of endothelium-derived relaxing factor (EDRF), which appears to be impaired in vessels chronically exposed to hypertension, may involve mobilization of arachidonate from phospholipids. In this study the effects of arachidonate deficiency on endothelium-dependent responses were examined in rat isolated aorta. 2. Weanling rats were fed an essential fatty acid-deficient (EFAD) diet for 8 weeks which reduced plasma and aortic phospholipid arachidonate content from 17 to 1.8% and from 21 to 8%, respectively. After this time the rats were killed and the reactivity of aortic rings was studied in organ baths. 3. In aortic rings from control rats the concentration-response curves for the contractile action of phenylephrine were shifted to the left 3.5-fold by removal of the endothelium, and the maximum was not altered. 4. In contrast, in EFAD rings with endothelium, the maximal vasoconstriction to phenylephrine was less than in control rings, and removal of the endothelium increased the maximum (from 1.9 +/- 0.2 to 3.2 +/- 0.1 g, P less than 0.05) and reduced the EC50 7-fold. 5. In EFAD rings precontracted with phenylephrine (0.3 mumol/l) the relaxations produced by the endothelium-dependent dilator acetylcholine were not significantly different from those produced in control rings. The dilator actions of sodium nitroprusside were also similar in EFAD and control rings. 6. Thus, endothelium-dependent dilatation in the aorta is not impaired by partial depletion of phospholipid arachidonate. However, contractile responses to alpha-adrenoceptor agonists are depressed by spontaneously released EDRF in rat aorta, so that the results suggest that depletion of phospholipid arachidonate either augments spontaneous release of EDRF, or impairs EDRF inactivating mechanisms.