Blood pressure and impairment of endothelium-dependent relaxation in spontaneously hypertensive rats

Summary Correlation between hypertension and impairment of endothelium-dependent relaxation was demonstrated using aortae from certain strains of rats with various levels of spontaneous hypertension. It was also observed that the impairment of endothelium-dependent relaxation is the secondary change due to hypertension, and the level and duration of hypertension is the determinant factor of the impairment.     

Platelets, endothelium and blood vessel wall

Aggregating platelets cause contraction of vascular smooth muscle, because they release serotonin and thromboxane A2. If the platelets aggregate in a blood vessel with intact intima, the platelet-products cause endothelium-dependent relaxation of the underlying smooth muscle. Hence, the presence of an intact intima considerably reduces the vasospastic response to platelet-aggregation. The major platelet products which trigger endothelium-dependent relaxations are the adenine nucleotides and serotonin. The ability of the endothelium to prevent platelet-induced vasospasm is augmented after chronic intake of cod liver oil, but is reduced after previous intimal injury.     

Acetylcholine induced endothelial-dependent vasodilation increases as artery diameter decreases in the rabbit ear

Isolated resistance vessels in the rabbit ear preconstricted with histamine were relaxed by acetylcholine by a proportionately greater amount than the central ear artery. The relaxation was antagonized by atropine and also by endothelium removal. Our studies represent the first direct evidence that endothelium-dependent dilation can occur in resistance vessels.     

Acetylcholine induced endothelial-dependent vasodilation increases as artery diameter decreases in the rabbit ear

Summary Isolated resistance vessels in the rabbit ear preconstricted with histamine were relaxed by acetylcholine by a proportionately greater amount than the central ear artery. The relaxation was antagonized by atropine and also by endothelium removal. Our studies represent the first direct evidence that endothelium-dependent dilation can occur in resistance vessels.Acknowledgments. We thank Christine Quinn for her careful technical assistance in the use of the myographs and Daniel Netto for construction of the small vessel myographs. The tungsten wire used for mounting the vessels was given by Westinghouse Corporation Lamp Division. This work was supported by American Heart Association Fellowship 608 and National Heart, Lung, and Blood Institute Grant HL-32985.     

Endothelium-derived nitric oxide and vascular physiology and pathology

In 1980, Furchgott and Zawadzki demonstrated that the relaxation of vascular smooth muscle cells in response to acetylcholine is dependent on the anatomical integrity of the endothelium. Endothelium-derived relaxing factor was identified 7 years later as the free radical gas nitric oxide (NO). In endothelium, the amino acid L-arginine is converted to L-citrulline and NO by one of the three NO synthases, the endothelial isoform (eNOS). Shear stress and cell proliferation appear to be, quantitatively, the two major regulatory factors of eNOS gene expression. However, eNOS seems to be mainly regulated by modulation of its activity. Stimulation of specific receptors to various agonists (e.g., bradykinin, serotonin, adenosine, ADP/ATP, histamine, thrombin) increases eNOS enzymatic activity at least in part through an increase in intracellular free Ca²⁺. However, the mechanical stimulus shear stress appears again to be the major stimulus of eNOS activity, although the precise mechanisms activating the enzyme remain to be elucidated. Phosphorylation and subcellular translocation (from plasmalemmal caveolae to the cytoskeleton or cytosol) are probably involved in these regulations. Although eNOS plays a major vasodilatory role in the control of vasomotion, it has not so far been demonstrated that a defect in endothelial NO production could be responsible for high blood pressure in humans. In contrast, a defect in endothelium-dependent vasodilation is known to be promoted by several risk factors (e.g., smoking, diabetes, hypercholesterolemia) and is also the consequence of atheroma (fatty streak infiltration of the neointima). Several mechanisms probably contribute to this decrease in NO bioavailability. Finally, a defect in NO generation contributes to the pathophysiology of pulmonary hypertension. Elucidation of the mechanisms of eNOS enzyme activity and NO bioavailability will contribute to our understanding the physiology of vasomotion and the pathophysiology of endothelial dysfunction, and could provide insights for new therapies, particularly in hypertension and atherosclerosis.     

Dopamine-induced relaxation in human pulmonary arteries

Dose-dependent relaxations were induced by dopamine in human pulmonary arteries that had been contracted with prostaglandin F2 alpha without alpha-adrenergic blocking agents. The dopamine-induced relaxation was inhibited by haloperidol and fluphenazine, but not by domperidone, suggesting that this relaxation was mediated via DA1 receptors.     

Responses of monkey, rabbit and dog internal carotid arteries to atrial natriuretic factor

Effects of atrial natriuretic factor (ANF) on monkey, rabbit and dog internal carotid arteries were investigated. ANF caused a concentration-dependent relaxation in arterial strips submaximally precontracted with noradrenaline, 5-hydroxytryptamine, or high-potassium solution (10-30 mM). The response was greatest in the monkey arteries and least in the dog arteries. These results suggest that there is a marked species difference in the ANF-induced relaxation of the internal carotid arteries.     

Responses of monkey,rabbit and dog internal carotid arteries to atrial natriuretic factor

Summary Effects of atrial natriuretic factor (ANF) on monkey, rabbit and dog internal carotid arteries were investigated. ANF caused a concentration-dependent relaxation in arterial strips submaximally precontracted with noradrenaline, 5-hydroxytryptamine, or high-potassium solution (10–30 mM). The response was greatest in the monkey arteries and least in the dog arteries. These results suggest that there is a marked species difference in the ANF-induced relaxation of the internal carotid arteries.     

Examination of the fundus of the eye of renal hypertensive dogs

Summary Only 1 of 7 dogs with long-standing renovascular hypertension showed clear changes in the fundus. No distinct retinopathy was seen in the others. Ophthalmoscopy alone is thus of limited value in assessing the progress of benign hypertension in the dog.     

Variations in cardiac noradrenaline content during sodium loading in hypertension prone and resistant rats

Summary The cardiac catecholamine content of Sabra rats and their 2 genetically derived substrains, hypertension prone and resistant rats, was studied by high pressure liquid chromatography and electrochemical detection. Both in the control period and after sodium and DOCA administration the cardiac noradrenaline level is higher in hypertension resistant rats than in Sabra rats, and also higher than in hypertension prone rats. This finding suggests that a reduction of the cardiac sympathetic nervous tone is involved in the genetic resistance to sodium.     

Isometric relaxation in rat myocardium: load dependence and influence of caffeine

When caffeine plus calcium is added to the perfusing medium, isometric relaxation of rat myocardium is no longer affected by length changes occurring during the twitch. The dependence of isometric relaxation on the initial muscle length is still present and more pronounced after caffeine addition.     

Isometric relaxation in rat myocardium: Load dependence and influence of caffeine

Summary When caffeine plus calcium is added to the perfusing medium, isometric relaxation of rat myocardium is no longer affected by length changes occurring during the twitch. The dependence of isometric relaxation on the initial muscle length is still present and more pronounced after caffeine addition.     

The endothelium-dependent relaxation of human middle cerebral artery: effects of activated neutrophils.

Neutrophils, activated by 4 beta-phorbol-12 beta-myristate-13 alpha-acetate, decreased acetylcholine-induced relaxation of strips of human middle cerebral artery precontracted with noradrenaline. This effect was prevented by catalase, but not by superoxide dismutase. Nifedipine, propranolol and, less markedly, captopril reduced the decrease in acetylcholine-induced relaxation. Aspirin and dipyridamole did not reduce it.     

Influences of temperature change on the relaxation and amplitude inhibition by noradrenaline in the rabbit jejunum.

In the rabbit jejunum, the elevation of temperature within the range of 25-37 degrees C diminished the sensitivity to noradrenaline (NA) for both the relaxation and amplitude inhibition. The relaxation by NA was mainly mediated via adrenergic beta-receptors at 25, 30 or 37 degrees C. The amplitude inhibition was mediated via alpha-receptors at 37 degrees C, and both alpha- and beta-receptors at 30 or 25 degrees C.     

13C NMR-study of flexibilide,an anti-inflammatory agent from a soft cora

Summary The use of¹³C spin-lattice relaxation measurements as a probe of structure in solution is illustrated for flexibilide. Analysis of quaternary carbon relaxation behaviour indicates that the structure in solution differs from the crystal structure. The effects of lanthanide shift and relaxation reagents on¹³C spectral parameters are also reported.Acknowledgment. We thank R.J. Wells, RRIMP, for helpful discussions.     

Endothelium-dependent relaxation induced by sodium fluoride in the rabbit ear artery

Sodium fluoride (NaF) produced concentration-dependent relaxation of isolated rabbit ear artery precontracted with norepinephrine. In contrast, an arterial preparation with the endothelium rubbed off did not relax, but contracted in response to NaF. NaF-induced relaxation was not influenced by indomethacin but was inhibited by methylene blue or NG-monomethyl-L-arginine. The results indicate that NaF relaxes the artery by releasing a so-called EDRF.     

Endothelium-dependent relaxation induced by sodium fluoride in the rabbit ear artery

Summary Sodium fluoride (NaF) produced concentration-dependent relaxation of isolated rabbit ear artery precontracted with norepinephrine. In contrast, an arterial preparation with the endothelium rubbed off did not relax, but contracted in response to NaF. NaF-induced relaxation was not influenced by indomethacin but was inhibited by methylene blue or N^G-monomethyl-L-arginine. The results indicate that NaF relaxes the artery by releasing a so-called EDRF.     

Evidence of abnormalities in net sodium and potassium fluxes in erythrocytes of patients with essential hypertension]

A new and simple laboratory test for measuring net Na+ and K+ fluxes in Na+-loaded/K+-depleted human erythrocytes was developed and applied to hypertension. Moderate essential hypertension was characterized by a constant increase in net K+ influx; more severe cases showed a drop in net Na+ efflux. Na+ and K+ erythrocyte fluxes were found to be normal in hypertension of renal origin.     

Mediation by nitric oxide of neurally-induced human cerebral artery relaxation

Human cerebral artery strips relaxed in response to non-adrenergic, non-cholinergic vasodilator nerve stimulation by electrical pulses or nicotine. The relaxation response was abolished by treatment with N^G-nitro-L-arginine, a nitric oxide synthase inhibitor; the inhibitory effect was reversed by L-, but not D-, arginine. Nitric oxide-induced relaxation was unaffected. These findings support the hypothesis that nitric oxide plays a crucial role, possibly as neurotransmitter, in transmitting information from vasodilator nerve to smooth muscle in human cerebral arteries.     

Development of high blood pressure in spontaneously hypertensive rats is delayed by treatment with cyclosporin at an early age

In spontaneously hypertensive rats the effect of the T-cell inhibitor cyclosporin was studied at different ages. If treatment was started at the age of 2 weeks the development of hypertension was delayed, but the ultimate level of blood pressure was not affected. These results indicate the involvement of immune mechanisms in the early development of hypertension in spontaneously hypertensive rats.