摘要:

This study characterized the nature of the response to platelet activating factor (PAF) in the cerebral microcirculation of the newborn pig. Pig arterioles were observed directly using a closed cranial window in chloralose-anesthetized piglets. Topical application of 10-100 ng/ml PAF produced dose-dependent decreases in pial arteriolar diameter; diameters were 193 ± 27 γ for control, 167 ± 25 γ at 10 ng/ml, and 129 ±21 γ at 100 ng/ml. Topical application of 30-300 ng/ml norepinephrine and 3-30 ng/ml U46619, a purported thromboxane A2receptor agonist, also produced dose-dependent decreases in pial arteriolar diameter. After topical administration of U66985 (1 /mg/ml), a putative PAF antagonist, responses to PAF were attenuated significantly, but responses to norepinephrine and U46619 were unchanged. Moreover, intravenously administered U66985 (0.1 mg/kg) antagonized PAF responses as well. Responses to PAF were unchanged after cyclooxygenase and leukotriene receptor inhibition. Further, PAF did not increase cortical subarachnoid cerebrospinal fluid prostaglandin or leukotriene levels. These data indicate that PAF is a potent constrictor of cerebral arterioles in newborn pigs and that its mechanism of action is independent of formation of cyclooxygenase and lipoxygenase products of arachidonic acid metabolism. These data also suggest that U66985 may be a selective PAF antagonist that crosses the blood-brain barrier. Since PAF is an endogenous lipid released from a variety of tissues and may be an important mediator of inflammation and allergic reaction, PAF could be involved in the pathophysiology of the cerebral circulation in the perinatal period. (Circulation Research 1988;62:1-7)

ISSN:0009-7330    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

α1-Adrenoceptor stimulation of rat left ventricular papillary muscles by phenylephrine in the presence of propranolol resulted in rapid breakdown of phosphatidylinositol 4,5-bisphosphate (PI-4,5-P2) and a triphasic inotropic response in a concentration-dependent manner. The release of inositol trisphosphate (IP3) was maximum within 30 seconds and remained high for at least 30 minutes. The IP3formation was associated with a rapid, but small, increase in contractile force followed by a transient decline in the contractility prior to the development of a sustained and more pronounced positive inotropic response. Inhibition of PI-4,5-P2hydrolysis by the α1-adrenergic antagonist prazosin or the PI-4,5-P2phosphodiesterase Inhibitor neomycin blocked all components of the inotropic responses. Combined addition of 2,3-diphosphoglyceric acid, a competitive inhibitor of IP, phosphatase, with phenylephrine doubled the IP, formation and potentiated the initial phases of inotropic responses but had no effect on the sustained positive inotropic response. Nifedipine and Mn2+did not block the transient inotropic responses but inhibited the sustained positive inotropic response. α1-Adrenoceptor stimulation resulted in restoration of slow responses in the high K+-depolarized muscles in the time course similar to that of the development in the sustained positive inotropic response. Addition of phorbol-12,13-dibutyrate alone or in combination with caffeine or A23187 failed to produce a sustained positive inotropic effect, but pretreatment with this phorbol ester (1-100 nM) for 30 minutes resulted In dose-dependent potentiation ofa,-adrenoceptor-mediated sustained positive inotropic effect associated with enhanced slow responses. These results suggest that the inotropic effects mediated by cardiac α1-adrenoceptor stimulation occur through the phosphodiesteratic cleavage of PI-4,5-PI, such that IP, may produce transient inotropic effects by mobilizing intracellular Ca2+, whil e diacylglycerol, along with cofactors that are also generated on a,-adrenoceptor stimulation, may provoke a sustained positive inotropic effect by potentiating slow Ca2+channels through activation of protein kinase C.

ISSN:0009-7330    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Although group III and IV fibers are known to compose the afferent pathway of the reflex arc causing the pressor response to static muscular contraction, little is known about the neurotransmitters released by these muscle afferents. Somatostatin might be one of these neurotransmitters because this peptide is found in the terminals of fine afferent fibers ending in the dorsal horn of the lumbar spinal cord. Therefore, in chloralose-anesthetized cats, the reflex pressor response to static contraction was examined before and after subarachnoid injections onto the lumbosacral cord of a peptide antagonist to somatostatin. We found that before giving the antagonist, the pressor response to contraction of the triceps surae muscles in 12 cats averaged 33 ± 4 mm Hg, while 37 ± 7 minutes after giving the antagonist, the pressor response averaged only 18±3 nun Hg (p< 0.001). In contrast, the antagonist to somatostatin had no effect on either the pressor response to electrical stimulation of the cut central end of the sciatic nerve or the pressor response to stimulation of the posterior diencephalon. Furthermore, subarachnoid injection of a peptide antagonist to luteinlzing hormone-releasing hormone had no effect on the reflex pressor response to static contraction. Our findings are consistent with the hypothesis that somatostatin plays a role in the spinal transmission of the contraction-induced pressor reflex arising from hind limb skeletal muscle. (Circulation Research 1988;62:18-24)

ISSN:0009-7330    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Neuropeptide Y (NPY) is a vasoconstrictor peptide known to be present in the adrenal medulla, the terminal nerve endings, and in plasma. This study was designed to test whether NPY could prevent the acute blood pressure fall induced by endotoxin administration. Normotensive rats were subjected to adrenal demedullation on the right side and were either adrenalectomized or sham-operated on the left side. Eight to ten days later, NPY (0.07 μg/min i.v.) or its vehicle were infused for 95 minutes into these conscious, semirestrained rats. The same experiments were performed with rats that received an infusion of epinephrine (0.1 μg/min). These doses of NPY and epinephrine when given alone had no blood pressure effect. During the last 75 minutes of the 95-minute infusion, endotoxin (lipopolysaccharideEscherichia coli0.111:B4,10 μg/min i.v.) or its vehicle were administered. In rats with an intact adrenal gland, endotoxin failed to induce hypotension. In rats lacking a functioning adrenal medulla, however, endotoxin induced a pronounced mean blood pressure fall of 55 ± 11.6 mm Hg (mean± SEM). This blood pressure drop could be prevented equally well with NPY and with epinephrine infusion and averaged 11 ± 2.3 and 16 ± 2.4 mm Hg, respectively, at the end of the experiment. Additional rats were biadrenalectomized and supplemented with an excess of glucocorticoids and mineralocorticoids. In these rats also, NPY markedly attenuated the blood pressure fall resulting from endotoxemia. These data taken together indicate that in conscious rats with no adrenal medulla, the acute blood pressure fall induced by endotoxin administration is greatly enhanced. In these rats, a nonpressor dose of NPY prevents the hypotensive effect of endotoxin equally well as an epinephrine infusion.

ISSN:0009-7330    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Cardiac atria are thought to be the principle source of plasma atrial natriuretic factor (ANF), a potent natriuretic and diuretic peptide. Whether other ANF production sites are recruited in disease states exhibiting elevated plasma ANF levels is not known. Accordingly, in the cardiomyopathic hamster, an animal model of congestive heart failure with high circulating levels of ANF, contribution of ventricular tissue to total cardiac ANF production and storage was investigated. Measurements were made of immunoreactive ANF in plasma and in atrial and ventricular extracts as well as ANF mRNA levels in the atria and ventricles from normal and cardiomyopathic golden Syrian hamsters. Plasma ANF levels were higher in cardiomyopathic than in control animals. The atrial concentration of ANF (per milligram atrial weight) was 50% and 83% lower hi moderate and severe congestive heart failure, respectively, when compared with controls, while atrial ANF mRNA content of cardiomyopathic hamsters was not significantly different from normal hamsters. The ventricular concentration of ANF was 3 times and 7 times higher in animals in moderate and severe heart failure when compared with controls. In severe heart failure, ventricular ANF accounted for 23% of total cardiac stores of ANF. Ventricular ANF mRNA levels were 7 tunes and 13 times higher in hamsters in moderate and severe heart failure as compared with control animals. Therefore, significant increases in both ANF content and ANF mRNA in ventricles of hamsters in moderate to severe heart failure suggest that the ventricle could be an important source of ANF in congestive heart failure.

ISSN:0009-7330    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

The purpose of this study was to determine whether both α1- and α2-adrenergic receptors exist on vascular smooth muscle of microvessels and whether adrenergic constriction of anatomically distinct microvascular segments is differentially subserved by either receptor subtype. The cremaster skeletal muscle of anesthetized rats was acutely denervated and suspended in a Krebs bath containing cocaine, normetanephrine, and propranolol to block uptake, uptake, and β-receptors, respectively. Intravital microscopy was used to study large distributing arterioles (mean diameter, 100 μ, m), small precapillary arterioles (25 μm), and capacitance venules (140 μm). Concentration-response (diameter change) curves were obtained for bath-added agonists norepinephrine (mixedα1/α2), phenylephrine (α,), and B-HT 933 (α2) in the absence or presence of antagonists prazosin (α1) and yohimbine (α2). Apparent pD2(-log ED50) values for large arterioles and venules were, respectively, as follows: norepinephrine (7.41 and 7.15), phenylephrine (5.95 and 5.41), and B-HT 933 (5.05 and 5.06). Low concentrations of prazosin (10-8M) and yohimbine (10-7M) produced receptor subtype-selective antagonism and parallel, dextral displacement of norepinephrine curves for large arterioles and venules. The large arteriole pK8(-log KB) was 7.83 ± 0.65 for prazosin and 7.36 ± 0.46 for yohimbine. Higher concentrations of prazosin (10-7and 3 ± 10-7M) and yohimbine (10-6M) produced further dextral but nonparallel displacement of norepinephrine curves. In contrast, receptor subtype-selective concentrations of only yohimbine inhibited adrenergic constriction of small, precapillary arterioles; but prazosin had no effect at receptor subtype-selective concentrations. These data suggest that adrenergic regulation of large arterioles and venules in skeletal muscle uses both α1- and α2-adrenoceptors. Precapillary arterioles, however, may be subserved predominantly by α2-receptors.

ISSN:0009-7330    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Perfusion of isolated rat heart with L-methionine produced a positive inotropic effect that was temporally preceded, as well as accompanied, by an increase of methyl group incorporation intoN-methylated phospholipids of the myocardium. Maximal increase in contractile force development was associated with maximal methyl group incorporation. Both parameters showed a dose-related dependence on methionine and correlated positively (r= 0.965) upon regression analysis of the data. The presence of adenosine, L-homocysteine thiolactone and erythro-9-(2-hydroxy-3-nonyl) adenine in the perfusion medium inhibited the positive inotropic effect as well as the incorporation of methyl groups into phospholipids. Cycloleucine, an inhibitor ofS-adenosylmethionine synthetase, also reduced the increase in contractility by methionine. Methionine-induced positive inotropic effect could be modulated by varying Ca2+concentration in the perfusate and was inhibited by ryanodine, a blocker of sarcoplasmic reticular Ca2+release. These observations indicate that L-methionine may serve as a powerful positive inotropic agent and suggest that phospholipidN-methylation plays an important role in functional activity of rat heart.

ISSN:0009-7330    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Chronic hypertension is associated with hypertrophy of cerebral blood vessels. Previous studies of the mechanical properties of cerebral vessels in chronic hypertension have examined large cerebral arteries. The goals of this study were first to develop a method to examine vascular mechanics of cerebral arterioles in vivo and second to determine whether the stiffness of cerebral arterioles is altered hi the presence of chronic hypertension. We calculated circumferential stress and strain of pial arterioles in age-matched, anesthetized stroke-prone spontaneously hypertensive rats (SHRSP) and hi Wistar Kyoto rats (WKY) from measurements of pial arteriolar pressure, inner diameter, and wall thickness. Pial arteriolar pressure was measured with a servonull system. Smooth muscle of pial arterioles was deactivated with ethylenediaminetetraacetic acid (EDTA), and pressure-diameter relations were examined during step-wise reductions in pressure. Prior to deactivation of smooth muscle in 3-4-month-old rats, pial arteriolar pressure was greater in SHRSP than in WKY (110 ±4 versus 75 ±2 mm Hg [mean±SE];p< 0.05). Pial arteriolar diameter, which was measured at prevailing levels of pial arteriolar pressure, was less hi SHRSP than hi WKY (52 ± 5 versus 63 ± 3 μm;p< 0.05). Following deactivation of smooth muscle, diameter of pial arterioles at 70 mm Hg of pial arteriolar pressure was similar hi the two groups: 104 ±6 μm in SHRSP and 109 ±3 μm in WKY (p> 0.05). Wall thickness was 4.5 ±0.2 μm in SHRSP and 4.1 ±0.1 μm in WKY (p> 0.05). The stress-strain relation hi deactivated pial arterioles was shifted to the right hi SHRSP, which indicates that circumferential stiffness of pial arterioles is decreased in young SHRSP. To determine whether hypertrophy of pial arterioles, which occurs with maturation, is associated with increases in arteriolar stiffness, we examined stress-strain characteristics in 6-8-month-old SHRSP and WKY. In older rats, diameter of both active and deactivated pial arterioles was less in SHRSP than hi WKY. Wall thickness was significantly greater in SHRSP than in WKY (5.8 ±0.5 versus 3.8 ±0.2 μm;p< 0.05). The stress-strain relation, however, was shifted even further to the right in 6-8-month-old SHRSP with respect to WKY. We conclude that the stiffness of cerebral arterioles is decreased hi SHRSP with established hypertension despite pronounced vascular hypertrophy.

ISSN:0009-7330    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

A modified test of postextrasystolic potentiation achieved with a brief episode of rapid pacing followed by a 6-second pause (RPP maneuver) was used to evoke maximal force in isolated intact ferret right ventricular papillary muscles. Maximal RPP tensions were examined under length-clamped conditions and compared with the steady-state forces obtained when further increases in [Ca2+]0, did not further increase force and to the tensions recorded at the point of saturation of force when similarly length-clamped muscles were subjected to caffeine-induced tetanization. The results show that the calculated maximal twitch tension achieved with RPP is comparable to the 25-35 g/mm2observed in intact single skeletal muscle fibers. The study also shows that the beat-to-beat decay of the potentiated contraction is exponential. While the amount of the constant fractional beat-to-beat decay is a function of [Ca2+]0, it is not influenced by length. During the decay of potentiation, the ratio of the potentiation of any beat divided by that of the previous beat is a constant, called (x). With certain assumptions, it is shown that (x) is a measure of the fraction of activator calcium taken up by the sarcoplasmic reticulum in each beat and, in the steady state, the fraction of activator calcium that comes from the sarcoplasmic reticulum. The (x) amounted to 33%, 50%, and 65% when [Ca2+]0was 1.25, 2.50, and 5.0 mM, respectively. Thus, at 1.25 mM [Ca2+]0, some two thirds of the total calcium required to activate the myofilaments comes from the extracellular compartment during excitation and only one third is contributed via release from the sarcoplasmic reticulum. In the region of optimal myofilament overlap, RPP force-length curves are remarkably shallow and almost indistinguishable from the sarcomere length-tension relation observed in skinned single cardiac cells. Tetanus plateau tensions are significantly smaller than RPP forces at any length, and the slope of the tetanus force-length curves is greater than that obtained with RPP. Thus, and by exclusion, we also suggest that caffeine may exert significant downstream inhibitory effects.

ISSN:0009-7330    

出版商:OVID    

年代:1988

数据来源: OVID

摘要:

Several lines of evidence, including the reported ability of calcium channel blockers to prevent atherogenesis in cholesterol-fed rabbits, suggest that calcium mediates one or more of the pathologic changes in atherosclerosis. Moreover, it has long been known that calcium accumulates in atherosclerotic blood vessels. To test the hypothesis that a substantial fraction of this accumulated calcium is intracellular and to identify possible causes of this accumulation, calciumfluxesand contents were determined in aortic segments from cholesterol-fed rabbits and age-matched controls. A new method, based on45Ca efflux experiments and computer-assisted kinetic analysis, was used to measure intracellular and extracellular calcium contents (nmol calcium/g wet wt tissue) and fluxes. Total intracellular calcium increased from 269 ±11.6 to 1,300 ±352 nmol/g in cholesterol-fed animals compared with controls (p< 0.01). This change was sufficient to account for the observed increase in total tissue calcium from 4,190 ±211 to 5,240 ±477 nmol/g (p< 0.05). Thus, the fraction of tissue calcium that is intracellular increased significantly from 0.065 ±0.006 to 0.223 ±0.048 (p< 0.01) in experimental atherosclerosis. In addition, the data were quantitatively consistent with the hypothesis that these changes are brought about by a 4.8-fold increase in the plasma membrane calcium permeability of aortic smooth muscle cells. These results provide evidence that increased intracellular calcium is a possible mediator of cholesterol-induced atherogenesis.

ISSN:0009-7330    

出版商:OVID    

年代:1988

数据来源: OVID