摘要:

Intracellular calcium concentration ([Ca−2+]1)dependent activation of myosin light chain kinase and its phosphorylation of the 20-kd light chain of myosin is generally considered the primary mechanism responsible for regulation of contractile force in arterial smooth muscle. However, recent data suggest that the relation between [Ca2+]1, and myosin light chain phosphorylation is variable and depends on the form of stimulation. The dependence of myosin phosphorylation on [Ca2+]1, has been termed the “[Ca2+]1, sensitivity of phosphorylation.” The [Ca2+]1, sensitivity of phosphorylation is “high” when relatively small increases in [Ca2+]1, induce a large increase in myosin phosphorylation. Conversely, the [Ca2+]1, sensitivity of phosphorylation is “low” when relatively large increases in [Ca2+]1, are required to induce a small increase in myosin phosphorylation. There are two proposed mechanisms for changes in the [Ca2+]1, sensitivity of phosphorylation: Ca2+-dependent decreases in the [Ca2+]1, sensitivity of phosphorylation induced by phosphorylation of myosin light chain kinase by Ca2+-calmodulin protein kinase II and agonist-dependent increases in the [Ca2+]1, sensitivity of phosphorylation by inhibition of a myosin light chain phosphatase. I will review the proposed mechanisms responsible for the regulation of [Ca2+]1, and the [Ca2+]1, sensitivity of phosphorylation in arterial smooth muscle.

ISSN:0194-911X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Previous studies have shown that inhibition of the lipoxygenase pathway of arachidonic acid metabolism can prevent the development of elevated blood pressure in renin-dependent models of hypertension. Agents that inhibit the lipoxygenase pathway such as phenidone and the flavonoid baicalein can selectively attenuate contractile responses to angiotensin II in vivo as well as in isolated vascular tissue. In the present study, the effects of lipoxygenase inhibitors on pressor-induced changes in cytosolic calcium were examined in cultured rat vascular smooth muscle cells using the fluorescent dye fura-2. Two structurally unrelated lipoxygenase inhibitors, baicalein and 5,8,11-eicosatriynoic acid, attenuated angiotensin II-stimulated increases in cytosolic calcium in both normal and calcium-poor buffer. The addition of 5-, 12-, or 15(S)-hydroxyeicosatetraenoic acid alone to the cells had no acute effect on intracellular calcium concentration. However, the addition of 12(S)-hydroxyeicosatetraenoic acid but not 5- or I5(S)- hydroxyeicosatetraenoic acid restored the initial calcium response to angiotensin II in vascular smooth muscle cells pretreated with both inhibitors; 5,8,11-eicosatriynoic acid also reduced [Arg5]-vasopressin and endothelin-stimulated increases in intracellular calcium. The attenuation of vasopressor-induced calcium transients by agents that inhibit lipoxygenase may explain their observed hypotensive effects in vivo. Moreover, Hpoxygenase products, in particular 12(S)-hydroxyeicosatetraenolc acid, may act as mediators for the intracellular actions of angiotensin II and possibly other pressor hormones in vascular tissue by regulation of intracellular calcium metabolism.

ISSN:0194-911X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Vascular smooth muscle cell hypertrophy is a normal compensatory state that may play a pathogenic role in hypertension. Angiotensin II stimulates a hypertrophic response in cultured vascular smooth muscle cells. As part of the growth response, angiotensin II rapidly activates the Na+-H+exchanger, increasing Na+influx. Because Na+, K+-ATPase is the major cellular mechanism for regulating intracellular Na+, we studied the effects of angiotensin Il-induced hypertrophy on Na+, K+-ATPase expression and activity. Angiotensin II caused rapid increases in both steady-state Na+, K+-ATPase activity (ouabain-sensitive36Rb uptake) and intracellular [Na+]. Angiotensin II also caused a sustained increase in Na+, K+-ATPase at 24 hours with a 73% increase in maximal36Rb uptake per milligram protein and a fourfold increase in Na+, K+-ATPase α7–1 messenger RNA levels. Thus, angiotensin II hypertrophy was associated with rapid Increases in Na+, K+-ATPase activity due to increased Na+entry and sustained increases due to a specific increase in Na+, K+-ATPase expression. These data demonstrate dynamic regulation of Na+, K+-ATPase at the functional and molecular level and suggest that similar compensatory mechanisms should be present in vivo. Alterations in such compensatory pathways may be fundamental to the pathogenesis of hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The demonstration of all components of the renin-angiotensin system in vascular tissue has raised questions as to the precise location of the local angiotensin II generation within the vascular wall. We investigated the metabolism of angiotensin I to angiotensin II in the vascular wall in the isolated rabbit thoracic aorta. Angiotensin I (3×10−9M) applied into the aortic lumen was partially converted to angiotensin II (14% after 60 minutes), but most of the luminal angiotensin I was degraded to peptide fragments or diffused as intact angiotensin I, peptide fragments, or both, into the vessel wall. Incubation studies with [3H] angiotensin I revealed that angiotensin I or angiotensin I fragments mainly diffused into the medial layer of the aorta and to a lesser degree into the adventitia and the endothelium. After removal of the endothelium, angiotensin II generation could no longer be detected. Addition of the angiotensin converting enzyme inhibitor ramiprilat (10−7M) to the incubation medium led to a complete blockade of angiotensin II generation by endothelial angiotensin converting enzyme. Our results underline the importance of the endothelium for conversion of angiotensin I to angiotensin II and provide evidence that conversion of angiotensin I to angiotensin II is predominantly achieved by endothelial cells. They also support the concept of an endocrine versus autocrine/paracrine renin-angiotensin system where the endothelium of the vasculature is the critical target site for angiotensin II production by both systems and, thus, the most important site for the actions of angiotensin converting enzyme inhibitors.

ISSN:0194-911X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Angiotensinogen messenger RNA (mRNA) levels were measured in the brain (hypothalamus, lower brain stem, cerebellum), liver, kidneys, and adrenal glands of rats made hypertensive by ligation of the aorta between the renal arteries. We also measured renin mRNA in the kidneys of these renal hypertensive rats. The early phase of hypertension (day 6) was associated with significant increases in plasma renin activity and levels of circulating angiotensin II. The circulating renin-angiotensin system was not activated in the later phase of hypertension (day 24). Angiotensinogen mRNA levels were elevated in the lower brain stem of hypertensive rats at both stages of hypertension. In contrast, angiotensinogen mRNA levels in the hypothalamus were increased only at day 6 after aortic ligation. Decreased levels of angiotensinogen mRNA were observed in the cerebellum in both the early and later phases of the hypertension. Angiotensinogen mRNA levels in the adrenal gland below the ligature fell in the early phases but rose in the later phases of hypertension. Renin mRNA levels of the ischemic kidney remained elevated at both the early and later phases, whereas in both ischemic and nonischemic kidneys, levels of angiotensinogen mRNA remained below sham values throughout the period of study. These results indicate differential expression of renin-angiotensin system mRNAs in tissues of renal hypertensive rats. The differential changes in the expression of angiotensinogen mRNA over the course of development and maintenance of renal hypertension suggest that factors in addition to angiotensin II are important in modulating the expression of renin-angiotensin system genes.

ISSN:0194-911X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

To investigate the possible role of vascular angiotensin converting enzyme (ACE) in the development and maintenance of hypertension, we examined aortic ACE messenger RNA (mRNA) levels in two-kidney, one clip (2K1C) hypertensive rats. The blood pressure was increased remarkably at 4 weeks (early stage) after clipping and remained elevated at 12 weeks (chronic stage). The aorta ACE mRNA levels were significantly elevated in both early and chronic stages concurrently with the increases in aortic ACE activity and blood pressure. The plasma renin activity rose markedly at 4 weeks, but returned to the normal level at 12 weeks. Neither ACE activity in the lung and plasma, nor ACE mRNA level in the lung was altered at either stage. The aorta and liver angiotensinogen mRNA levels and renal renin mRNA level were increased at 4 weeks but decreased at 12 weeks. These results indicate that the acceleration of all components in the renin-angiotensin system may contribute to the development of 2K1C hypertension in the early stage. In the chronic stage, the increased vascular ACE induced by the elevated ACE mRNA levels in the aorta may play the primary role in the acceleration of local angiotensin II formation and thus may sustain the hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Animal studies suggest that some angiotensin coverting enzyme inhibitors augment endotheliumdependent vasorelaxation. We aimed to determine if captopril augments endothelium-dependent vasodilation in middle-aged hypertensive patients. By using strain-gauge plethysmography, forearm vasodilation evoked with intra-arteriaJ acetylchollne (4, 8, 16, and 24 μg/min) or nitroprusside (0.2, 0.4, 0.8, and 1.2 μg/min) was examined before and after captopril administration (25 mg per os). Before captopril, forearm vasodilation with acetylcholine was less in hypertensive patients (n= 12) than in age-matched (n= 7) or young (n= 7) normotensive subjects, but forearm vasodilation with nitroprusside did not differ among the three groups. Captopril improved forearm vasodilation in hypertensive patients (n= 7) with acetylcholine but nitroprusside did not In contrast, nifedipine (10 mg per os) did not alter forearm vasodilation with acetylcholine or nitroprusside in hypertensive patients (n= 5). The decreases in mean blood pressure caused by captopril and nifedipine in hypertensive subjects were comparable. Captopril did not alter forearm vasodilation with acetylcholine or nitroprusside in young normotensive subjects (n= 7). These results suggest that captopril in hypertensive patients may acutely improve impaired endothelium-dependent forearm vasodilation that does not result from reduction in blood pressure per se.

ISSN:0194-911X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The relation between the renin-angiotensin-aldosterone (RAA) system and carbohydrate metabolism and insulin sensitivity in essential hypertension has not been investigated systematically. Twenty nondiabetic patients (age, 49±1 years; body mass index (BM1), 26.1±0.4 kg/m2) with essential hypertension (blood pressure, 155±3/105±1 mm Hg) received an oral glucose tolerance test (OGTT) at the end of a 1-month placebo period and again monthly during 3 months of angiotensin converting enzyme (ACE) inhibition (cilazapril,5 mg/day). Furthermore, a two-step eughycemic insulin clamp was performed after placebo and again at the end of treatment Blood pressure fell by 7±4/10±3 mm Hg (p< 0.001), while BMI remained stable. On the euglycemic clamp, insulin-mediated (plasma insulin, 470pM) whole body glucose use averaged 42.5±1.6μmol· min−1· kg−1before and 43.6±1.9 after ACE inhibition (p= NS). Substrate concentrations and oxidative rates and energy expenditure (as estimated by indirect calorimetry) were not altered by ACE inhibition, either in the fasting state or in response to insulin. In contrast, oral glucose tolerance was significantly (p< 0.05) improved after treatment (area under OGTT curve (AUC), 240±24 versus 282±23 mmol 2 hr ·1−1). The latter change was associated with enhanced (+16%,p< 0.05) insulin responsiveness to glucose (estimated as the insulin AUC divided by the glucose AUC) throughout the 3 months of ACE inhibition. At baseline, both the OGTT and the clamp had a marked hypokalemic effect (mean decrements in plasma potassium of 0.75±0.05 and 0.92±0.05 rmmol/l, respectively) in association with plasma aldosterone reductions of 30% and 50%. Chronic ACE inhibition caused a further 20% (p< 0.03) lowering of plasma aldosterone concentrations but attenuated insulin-induced hypokalemia. Plasma sodium, which was unaltered by the pretreatment tests, fell during the posttreatment tests (by 3 mmol/1,p< 0.001). In the urine, the ratio of the fractional excretion of potassium to that of sodium was decreased by both oral glucose (−22%,p< 0.01) and ACE inhibition (−21%,p< 0.001). Higher plasma potassium levels before treatment predicted a better blood pressure response to ACE inhibition (r= 0.60,p< 0.005). In conclusion, in essential hypertension 1) chronic ACE inhibition does not interfere with insulin's effect on glucose uptake, substrate oxidation, or thennogenesis, but causes resistance to the potassium-lowering action of insulin; 2) this electrolyte change is associated with heightened insulin secretory response to glucose stimulation and improved oral glucose tolerance; and 3) higher plasma potassium levels predict a better blood pressure response to ACE inhibition.

ISSN:0194-911X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

This study examines the relation between sympathetic activity and in vivo insulin-mediated glucose metabolism in a rat model of acquired hypertension. Two groups of conscious, unrestrained rats were studied in the postabsorptive state: sham-operated normotensive rats (n= 10) and renal-wrapped hypertensive rats (n= 10). Mean arterial pressure was increased in the hypertensive compared with the normotensive group in the fed (184±9 versus 144±6 mm Hg;p< 0.01) and in the fasting (147±8 versus 112±7 mm Hg;p< 0.01) state. After a 24-hour fast, hepatic glucose production, plasma glucose, insulin, and norepinephrine concentrations were similar in the two groups. Blood pressure did not change in either group during the 3–milliunits/kg · min euglycemic insulin clamp study; however, plasma norepinephrine concentration rose significantly in hypertensive (207±24 versus 329±11 pg/ml;p< 0.05) but not in normotensive rats (229±23 versus 267±27 pg/ml;p= NS). During the insulin clamp study, the hepatic glucose production was similar in the hypertensive (3.8±0.8 mg/kg · min) compared with the normotensive (4.0±0–3 mg/kg · min) rats. Insulin-mediated glucose uptake was significantly higher in hypertensive than in normotensive rats (33.0±0.7 versus 25.8±0.8;p< 0.01). This increase was mostly due to a marked increase in skeletal muscle glycogen synthesis in the hypertensive versus the normotensive group (11.9±1.0 versus 6.9±0.8;p< 0.01), whereas the stimulation of whole body glycolysls (production of3H2O) was not significantly different in the two groups (14.7±0.8 versus 15.9±0.9 mg/kg · min in normotensive and hypertensive rats, respectively;p= NS). After euglycemic insulin infusion, plasma norepinephrine concentration increased in hypertensive but not in normotensive rats; however, the blood pressure did not change in either group. Peripheral insulin sensitivity is increased in rats with acquired sodium-sensitive hypertension. These results indicate that sodium-dependent hypertension is associated with enhanced response of the sympathetic nervous system to insulin and with increased insulin sensitivity.

ISSN:0194-911X    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Hyperinsulinemia supposedly contributes to hypertension in diabetes mellitus. We sought to determine if the renal and cardiovascular effects of insulin are preserved in diabetes despite resistance to its glucose-lowering effect We studied the effects of two doses of insulin (50 and 500 miliiunits/kg · hr−1), using the euglycemic clamp technique, on fractional sodium excretion, blood pressure, and heart rate in two groups of non-insulin-dependent diabetics: eight patients with and eight patients without hypertension. Hypertensive diabetics had higher basal insulin levels than normotensive diabetics (21.8±2.9 and 14.4±1.6 milliunits/l, respectively [mean±SEM];p= 0.03). The degree of insulin resistance, but not plasma insulin levels, correlated with the height of mean arterial blood pressure (r= 0.60 and 0.73 at the low and high insulin dose, respectively,p< 0.05). In contrast, the change in mean arterial blood pressure correlated negatively with the change in endogenous insulin levels during the control experiment (r= −0.41,p< 0.02). Exogenous insulin induced a similar reduction in fractional sodium excretion in normotensive and hypertensive diabetics (43 ±5.9% and 48±16.4% during the low insulin dose and 57±9.1% and 62±12.5% during the high insulin dose, respectively). A decline in blood pressure was noted that correlated with the whole body glucose uptake during the high insulin dose (r= 0.52,p< 0.05). Since heart rate response and plasma norepinephrine level during the insulin clamp were comparable in both groups, an abnormality of the baroreceptor reflex is suggested. It appears that insulin resistance, but not insulin, is primarily related to hypertension. At the same time, insulin may still exert some effect on blood pressure by way of its renal or vasodilatory, or both, action.

ISSN:0194-911X    

出版商:OVID    

年代:1992

数据来源: OVID