Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While the roles of the platelet-derived growth factors (PDGFs) in vascular smooth muscle cells (SMCs) continue to be elucidated, these cells, especially in their activated 'synthetic' state, have also been found to express, and proliferate in response to, many of the other families of polypeptide growth factors, such as the fibroblast growth factors. Other stimulators of DNA synthesis, and particularly of SMC hypertrophy, include the vasoconstrictor hormones such as angiotensin II, as well as physical forces, especially stretch or tension. For many of these ligands, multiple receptors have been identified and their means of signal transduction are being characterized rapidly. Regulatory regions of these genes are being identified as are transcription factors. Complex post-transcriptional regulation has also been shown by the findings that some growth factors are phosphorylated, or translocated to the nucleus or the extracellular matrix. Inhibitors have also been identified. These include some prostaglandins, calcium antagonists, agonists that activate guanylate and adenylate cyclases, inhibitors of angiotensin-converting enzyme, interferon gamma, and heparin. Future studies are likely to show that tyrosine phosphatases and recessive oncogenes also regulate growth. The existence of so many autocrine/paracrine mitogens--together with some experimental data--suggests some redundancy in the system as well as some additive effects. Redundancy may limit the efficacy of antibodies to a single growth factor to block cell proliferation. Their evolutionary conservation implies some unique roles for each growth factor but these have not been apparent from in vitro studies to date. Further insights are apt to come from the increasing recognition that growth factors have other effects--on cell attachment, migration, survival, production of extracellular matrix, thrombosis, vaso-constriction, regulation of cytokine synthesis, and inhibition of growth. Many of these effects may prove to be context-dependent, as with the case of growth inhibition by transforming growth factor-beta. Studies in monolayer cultures may not obtain the same results as studies using cocultures of endothelial and smooth muscle cells, or 3-dimensional matrix cultures, organ cultures, or in the intact animal. In vivo descriptive studies of growth factors expressed in vascular embryogenesis, hypertension, atherosclerosis, acute balloon injury and thrombosis are being supplemented by interventions such as infusions with growth factors, antibodies, and toxin conjugates. These studies, and studies using transgenic mice and homologous recombination, should yield information as to mechanisms and may also suggest new therapies.
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PMID:Smooth muscle cell growth factors. 181 90

The endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) or a closely related nitrosothiol derivative, and is formed from the amino acid, L-arginine. NO is rapidly inactivated locally, released into the blood stream and instantly destroyed by haemoglobin. EDRF-NO and NO generated from vasodilator nitrates work by activation of soluble guanylate cyclase, elevating cyclic guanosine monophosphate (GMP) levels to cause vasodilatation and inhibition of platelet aggregation. Endothelium-dependent vasodilatation is attenuated in hypertension, atherosclerosis and diabetes through either loss of endothelium or deficient formation of EDRF-NO. In these conditions exogenous nitrates may substitute for a failing endogenous mechanism.
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PMID:Endogenous nitrates--implications for treatment and prevention. 187 72

Plasma atrial natriuretic peptide (ANP), cyclic guanosine monophosphate (GMP) and renin activity (PRA) were measured in 13 patients with mitral stenosis 24 h before and 48 h after balloon valvotomy resulting in a fall in LA pressure from 23.4 +/- 2.2 to 10.5 +/- 0.8 mmHg (P less than 0.01). Before treatment, plasma ANP was higher during ambulation (128.1 +/- 18.5 pg ml-1) than in the supine posture (93.3 +/- 15.0 pg ml-1; P less than 0.01) and did not diminish after return to the erect posture (86.4 +/- 14.1 pg ml-1). A physiological response was restored after valvotomy with ANP plasma levels of 49.2 +/- 7.8 pg ml-1 in the initial ambulant period, 63.1 +/- 12.6 pg ml-1 in the supine posture and 44.6 +/- 8.7 pg ml-1 in the final erect posture. Postural variations of cyclic GMP were parallel to those of ANP. In contrast, LA hypertension did not abolish PRA postural response. During the three successive periods of ambulation, supine posture and erect posture PRA was 5.4 +/- 1.0, 2.8 +/- 0.6 and 5.5 +/- 1.2 ng h-1 ml-1, respectively, before treatment, whereas after treatment the values measured were 10.3 +/- 2.9, 2.3 +/- 0.7 and 7.0 +/- 2.5 ng h-1 ml-1 respectively. Variations of plasma ANP, cyclic GMP and PRA in response to postural changes were also studied in 10 healthy volunteers and in 12 uraemic patients with high plasma ANP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Atrial natriuretic peptide response to postural changes in patients with left atrial hypertension. 196 7

Nitric oxide first captured the interest of biologists when this inorganic molecule was found to activate cytosolic guanylate cyclase and stimulate cyclic guanosine monophosphate (GMP) formation in mammalian cells. Further studies led to the finding that nitric oxide causes vascular smooth muscle relaxation and inhibition of platelet aggregation by mechanisms involving cyclic GMP and that several clinically used nitrovasodilators owe their biological actions to nitric oxide. Nitric oxide possesses physicochemical and pharmacological properties that make it an ideal candidate for a short-term regulator or modulator of vascular smooth muscle tone and platelet function. Nitric oxide is synthesized by various mammalian tissues including vascular endothelium, macrophages, neutrophils, hepatic Kupffer cells, adrenal tissue, cerebellum, and other tissues. Nitric oxide is synthesized from endogenous L-arginine by a nitric oxide synthase system that possesses different cofactor requirements in different cell types. The nitric oxide formed diffuses out of its cells of origin and into nearby target cells, where it binds to the heme group of cytosolic guanylate cyclase and thereby causes enzyme activation. This interaction represents a novel and widespread signal transduction mechanism that links extracellular stimuli to the biosynthesis of cyclic GMP in nearby target cells. The small molecular size and lipophilic nature of nitric oxide enable communication with nearby cells containing cytosolic guanylate cyclase. The extent of transcellular communication is limited by the short half-life of nitric oxide, thereby ensuring a localized response. Labile nitric oxide-generating molecules such as S-nitrosothiols may be involved as precursors or effectors. Further research will provide a deeper understanding of the biology of nitric oxide and the nature of associated pathophysiological states.
Hypertension 1990 Nov
PMID:Nitric oxide. A novel signal transduction mechanism for transcellular communication. 197 98

Endothelium-dependent relaxation of carotid arteries and changes in levels of cyclic (c)GMP between stroke-prone spontaneously hypertensive (SHRSP) and Wistar-Kyoto (WKY) rats have been compared. The concentration-response curve for acetylcholine (ACh)-induced relaxation was shifted to the right in carotid arteries from SHRSP. Relaxation responses produced by calcimycin (A 23187) and melittin, both endothelium-dependent agents, were depressed in carotid arteries from SHRSP. Relaxation responses produced by sodium nitroprusside and 8-Br-cGMP were similar to those in strips from WKY. ACh-induced production of cGMP was significantly decreased in carotid arteries from SHRSP when compared with the level for similarly treated strips from WKY. These results suggest that functional changes in endothelium, but not guanylate cyclase activity or cGMP sensitivity in the carotid arteries, may occur in hypertension. Thus, impaired endothelium-dependent relaxation in SHRSP may play an important role in hypertensive vascular diseases such as stroke.
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PMID:Impairment of endothelium-dependent relaxation and changes in levels of cyclic GMP in carotid arteries from stroke-prone spontaneously hypertensive rats. 198 99

The majority of cases of impotence are associated with vascular risk factors such as diabetes, hypercholesterolemia, hypertension and smoking. These factors induce impairment of endothelium-dependent relaxation of blood vessels in man and in experimental animals. In this study the effects of hypercholesterolemia on the reactivity of rabbit corpus cavernosum smooth muscle strips to endothelium-dependent and endothelium-independent agents were investigated. New Zealand White rabbits (n = 14) were randomly divided into control and treatment groups. The control group (n = 7) received a regular diet while the treatment group (n = 7) was fed a diet of 0.5% cholesterol and 4% peanut oil for 10 weeks. Animals were then sacrificed and the corporal tissue studied in organ chambers for isometric tension measurement. Tissue was contracted with phenylephrine and concentration-dependent relaxation to acetylcholine, in the presence and absence of indomethacin, and to nitroprusside were examined. Blood level of cholesterol in the cholesterol-fed group was significantly higher compared to the control group. Contractions to phenylephrine were similar in both groups. Hypercholesterolemia, however, inhibited relaxation to acetylcholine but did not alter relaxation to nitroprusside, a cyclic guanosine monophosphate (cGMP)-dependent, direct smooth muscle dilator. Indomethacin enhanced the relaxations to acetylcholine in both control and cholesterol-fed groups but did not correct the difference in the relaxation to acetylcholine between both groups. It is concluded that hypercholesterolemia impairs endothelium-mediated relaxation of rabbit corpus cavernosum smooth muscle. The mechanism for the endothelial dysfunction does not appear to involve alteration in cyclooxygenase products of arachidonate or the cGMP-dependent relaxation of corporal smooth muscle. Impairment of endothelium-dependent relaxation of corporal smooth muscle may contribute to the pathophysiology of impotence associated with hypercholesterolemia in man.
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PMID:Hypercholesterolemia impairs endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle. 205 97

The effects of an orally active inhibitor (UK 79300) of the neutral metalloendopeptidase EC 3.4.24.11 were investigated in six healthy male volunteers maintained on a constant diet (150 mmol sodium/day and 80 mmol potassium/day). Subjects were studied in a random order, single-blind study on two occasions, each 48 hours in length, when they were given UK 79300 (25 or 50 mg p.o.) or placebo at 12-hour intervals (each agent for 24 hours). The endopeptidase inhibitor enhanced plasma concentrations of atrial natriuretic factor in association with suppression of both plasma renin activity and aldosterone concentrations. Twenty-four-hour urinary excretion of sodium was doubled by UK 79300, and the urinary excretion rates of phosphorus, atrial natriuretic factor immunoreactivity, and cyclic guanosine monophosphate were also significantly enhanced, whereas urinary aldosterone excretion was halved. The profile of biological effects closely paralleled those previously reported with low dose infusions of atrial natriuretic factor in humans and animals. Therapeutic trials of such inhibitors are now indicated for hypertension or heart failure together with further studies to clarify the underlying mechanisms of action.
Hypertension 1990 Sep
PMID:Inhibition of endopeptidase EC 24.11 in humans. Renal and endocrine effects. 214 60

The arterial vasodilator properties of the dihydropyridine calcium antagonist amlodipine were compared with the effects of vascular muscle cyclic guanosine monophosphate production by sodium nitroprusside and with the effects of a combined infusion of amlodipine and the nondihydropyridine calcium antagonist verapamil in 8 untreated patients with primary hypertension. Arterial vasodilation was assessed by measurement of changes of forearm blood flow by mercury in Silastic strain-gauge plethysmography during brachial artery drug infusions. Forearm blood flow increased during amlodipine infusions (0.4 to 45 micrograms/min/100 ml forearm tissue) from 2.9 +/- 1.7 to a maximum of 23.6 +/- 7.6 ml/min/100 ml (687%), while sodium nitroprusside caused an increase from 3.0 +/- 1.8 to 16.2 +/- 5.4 ml/min/100 ml (449%), attesting to the importance of transmembrane calcium influx for the maintenance of vascular tone. The addition of verapamil 40 micrograms/min/100 ml to an infusion of amlodipine 44.5 micrograms/min/100 ml resulted in a further increase of forearm blood flow, from 23.6 +/- 7.6 to 34.4 +/- 9.8 ml/min/100 ml (p less than 0.05). The precise mechanisms of this finding have yet to be elucidated but may be due to interactions of the effects of the binding of these 2 chemically and pharmacologically different calcium antagonists to distinct binding sites at calcium channels. The clinical relevance of this observation for the treatment of coronary artery disease and systemic hypertension needs further study.
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PMID:Arterial vasodilator effects of the dihydropyridine calcium antagonist amlodipine alone and in combination with verapamil in systemic hypertension. 214 37

The effects of SCH 34826, an orally active neutral metalloendopeptidase inhibitor, on responses to atrial natriuretic factor-(103-125) or -(99-126) and on blood pressure were evaluated in rats. SCH 34826 (10, 30, and 90 mg/kg s.c. and 90 mg/kg p.o.) potentiated the antihypertensive action of atrial natriuretic factor (30 micrograms/kg i.v.) in conscious spontaneously hypertensive rats. SCH 34826 (90 mg/kg) also potentiated the diuretic and natriuretic responses to atrial natriuretic factor (30 micrograms/kg i.v.) as well as the plasma levels achieved after peptide injection. SCH 34826 significantly reduced blood pressure in the conscious deoxycorticosterone acetate-salt hypertensive rat, at doses of 90 mg/kg s.c. (-35 +/- 12 mm Hg), 10 mg/kg p.o. (-30 +/- 7 mm Hg), and 90 mg/kg p.o. (-45 +/- 6 mm Hg). SCH 34826 was devoid of acute antihypertensive activity in the spontaneously hypertensive rat but reduced blood pressure by day 3 of a 5-day treatment schedule. SCH 34826 (90 mg/kg s.c.) enhanced urine volume output in the deoxycorticosterone acetate-salt rat (2.78 +/- 0.6 vs. 1.27 +/- 0.3 ml/100 g/3 hr in vehicle-control rats, p less than 0.05). SCH 34826 (90 mg/kg s.c.) increased plasma levels of atrial natriuretic factor at 1 hour (753 +/- 89 vs. 451 +/- 79 pg/ml in vehicle-treated rats, p less than 0.05) but not 3 hours after dosing. The renal excretion of atrial natriuretic factor (3,092 +/- 1,089 vs. 21 +/- 6 pg/100 g/3 hr in vehicle-treated rats, p less than 0.05) and cyclic guanosine monophosphate (2,131 +/- 509 vs. 879 +/- 168 pg/100 g/3 hr in vehicle-treated rats, p less than 0.05) was markedly elevated by SCH 34826 in deoxycorticosterone acetate-salt rats. These studies suggest that neutral endopeptidase inhibition may represent a new approach to treatment of some forms of hypertension.
Hypertension 1990 Feb
PMID:Atrial natriuretic factor-potentiating and antihypertensive activity of SCH 34826. An orally active neutral metalloendopeptidase inhibitor. 215 4

Two subclasses of cyclic guanosine monophosphate (GMP)-specific phosphodiesterases were identified in vascular tissue from several beds. The activity of one subclass (phosphodiesterase IB) was stimulated severalfold by calmodulin and selectively inhibited by the phosphodiesterase inhibitor TCV-3B. The activity of the other subclass (phosphodiesterase IC) was not stimulated by calmodulin and was selectively inhibited by the phosphodiesterase inhibitor M&B 22,948. To assess the involvement of both subclasses in regulating cyclic GMP-dependent responses, the ability of TCV-3B and M&B 22,948 to potentiate the in vitro and in vivo responses to the endogenous guanylate cyclase stimulator atrial natriuretic factor (ANF) was evaluated. Both TCV-3B and M&B 22,948 relaxed isolated rabbit aortic and pulmonary artery rings and also potentiated the relaxant effect of ANF. In addition, both inhibitors produced small increases in urine flow and sodium excretion in anesthetized rats and potentiated the diuretic and natriuretic responses to exogenous ANF. M&B 22,948 (30 micrograms/kg/min) produced a threefold increase in the natriuretic response to simultaneously administered ANF, and TCV-3B (10 micrograms/kg/min) produced a twofold increase in the response to ANF. The results of the present experiments suggest that both the calmodulin-sensitive and calmodulin-insensitive subclasses of cyclic GMP-specific phosphodiesterase play a role in regulating the in vitro and in vivo response to ANF.
Hypertension 1990 May
PMID:Subclasses of cyclic GMP-specific phosphodiesterase and their role in regulating the effects of atrial natriuretic factor. 215 39


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