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

Two independent series of biomedical investigations have led to the discovery that the atria constitute a peptide-secreting endocrine gland. The first investigation is mainly morphological and started with the finding that mammalian atrial (but not ventricular) cardiocytes contain "dense bodies." These "dense bodies," later called "specific granules," were found to be different from lysosomes; to be made up of proteins; and to incorporate both 3H-leucine and 3H-fucose in a pattern typical of peptide-secreting endocrine cells. The finding that rat atrial granulation varied with the sodium and water balance led to the crucial observation that atrial extracts have natriuretic and diuretic effects. In less than five years, this new natriuretic hormone has been purified, sequenced and synthesized, and its CDNA and gene have been cloned. The atrial natriuretic factor (ANF) gene has been assigned to the distal short arm of chromosome 1 in band 1P36, while the mouse gene is localized in chromosome 4. The native and synthetic hormones exert identical wide ranging effects (possibly through particulate guanylate cyclase stimulation and adenylate cyclase inhibition) on the kidney, blood vessels, adrenal cortex, and pituitary. Physiopathologic implications of the hormone in experimental hypertension, congestive heart failure, and expansion of blood volume are already beginning to emerge. Concurrently, the search for the function of natriuretic hormones or factors (through studies of negative pressure breathing, atrial distension experiments, head-out water immersion, expansion of blood volume, Na+/K+-ATPase inhibition, and parabiosis experiments in Dahl rats) has provided a general framework within which to interpret this new cardiac function.
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PMID:The heart as an endocrine gland. 302 9

alpha 2-Adrenoceptors were first described pharmacologically ten years ago. Within three years their capacity to inhibit adenylate cyclase had been demonstrated in many tissues. They were demonstrated biochemically in the kidneys in 1981 even before any renal physiological effects of their activation were known. They predominate numerically over alpha 1-adrenoceptors in renal membranes and their density is increased in genetic forms of rat hypertension. alpha 1-Adrenoceptors normally mediate the vasoconstriction and sodium- and water-retaining effects of sympathetic neuronally released norepinephrine. Norepinephrine or epinephrine must be infused to activate alpha 2-adrenoceptors, suggesting that renal alpha 2-adrenoceptors are extrajunctional, whereas alpha 1-adrenoceptors are postjunctional. When alpha 1-adrenoceptors are chronically blocked, renal alpha 2-adrenoceptor density increases and they assume a location at postjunctional sites, the otherwise exclusive domain of alpha 1-adrenoceptors. Results from microdissection studies have established that alpha 2-adrenoceptors are present on most segments of the nephron and that their activation can suppress adenosine 3,'5'-cyclic monophosphate (cAMP) accumulation induced by most renal hormones. However, failure of alpha 2-adrenoceptor activation to suppress cAMP accumulation in some tubular segments induced by certain hormones suggests compartmentalization of adenylate cyclase regulation that is hormone-function specific. In view of the potent inhibitory effects of alpha 2-adrenoceptor stimulation on hormone activated cAMP accumulation in several discrete areas of the nephron, we suggest that alpha 2-adrenoceptors fulfill important regulatory role(s) in renal function. To date, alpha 2-adrenoceptor activation has been shown to reverse vasopressin-induced sodium and water retention, and arachidonic acid- and furosemide-induced cAMP, sodium, and water excretion in the isolated perfused kidney. Thus the effects are qualitatively and quantitatively dependent in these studies on the hormone being infused and are therefore hormone-function specific. Physiological effects of alpha 2-adrenoceptor activation of thyrocalcitonin and on parathyroid hormone-induced effects have not been studied. alpha 2-Adrenoceptor activation can inhibit renin release in some model systems and can activate a sodium-hydrogen antiporter system in proximal tubules. The physiological roles of these actions are unknown.
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PMID:Renal alpha 2-adrenoceptors and the adenylate cyclase-cAMP system: biochemical and physiological interactions. 302 68

To determine the mechanism of blunted sympathetic reflex responses in early renovascular hypertension, we measured inotropic and chronotropic responses of the heart to beta-adrenergic stimulation in vivo and myocardial beta-adrenergic receptor number and adenylate cyclase activity in 10 dogs during an early stage of one-kidney renal hypertension. Mean aortic pressure was higher in the hypertensive dogs (152 +/- 4 mm Hg) than in eight sham-operated dogs (122 +/- 1 mm Hg; p less than 0.001), but heart rate, cardiac output, and left atrial pressure did not differ between the two groups. Blood pressure reduction with a direct-acting vasodilator, pinacidil, resulted in marked increases in heart rate (+97 +/- 12 beats/min) and rate of change of left ventricular pressure (dP/dt; +1447 +/- 367 mm Hg/sec) in normotensive dogs but only blunted heart rate (+54 +/- 12 beats/min) and minimal left ventricular dP/dt (+376 +/- 264 mm Hg/sec) responses in hypertensive dogs. In contrast, intravenously administered isoproterenol produced similar increases in heart rate and left ventricular dP/dt in the two groups. These two groups also did not differ in either left ventricular beta-adrenergic receptor number and affinity or basal, isoproterenol-stimulated, and fluoride-stimulated adenylate cyclase activity. Thus, despite blunted reflex responses to blood pressure reduction, hypertensive dogs showed neither reduction in chronotropic and inotropic responses to direct beta-adrenergic stimulation nor beta-adrenergic desensitization of the myocardium, as assessed by beta-adrenergic receptor number and adenylate cyclase activity. Blunted reflex responses in this model of early hypertension must be due to factors operating at some locus other than the beta-adrenergic receptor-adenylate cyclase complex.
Hypertension 1987 May
PMID:Preserved cardiac beta-adrenergic sensitivity in early renovascular hypertension. 303 89

Inotropic responses to isoproterenol of hypertrophied hearts have been shown to be decreased. We have previously reported that in 13-week-old spontaneously hypertensive rats (SHR) this decrease is probably due to decreased beta-adrenergic receptor number, while in hearts from two kidney-one clip renal hypertensive rats (2K-1C RHR), this is due to a decreased nucleotide regulatory protein activity. We now show that changes in 2K-1C RHR are time dependent. One week after instituting development of hypertension the heart is already hypertrophied. Biochemical changes consistent with decreased glucagon receptors are seen, as well as beginning changes consistent with decreases in the nucleotide regulatory protein activity. By two weeks this is more evident. Hypertrophy and biochemical changes can be reversed up to six weeks, but by ten weeks the activity of the catalytic subunit of the adenylate cyclase system is decreased. In 1K-1C RHR, biochemical changes in the cyclase system are accelerated as compared with the 2K-1C model. In SHR, changes in 24-week-old rats are the same as in the 13-week-old rats. It is concluded that in cardiac hypertrophy associated with different models of hypertension the decreased inotropic responsiveness to isoproterenol is associated with different biochemical defects in the beta-adrenergic receptor response coupling pathway, and that reversal in function occurs only when there is no apparent change in the catalytic subunit of the adenylate cyclase complex.
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PMID:Adenylate cyclase activity during development and reversal of cardiac hypertrophy. 316 Aug 64

Sensitivity to adrenaline-antagonism of the inhibitory effect of PGI2 on thrombin-induced increase in [Ca2+]i was measured in platelets from normotensive and untreated hypertensive subjects. Platelets from hypertensive subjects exhibited an increased sensitivity to adrenaline. This effect was more pronounced in younger patients with hypertension, and suggests an increased adenylate cyclase sensitivity in the early hypertension. The data also indicate that a mechanism linked to calcium-influx plays an important role in older hypertensives. This may explain the greater efficacy of calcium entry blockers in older hypertensive patients with essential hypertension.
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PMID:Hormonal modulation of intracellular free calcium in platelets from normotensive and hypertensive subjects. 388 86

We activated three known components of the adenylate cyclase system in renal membranes from spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. The basal adenylate cyclase activity and responses to plasma membrane receptor activation by parathyroid hormone, isoproterenol and vasopressin were not different between the two strains. The response to prostaglandin E2 (PGE2), however, was less in the SHR than in the WKY at five, (P less than 0.05), 12 (P less than 0.01) and 16 (P less than 0.01) weeks of age. Activation of either the guanosine-5'-triphosphate (GTP) binding regulatory protein (N) with sodium fluoride (NaF) and guanyl-5'-yl-imidodiphosphate [Gpp(NH)p], or the catalytic unit with manganese chloride (MnCl2) or forskolin were not different between the two groups. When the medullary and cortical plasma membrane adenylate cyclase responses were studied separately, the observed decreased response to PGE2 (of SHR) was found to be entirely in the cortex. Also, the NaF response was reduced in the cortical region of the 12-week-old rats, a finding suggesting a possibility of a post receptor defect. These results show that there is a defective renal adenylate cyclase response specific to prostaglandin E2 in SHR. This defect could be related to the development of hypertension, by changing the natriuretic and/or renal vasodilating effects of these prostaglandins.
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PMID:Defective renal adenylate cyclase response to prostaglandin E2 in spontaneously hypertensive rats. 392 77

In the aortas and mesenteric arteries from spontaneous hypertensive rats and in the aortas from stress- and desoxycorticosterone-acetate-hypertensive rats, the intracellular cGMP: cAMP ratios were significantly elevated when compared to the ratios in the aortas of the respective controls. Decreases in the intracellular cAMP or cGMP levels were consistently associated with increased activity of the cyclic-nucleotide-specific low K(m) phosphodiesterase (3':5'-cAMP 5' nucleotidohydrolase, EC 3.1.4.17). Increases in intracellular cGMP levels were associated with elevated guanylyl cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2] activity. Furthermore, adenylyl cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] activity was less sensitive to stimulation by the beta-adrenergic stimulant isoproterenol in both the aortas and the hearts of the hypertensive animals. These changes could provide the biochemical basis for the (a) increased vascular smooth muscle tone and peripheral resistance observed in these animals, (b) increased reactivity to norepinephrine, and (c) decreased ability of aortas from hypertensive rats to relax. The presence of these same effects in different etiologic types of hypertension indicates that this aberration in cyclic nucleotide metabolism may represent a common metabolic defect basic to the hypertensive syndrome irrespective of etiology.
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PMID:Aberrations of cyclic nucleotide metabolism in the hearts and vessels of hypertensive rats. 415 74

An acute hot stress caused a sharp increase in plasma cyclic AMP and cyclic GMP in both spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). This hot stress-induced increase in plasma cyclic AMP was observed even after chemical sympathectomy elicited by 6-hydroxydopamine or depleting the catecholamine stores in adrenergic neurons by tyramine or reserpinization, but was no longer observable after beta-adrenergic blockade by propranolol, blockade of autonomic ganglia by hexamethonium, adrenodemedullation or anesthesia by pentobarbital. These results indicate that the initial stimulation of the central nervous system evoked the release of catecholamines from the adrenal medulla which could activate adenylate cyclase via the stimulation of beta-adrenoceptors on the cell surface. The increment of plasma cyclic GMP was not influenced by prior blockade of the peripheral autonomic nervous system, but was totally abolished by pentobarbital, indicating that cyclic GMP generated within the central nervous system in response to the hot stress would be directly related to its increase in the peripheral blood stream. The plasma cyclic AMP and cyclic GMP responses were greater in adult SHR than in young SHR and young and matured WKY. The predominant response of plasma cyclic AMP might be due to a greater release of catecholamine from the adrenal medulla in matured SHR. The hyperresponse of plasma cyclic GMP in adult SHR remains to be fully elucidated. The increased cyclic nucleotide responses in SHR might be an important factor in the maintenance of hypertension.
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PMID:Plasma cyclic nucleotides in spontaneously hypertensive rats: hyperresponse to acute hot stress. 608 98

Abnormalities of platelet aggregation and cyclic nucleotide metabolism are present in hypertension. We observed a greater increase in the level of cyclic adenosine monophosphate (AMP) after prostaglandin E1 (PGE1) stimulation and a lack of decrease of this cyclic nucleotide by epinephrine in platelets from spontaneously hypertensive rats (SHR) as compared to normotensive rats. The difference in cyclic AMP production between SHR and control rats in response to PGE1 is dependent upon platelet exposure to calcium. Since calcium and cyclic AMP are closely related and are both abnormally regulated in hypertension, we have studied the effect of calcium on adenylate cyclase activity. We show here that two forms of endogenous calcium-dependent proteases (membrane-bound and soluble) stimulate the basal activity and the hormonal responsiveness of adenylate cyclase. The sensitivity of calcium-dependent proteolytic control of adenylate cyclase to very-low concentrations of calcium indicates that the regulation may be physiologically important. Furthermore, calcium exerts a greater influence on platelet adenylate cyclase from SHR than on that from normotensive rats. The adenylate cyclase defect seems to be located in the membrane fraction and may, therefore, result from an increase in the activity of the membrane-bound calcium-protease or may be intrinsic to adenylate cyclase itself. The exact site that is sensitive to proteolysis remains to be established.
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PMID:Calcium-dependent proteolytic stimulation of adenylate cyclase in platelets from spontaneously hypertensive rats. 608 83

We have assessed the presence of VIP/PHI/secretin receptors in heart by: (1) testing the ability of the corresponding peptides to activate adenylate cyclase in cardiac membranes from rat, dog, Cynomolgus monkey and man, and (2) examining the ability of the same peptides to exert inotropic and chronotropic effects on heart preparations from rat and Cynomolgus monkey in vitro. Based on their affinity for natural peptides and synthetic analogs, two types of VIP/PHI/secretin receptors were characterized: the relatively nonspecific "secretin/VIP receptor" of rat heart (that is "secretin-preferring" only in that secretin was more efficient than VIP in stimulating adenylate cyclase), and the "VIP/PHI-preferring" receptor of man, monkey and dog heart. Four physiopathological situations affecting secretin/VIP receptors in rat heart were explored: In male rats from the Okamoto strain and the Lyon strain, two strains presenting spontaneous hypertension, heart membranes exhibited a markedly decreased response of adenylate cyclase to secretin/VIP, with lesser alterations in the responses to isoproterenol and glucagon. This impairment developed in parallel with the occurrence of hypertension and was reproduced in normotensive rats submitted to chronic isoproterenol treatment (but not in Goldblatt hypertensive rats). These findings are consistent with a hyperactivity of norepinephrine pathways in spontaneously hypertensive rats, leading to a reduced number of cardiac post-junctional secretin/VIP receptors bound to adenylate cyclase. Heart membranes from genetically obese (fa/fa) Zucker rats also exhibited severely decreased responses to secretin/VIP with lesser alterations in the responses to glucagon and isoproterenol. These anomalies were specific for the heart, and developed in concomitance with obesity. The first anomaly could not be corrected by severe food restriction. Secretin stimulation of heart adenylate cyclase was also selectively altered in streptozotocin-diabetic rats. Thus, two types of diabetic cardiomyopathy were characterized by a severe local alteration of secretin/VIP receptors coupled to adenylate cyclase. Hypothyroidism, provoked in rat by thyroidectomy or propylthiouracil treatment, again induced a marked decrease in secretin-stimulated cardiac adenylate cyclase activity. In rat papillary muscle electrically stimulated in vitro, secretin exerted a positive inotropic effect. This effect was reduced in obese (fa/fa) Zucker rats. In rat right atrium, secretin also exerted a positive chronotropic effects.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Heart receptors for VIP, PHI and secretin are able to activate adenylate cyclase and to mediate inotropic and chronotropic effects. Species variations and physiopathology. 608 34


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