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

We recently reported the novel finding of expression and function of connexin45 (Cx45) in cerebrovascular smooth muscle cells. We examined the hypothesis that Cx45 is altered in hypertension. Immunoblots for Cx45 showed a significant increase in Cx45 in cerebral arteries from adult spontaneously hypertensive rats (SHR) compared with adult Wistar-Kyoto (WKY) rats, with no difference in aorta or femoral artery. Patch-clamp of cerebral smooth muscle cells pairs from SHR versus WKY showed a significantly steeper voltage dependence of deactivation and partial block of junctional currents by quinine and by a peptide that interferes with docking of Cx45, consistent with dominance of functional Cx45 channels in SHR. We examined potential roles of blood pressure versus angiotensin in elevated Cx45 in SHR by measuring Cx45 protein in 4 groups: (1) long-term administration in Wistar rats of the nitric oxide synthase inhibitor L-NAME; (2) long-term administration in SHR of the ACE inhibitor captopril; (3) long-term administration in Wistar rats of angiotensin; and (4) exposure of basilar artery segments in organ culture to angiotensin. Blood pressure was significantly elevated in groups 1 and 3 and was normal in group 2. In groups 1, 2, and 4, there was no significant change in Cx45 protein. In group 3, there was a modest but insignificant increase in Cx45 protein but no change in voltage dependence of deactivation of junctional currents. Overall, our data show increased Cx45 in SHR that is unlikely to be due to either elevated blood pressure or to angiotensin. Relative dominance of Cx45 over Cx43 in cerebral vessels may predispose SHR to ischemic stroke.
Hypertension 2002 Dec
PMID:Increase in Cx45 gap junction channels in cerebral smooth muscle cells from SHR. 1246 83

Gap junction channels provide the basis for the electrical syncytial properties of the heart as a communicating electrical network. Cardiac gap junction channels are predominantly composed of connexin 40 or connexin 43. The conductance of these channels (g(j)) can be regulated pharmacologically: substances which activate protein kinase C, protein kinase A or protein kinase G may alter Cx43 gap junction conductance. However, for PKC, this seems to be subtype specific. Thus, antiarrhythmic peptides can enhance g(j) via activation of PKCepsilon, while FGF-2 reduces g(j) via PKCepsilon. Lipophilic drugs can uncouple the channels. Besides an acute regulation of g(j), the expression of the cardiac connexins can also be regulated. A decrease in Cx43 with a concomitant increase in Cx40 has been found in end-stage failing hearts, while in renovascular hypertension, an increase in Cx43 has been described. Mediators like endothelin-1, angiotensin-II, TGF-beta, VEGF, and cAMP have been shown to increase Cx43. Interestingly, endothelin-1 and angiotensin-II increased Cx43 but did not affect Cx40 expression. In contrast, in humans suffering from atrial fibrillation (AF), the content in Cx40 can be enhanced while Cx43 was unaltered, although in several other studies, other changes of the cardiac connexins were found, which might be related to the type of AF. Regarding the role of calcium, the content in both Cx40 and Cx43 was decreased in cultured neonatal rat cardiomyocytes after 24 h administration of 100 nM verapamil. Thus, gap junctional channels can be affected pharmacologically either acutely by modulating gap junction conductance or chronically by altering gap junction protein expression. Interestingly, it appears that the expression of Cx43 and Cx40 can be differentially regulated.
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PMID:Pharmacological modulation and differential regulation of the cardiac gap junction proteins connexin 43 and connexin 40. 1256 16

Gap-junctional communication coordinates the behavior of individual cells in arterioles. Gap junctions are formed by connexins 40 (Cx40), Cx43, Cx37, and Cx45 in the vasculature. Previously, we have shown that lack of Cx40 impairs conduction of dilatory signals along arterioles. Herein, we examined whether hypertension is present in conscious animals and whether this is a direct effect or due to secondary mechanisms. Mean arterial pressure was elevated by 20-25 mmHg in conscious Cx40-deficient mice (Cx40(-/-)) compared with wild-type controls in both sexes. Differences in heart rate were not observed. Blockade of NO synthase increased pressure equally in both genotypes. Conversely, the angiotensin AT(1)-receptor antagonist, candesartan, decreased pressure to similar extents in Cx40(-/-) and wild-type mice. Acetylcholine and sodium nitroprusside (0.05-15 nmol) were equally potent and effective in decreasing pressure and inducing dilatory responses in the microcirculation. However, in contrast to wild type, Cx40(-/-) arterioles exhibited spontaneous, irregular vasomotion leading temporarily to complete vessel closure. We conclude that loss of Cx40 is associated with hypertension independent of the action of angiotensin II. It is also not related to an altered efficacy of NO or other endothelial dilators. However, the observed irregular vasomotion suggests that peripheral vascular resistance is affected.
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PMID:Lack of vascular connexin 40 is associated with hypertension and irregular arteriolar vasomotion. 1270 Mar 62

Blockade of the renin-angiotensin system improves the impaired endothelium-dependent relaxations associated with hypertension and aging, partly through amelioration of endothelium-derived hyperpolarizing factor (EDHF)-mediated responses. Although the nature of EDHF is still controversial, recent studies have suggested the involvement of gap junctions in EDHF-mediated responses. Gap junctions consist of connexins (Cx), and we therefore tested whether the expression of Cx in vascular endothelial cells would be altered by hypertension and antihypertensive treatment. Spontaneously hypertensive rats (SHR) were treated with either the angiotensin II type 1 receptor antagonist candesartan or the combination of hydralazine and hydrochlorothiazide for 3 mo from 5 to 8 mo of age. Confocal laser scanning microscopy after immunofluorescent labeling with antibodies against Cx37, Cx40, and Cx43 revealed that the expression of Cx37 and Cx40 in endothelial cells of the mesenteric artery was significantly lower in SHR than in WKY. Treatment with candesartan, but not the combination of hydralazine and hydrochlorothiazide, significantly increased the expression of Cx37 and Cx40, although blood pressure decreased similarly. On the other hand, the expression of Cx43, though scarce and heterogeneous, was increased in SHR compared with WKY, and candesartan treatment lowered the expression of Cx43. These findings suggest that renin-angiotensin system blockade corrects the decreased expression of Cx37 and Cx40 in arterial endothelial cells of hypertensive rats, partly independently of blood pressure, whereas the expression of Cx43 changed in the opposite direction. It remains to be clarified whether these changes in Cx37 and Cx40 are related to endothelial function, particularly that attributable to EDHF.
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PMID:Angiotensin II receptor blockade corrects altered expression of gap junctions in vascular endothelial cells from hypertensive rats. 1501 32

Gap junction channels provide an enclosed conduit for direct exchanges of signalling molecules, including ions and small metabolites between cells. This system of communication allows cells to monitor the functional state of their neighbours, and is rapidly modulated to continuously adapt to the immediate needs of groups of coupled cells. In the major arteries, endothelial cells may express three connexins isotypes, namely Connexin 37 (Cx37), Cx40 and Cx43, whereas the underlying smooth muscle cells may express Cx37, Cx40, Cx43 and Cx45. Moreover, myoendothelial gap junctions have also been shown to be involved in the regulation of vascular tone. This review highlights the regulation of vessel connexins in response to injury, as observed during experimental hypertension or wound repair, as well as the consequences of loss of one connexin in different transgenic null mice. In view of the major endocrine role of the kidney in the control of blood pressure, we also discuss the distribution of connexins in the kidney vasculature. Cx40 is present between endothelial cells of vessels and glomeruli, as well as between renin-secreting cells, the modified smooth muscle cells which form the wall of the terminal part of afferent arterioles. Modulation of Cx40 expression in a model of renin-dependent hypertension suggests that this connexin may be implicated in the function of renin-secreting cells. Finally, to address the possible regulation of connexin expression by fluid pressure, we summarize the effects of elevated transmural urine pressure on bladder Cx43 expression.
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PMID:Contribution of connexins to the function of the vascular wall. 1509 54

The present study was designed to elucidate whether the conduction of vasomotor responses mediated by endothelium-derived hyperpolarizing factor (EDHF) in rat mesenteric arteries is altered during hypertension. Iontophoresed acetylcholine (ACh; 500 ms) caused EDHF-mediated hyperpolarization and vasodilatation at the local site and these responses spread through the endothelium to remote sites in 12-week-old Wistar-Kyoto rats (WKY). Conducted responses were significantly attenuated in age-matched spontaneously hypertensive rats (SHR) although the rate of decay with distance did not change. Inhibition of inwardly rectifying potassium (Kir) channels (30 microM barium) eliminated the difference between WKY and SHR by attenuating conducted responses in WKY but not SHR. At the local site, barium (30 microM) significantly reduced the duration but not the amplitude of ACh-induced hyperpolarization in WKY only. Barium had no effect when the iontophoretic stimulus was reduced to 350 ms. After blockade of EDHF in SHR, ACh elicited a depolarization which our indirect data suggest spreads along the vessel in the endothelium. Messenger RNA expression of Kir2.0 genes did not differ between the strains nor did the amplitude of K(+)-induced hyperpolarization, which was abolished by disruption of the endothelium. Immunohistochemistry revealed a decrease in connexin (Cx)37 but not Cx40 or Cx43 protein in endothelial cells of SHR compared to WKY. Results suggest that conduction of EDHF-mediated responses in WKY, but not in SHR, is facilitated by activation of Kir channels at the site of ACh application and not by differences in endothelial connexin expression. Lack of Kir channel involvement in hypertension may result from reduction in the duration of the hyperpolarization due to the development of ACh-mediated depolarization, rather than to any difference in Kir subunit expression or function.
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PMID:Attenuation of conducted vasodilatation in rat mesenteric arteries during hypertension: role of inwardly rectifying potassium channels. 1555 Apr 69

Four connexin (Cx) molecules, namely Cx37, Cx40, Cx43 and Cx45, are expressed in the gap junctions that exist within and between the cellular layers of arteries. Endothelial cells are well coupled by large gap junctions expressing Cx37, Cx40 and, to a lesser extent, Cx43, whose expression may be more subject to regulation by physical factors. Smooth muscle cells are more heterogeneously coupled by gap junctions that are small and rare. The identity of the Cx expressed in the media may vary among different arteries. Myoendothelial gap junctions are small and more common in resistance arteries with fewer layers of smooth muscle cells. Given the small size of these gap junctions and the rapid turnover rate of Cxs, homocellular coupling in the media and heterocellular coupling between the cell layers may be subject to more dynamic control than coupling in the endothelium. Vascular gap junctions have been implicated in a number of vasomotor responses that may regulate vascular tone and blood pressure. These include the mechanism of action of the vasodilator, endothelium-derived hyperpolarizing factor (EDHF), the myogenic constriction to intramural pressure increase, the spontaneous or agonist-induced vasomotion of arteries and arterioles and the spreading vasodilation and constriction observed in microcirculatory networks. Few data are available on Cx expression in the media of resistance arteries during hypertension. Changes in the expression of Cx43 described in the media of the aorta of hypertensive rats vary with the hypertensive model studied and are likely to represent adaptations to structural changes in the vascular wall. In contrast, in the endothelium of the caudal and mesenteric arteries of spontaneously hypertensive rats, expression of Cxs is significantly decreased compared with arteries from normotensive rats and this decrease is reversed by inhibitors of the renin-angiotensin system. During hypertension, the activity of EDHF is decreased in the mesenteric artery, but this occurs much later than the initial increase in blood pressure and the decrease in endothelial Cxs, suggesting that changes in EDHF may not be causally related to hypertension or to the changes in endothelial Cxs. Upregulation of the myogenic response and the incidence of vasomotion has been reported in hypertension. Little is currently known of the effects of hypertension on spreading vasomotor responses. Deletion of specific Cxs in genetically modified mice is complicated by neonatal lethality or coordinate regulation and compensatory changes in the remaining Cxs. Nevertheless, mice in which Cx40 has been deleted are hypertensive and spreading vasodilatory responses are significantly impaired. Determination of a role for specific Cxs in the control of blood pressure must await the development of animals in which Cx expression can be modulated in a more complex temporal and tissue-specific manner.
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PMID:Vascular gap junctions and implications for hypertension. 1555 5

To investigate the function of Cx43 during hypertension, we studied the mouse line Cx43KI32 (KI32), in which the coding region of Cx32 replaces that of Cx43. Within the kidneys of homozygous KI32 mice, Cx32 was expressed in cortical and medullary tubules, as well as in some extra- and intraglomerular vessels, i.e., at sites where Cx32 and Cx43 are found in WT mice. Under such conditions, renin expression was much reduced compared with that observed in the kidneys of WT and heterozygous KI32 littermates. After exposure to a high-salt diet, all mice retained a normal blood pressure. However, whereas the levels of renin were significantly reduced in the kidneys of WT and heterozygous KI32 mice, reaching levels comparable to those observed in homozygous littermates, they were not further affected in the latter animals. Four weeks after the clipping of a renal artery (the 2-kidney, 1-clip [2K1C] model), 2K1C WT and heterozygous mice showed an increase in blood pressure and in the circulating levels of renin, whereas 2K1C homozygous littermates remained normotensive and showed unchanged plasma renin activity. Hypertensive, but not normotensive, mice also developed cardiac hypertrophy. The data indicate that replacement of Cx43 by Cx32 is associated with decreased expression and secretion of renin, thus preventing the renin-dependent hypertension that is normally induced in the 2K1C model.
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PMID:Connexin43-dependent mechanism modulates renin secretion and hypertension. 1644 62

Hemodynamic forces play a critical role in atherogenesis, as evidenced by the focal pattern of development of atherosclerotic lesions. Whereas disturbed flow in the branches and curved regions of large arteries is proatherogenic, laminar flow in the straight parts of vessels is atheroprotective. In addition, hypertension and age-related changes in arterial stiffness are important risk factors of the disease. Hemodynamic forces induce various changes in the structure and function of vascular endothelium, many of which reflect alterations in gene expression. Endothelial cells are linked by gap junctions, which facilitate the propagation of electrical and chemical signals along the vascular wall. Using an in vitro perfusion system, we investigated the effects of pulsed unidirectional and oscillatory flows in combination with different levels of hydrostatic pressure and circumferential stretch on the expression of Cx43 in endothelial cells. Our results show that shear stress and circumferential stretch, but not pressure, modulate the expression of Cx43. In view of the distribution of this protein along the vascular tree, our findings provide new insights into the role of mechanical forces on gap junctional communication in regions prone to the development of atherosclerosis.
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PMID:Shear stress and cyclic circumferential stretch, but not pressure, alter connexin43 expression in endothelial cells. 1653 21

Renin secretion is regulated by coordinated signaling between the various cells of the juxtaglomerular apparatus. The renin-secreting cells (RSC), which play a major role in the control of blood pressure, are coupled to each other and to endothelial cells by Connexin40 (Cx40)-containing channels. In this study, we show that Cx40 knockout (Cx40-/-) mice, but not their heterozygous littermates, are hypertensive due to the increase in the number of RSC, renin biosynthesis, and plasma renin. Treatment with the angiotensin II receptor AT1 antagonist candesartan or the angiotensin II-converting enzyme inhibitor ramipril reduced the blood pressure of the Cx40-/- mice to the same levels seen in wild-type (WT) mice. The elevated blood pressure of the knockout mice was not affected by clipping one renal artery (2K1C, renin-dependent model of hypertension) or after a high salt diet. Under these conditions, however, Cx40-/- mice showed an altered production and release of renin. The renin mRNA ratio between the clipped and the non-clipped kidney was lower in the knockout than in the WT 2K1C mice. This indicates that the response to a change in blood pressure was altered. The RSC of the Cx40-/- mice did not have a compensatory increase in the levels of either Cx43 or Cx37. Our data show that renin secretion is dependent on Cx40 and suggest the Cx40-/- mice may be a genetic model of renin-dependent hypertension.
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PMID:Connexin40 regulates renin production and blood pressure. 1788 39


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