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

Low-voltage-activated T-type Ca2+ channels are present in most excitable tissues including the heart (mainly pacemaker cells), smooth muscle, central and peripheral nervous systems, and endocrine tissues, but also in non-excitable cells, such as osteoblasts, fibroblasts, glial cells, etc. Although they comprise a slightly heterogeneous population, these channels share many defining characteristics: small conductance (< 10 pS), similar Ca2+ and Ba2+ permeabilities, slow deactivation, and a voltage-dependent inactivation rate. In addition, activation at low voltages, rapid inactivation, and blockade by Ni2+ are classical properties of T-type Ca2+ channels, which are less specific. T-type Ca2+ channels are weakly blocked by standard Ca2+ antagonists. Pharmacological blockers are scarce and often lack specificity and/or potency. The physiological modulation of T-type Ca2+ currents is complex: they are enhanced by endothelin-1, angiotensin II (AT1-receptor), ATP, and isoproterenol (cAMP-independent), but are reduced by angiotensin II (AT2-receptor), somatostatin and atrial natriuretic peptide. Norepinephrine enhances these currents in some cells but decreases them in others. T-type Ca2+ currents have many known or suggested physiological and pathophysiological roles in growth (protein synthesis, cell differentiation, and proliferation), neuronal firing regulation, some aspects of genetic hypertension, cardiac hypertrophy, cardiac fibrosis, cardiac rhythm (normal and abnormal), and atherosclerosis. Mibefradil is a new Ca2+ antagonist that is effective in hypertension and angina pectoris. Its favorable pharmacological profile and limited side effects appear to be related to selective block of T-type Ca2+ channels: mibefradil reduces vascular resistance and heart rate without negative inotropy or neurohormonal stimulation, and it also has significant antiproliferative actions.
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PMID:T-type Ca2+ channels and pharmacological blockade: potential pathophysiological relevance. 951 67

We evaluated the endogenous action of angiotensin II (AII) and its active metabolite, angiotensin III (AIII), at the nucleus tractus solitarii (NTS) in the modulation of baroreceptor reflex (BRR) response, and the subtype(s) of angiotensin receptors involved in this process. Adult, male Sprague-Dawley rats that were anesthetized and maintained with pentobarbital sodium were used. Bilateral microinjection of AII or AIII (10, 20 or 40 pmol) into the NTS significantly and dose-dependently suppressed the BRR response, which was evoked by transient hypertension induced by phenylephrine (5 micrograms/kg, i.v.). The suppressive effect of AII (40 pmol) was reversed by co-administration of the non-peptide AT1 receptor antagonist, losartan (1.6 nmol), but only partially by the non-peptide AT2 receptor antagonist, PD-123319. On the other hand, both angiotensin receptor antagonists appreciably reversed the depressive action of AIII (40 pmol). Blocking the endogenous activity of the angiotensins by microinjection into the bilateral NTS of losartan (1.6 nmol) or PD-123319 (1.6 nmol) elicited a significant enhancement of the BRR response. An interruption of the conversion of AII to AIII with the aminopeptidase A inhibitor, amastatin (3.3 nmol), attenuated, but did not eliminate, the AII-induced inhibition of the BRR response. We conclude that whereas the endogenous AIII may exert a tonic inhibitory modulation on the BRR response by acting on both the AT1 and AT2 receptor subtypes, the same action of the endogenous AII engaged only the AT1 receptor subtype at the NTS. Furthermore, at least part of the suppressive action of AII may result from its metabolic conversion to AIII.
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PMID:Participation of AT1 and AT2 receptor subtypes in the tonic inhibitory modulation of baroreceptor reflex response by endogenous angiotensins at the nucleus tractus solitarii in the rat. 951 51

Oleic acid and angiotensin II (Ang II) are elevated and may interact to accelerate vascular disease in obese hypertensive patients. We studied the effects of oleic acid and Ang II on growth responses of rat aortic smooth muscle cells (VSMCs). Oleic acid (50 micromol/L) raised thymidine incorporation by 50% at 24 hours and cell number by 55% at 6 days (P<.05). Ang II (10(-11) to 10(-6) mol/L) did not significantly increase thymidine incorporation or VSMC number. Combining Ang II and 50 micromol/L oleic acid doubled thymidine incorporation and VSMC number. Losartan, an angiotensin type 1 (AT1) receptor antagonist, blocked the synergistic interaction between Ang II and oleic acid, whereas the AT2 receptor antagonist PD 123319 did not. Protein kinase C inhibition and downregulation, as well as inhibition of extracellular signal-regulated kinase (ERK) activation by PD 98059, eliminated the rise of thymidine incorporation in response to oleic acid and the synergistic interaction with Ang II. However, the response to 10% fetal bovine serum was unaffected. An antisense oligodeoxynucleotide to ERK-1 and ERK-2 reduced ERK protein expression and activation by 83% and 75%, respectively. Antisense prevented the rise of thymidine incorporation in response to oleic acid and the synergy with Ang II. Antisense reduced but did not prevent increased thymidine incorporation in response to serum. The data indicate that oleic acid and Ang II exert a synergistic mitogenic effect in VSMCs and suggest an important role for the AT1 receptor, PKC, and ERK in this synergy. The observations raise the possibility that a synergistic mitogenic interaction between oleic acid and Ang II accelerates vascular remodeling in obese hypertensive patients.
Hypertension 1998 Apr
PMID:Oleic acid and angiotensin II induce a synergistic mitogenic response in vascular smooth muscle cells. 953 24

Our studies on angiotensin II receptor subtype 1A (AT1A) knockout mice define how endogenous receptors other than AT1A receptors stimulate changes in cytosolic calcium concentration ([Ca2+]i) in cultured aortic vascular smooth muscle cells (VSMCs). Wild-type cells have a 1.7 ratio of AT1A/AT1B receptor mRNA as determined by semiquantitative reverse transcriptase-polymerase chain reaction. Mutant cells express AT1B receptor mRNA but not that for the AT1A receptor. In wild-type cells with AT1A present, Ang II (10(-7) mol/L) produces a characteristic rapid peak increase in [Ca2+]i of 150 to 180 nmol/L, followed by a plateau phase characterized by a sustained 70 to 80 nmol/L increase in [Ca2+]i. An unexpected finding was that the magnitude and time-dependent pattern of [Ca2+]i changes produced by Ang II were similar in cells that lacked AT1A receptors but possessed AT1B receptors. The response in mutant cells indicates effective coupling of an Ang II receptor to one or more second messenger systems. The similarity of response patterns between cells with and without AT1A receptors suggests that non-AT1A receptors are functionally linked to similar signal transduction pathways in mutant cells. The fact that mutant and wild-type cells exhibit similar patterns of calcium mobilization and entry supports the notion that AT1A and non-AT1A receptors share common signal transduction pathways. The AT2 receptor ligands PD-123319 and CGP-42112 do not alter Ang II effects in either VSMC type, suggesting a paucity of AT2 receptors and/or an absence of their linkage to [Ca2+]i pathways. The nonpeptide AT1 receptor blocker losartan antagonizes Ang II-induced [Ca2+]i increases in both cell groups, supporting mediation by native AT1B receptors and effective coupling of this subtype to second messenger systems leading to calcium entry and mobilization. Our results demonstrate that Ang II causes calcium signaling in AT1A-deficient VSMCs that is mediated by an endogenous losartan-sensitive AT1B receptor.
Hypertension 1998 May
PMID:Angiotensin AT1B receptor mediates calcium signaling in vascular smooth muscle cells of AT1A receptor-deficient mice. 957 31

1. Dahl Iwai salt-sensitive (DS) rats have been reported as becoming hypertensive with left ventricular hypertrophy (LVH) and heart failure when on a high-salt diet. Their circulating renin-angiotensin system (RAS) has been reported to be suppressed. To evaluate the role of angiotensin II (AngII) type 1 and type 2 receptors (AT1 and AT2, respectively) in LVH, we compared cardiac AT1 and AT2 receptors in 10-week-old DS rats and Dahl Iwai salt-resistant (DR) rats. 2. Seven pairs of 6-week-old male DS and DR rats were fed either a low- or high-salt diet (0.3 or 8% NaCl, respectively) for 4 weeks. Left ventricular AngII receptors were measured by radioligand binding assays using [125I]-[Sar1,Ile8]-AngII in plasma membrane fractions from these four groups. The AT1 and AT2 receptors were distinguished using their specific antagonists CV 11974 and PD 123319, respectively. 3. The high-salt diet increased blood pressure and the left ventricle:bodyweight ratio in DS rats. However, neither Bmax for AT1 and AT2 receptors nor Kd for [125I]-[Sar1,Ile8]-AngII differed between the groups. These results are different from those of other reports of pressure-overload LVH, such as spontaneously hypertensive rats or renovascular hypertension rats, in which AT1 and AT2 receptors were reported to be up-regulated.
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PMID:Angiotensin II receptors in cardiac left ventricles of Dahl rats. 959 May 78

Arterial hypertension is associated with marked changes in the structure of both resistance and large arteries. The renin-angiotensin system is largely involved in these alterations; chronic blockade of the renin-angiotensin system prevents and/or reverses most of the alterations of the vasculature in experimental and clinical hypertension. In this review we have analysed the differential role of AT1 and AT2 receptors in the response of the vessels to arterial hypertension. It emerges that the relative involvement of each receptor depends on cell type, the studied specie, and experimental condition. Several points must be investigated in the near future, and especially: (1) the precise role of angiotensin receptors in different cell types and different stages of differentiation; (2)the transduction pathway used by the AT2 receptor in different cell types; (3) the possible interactions between the two receptor subtypes; and finally, (4) a possible role of (a) new subtype(s) of angiotensin II receptor.
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PMID:The potential role of angiotensin II in the vasculature. 965 48

It has been shown that aldosterone potentiates the action of angiotensin II (Ang II) in cultured rat vascular smooth muscle cells solely by increasing the number of Ang II receptors. The mechanisms responsible for aldosterone-Ang II interactions in the adrenal gland are unknown. The present study was designed to investigate the effect of aldosterone on expression of Ang II receptor subtypes (AT1 and AT2) in the adrenal gland. Seven-week-old male Wistar rats were treated for 2 weeks with either aldosterone (0.05 microg/h, n=14) or vehicle (n=14) by use of implanted osmotic minipumps. Systolic blood pressure was not altered by aldosterone treatment. Plasma aldosterone levels were higher in aldosterone-treated rats (181+/-53 pg/mL) compared with vehicle-treated rats (33+/-21 pg/mL, P<0.05). Northern blot analysis and radioligand binding assay showed that adrenal AT1 mRNA levels and AT1 receptor density in aldosterone-treated rats were not statistically different from those of vehicle-treated rats. However, immunohistochemical studies showed that the highest adrenal AT1 receptor expression was shifted from the zona glomerulosa to the zona fasciculata after aldosterone treatment. In contrast, adrenal AT2 mRNA and AT2 receptor density in aldosterone-treated rats were decreased by approximately 50% and 40%, respectively, compared with vehicle-treated rats (P<0.05). Aldosterone-induced decrease in adrenal AT2 receptor expression occurred mainly in the medulla. Thus, aldosterone differentially modulates the expression of AT1 and AT2 receptors in the adrenal gland. Although the function of the AT2 receptor in the adrenal gland is largely unknown, our data indicate that aldosterone may modulate the effect of Ang II by altering the location of AT1 receptors and by reducing the number of AT2 receptors in the adrenal gland.
Hypertension 1998 Jul
PMID:Differential regulation of angiotensin II receptor subtypes in the adrenal gland: role of aldosterone. 967 39

Angiotensin II exerts its effects on cardiovascular function and water and sodium homeostasis by interacting with plasma membrane receptors on target organs. The existence of subtype 2 angiotensin II (AT2) receptors in the rat heart has been demonstrated by ligand binding and reverse transcription-polymerase chain reaction. In the present study, the expression and localization of AT2 receptor protein in the rat heart was investigated using an antipeptide polyclonal antibody against the native rat AT2 receptor by light microscopic immunocytochemistry and Western blot analysis. In frozen tissue sections, positive immunostaining was observed in the myocardium and coronary vessels throughout the ventricle and atrium of neonatal and young rat hearts. Coronary vessels of the neonatal heart were more intensely stained compared with the surrounding myocardium. Positive immunoreactivity in the coronary vessels of young rats was localized to vascular endothelium but not in the smooth muscle cells. Preadsorption controls were all negative. Western blot analysis showed that the AT2 receptor protein (approximately 44 kDa) was detectable from the AT2 receptor-transfected COS-7 cells and neonatal rat cardiac myocytes but not from fibroblasts or young rat aortic smooth muscle cells. The neonatal rat heart expressed significantly more AT2 receptors than young rat heart. These data provide the first direct evidence for the expression and localization of AT2 receptor protein in the rat heart.
Hypertension 1998 Jul
PMID:Immunolocalization of subtype 2 angiotensin II (AT2) receptor protein in rat heart. 967 41

Angiotensin AT1 receptor antagonists represent a new class of drugs for the treatment of hypertension. They are specific for the renin-angiotensin system, selective for the angiotensin AT1 receptor, and act independently of the angiotensin II synthetic pathway. Blockade of the renin-angiotensin system at the receptor level should therefore be more complete. The high circulating levels of angiotensin II following angiotensin AT1 receptor blockade could be beneficial in stimulating other unblocked angiotensin receptors, especially the AT2 receptor. It has been proposed that the angiotensin AT2 receptor, which is re-expressed or up-regulated during pathological circumstances, counterbalances the effect of the stimulation of the angiotensin AT1 receptor. Through this mechanism, angiotensin AT1 antagonists may be superior to ACE inhibitors in cardiac and vascular remodelling as well as in kidney insufficiency. Long-term trials are required to demonstrate the possible clinical superiority of this new class of antihypertensive agents.
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PMID:Does blockade of angiotensin II receptors offer clinical benefits over inhibition of angiotensin-converting enzyme? 967 17

Our recent studies have shown that the nonpeptide angiotensin II (Ang II) antagonist losartan interacts with thromboxane A2/prostaglandin H2 receptors and inhibits the thromboxane A2 (TxA2) analog U46619-induced vasoconstriction in canine coronary arteries. In this study, we further investigated whether losartan prevents TxA2-induced platelet aggregation and vasoconstriction in spontaneously hypertensive rats (SHRs). Pretreatment with losartan (10 microM) significantly reduced U46619-induced, concentration-dependent washed platelet aggregation. The inhibition is specific for losartan, because another Ang II AT1-receptor antagonist, CV11974 (10 microM), an active metabolite of TCV116, did not block the platelet aggregation caused by U46619. In addition, losartan (10 microM) augmented acetylcholine (ACH)-induced nitric oxide (NO)-dependent vasodilation and abolished the ACH-induced endothelium-derived contracting factor (EDCF)-mediated vasoconstriction in the aortic rings from adult SHRs. U46619 produced dose-dependent vasoconstriction in aortic vessels of SHRs, which was demonstrated to be blocked by the potent, selective TxA2/PGH2 receptor antagonist SQ29,548. Pretreatment with losartan (10(-6)-10(-5) M) inhibited the contractile response of U46619 and shifted the concentration-response curve to the right in a dose-dependent manner. The effective concentration at half maximal contraction (EC50) of U46619 was increased 2.5- and 7.6-fold in the presence of 1 and 10 microM losartan, respectively, without changes in maximal contraction. The active metabolite of losartan, EXP3174, at 1 microM also competitively inhibited U46619-induced contractions in aortic rings of SHRs. In contrast, neither the AT1-receptor antagonist CV11974, the AT2 antagonist PD123319, nor the angiotensin-converting enzyme inhibitor lisinopril, each at concentrations of 1 microM, had any effect on the U46619-induced constriction in aortic rings. In conclusion, losartan, acting as both AT1- and TxA2/PGH2-receptor antagonists, may enhance its therapeutic profile in the treatment of hypertension and cardiovascular disease.
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PMID:Losartan inhibits thromboxane A2-induced platelet aggregation and vascular constriction in spontaneously hypertensive rats. 970 Sep 80


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