Regulation of therapeutic apoptosis: a potential target in controlling hypertensive organ damage

2005 ◽  
Vol 83 (1) ◽  
pp. 29-41 ◽  
Author(s):  
Denis deBlois ◽  
Bun-Seng Tea ◽  
Diane Beaudry ◽  
Pavel Hamet
Keyword(s):  
Cell Growth ◽  
Spontaneously Hypertensive Rat ◽  
Cardiac Fibroblasts ◽  
Beta Blockers ◽  
Blood Pressure Reduction ◽  
Renin Angiotensin System ◽  
Organ Damage ◽  
Cell Subpopulation ◽  
Channel Blockers ◽  
Spontaneously Hypertensive

Cell growth and survival are potential therapeutic targets for the control of complications associated with hypertension. In most cardiovascular disorders, cardiac fibroblasts and large-vessel smooth muscle cells can replicate and thus contribute to the disease. We propose that cardiovascular hyperplasia may be reversed via therapeutic apoptosis induction with drugs that are safe and already used in the clinic. We first reported that, irrespective of the drug class, those drugs that are able to induce regression of cardiovascular hypertrophy are also able to reverse cardiovascular hyperplasia via apoptosis. Drugs active in this regard include inhibitors of the renin-angiotensin system, calcium channel blockers, and beta-blockers. Moreover, the effects of these drugs on cell survival is not merely secondary to blood pressure reduction. Therapeutic apoptosis in the cardiovascular system of the spontaneously hypertensive rat is characterized by a rapid and transient onset following initiation of antihypertensive treatment. Herein, the induction and termination of therapeutic apoptosis during drug treatment of hypertension will be briefly reviewed and supported by novel data suggesting that reversal of cardiovascular hyperplasia is associated with reduced cell growth and a resistance to further induction of therapeutic apoptosis, as shown in spontaneously hypertensive rats receiving an intermittent regime of nifedipine therapy. We propose that the presence of a cell subpopulation with defective cell cycle regulation may determine organ susceptibility to undergo therapeutic apoptosis.Key words: apoptosis, hypertension, hyperplasia, growth, nifedipine.

scholarly journals Increases in plasma trans-EETs and blood pressure reduction in spontaneously hypertensive rats

2011 ◽  
Vol 300 (6) ◽  
pp. H1990-H1996 ◽  
Author(s):  
Houli Jiang ◽  
John Quilley ◽  
Anabel B. Doumad ◽  
Angela G. Zhu ◽  
John R. Falck ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Spontaneously Hypertensive Rat ◽  
Blood Pressure Reduction ◽  
Maximal Velocity ◽  
Spontaneously Hypertensive ◽  
Cis And Trans Isomers ◽  
Wistar Kyoto Rat ◽  
Wistar Kyoto ◽  
Cis And Trans ◽  
Cis Isomer

Epoxyeicosatrienoic acids (EETs) are vasodilator, natriuretic, and antiinflammatory lipid mediators. Both cis- and trans-EETs are stored in phospholipids and in red blood cells (RBCs) in the circulation; the maximal velocity ( Vmax) of trans-EET hydrolysis by soluble epoxide hydrolase (sEH) is threefold that of cis-EETs. Because RBCs of the spontaneously hypertensive rat (SHR) exhibit increased sEH activity, a deficiency of trans-EETs in the SHR was hypothesized to increase blood pressure (BP). This prediction was fulfilled, since sEH inhibition with cis-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid (AUCB; 2 mg·kg−1·day−1 for 7 days) in the SHR reduced mean BP from 176 ± 8 to 153 ± 5 mmHg ( P < 0.05), whereas BP in the control Wistar-Kyoto rat (WKY) was unaffected. Plasma levels of EETs in the SHR were lower than in the age-matched control WKY (16.4 ± 1.6 vs. 26.1 ± 1.8 ng/ml; P < 0.05). The decrease in BP in the SHR treated with AUCB was associated with an increase in plasma EETs, which was mostly accounted for by increasing trans-EET from 4.1 ± 0.2 to 7.9 ± 1.5 ng/ml ( P < 0.05). Consistent with the effect of increased plasma trans-EETs and reduced BP in the SHR, the 14,15- trans-EET was more potent (ED50 10−10 M; maximum dilation 59 ± 15 μm) than the cis-isomer (ED50 10−9 M; maximum dilation 30 ± 11 μm) in relaxing rat preconstricted arcuate arteries. The 11,12-EET cis- and trans-isomers were equipotent dilators as were the 8,9-EET isomers. In summary, inhibition of sEH resulted in a twofold increase in plasma trans-EETs and reduced mean BP in the SHR. The greater vasodilator potency of trans- vs. cis-EETs may contribute to the antihypertensive effects of sEH inhibitors.

Onset of glomerular hypertension with aging precedes injury in the spontaneously hypertensive rat

2000 ◽  
Vol 278 (5) ◽  
pp. F839-F846 ◽  
Author(s):  
Evelyn M. Tolbert ◽  
Joseph Weisstuch ◽  
Helen D. Feiner ◽  
Lance D. Dworkin
Keyword(s):  
Spontaneously Hypertensive Rat ◽  
Renin Angiotensin System ◽  
Systemic Blood Pressure ◽  
Renal Hemodynamics ◽  
Glomerular Sclerosis ◽  
Compensatory Response ◽  
Spontaneously Hypertensive ◽  
Glomerular Hypertension ◽  
Wistar Kyoto ◽  
Endogenous Activity

The changes in renal hemodynamics that develop with aging in spontaneously hypertensive rats (SHR) were examined. Micropuncture studies revealed that glomerular capillary pressure was elevated in SHR at 9 mo of age compared with 3-mo-old SHR and 9-mo-old normotensive Wistar-Kyoto rats. Glomerular hypertension developed because of a small increase in systemic blood pressure and a decline in preglomerular vascular resistance, allowing transmission of elevated systemic pressure to the glomerular capillaries. The hemodynamic alterations were not a compensatory response to injury, inasmuch as vascular and glomerular morphology were normal in 9-mo-old SHR. To determine the mechanism of these changes, the activity of several vasoactive systems was examined. Similar changes in renal hemodynamics were observed in young and old SHR after blockade of nitric oxide production and after intravenous administration of endothelin. However, ANG II produced a proportionally greater reduction in glomerular filtration rate than renal blood flow in older SHR. These data suggest that reduced endogenous activity of the renin-angiotensin system leads to glomerular hypertension in aging SHR. Late development of glomerular hypertension may contribute to the subsequent appearance of glomerular sclerosis and progressive renal failure in these rats.

Hypothalamic angiotensin receptor subtypes in normotensive and hypertensive rats

1998 ◽  
Vol 275 (2) ◽  
pp. H703-H709 ◽  
Author(s):  
N. L. Han ◽  
M. K. Sim
Keyword(s):  
Angiotensin Ii ◽  
Spontaneously Hypertensive Rat ◽  
Renin Angiotensin System ◽  
Receptor Subtypes ◽  
Spontaneously Hypertensive ◽  
Hypertensive Rat ◽  
Angiotensin Iii ◽  
Displacement Experiments ◽  
Wistar Kyoto Rat ◽  
Wistar Kyoto

The binding of125I-labeled [Sar1,Ile8]angiotensin II to the hypothalamic membranes of the normotensive Wistar-Kyoto rat (WKY) and the spontaneously hypertensive rat (SHR) was studied. Displacement experiments with four centrally active angiotensins, losartan, and PD-123319 confirm the known existence of angiotensin AT1 and AT2 receptors in the rat hypothalamus. The values of the inhibitory constants for angiotensin II and PD-123319 in the SHR were significantly lower than the corresponding values in the WKY, indicating the possible existence of high-affinity hypothalamic AT1 and AT2 receptors for the two ligands in the SHR. The angiotensin AT1receptor was further separated into a 5′-guanylyl imidodiphosphate-sensitive and -nonsensitive subtype, indicating that one of the subtypes is G protein coupled. The SHR has significantly higher numbers of measurable AT1-receptor subtypes as well as AT2 receptor subtypes. The former data support the findings of other investigators showing that the hypothalamus of the SHR expressed more AT1A and AT1B mRNAs than that of the normotensive rat. Des-Asp1-angiotensin I, which is known to attenuate the central pressor action of angiotensin II and angiotensin III, acts on both the AT1 and AT2 receptors, although it has a higher affinity for the AT1receptors. The overall increase in the number of AT1 and AT2 receptors in the SHR is in line with the contention that the brain of the hypertensive rat, compared with that of the WKY, has a hyperactive renin-angiotensin system.

scholarly journals CRISPR/Cas9 Mediated Deletion of the Angiotensinogen Gene Reduces Hypertension

Hypertension ◽  
2021 ◽  
Author(s):  
Hualing Sun ◽  
Conrad P. Hodgkinson ◽  
Richard E. Pratt ◽  
Victor J. Dzau
Keyword(s):  
Blood Pressure ◽  
Spontaneously Hypertensive Rat ◽  
Renin Angiotensin System ◽  
Pressure Control ◽  
Spontaneously Hypertensive ◽  
Sustained Reduction ◽  
Short Palindromic Repeat ◽  
Spontaneously Hypertensive Rat Model ◽  
Agt Gene

Hypertension is a major contributor to the global burden of disease. Unfortunately, hypertension is controlled in less than one-fifth of patients worldwide due to either failure to treat or lack of compliance to medication. An ideal therapy would be administered one time only and yield lifelong blood pressure control. We investigated our hypothesis that CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9)-mediated disruption of a key gene in the renin-angiotensin system, AGT (angiotensinogen), specifically in the liver, would result in sustained and possibly lifelong reduction in blood pressure. We demonstrated in vitro that the CRISPR/Cas9 system led to a significant reduction in AGT expression in hepatocytes. Delivery of the CRISPR/Cas9 system into the liver via the hepatocyte-targeting adeno-associated virus 8 reduced both AGT expression (40% decrease) and circulating AGT levels (30% decrease). In the SHR (spontaneously hypertensive rat) model of hypertension, CRISPR/Cas9-mediated loss of AGT expression reduced blood pressure in adult animals with established hypertension and prevented the spontaneous development of hypertension in young SHR. Moreover, reductions in blood pressure were prolonged and sustained up to 1 year of follow-up. In addition, the partial disruption of the hepatic AGT gene was sufficient to control hypertension but did not affect the homeostatic response to cardiovascular stress such as sodium depletion and furosemide. In summary, we have demonstrated that targeting the CRISPR/Cas9 system to hepatic AGT results in sustained reduction of blood pressure and is a potential therapy to achieve sustained and possibly lifelong control of human hypertension.

SCOPE AND NEED OF COMBINATION OF ANTIHYPERTENSIVE DRUGS

INDIAN DRUGS ◽  
2012 ◽  
Vol 49 (05) ◽  
pp. 5-19
Author(s):  
S. R Pattan ◽  
◽  
A. O. Zanwar ◽  
N. B Wabale ◽  
U. B. Shetkar
Keyword(s):  
Blood Pressure ◽  
Ace Inhibitors ◽  
Antihypertensive Drugs ◽  
Beta Blockers ◽  
Blood Pressure Reduction ◽  
Pressure Control ◽  
Channel Blockers ◽  
Once Daily ◽  
First Line Therapy ◽  
Dose Combination

The recommendation for first-line therapy for hypertension remains a beta blocker or diuretic given in a low dosage. A target blood pressure of less than 140/90 mm Hg is achieved in about 50 percent of patients treated with monotherapy; two or more agents from different pharmacological classes are often needed to achieve adequate blood pressure control. Single-dose combination antihypertension therapyis an important option that combines efficacy of blood pressure reduction and a low side effect profilewith convenient once-daily dosing to enhance compliance. Combination antihypertensives include combined agents from the following pharmacological classes: diuretics and potassium-sparing diuretics,beta blockers and diuretics, angiotensin-converting enzyme (ACE) inhibitors and diuretics, angiotensin-II antagonists and diuretics and calcium channel blockers and ACE inhibitors.

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