Calcium Channel Blockade with Verapamil: Effects on Blood Pressure, Renal, and Myocardial Adrenergic, Cholinergic, and Calcium Channel Receptors in Inbred Dahl Hypertension-Sensitive (S/JR) and Hypertension-Resistant (R/JR) Rats

McCaughran, James A.; Juno, Charles J.

doi:10.1093/ajh/1.3.255s

Cited by 4 publications

(2 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We did not observe any effect of verapamil on Cav1.2 mRNA or protein expression in vivo . Our results are in agreement with multiple prior studies showing that there is no change in calcium channel protein expression following in vivo verapamil treatment, as assessed by dihydropyridine binding analysis (McCaughran & Juno, 1988; Lonsberry et al 1992, 1994; Chapados et al 1992).…”

Section: Discussionsupporting

confidence: 93%

Robust L‐type calcium current expression following heterozygous knockout of the Cav1.2 gene in adult mouse heart

Rosati

Yan

Lee

et al. 2011

The Journal of Physiology

View full text Add to dashboard Cite

Non-technical summary Appropriate regulation of ion channel expression is critical for the maintenance of both electrical stability and normal contractile function in the heart. A classic way to study the robustness of biological systems is to examine the effects of changes in gene dosage. We have studied how the heart responds to changes in the L-type calcium channel gene dosage. Homozygous Cav1.2 knockout in the adult heart is lethal, without compensatory responses in expression of other calcium channel genes. Following heterozygous knockout, Cav1.2 mRNA levels are not buffered, Cav1.2 membrane protein levels are partly buffered and L-type calcium current expression is relatively well buffered. These data are consistent with a passive model of Cav1.2 biosynthesis that includes saturated steps, which act to buffer Cav1.2 protein and L-type calcium current expression. The results suggest that there is little or no homeostatic regulation of calcium current expression in either heterozygous or homozygous knockout mice.Abstract Mechanisms that contribute to maintaining expression of functional ion channels at relatively constant levels following perturbations of channel biosynthesis are likely to contribute significantly to the stability of electrophysiological systems in some pathological conditions. In order to examine the robustness of L-type calcium current expression, the response to changes in Ca 2+ channel Cav1.2 gene dosage was studied in adult mice. Using a cardiac-specific inducible Cre recombinase system, Cav1.2 mRNA was reduced to 11 ± 1% of control values in homozygous floxed mice and the mice died rapidly (11.9 ± 3 days) after induction of gene deletion. In these homozygous knockout mice, echocardiographic analysis showed that myocardial contractility was reduced to 14 ± 1% of control values shortly before death. For these mice, no effective compensatory changes in ion channel gene expression were triggered following deletion of both Cav1.2 alleles, despite the dramatic decay in cardiac function. In contrast to the homozygote knockout mice, following knockout of only one Cav1.2 allele, cardiac function remained unchanged, as did survival. Cav1.2 mRNA expression in the left ventricle of heterozygous knockout mice was reduced to 58 ± 3% of control values and there was a 21 ± 2% reduction in Cav1.2 protein expression. There was no significant reduction in L-type Ca 2+ current density in these mice. The results are consistent with a model of L-type calcium channel biosynthesis in which there are one or more saturated steps, which act to buffer changes in both total Cav1.2 protein and L-type current expression.

show abstract

Section: Discussionsupporting

confidence: 93%

Robust L‐type calcium current expression following heterozygous knockout of the Cav1.2 gene in adult mouse heart

Rosati

Yan

Lee

et al. 2011

The Journal of Physiology

View full text Add to dashboard Cite

show abstract

“…This was true for SHR subjected to subtotal nephrectomy [ 45 ], DOCA-salt treatment [ 46 ], high-salt intake [ 47 ], or chronic NO synthase inhibition [ 48 ] and for salt-sensitive Dahl rats [ 49 – 52 ]. The absence of major antihypertensive effects of chronic Rho kinase inhibition in spontaneous or salt hypertension contrasts with the pronounced long-term BP reduction induced by chronic administration of L-VDCC blockers [ 53 – 55 ]. Our recent studies on the role of calcium entry and calcium sensitization in the control of vascular tone and blood pressure indicated a close cooperation of both signaling pathways in normotensive or hypertensive animals (for review see [ 28 ]).…”

Section: Discussionmentioning

confidence: 99%

Basal and Activated Calcium Sensitization Mediated by RhoA/Rho Kinase Pathway in Rats with Genetic and Salt Hypertension

Behuliak

Bencze

Vaněčková

et al. 2017

BioMed Research International

View full text Add to dashboard Cite

Calcium sensitization mediated by RhoA/Rho kinase pathway can be evaluated either in the absence (basal calcium sensitization) or in the presence of endogenous vasoconstrictor systems (activated calcium sensitization). Our aim was to compare basal and activated calcium sensitization in three forms of experimental hypertension with increased sympathetic tone and enhanced calcium entry—spontaneously hypertensive rats (SHR), heterozygous Ren-2 transgenic rats (TGR), and salt hypertensive Dahl rats. Activated calcium sensitization was determined as blood pressure reduction induced by acute administration of Rho kinase inhibitor fasudil in conscious rats with intact sympathetic nervous system (SNS) and renin-angiotensin system (RAS). Basal calcium sensitization was studied as fasudil-dependent difference in blood pressure response to calcium channel opener BAY K8644 in rats subjected to RAS and SNS blockade. Calcium sensitization was also estimated from reduced development of isolated artery contraction by Rho kinase inhibitor Y-27632. Activated calcium sensitization was enhanced in all three hypertensive models (due to the hyperactivity of vasoconstrictor systems). In contrast, basal calcium sensitization was reduced in SHR and TGR relative to their controls, whereas it was augmented in salt-sensitive Dahl rats relative to their salt-resistant controls. Similar differences in calcium sensitization were seen in femoral arteries of SHR and Dahl rats.

show abstract

Lessons from rat models of hypertension from Goldblatt to genetic engineering

Pinto

Paul

Ganten

1998

Cardiovascular Research

283

181

View full text Add to dashboard Cite

Over the past 50 years various animal models of hypertension have been developed, predominantly in the rat. In this review we discuss the use of the rat as a model of hypertension, and evaluate what these models have taught us. Interestingly, the spontaneously hypertensive rat (SHR) is by far the most widely used rat model, although it reflects only a rare subtype of human hypertension, i.e. primary hypertension that is inherited in a Mendelian fashion. Many other aspects of the etiology of hypertension are found in other rat models, but these models are less frequently employed. The widespread use of the SHR suggests that this rat model is often chosen without considering alternative (and possibly better suited) models. To illustrate the importance of the choice for a particular model, we compared the natural history and response to antihypertensive drugs in different rat models of hypertension (SHR, Dahl, deoxycorticosterone acetate (DOCA)-salt, two-kidney one-clip, transgenic TGR(mRen2)27. This revealed that the outcome of hypertension can be similar in some respects, as all models exhibit cardiac hypertrophy, and all demonstrate impaired endothelium-dependent relaxations. However, the more severe forms of end-organ damage such as heart failure, stroke and kidney failure, occur only in some models and then only in a subset of the hypertensive rats. The effects of antihypertensives varies even more in the different models: antihypertensive treatment only attenuates end-organ damage if it decreases blood pressure. Moreover, if a given antihypertensive is effective, it sometimes even attenuates end-organ damage in nonhypotensive doses. On the other hand, some agents do decrease blood pressure but do not prevent end-organ damage (e.g. hydralazine in SHR). Furthermore, not all classes of antihypertensives are equally effective in all rat models of hypertension: endothelin-receptor antagonists are not effective in SHR, but have beneficial effects in the DOCA-salt model. The comparison of models, and the comparison of treatment effects suggests that end-organ damage critically depends upon not only on the stress imposed by high blood pressure and its underlying biochemical disturbance, but also upon the ability of the organism to recruit adequate 'coping' mechanisms. These coping mechanisms deserve greater attention, as failure to recruit such mechanisms may indicate an increased risk. The current development of transgenic techniques will provide new opportunities, to develop specific models to address this balance between stress and coping.

show abstract

Calcium Channel Blockade with Verapamil: Effects on Blood Pressure, Renal, and Myocardial Adrenergic, Cholinergic, and Calcium Channel Receptors in Inbred Dahl Hypertension-Sensitive (S/JR) and Hypertension-Resistant (R/JR) Rats

Cited by 4 publications

References 0 publications

Robust L‐type calcium current expression following heterozygous knockout of the Cav1.2 gene in adult mouse heart

Robust L‐type calcium current expression following heterozygous knockout of the Cav1.2 gene in adult mouse heart

Basal and Activated Calcium Sensitization Mediated by RhoA/Rho Kinase Pathway in Rats with Genetic and Salt Hypertension

Lessons from rat models of hypertension from Goldblatt to genetic engineering

Contact Info

Product

Resources

About