Regulation by chronic drug administration of neuronal and cardiac calcium channel, beta-adrenoceptor and muscarinic receptor levels

Gengo, Peter J.; Skattebøl, A.; Moran, John F.; Gallant, Samuel; Hawthorn, M.; Triggle, David J.

doi:10.1016/0006-2952(88)90135-9

Cited by 46 publications

(10 citation statements)

References 33 publications

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“…Panza et al [5] showed a down-regulation in the number o f [2H]nitrendipine binding sites in membranes prepared from mouse brain tissue after long-term oral administration (28 days) with nifedipine (280 mg/kg/day) and verapamil (270 mg/kg/day) but not with diltiazem (380 mg/kg/day). A down-regulation in the number o f brain and cardiac C a 2+ channels was shown by Gengo et al [6] in rats receiving chronic intravenous administration o f nifedi pine (0.864 and 8.640 mg/kg/day) for 20 days. We have previously reported a down-regula tion in the number o f cardiac C a 2+ channel but only after chronic, high-dose verapamil administration via slow-release implantable pellets (11.9 mg/kg/day) in rats [8], In opposi tion to these studies, Nishiyama et al [7] found no change in the C a 2+ channel density after chronic oral treatment with 100 mg/kg/ day of nifedipine for 2 weeks.…”

Section: Discussionmentioning

confidence: 80%

“…A reduction in the number o f brain C a 2+ channels in mice [5] and rats [6] were observed after >20 days o f admin istration o f nifedipine or verapamil. However, the data in heart tissue is more controversial.…”

Section: Introductionmentioning

confidence: 96%

“…However, the data in heart tissue is more controversial. Gengo et al [6] reported that 20 days o f intra venous nifedipine down-regulated the C a 2+ channel whereas Nishiyama et al [7] found that 14 days o f oral nifedipine treatment in duced no significant effect. More recent work demonstrated that the cardiac C a 2+ channel was very resistant to verapamil administra tion.…”

Section: Introductionmentioning

confidence: 99%

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Effect of High-Dose Verapamil Administration on the Ca<sup>2+</sup> Channel Density in Rat Cardiac Tissue

et al. 1994

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It is well known that β-adrenergic receptors will down-regulate in the presence of high circulating levels of β-adrenergic agonists over extended periods of time. However, less is known with respect to the effect of Ca²⁺ channel antagonists on their receptors. The purpose of this study was to determine if chronic administration of high dosages of verapamil (in the toxic range) could alter the density of Ca²⁺ channels in the heart as determined by [³H]PN 200-110 binding. A range of high verapamil concentrations was administered to rats via s.c. implantable slow-release pellets or s.c. injection. An increasing rate of mortality was observed as the dose of verapamil administered increased. Quantitation of serum verapamil concentrations demonstrated that the s.c. slow release implantable pellets were not releasing the drug evenly and instead released toxic quantities of drug during the first 24 h after implantation. Serum verapamil levels determined from verapamil-injected animals demonstrated a dose-dependent increase in circulating levels. No significant alterations in Ca²⁺ channel characteristics (B_max and K_d) were noted in cardiac tissue obtained from either treatment regime. Our results demonstrate that implantable pellets are not a reliable administration method for verapamil and cardiac Ca²⁺ channels are unusually resistant to biochemical alterations even after administration of verapamil dosages in the toxic range.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Effect of High-Dose Verapamil Administration on the Ca<sup>2+</sup> Channel Density in Rat Cardiac Tissue

et al. 1994

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“…A host of cardiac alterations consistent with the pathogenesis of heart failure have been revealed following continuous ISO infusion with subcutaneously implanted osmotic pumps [76,90,132,139,142,144,146,157,[160][161][162][163][164][165][166][167]. Infusion of 2.4 mg/kg/day ISO in Wistar rats caused less than 5% mortality while it altered gene expression in a strikingly similar magnitude and time-course as aortic constriction through day 8 of infusion; however, most of these changes reverted after 26 days of infusion [132].…”

Section: Pharmacological Modelsmentioning

confidence: 99%

Merits of Non-Invasive Rat Models of Left Ventricular Heart Failure

et al. 2011

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Heart failure (HF) is characterized as a limitation to cardiac output that prevents the heart from supplying tissues with adequate oxygen and predisposes individuals to pulmonary edema. Impaired cardiac function is secondary to either decreased contractility reducing ejection (systolic failure), diminished ventricular compliance preventing filling (diastolic failure), or both. To study HF etiology, many different techniques have been developed to elicit this condition in experimental animals, with varying degrees of success. Among rats, surgically induced HF models are the most prevalent, but they bear several shortcomings, including high mortality rates and limited recapitulation of the pathophysiology, etiology, and progression of human HF. Alternatively, a number of non-invasive HF induction methods avoid many of these pitfalls, and their merits in technical simplicity, reliability, survivability, and comparability to the pathophysiologic and pathogenic characteristics of HF are reviewed herein. In particular, this review focuses on the primary pathogenic mechanisms common to genetic strains (spontaneously hypertensive and spontaneously hypertensive heart failure), pharmacological models of toxic cardiomyopathy (doxorubicin and isoproterenol), and dietary salt models, all of which have been shown to induce left ventricular HF in the rat. Additional non-invasive techniques that may potentially enable the development of new HF models are also discussed.

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“…Changes in the density and function of L-type voltage-sensitive calcium channels have been reported in the myocardium of patients with end-stage heart failure and in animal models of this syndrome. There are no clear explanations for these cellular changes, but exposure of excitable systems to overactivation or decreased stimulation is now fully established to result in the compensatory processes described as desensitization (downregulation) or supersensitization (upregulation), respectively (10,28,31,32,88). The cellular signal responsible for the changes in L-type calcium channel density awaits definition; however, from the available data to date it appears that changes in these channels do not take place early in the development of cardiovascular disease.…”

Section: Discussionmentioning

confidence: 99%

Physiologic and emerging pathophysiologic role of cardiac calcium channels

Gengo

1996

Heart Failure Rev

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The link between cardiac contractile dysfunction in patients with end-stage heart failure and aberrant myocardial intracellular calcium handling is now well established. The precise intracellular protein(s) responsible for this breakdown in calcium handling is at present unclear. However, a number of distinct sarcolemmal (L-type, N-type, Ttype, P-type, Q-type) and sarcoplasmic reticular (calcium release, ryanodine) calcium channels that have been defined on a biophysical, biochemical, and molecular basis lend valuable insights into possible factors that may contribute to the abnormal calcium handling in the hearts of these patients. What is now clear is that cardiac muscle contraction is a rigorously regulated event that follows the organized cycling of calcium from the sarcoplasmic reticulum (SR) into the cytosol and back into the SR, and that this cycle follows the graded entry of trigger calcium that enters the cell through the voltage-sensitive calcium channel. Furthermore, the voltage-dependent properties of potential-dependent calcium channels provide the underpinning for the vascular selectivity of the clinically available calcium channel drugs. Moreover, it has also been reported that the efficacy of these agents is augmented in pathologic (ischemic) tissue owing to the state dependence of these channels. Recently, the basis for the critical role of the SR in calcium signaling has started to emerge. The SR calcium handling proteins (SR calcium release channel/ryanodine receptor, SR Ca 2+ ATPase, phospholamban, calsequestrin) play a critical role in maintaining intracellular free ionized calcium concentrations ([Ca2+]i), which therefore regulate systolic and diastolic function on a beat-to-beat basis within the cardiac cell. This rigorous control of [Ca2+]i is in part the result of the highly developed junctional regions of the cardiac SR. Elucidation of the calcium handling process in these regions and the potential damage resulting from cardiovascular disease has been greatly aided by the invaluable molecular tool, ryanodine. From an expanding volume of information provided by animal models of ischemia, hypertrophy, and heart failure, it now appears that changes in cardiac voltage-sensitive calcium channels are likely to be the result of a secondary process that may not be directly linked to the onset of these cardiovascular diseases. Conversely, the regulation of ryanodine receptors has been suggested to be a mechanism initiating the decline in myocardial contractility leading to heart failure. These reports have been supported by studies demonstrating SR calcium release channel/ryanodine receptor changes in pressure overload hypertrophy and myocardial ischemia. Further support for the role of SR calcium release channels in cardiovascular disease is found in reports that couple leaking SR channels with ischemia and cardiac failure. These results suggest that changes in SR calcium handling proteins may be critically linked to cardiovascular disease. A more central question stemming from these results is ...

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Regulation by chronic drug administration of neuronal and cardiac calcium channel, beta-adrenoceptor and muscarinic receptor levels

Cited by 46 publications

References 33 publications

Effect of High-Dose Verapamil Administration on the Ca<sup>2+</sup> Channel Density in Rat Cardiac Tissue

Effect of High-Dose Verapamil Administration on the Ca<sup>2+</sup> Channel Density in Rat Cardiac Tissue

Merits of Non-Invasive Rat Models of Left Ventricular Heart Failure

Physiologic and emerging pathophysiologic role of cardiac calcium channels

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