Mechanisms underlying afterload-induced exacerbation of myocardial infarct size

Role of T-Type Ca2+ channel

Mahmood S Mozaffari, Champa Patel, Stephen W. Schaffer

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

One consequence of elevated afterload pressure is the activation of the angiotensin II type 1 receptor and nonspecific cation channels with subsequent Ca2+ accumulation via the Na+/H+-Na +/Ca2+ exchanger combination and the T-type or L-type Ca2+ channels. Intracellular Ca2+ overload is cytotoxic, in part, by inducing the mitochondrial permeability transition (MPT) pore. Therefore, we tested the hypotheses that: (1) increased afterload pressure worsens myocardial ischemia-reperfusion injury in healthy heart, (2) the Na +/H+-Na+/Ca2+ exchanger combination and both the T-type and L-type Ca2+ channels are involved in the exacerbating impact of high afterload pressure on infarct size, and (3) elevated afterload enhances infarct size in part via the MPT pore. Accordingly, the effect of candesartan (angiotensin II type 1 receptor antagonist), cariporide (inhibitor of the Na+/H+ exchanger), mibefradil (T-type Ca2+ channel blocker), diltiazem (L-type Ca2+ channel blocker), or cyclosporine A (inhibitor of MPT pore) were examined. The elevation in afterload pressure from 80 to 160 cmH2O increased baseline myocardial performance but caused larger infarcts and worsened recovery of mechanical function after ischemia reperfusion. Whereas mibefradil abrogated the effect of high afterload pressure on infarct size, the other agents reduced infarct size at both afterload pressures. Hearts exposed to mibefradil, diltiazem, or cariporide displayed greater functional recovery than those exposed to candesartan or cyclosporine A, revealing that an uncoupling exists between reduced cell death and recovery of mechanical function of the viable portions of the myocardium. The data also uncovered an important link between pressure-mediated exacerbation of infarct size and T-type Ca2+ channel activity.

Original languageEnglish (US)
Pages (from-to)912-919
Number of pages8
JournalHypertension
Volume47
Issue number5
DOIs
StatePublished - May 1 2006

Fingerprint

Myocardial Infarction
Mibefradil
Pressure
Sodium-Hydrogen Antiporter
Diltiazem
Recovery of Function
Cyclosporine
Angiotensin II Type 1 Receptor Blockers
Myocardial Reperfusion Injury
Angiotensin Type 1 Receptor
Reperfusion Injury
Reperfusion
Myocardial Ischemia
Cations
Myocardium
Cell Death
Ischemia
mitochondrial permeability transition pore
cariporide
candesartan

Keywords

  • Angiotensin II
  • Calcium channel blockers
  • Cyclosporin
  • Myocardial reperfusion injury
  • Rats

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Mechanisms underlying afterload-induced exacerbation of myocardial infarct size : Role of T-Type Ca2+ channel. / Mozaffari, Mahmood S; Patel, Champa; Schaffer, Stephen W.

In: Hypertension, Vol. 47, No. 5, 01.05.2006, p. 912-919.

Research output: Contribution to journalArticle

@article{48df87c4cbe74174ba1e2eaec396b2b8,
title = "Mechanisms underlying afterload-induced exacerbation of myocardial infarct size: Role of T-Type Ca2+ channel",
abstract = "One consequence of elevated afterload pressure is the activation of the angiotensin II type 1 receptor and nonspecific cation channels with subsequent Ca2+ accumulation via the Na+/H+-Na +/Ca2+ exchanger combination and the T-type or L-type Ca2+ channels. Intracellular Ca2+ overload is cytotoxic, in part, by inducing the mitochondrial permeability transition (MPT) pore. Therefore, we tested the hypotheses that: (1) increased afterload pressure worsens myocardial ischemia-reperfusion injury in healthy heart, (2) the Na +/H+-Na+/Ca2+ exchanger combination and both the T-type and L-type Ca2+ channels are involved in the exacerbating impact of high afterload pressure on infarct size, and (3) elevated afterload enhances infarct size in part via the MPT pore. Accordingly, the effect of candesartan (angiotensin II type 1 receptor antagonist), cariporide (inhibitor of the Na+/H+ exchanger), mibefradil (T-type Ca2+ channel blocker), diltiazem (L-type Ca2+ channel blocker), or cyclosporine A (inhibitor of MPT pore) were examined. The elevation in afterload pressure from 80 to 160 cmH2O increased baseline myocardial performance but caused larger infarcts and worsened recovery of mechanical function after ischemia reperfusion. Whereas mibefradil abrogated the effect of high afterload pressure on infarct size, the other agents reduced infarct size at both afterload pressures. Hearts exposed to mibefradil, diltiazem, or cariporide displayed greater functional recovery than those exposed to candesartan or cyclosporine A, revealing that an uncoupling exists between reduced cell death and recovery of mechanical function of the viable portions of the myocardium. The data also uncovered an important link between pressure-mediated exacerbation of infarct size and T-type Ca2+ channel activity.",
keywords = "Angiotensin II, Calcium channel blockers, Cyclosporin, Myocardial reperfusion injury, Rats",
author = "Mozaffari, {Mahmood S} and Champa Patel and Schaffer, {Stephen W.}",
year = "2006",
month = "5",
day = "1",
doi = "10.1161/01.HYP.0000209940.65941.46",
language = "English (US)",
volume = "47",
pages = "912--919",
journal = "Hypertension",
issn = "0194-911X",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

TY - JOUR

T1 - Mechanisms underlying afterload-induced exacerbation of myocardial infarct size

T2 - Role of T-Type Ca2+ channel

AU - Mozaffari, Mahmood S

AU - Patel, Champa

AU - Schaffer, Stephen W.

PY - 2006/5/1

Y1 - 2006/5/1

N2 - One consequence of elevated afterload pressure is the activation of the angiotensin II type 1 receptor and nonspecific cation channels with subsequent Ca2+ accumulation via the Na+/H+-Na +/Ca2+ exchanger combination and the T-type or L-type Ca2+ channels. Intracellular Ca2+ overload is cytotoxic, in part, by inducing the mitochondrial permeability transition (MPT) pore. Therefore, we tested the hypotheses that: (1) increased afterload pressure worsens myocardial ischemia-reperfusion injury in healthy heart, (2) the Na +/H+-Na+/Ca2+ exchanger combination and both the T-type and L-type Ca2+ channels are involved in the exacerbating impact of high afterload pressure on infarct size, and (3) elevated afterload enhances infarct size in part via the MPT pore. Accordingly, the effect of candesartan (angiotensin II type 1 receptor antagonist), cariporide (inhibitor of the Na+/H+ exchanger), mibefradil (T-type Ca2+ channel blocker), diltiazem (L-type Ca2+ channel blocker), or cyclosporine A (inhibitor of MPT pore) were examined. The elevation in afterload pressure from 80 to 160 cmH2O increased baseline myocardial performance but caused larger infarcts and worsened recovery of mechanical function after ischemia reperfusion. Whereas mibefradil abrogated the effect of high afterload pressure on infarct size, the other agents reduced infarct size at both afterload pressures. Hearts exposed to mibefradil, diltiazem, or cariporide displayed greater functional recovery than those exposed to candesartan or cyclosporine A, revealing that an uncoupling exists between reduced cell death and recovery of mechanical function of the viable portions of the myocardium. The data also uncovered an important link between pressure-mediated exacerbation of infarct size and T-type Ca2+ channel activity.

AB - One consequence of elevated afterload pressure is the activation of the angiotensin II type 1 receptor and nonspecific cation channels with subsequent Ca2+ accumulation via the Na+/H+-Na +/Ca2+ exchanger combination and the T-type or L-type Ca2+ channels. Intracellular Ca2+ overload is cytotoxic, in part, by inducing the mitochondrial permeability transition (MPT) pore. Therefore, we tested the hypotheses that: (1) increased afterload pressure worsens myocardial ischemia-reperfusion injury in healthy heart, (2) the Na +/H+-Na+/Ca2+ exchanger combination and both the T-type and L-type Ca2+ channels are involved in the exacerbating impact of high afterload pressure on infarct size, and (3) elevated afterload enhances infarct size in part via the MPT pore. Accordingly, the effect of candesartan (angiotensin II type 1 receptor antagonist), cariporide (inhibitor of the Na+/H+ exchanger), mibefradil (T-type Ca2+ channel blocker), diltiazem (L-type Ca2+ channel blocker), or cyclosporine A (inhibitor of MPT pore) were examined. The elevation in afterload pressure from 80 to 160 cmH2O increased baseline myocardial performance but caused larger infarcts and worsened recovery of mechanical function after ischemia reperfusion. Whereas mibefradil abrogated the effect of high afterload pressure on infarct size, the other agents reduced infarct size at both afterload pressures. Hearts exposed to mibefradil, diltiazem, or cariporide displayed greater functional recovery than those exposed to candesartan or cyclosporine A, revealing that an uncoupling exists between reduced cell death and recovery of mechanical function of the viable portions of the myocardium. The data also uncovered an important link between pressure-mediated exacerbation of infarct size and T-type Ca2+ channel activity.

KW - Angiotensin II

KW - Calcium channel blockers

KW - Cyclosporin

KW - Myocardial reperfusion injury

KW - Rats

UR - http://www.scopus.com/inward/record.url?scp=33646123537&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646123537&partnerID=8YFLogxK

U2 - 10.1161/01.HYP.0000209940.65941.46

DO - 10.1161/01.HYP.0000209940.65941.46

M3 - Article

VL - 47

SP - 912

EP - 919

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 5

ER -