Intracellular and Extracellular Angiotensin II Enhance the L-Type Calcium Current in the Failing Heart

Abstract

Abstract-The influence of intracellular and extracellular angiotensin II (Ang II) on the L-type calcium current of cardiomyocytes isolated from cardiomyopathic hamsters was investigated. The results indicated that Ang II (10 Ϫ8 mmol/L), added to the bath, increased the peak inward calcium current (I Ca ) density by 37Ϯ3.4% (PϽ0.05), an effect that depends on the activation of protein kinase C. Intracellular administration of the same dose of Ang II (10 Ϫ8 mmol/L) also elicited an increase of peak I Ca density but enhanced the rate of I Ca inactivation, an effect not seen with extracellular Ang II. Moreover, in control animals, no change in the rate of I Ca inactivation was seen with intracellular Ang II. Thapsigargin (1 mol/L), a potent inhibitor of sarcoplasmic reticulum (SR) ATPase, which depletes the SR, decreased the rate of I Ca inactivation elicited by intracellular Ang II, although the cytoplasmic calcium concentration was highly buffered with 10 mmol/L EGTA. These findings might indicate that intracellular Ang II releases calcium from the SR and inactivates I Ca . The effect of intracellular Ang II on peak I Ca was not altered by extracellular losartan (10 Ϫ7 mmol/L), supporting the notion that the peptide acted intracellularly. Other studies showed that intracellular Ang I administration (10 Ϫ8 mmol/L) enhanced the peak I Ca density and the rate of I Ca inactivation, an effect that was reduced by intracellular enalaprilat (10 Ϫ8 mmol/L). Moreover, intracellular enalaprilat by itself reduced the peak I Ca density. These observations might indicate that endogenous Ang II is contributing to I Ca modulation in the failing heart. Key Words: angiotensin Ⅲ heart failure Ⅲ calcium current T he concept of a cardiac renin-angiotensin system 1 gained support with the demonstration that: (1) angiotensin I (Ang I) is converted to Ang II in the isolated and perfused heart; 2 (2) the angiotensin-converting enzyme (ACE) has been found around the nucleus of heart cells in culture 3 ; and (3) ACE inhibitors prevent cardiac remodeling, an effect independent of the change in blood pressure. 4 However, in normal heart, renin mRNA levels 5 and renin content are negligible in nephrectomized rats. 6 Moreover, no renin is released from the isolated and perfused rat heart, 7 which suggests that cardiac renin is attributable to its uptake from plasma. However, under some conditions, such as stretch, renin gene expression is enhanced, 8 and overexpression of angiotensinogen gene in normal mice leads to hypertrophy of the right and left ventricles and to an increase of Ang II levels in both ventricles without any change in arterial blood pressure. 9,10 Furthermore, a second renin gene transcript that may code for intracellular renin because it lacks the coding zone of the secretory signal peptide is upregulated in the left ventricle after myocardial infarction. 11 Moreover, cardiac angiotensinogen is upregulated after myocardial infarction. 12 These observations support the notion that renin and Ang II can be formed inside the hear...

Carotid body function in heart failure

“…Recent studies have shown that intracellular administration of Ang II increases the peak inward calcium current density and decreases the junctional conductance via intracellular AT 1 R in cardiac myocytes (De Mello & Monterrubio, 2004), and intracellular application of an AT 1 R antagonist abolishes the effect of intracellular Ang II. It seems likely that the enhanced sensitivity of IK to hypoxia in CB glomus cells in CHF may be due to elevation of intracellular Ang II binding to intracellular AT 1 R. This notion is evidenced by our observation that intracellular administration of L158,809 (added to the recording pipette solution) blunted the sensitivity of I K to hypoxia in the CB glomus cells from CHF rabbits ).…”

Acetylcholine-regulated K+ current remodelling in the atrium after myocardial infarction and valsartan administration

“…Intracellular angiotensin II reduced the L-type Ca 2+ current in rat ventricular cells, whereas the opposite was observed in hamsters (18). Angiotensin II increases the L-type Ca 2+ current through protein kinase C-dependent pathways (19). The T-type Ca 2+ current is increased by angiotensin II stimulation (20).…”

Voltage-Dependent Calcium Currents Are Enhanced in Nucleus of the Solitary Tract Neurons Isolated From Renal Wrap Hypertensive Rats

“…Virtually identical increases in HVA current were observed in ventricular myocytes isolated from rats in heart failure. 16 In the absence of a change in membrane permeability, possible explanations for the increased HVA current include alterations in the number of VGCCs and/or modulation of the channel by intracellular signal transduction pathways.…”