Stretch-induced alkalinization of feline papillary muscle: an autocrine-paracrine system.
Myocardial stretch is a well-known stimulus that leads to hypertrophy. Little is known, however, about the intracellular pathways involved in the transmission of myocardial stretch to the cytoplasm and nucleus. Studies in neonatal cardiomyocytes demonstrated stretch-induced release of angiotensin II (Ang II). Because intracellular alkalinization is a signal to cell growth and Ang II stimulates the Na+/H+ exchanger (NHE), we studied the relationship between myocardial stretch and intracellular pH (pHi). Experiments were performed in cat papillary muscles fixed by the ventricular end to a force transducer. Muscles were paced at 0.2 Hz and superfused with HEPES-buffered solution. pHi was measured by epifluorescence with the acetoxymethyl ester form of the pH-sensitive dye 2',7'-bis(2-carboxyethyl)-5,6-carboxyfluorescein (BCECF-AM). Each muscle was progressively stretched to reach maximal developed force (Lmax) and maintained in a length that was approximately 92% Lmax (Li). During the "stretch protocol," muscles were quickly stretched to Lmax for 10 minutes and then released to Li; pHi significantly increased during stretch and came back to the previous value when the muscle was released to Li. The increase in pHi was eliminated by (1) specific inhibition of the NHE (EIPA, 5 micromol/L), (2) AT1-receptor blockade (losartan, 10 micromol/L), (3) inhibition of protein kinase C (PKC) (chelerythrine, 5 micromol/L), (4) blockade of endothelin (ET) receptors with a nonselective (PD 142,893, 50 nmol/L) or a selective ETA antagonist (BQ-123, 300 nmol/L). The increase in pHi by exogenous Ang II (500 nmol/L) was also reduced by both ET-receptor antagonists. Our results indicate that after myocardial stretch, pHi increases because of stimulation of NHE activity. This involves an autocrine-paracrine mechanism in which protein kinase C, Ang II, and ET play crucial roles.
Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Calle 60 y 120 S/N, 1900 La Plata, Argentina.
H E
HE
Cingolani
B V
BV
Alvarez
I L
IL
Ennis
M C
MC
Camilión de Hurtado
D000468:Alkalies; D000470:Alkaloids; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D019898:Autocrine Communication / Q000502:physiology*; D053119:Benzophenanthridines; D002415:Cats; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D019808:Losartan / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000201:enzymology; D009842:Oligopeptides / Q000494:pharmacology; D010210:Papillary Muscles / Q000166:cytology / Q000502:physiology*; D019899:Paracrine Communication / Q000502:physiology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology
D000468:Alkalies; D000470:Alkaloids; D000889:Anti-Arrhythmia Agents; D053119:Benzophenanthridines; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010617:Phenanthridines; D017923:Sodium-Hydrogen Exchangers; D000804:Angiotensin II; C076213:PD 142893; D000584:Amiloride; C016299:chelerythrine; D011493:Protein Kinase C; D019808:Losartan; C072247:cyclo(Trp-Asp-Pro-Val-Leu); C039614:ethylisopropylamiloride