EFFECTS OF ADRENERGIC AND MUSCARINIC AGONIST STIMULATION ON IP3 AND CYCLIC-NUCLEOTIDE LEVELS IN THE PRESSURE OVERLOADED RAT-HEART

In this study, the dynamic interrelationships between myocardial funct ional state and changes in the second messenger content in pressure-ov erloaded hypertrophied hearts were investigated. Forty-three rat heart s were used after partial clamping of the abdominal aorta. The isolate d hearts were perfused with Krebs-Henseleit buffer and allocated to pe rfusion for 20 s or 40 min as controls (n=12); or with noradrenaline ( 10(-6) moll(-1), n=11); carbachol (3x10(-7) mol l(-1), n = 9); or nora drenaline plus carbachol (10(-6) mol l(-1) + 3 x 10(-7) mol l(-1), res pectively, n=11).(max)dP/dt increased more than 2-fold already after 2 0 s on noradrenaline stimulation, followed by a significant increase i n cAMP. After 40 min,(max)dP/dt was lower than the maximal value, alth ough higher than controls. cAMP was also decreased, but still signific antly higher than controls. Perfusion with noradrenaline plus carbacho l produced the same changes in (max)dP/dt as those seen after noradren aline stimulation alone, but failed to increase cAMP content after bot h 20s and 40 min. The inositol trisphosphate (IP3) content was increas ed 40 min of control perfusion (p<0.05). Noradrenaline and carbachol, separately, produced an increase in IF3 content already after 20 s (p< 0.05). The combination of noradrenaline plus carbachol also produced a n increase of IP3 (p<0.05; compared to controls), but to a lesser exte nt when compared either to noradrenaline or carbachol (p<0.05). After 40 min of perfusion, IP3 was in the same range regardless of added ago nist(s) and still slightly above control level (p<0.05). The early inc rease in maxdP/dt induced by noradrenaline or the combination of norad renaline plus carbachol was not paralleled by a decrease in ATP conten t. This was also the case upon addition of carbachol alone. However, a fter 40 min of agonistic perfusion, ATP levels were substantially decr eased. In conclusion, myocardial IP3 content in pressure-overloaded hy pertrophied hearts was not different from that of sham-operated hearts . After agonistic stimulation, an early increase in IP3 formation was seen. Attenuation of the IF, response by combined stimulation with nor adrenaline and carbachol was initially present in pressure-overloaded hypertrophied hearts. After 40 min no attenuation was found for either IP3 or for cAMP content, suggestive of induction of a desensitization .