Effects of adrenergic and muscarinic agonist stimulation on IP₃ and cyclic nucleotide levels in the pressure overloaded rat heart

Abstract

In this study, the dynamic interrelationships between myocardial functional state and changes in the second messenger content in pressure-overloaded hypertrophied hearts were investigated. Forty-three rat hearts were used after partial clamping of the abdominal aorta. The isolated hearts were perfused with Krebs-Henseleit buffer and allocated to perfusion for 20 s or 40 min as controls (n = 12); or with noradrenaline (10^-6 mol I^-1, n= 11); carbachol (3 x l0^-7 mol I^-1 n = 9): or noradrenaline plus carbachol (10^-6 mol I^-1 + 3xl0^-7 mol 1^-1. respectively, n= 11). _maxdP/dt increased more than 2-fold already after 20 s on noradrenaline stimulation, followed by a significant increase in cAMP. After 40 min, _maxdP/dt was lower than the maximal value, although higher than controls. cAMP was also decreased, but still significantly higher than controls. Perfusion with noradrenaline plus carbachol produced the same changes in ^maxdP/dt as those seen after noradrenaline stimulation alone, but failed to increase cAMP content after both 20 s and 40 min. The inositol trisphosphate (IP₃) content was increased 40 min of control perfusion (p < 0.05). Noradrenaline and carbachol, separately, produced an increase in IP₃ content already after 20 s (p < 0.05). The combination of noradrenaline plus carbachol also produced an increase of IP, (p < 0.05: compared to controls), but to a lesser extent when compared either to noradrenaline or carbachol (p < 0.05). After 40 min of perfusion. IP, was in the same range regardless of added agonist(s) and still slightly above control level (p < 0.05). The early increase in _maxdP/dt induced by noradrenaline or the combination of noradrenaline plus carbachol was not paralleled by a decrease in ATP content. This was also the case upon addition of carbachol alone. However, after 40 min of agonistic perfusion, ATP levels were substantially decreased. In conclusion, myocardial IP₃ content in pressure-overloaded hypertrophied hearts was not different from that of sham-operated hearts. After agonistic stimulation, an early increase in IP₃ formation was seen. Attenuation of the IP₃ response by combined stimulation with noradrenaline 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.

Key Words:

• carbachol
• cyclic nucleotides
• inositol trisphosphate
• muscarinicreceptor
• myocardium
• noradrenaline
• pressure overloaded
• rat
• trisphosphate
• β-receptor