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Correlation of Cyclic Amp and Cyclic Gmp Levels With CORRELATION OF CYCLIC AMP AND CYCLIC GMP LEVELS WITH CHANGES IN CONTRACTILE FORCE OF DOG VENTRICULAR MYOCARDIUM DURING CHOLINERGIC ANTAGONISM OF POSITIVE INOTROPIC ACTIONS OF HISTAMINE, GLUCAGON, THEOPHYLLINE AND PAPAVERINE Masao ENDOH Department of Pharmacology, Tohoku University School of Medicine, Sendai 980, Japan Accepted August 6, 1979 Abstract-On the dog isolated right ventricular muscle, experiments were carried out in order to elucidate the characteristics of the cholinergic antagonism against the positive isotropic action (PIA) induced via different subcellular mechanisms. The relationship between cyclic AMP and cyclic GMP levels, and contractile force during cholinergic antagonism was assessed. Carbachol (10 ,tM) by itself decreased only slightly the tension developed, but inhibited prominently the PlAs of isoprenalinc, histamine, glucagon, theophylline and papaverine. The action of dibutyryl cyclic AMP was inhibited less than PIAs of other agents mentioned above. In contrast, carbachol did not affect the PIAs of calcium and g-strophanthin. The antagonism by carbachol of PIAs of isoprenaline, histamine, glucagon, theophylline and papaverine was accompanied by a reduction of the intracellular cyclic AMP level elevated previously by these agents, and by an elevation of the intracellular cyclic GMP level. A good correlation was found between changes in the tension developed, and cyclic AMP and cyclic GMP levels during the cholinergic antagonism of PIAs induced by these agents in the dog ventricular myocardium. In the mammalian ventricular myocardium, cholinergic stimulation via vagus nerve or by acetylcholine (ACh) affected the contractile force less than that of atrial muscle (1-4). Hollenberg and coworkers (5) found first that ACh infused into a coronary artery in dogs caused only a slight negative inotropic action, but that ACh infused in the same concen tration during sympathetic stimulation or during noradrenaline infusion induced a profound myocardial depression. These observations were confirmed in the dog (6-8), rabbit and turtle (9), and cat (10) hearts. The subcellular mechanisms underlying these adrenergic-cholinergic interactions were elucidated by the observations that cyclic AMP and cyclic GMP exerted the opposing regulatory action on the myocardial contraction (11-14). It was shown that the PIA of ,3-adrenoceptor stimulation was accompanied by an increase in cyclic AMP levels and by a concomitant decrease in cyclic GMP levels in the isolated perfused rat heart (15); ACh induced negative isotropic effect was associated with an elevation of cyclic GMP levels and with the opposite change in cyclic AI\IP levels iii the same preparation (10, 17). Based on these and their own findings in the guinea-pig heart (18), it has been proposed that the anti-adrenergic effects of cholinergic stimulation in the mammalian ventricular muscle may be mediated by the specific antagonism of the intracellular actions of cyclic AMP by cyclic GMP. Besides ,3-adrenoceptor stimulants which stimulate adenylate cyclase , histamine (19-21) and glucagon (22, 23), as well as cyclic AMP phosphodiesterase (PDE) inhibitors, theophyl line (24) and papaverine (25, 26) increased cyclic AMP levels during induction of their positive inotropic actions. How the intracellular cyclic AMP and cyclic GMP levels cor relate with contractile force during interaction of the cholinergic stimulation with these positive inotropic stimuli in the mammalian ventricular myocardium was investigated and the findings are reported herein. MATERIALS AND METHODS Mongrel dogs of either sex (7-13 kg) were anesthetized with sodium pentobarbital (30 mg/kg, i.v.) and given heparin (500 units/kg). The heart was excised, and trabeculae carneae of the right ventricular wall (smaller than 1 mm in diameter) were isolated and suspended in a 20 ml organ bath containing Krebs-Henseleit solution. The solution was equilibrated with 95% 02 and 5 % CO, at a temperature of 37'C. The muscle was electri cally driven by square wave pulses of 5 msec duration and a voltage just above the threshold at a rate of 0.5 Hz. The muscle length was adjusted to Lmax, where the tension developed was maximal, during an equilibration time of 1 hr. The tension developed was recorded isometrically on an ink-writing oscillograph (San-ei Instrument) by the use of force displace ment transducers (Grass FTO3B; Shinkoh UL). After an equilibration period, concen trations of cardiotonic agents as determined in preliminary experiments were added to the bath. When the tension developed reached a steady level, carbachol was administered. The maximal tension developed in each muscle was determined by administering calcium (10-12.5 mM) at the end of each experiment. Positive inotropic effects of drugs were expressed as the percentage of the maximal contraction or as the percentage of the basal tension developed. Experiments, except for those with isoprenaline, were carried out in the presence of 30 nM pindolol in order to avoid the ;3-adrenoceptor stimulation evoked by the noradrenaline released. All experiments for chemical assay were carried out in the paired muscle isolated from the same heart in the presence of agonists alone and agonists plus carbachol. Three minutes after the administration of carbachol in the presence of each agonist, muscles were removed from the organ bath, frozen immediately in liquid nitrogen and homogenized in 0.5 ml of 5 % trichloroacetic acid, as described in detail in the previous paper (27). After homogeni zation, 100 ,' l portions of the supernatant were extracted five times with I ml of ether after adding I N HCI. The cyclic AMP and cyclic GMP contents were determined by the radio immunoassay methods after succinylation of the nucleotides (28-31). Levels of cyclic nucleotides in the muscle were expressed as pmol/mg wet weight of the tissue. Values were given as means-S.E. Statistical significance between mean values was estimated by means of Student's t-test for paired comparison. A P value of smaller than 0.05 is con sidered to be significant. Drugs Used: (--)-Isoprenaline hydrochloride (Nikken Kagaku, Nagoya); glucagon novo (glucagon hydrochloride; Novo Industri, Copenhagen); histamine dihydrochloride, theophylline (Wako, Osaka); papaverine hydrochloride (Iwaki Seiyaku, Tokyo); dibutyryl cyclic AMP sodium (Daiichi Seiyaku, Tokyo); g-strophanthin (E. Merck, Darmstadt); carbachol chloride (K & K Laboratories, New York); (_T'_)-pindolol base (Sandoz, Basel); the anti-cyclic AMP and -cyclic GMP sera and ('23I)-succinyl cyclic AMP and cyclic GMP tyrosine methyl ester (Yamasa Shoyu Co., Choshi). The solution of isoprenaline was prepared in 1 % ascorbic acid on each experimental day and diluted with 0.9 % saline solution. Glucagon and histamine were dissolved in saline on each experimental day. These solutions were kept ice-cooled during experiments. RESULTS Influence of carbachol on the basal tension developed and on positive inotropic actions induced by various agents: Effects of 10 /iM carbachol on the basal tension developed, and on positive inotropic actions of isoprenaline, glucagon, histamine, papaverine, theophyl line and dibutyryl cyclic AMP (dbcAMP) are shown in Fig. 1. Carbachol (10 /tM) alone decreased only slightly the basal tension developed. The same concentration of carbachol caused prominent negative inotropic actions, when administered under conditions of myocardial stimulation produced by isoprenaline, glucagon, histamine, papaverine or theophylline. The inhibitory action of carbachol on the positive inotropic response to dbcAMP was less marked. In contrast to the prominent inhibitory action of carbachol on response to the agents FIG. 1. Effects of 10 f1M carbachol (Carb) on the basal tension developed and on positive inotropic actions of isoprenaline (Iso, I tiM), glucagon (Glu, 10 pM), histamine (Hist, 1 mM), papaverine (Papav, 30 pM), theophylline (Theoph, 1 mM) and of dbcAMP (1 mM) in the dog isolated right ventricular myocardium. Experi ments with glucagon, histamine, papaverine, theophylline and dbcAMP were performed in the presence of 30 nM pindolol. The horizontal bar indicates 10 min except for isoprenaline; for isoprenaline, 5 min. Fro. 2. Influence of 10 ;tM carbachol (Carb) on positive inotropic actions of CaCl2 (5 mM) and g-strophanthin (g-Stroph, I ' M). F1cG.3. Effects of 10 ;tM carbachol on positive inotropic actions induced by various cardiotonic agents on the dog isolated right ventricular muscle. Iso: isoprenaline; Glu: glucagon; Hist: histamine; Papav: papaverine: Theoph: theophylline; g-Stroph: g-strophanthin. Numbers in parentheses represent number of experi ments. Vertical bars indicate S.E. of the mean. shown above, carbachol (10 ,N) failed to inhibit positive inotropic actions of calcium or g-strophanthin (Fig. 2), the actions of which occurred with no change in the intracellular cyclic AMP level (24, 32). The summarized data of these experiments are presented in Fig. 3. Changes in the tension developed caused by carbachol (10 ; tM) under myocardial stimulation produced by isoprenaline, glucagon, histamine, papaverine, theophylline or dbcAMP were highly sig nificant (P<0.001 for each agonist). Actions of calcium and g-strophanthin were not significantly affected by carbachol. Influence of carbachol on cyclic AMP and cyclic GMP levels during clrolinergic antagonism of positive inotropic actions: Intracellular cyclic AMP and cyclic GMP levels were deter mined when positive inotropic actions were caused by isoprenaline, histamine, glucagon,
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