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The previously described ability of reserpine and parachlorophenylalanine to induce the accumulation of lipid droplets in ventricular cardiac muscle cells of the bat was investigated. Lipid droplet accumulation was assessed qualitatively by light microscopy and quantitatively by morphometric analysis of electron micrographs. An hypothesis that the action of the drugs was an indirect one, mediated by the cardiac adrenergic innervation, was framed and tested. Lipid droplet accumulation occurred during a time of intense sympathetic activity, that of arousal from hibernation. The ability of the two drugs to produce the effect was antagonized by prior sympathectomy with 6-hydroxy-dopamine.The effect was mimicked by administration of exogenous norepinephrine together with inhibitors of its catabolic enzymes, monoamine oxidase and catechol-omethyl transferase. These observations are all consistent with the initial hypothesis and raise the possibility that endogenous norepinephrine in the cardiac sympathetic innervation might be, at least potentially, auto-toxic.The accumulation ad lipid droplets in cardiac muscle cells of the bat's cardiac ventricle has been observed in animals treated with the drug reserpine (Hagopian et al., '72). Similar chainges have also been induced in the hearts of active bats by the administration of parachlorophenylalanine (PCPA: Hagopian et al., '73a). Reserpine depIetes tissues of both serotonin and catecholamines (Carlsson, '66, for references) while PCPA, a tryptophan hydroxylase inhibitor, essentially depletes only serotonin (Koe and Weissman, ' 168). In subsequent experiments bats were given 6-hydroxydopamine (6-HD: Hagopian et al., '73b), a drug known to cause depletion of norepinephrine (NE) from tissues by effecting a chemical sympathectomy (Malmfors and Thoenen, '71). 6-HD did deplete the bat's heart of NE and evidence of degeneration of adrenergic axon terminals was obtained. However, no lipid accumulation in cardiac muscle cells was associated with these effects of the drug (Hagopian et al., '73b droplets to accumulate in cardiac muscle cells and, in the previous instance (after PCPA) lipid droplets could be induced to accumulate without an accompanying depletion of catecholamines. Therefore, it seems clear that depletion of catecholamines is not causally related to lipid droplet accumulation in cardiocytes. The action of PCPA and reserpine must be explained in other terms. The effect of PCPA is particularly interesting since the heart contains very little serotonin (Snyder et al., '65). This raises the possibility that lipid droplet accumulation may be an indirect effect of the drugs, resulting from their action on the central nervous system and mediated through the cardiac innervation.The catecholamines, isoproterenol and NE, have been reported to induce a cardiomyopathy associated with lipid accumulation in cardiac muscle cells (Ferrans et al., '64; Regan et al., '72). These observations suggest that adrenergic nerves may provide the common pathway used by the drugs to...
The previously described ability of reserpine and parachlorophenylalanine to induce the accumulation of lipid droplets in ventricular cardiac muscle cells of the bat was investigated. Lipid droplet accumulation was assessed qualitatively by light microscopy and quantitatively by morphometric analysis of electron micrographs. An hypothesis that the action of the drugs was an indirect one, mediated by the cardiac adrenergic innervation, was framed and tested. Lipid droplet accumulation occurred during a time of intense sympathetic activity, that of arousal from hibernation. The ability of the two drugs to produce the effect was antagonized by prior sympathectomy with 6-hydroxy-dopamine.The effect was mimicked by administration of exogenous norepinephrine together with inhibitors of its catabolic enzymes, monoamine oxidase and catechol-omethyl transferase. These observations are all consistent with the initial hypothesis and raise the possibility that endogenous norepinephrine in the cardiac sympathetic innervation might be, at least potentially, auto-toxic.The accumulation ad lipid droplets in cardiac muscle cells of the bat's cardiac ventricle has been observed in animals treated with the drug reserpine (Hagopian et al., '72). Similar chainges have also been induced in the hearts of active bats by the administration of parachlorophenylalanine (PCPA: Hagopian et al., '73a). Reserpine depIetes tissues of both serotonin and catecholamines (Carlsson, '66, for references) while PCPA, a tryptophan hydroxylase inhibitor, essentially depletes only serotonin (Koe and Weissman, ' 168). In subsequent experiments bats were given 6-hydroxydopamine (6-HD: Hagopian et al., '73b), a drug known to cause depletion of norepinephrine (NE) from tissues by effecting a chemical sympathectomy (Malmfors and Thoenen, '71). 6-HD did deplete the bat's heart of NE and evidence of degeneration of adrenergic axon terminals was obtained. However, no lipid accumulation in cardiac muscle cells was associated with these effects of the drug (Hagopian et al., '73b droplets to accumulate in cardiac muscle cells and, in the previous instance (after PCPA) lipid droplets could be induced to accumulate without an accompanying depletion of catecholamines. Therefore, it seems clear that depletion of catecholamines is not causally related to lipid droplet accumulation in cardiocytes. The action of PCPA and reserpine must be explained in other terms. The effect of PCPA is particularly interesting since the heart contains very little serotonin (Snyder et al., '65). This raises the possibility that lipid droplet accumulation may be an indirect effect of the drugs, resulting from their action on the central nervous system and mediated through the cardiac innervation.The catecholamines, isoproterenol and NE, have been reported to induce a cardiomyopathy associated with lipid accumulation in cardiac muscle cells (Ferrans et al., '64; Regan et al., '72). These observations suggest that adrenergic nerves may provide the common pathway used by the drugs to...
Reserpine has been demonstrated in previous studies to induce the accumulation of lipid droplets in ventricular cardiac muscle cells of bats and this effect has been attributed to mediation by the sympathetic nervous system. The present study was done to evaluate the species specificity of this action of the drug. Reserpine caused lipid droplet accumulation in cardiocytes of guinea pigs and mice. However, in contrast to the action of the drug in bats, this action of reserpine in guinea pigs and mice could not be antagonized by chemical sympathectomy with 6-hydroxydopamine or by treatment of animals with phenoxybenzamine, atropine or hexamethonium. Like reserpine, fasting for as little as 24 hours induced lipid droplet accumulation in cardiocytes of guinea pigs and mice. This effect also could not be prevented by treatment with 6-hydroxydopamine indicating that the sympathetic nervous system was not involved in its mediation. Force-feeding guinea pigs given reserpine prevented the accumulation of lipid droplets normally induced by this drug. It is concluded that the lipid droplet accumulation in the hearts of guinea pigs that follows administration of reserpine is not due to a direct cardiotoxicity of the drug but is secondary to the failure of drug-treated animals to eat. Since the autonomic nervous system appears to mediate reserpine's cardiotoxicity in bats, the species difference revealed by these experiments probably results from an underlying physiological difference in the nervous systems of these animals.Reserpine has been shown to induce lipid droplet accumulation (LDA) in cardiocytes of bats (Hagopian e t al., '72). This change is antagonized by pretreatment of bats with 6-hydroxydopamine (6-HD1, phenoxybenzamine, or atropine (Hagopian e t al., '73; Hagopian e t al., '75). The change is also seen during the first 1-4 hours following arousal of bats from hibernation (Hagopian e t al., '73b). Moreover, lipid droplets accumulate in the heart when bats are injected with exogenous norepinephrine (NE) or the tryptophan hydroxylase inhibitor parachlorophenylalanine (PCPA) (Nunez e t al., '75; Hagopian e t al., '73b). A hypothesis has been put forward ascribing LDA to sympathetic neural activity (Nunez e t al., '75).The present experiments were done t o determine if LDA of the kind induced in bats by reserpine is a species-specific phenomenon, or whether other mammals also develop the change. Guinea pigs and mice were used as experimental animals and LDA was assessed histochemically and biochemically. Although reserpine does induce LDA in these other animals, the change does not seem to be a primary one and the data derived from the guinea pigs and mice is not comparable to that from bats. In guinea pigs and mice starvation for as little as 24 hours causes LDA and it is likely that LDA following administration of reserpine is secondary to these animals' failure to eat. MATERIALS A N D METHODS AnimalsAdult male Hartley guinea pigs (300-350 gm) and Swiss white mice (10-35 gm) were used in this study. All...
The adrenergic innervation of the heart of the bat (Miniopterus schreibersii) was studied with a fluorescence histochemical technique. The appearance and distribution pattern of the terminal adrenergic nerve fibers demonstrated in the atria, sinoatrial and atrioventricular nodes, and ventricles is typically mammalian. Fine varicose adrenergic fibers run in and parallel to the ventricular muscle where they are common and uniformly distributed. Indian ink perfusion of the coronary vasculature demonstrates the high density of vessels in the ventricles, but obscures the terminal innervation of the ventricular muscle. This alone, or in combination with the apparent seasonal change in the terminal innervation of the ventricles, may explain the inability of previous workers to identify an adrenergic ventricular innervation in the bat Nyctalus noctula. The adrenergic ventricular innervation might be involved in the large increases in cardiac output associated with the commencement of flight and in the massive sympathetic activation that mediates arousal from torpor.
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