A study on possible modulating and direct effects of gamma2-MSH and ACTH-(1-24) on the cardiovascular system of the rat.
In conscious rats, gamma2-melanocyte-stimulating hormone (gamma2-MSH) dose-dependently increases blood pressure and heart rate, whereas adrenocorticotropin-(1-24) [ACTH-(1-24)] dose-dependently decreases blood pressure, an effect which was accompanied by a reflectory tachycardia. As the exact mechanism involved in these cardiovascular effects of the two melanocortins is as yet not known, we undertook a series of experiments to investigate the possibility that these peptides have modulating or direct effect on the cardiovascular system of the rat. In pithed rats gamma2-MSH, administered intravenously (i.v.) in doses of 5-200 nmol/kg, had no significant effect on systolic and diastolic blood pressure and on heart rate, whereas ACTH-(1-24), 5-500 nmol/kg, i.v., dose-dependently decreased blood pressure and increased heart rate. Infusion of gamma2-MSH, 10(-8) M, or ACTH-(1-24), 10(-6) M, in the isolated perfused rat heart did not significantly affect left ventricular pressure or coronary flow. Pretreatment with either gamma2-MSH or ACTH-(1-24) did not modify the responsiveness of the myocardium and coronary vasculature to salbutamol and phenylephrine. Neither gamma2-MSH nor ACTH-(1-24) did affect the vascular contractile machinery of skinned vascular smooth muscles of the rabbit with respect to Ca2+ handling in the cell, as measured by its sensitivity to exogenously applied Ca2+. Gamma2-MSH had no effect on blood pressure and heart rate in pithed rats in which postganglionic sympathetic outflow was stimulated by 1,1-dimethyl-4-phenylpiperazinium (DMPP), nor in pithed rats in which preganglionic sympathetic outflow was stimulated electrically. A dose of 15 nmol/kg ACTH-(1-24) had no significant influence on preganglionic outflow to the cardiac and vascular structures in pithed rats. These data show that gamma2-MSH does not exert its cardiovascular effects via a peripheral site of action at the level of the vascular system and the heart, nor directly on pre- or postganglionic sympathetic outflow. These results are in support for the notion that the peptide acts via a brain region localised outside the blood-brain barrier. The acute depressor effect of ACTH-(1-24), however, seems to be due to a direct effect on the vasculature in the periphery.
Van Bergen
P
P
Department of Medical Pharmacology, Rudolf Magnus Institute for Neurosciences, Utrecht University, The Netherlands.
Vleeming
W
W
Van Heijst
B G
BG
Versteeg
D H
DH
De Wildt
D J
DJ
D000818:Animals; D001338:Autonomic Fibers, Postganglionic / Q000187:drug effects / Q000502:physiology; D001339:Autonomic Fibers, Preganglionic / Q000187:drug effects / Q000502:physiology; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000494:pharmacology; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D002319:Cardiovascular System / Q000187:drug effects*; D003243:Consciousness / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D003366:Cosyntropin / Q000494:pharmacology*; D003655:Decerebrate State / Q000503:physiopathology; D003971:Diastole; D004305:Dose-Response Relationship, Drug; D004525:Efferent Pathways / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011169:Portal Vein / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D017779:Sympathetic Fibers, Postganglionic / Q000187:drug effects / Q000502:physiology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D013599:Systole; D016277:Ventricular Function, Left / Q000187:drug effects
D003366:Cosyntropin; D009074:Melanocyte-Stimulating Hormones; D002118:Calcium