Date of Award
Doctor of Philosophy (Ph.D.)
Donald Y. Shirachi
First Committee Member
Joseph V. Levy
Second Committee Member
Marvin H. Malone
Third Committee Member
Fourth Committee Member
Alice Jean Matuszak
Cyclic adenosine 3’,5’-monophosphate (cAMP) was first described as the mediator of the glycogenolytic effect of epinephrine and glucagon in the liver almost two decades ago. It has since been found that cAMP may mediate the effects of a number of hormones and neurohormones, and this observation has led to the development of the second messenger hypothesis of hormone action. According to the second messenger theory, the hormone or first messenger brings information to the cell, whereas, the second messenger (cAMP) transfers this information into intracellular events. More recent evidence has described the existence of an additional second messenger, cyclic guanosine 3’,5’-monophosphate (cGMP). In some instances, the physiological response produced by a rise in the intracellular concentration of cGMP is opposite to that elicited by cAMP. This has led to the hypothesis that these cyclic nucleotides have antagonist regulatory roles in cell function.
cAMP and cGMP have been proposed to be second messengers responsible, at least in part, for the actions of hormones which modify vascular smooth muscle tone. The current hypothesis describing this relationship envisions an increase in vascular tone to be the result of either an increase in the tissue levels of cGMP or a decrease in cAMP, while, an increase in cAMP or a decrease in cGMP leads to the relaxation of vascular smooth muscle. There have been recent reports of an elevated ratio of cGMP to cAMP in the vascular tissues of the stress, DOCA, neurogenic, and spontaneously hypertensive rats which could explain the increased vascular smooth muscle tone and peripheral resistance in these animals. The enzymatic mechanisms responsible for the altered cyclic nucleotide metabolism was unclear. Thus, one of the aims of this research was not only to clarify, but to give additional insight concerning the relative roles of adenyl cyclase and phosphodiesterase (PDE) activity in regulating the intracellular levels of cAMP in the aorta of the spontaneously hypertensive rat (SHR). A second objective was to determine whether there was a correlation between the level of blood pressure in the SHR and the ration of cGMP to cAMP in the aorta.
Using a combination of cell-free and intact cell assay systems, we have demonstrated that the activity of adenyl cyclase, both basal and beta-adrenergic stimulated, was significantly decreased in the SHR aorta. The apparent affinity of isoproterenol for the receptor, the km for ATP, and the magnesium and pH dependent activities were similar to that observed in the control. There was a decrease in the activity of the low km form of PDE in the SHR aorta, however, there was no difference in the apparent affinity for cAMP or in the magnesium or pH dependent activities. On the basis of this data, we would like to propose that the low cAMP levels in the SHR result from a decrease in the concentration of adenyl cyclase protein in the vascular smooth muscle. The concentration of PDE protein has apparently decreased secondarily to be consistent with the new steady-state levels of cAMP.
Compared to the normotensive control, cAMP levels in the SHR aorta were initially low in the prohypertensive SHR and decreased further as the animal grew older and the blood pressure increased. The levels in the control remained constant throughout the same period. At the prehypertensive age, cGMP concentration in the SHR aorta was similar to the observed in the control, but as the blood pressure increased in the SHR, cGMP remained at this level, whereas, the concentration in age-matched normotensive controls had diminished. Chronic antihypertensive therapy in the mature SHR did not affect cAMP, but lowered cGMP to the levels found in the normotensive vessel. Based on these studies, it is suggested that the alteration in cAMP metabolism has occurred prior to the increase in blood pressure, while cGMP levels are changing as a result of the hypertension.
Taylor, John Edward. (1977). The Biochemistry Of Vascular Smooth Muscle In The Spontaneously Hypertensive Rat. University of the Pacific, Dissertation. https://scholarlycommons.pacific.edu/uop_etds/3435