The cardiovascular system has an inherent ability to regulate, up or down, its own responsivity to endogenous and exogenous agents inversely dependent upon the level of stimulation. This phenomenon of sub or supersensitivity has previously been associated with rebound sympathetic activity that occurs when some antihypertensive agents are abruptly discontinued, and recently proposed as a possible component of the tolerance that is sometimes seen in prolonged treatment of congestive heart failure with vasodilators. This proposal is directed towards the delineation of any changes in sensitivity that occur in both macro and microcirculation in animals in which relaxation is chronically maintained by three different mechanisms (salbutamol-beta2 stimulation; prazonsin-alpha1 inhibiton; hydralazine-direct, beyond-receptor-activation. Primary emphasis will be on changes in responsivity to relaxants, but indirectly mediated or compensatory changes in vasoconstrictor mechanisms will also be quantitated. In rabbit aorta and renal artery extensive definition of vasodilator effects on tension responses and unstimulated and agonist-stimulated Ca++ binding, release and fluxes in terms of total, La+++ resistant, and EGTA resistant pools will be used comparatively to characterize, as completely as possible, sensitivity changes in pretreated groups, as well as the cellular mechanisms of action of each vasodilator. Studies in the microcirculation using intravital television microscopy (diameter, velocity and flow relationships) will delineate sensitivity changes to vasodilators and vasoconstrictors on network (affecting all vessels simultaneously) or at a single site on a single microvessel basis within four branching orders (1st,2nd,3rd, or 4th order arterioles), in rat cremaster muscle. Primary emphasis will be on elucidation of the modulation and interactions of alpha and beta receptors at each level, as well as non-specific, beyond the receptor effects in control and pretreated animals. The evolving hypothesis implies that a few basic cellular mechanisms are involved in initiation and maintenance of tone, and subsequent relaxation, that are functional in all vessels; however, the relative importance of each varies in vessels of similar diameter in different beds and between vessels of different diameters within the same or different beds.
