Pharmacology of arterioles: Some aspects of variability in response to norepinephrine, histamine, and 5-hydroxytryptamine

Abstract

Norepinephrine application results in constriction in small arterioles, whether applied topically in small volumes, iontophoretically, or intraluminally (4-9,11,12). At the level of the smallest arterioles, histamine produces a dilation (20,29,30). More work is needed both to clarify the role of H1 and H2 receptors in vascular beds other than pial circulation, and of course, to expand our knowledge of the complex dilator-constrictor responses to 5-hydroxytryptamine in a variety of tissues. The mechanisms of action of norepinephrine have been most thoroughly explored of the three agents discussed here (1). Norepinephrine combines with the α-receptor resulting in depolarization. In response to this action, calcium permeability is increased and calcium is released from internal stores. This increase in internal calcium concentration activates the contractile elements and ultimately is recorded as arteriolar constriction. Although specific mechanisms involving the actions of histamine and 5-hydroxytryptamine have not been so rigorously described, it is possible to speculate that the relaxations observed at the microcirculatory level must be related to removal of the activator ion from the cytoplasm by either cellular sequestration or assisted dillusion to the extracellular space. Inherent in in vivo preparations are a number of factors that may result in variable responses. These differences include anesthetic levels (40), alterations in wall stress (11), sites of application (12), concentrations of other vasoactive agents (19,20,21,26), tissue differences (2), and mode of application (4). For repeatable responses with topical application, even and consistent distribution of the pharmacologic agent in the superfusion solution is required. When intraluminal administration is used, variable mixing in the blood, as well as differences in drug metabolism and distribution, may contribute to varied responses. Future work on the pharmacology of arterioles will require systematic studies of the microcirculation with these and other vasoactive agents. First, the level of branching and control diameter and wall stress must be systematically evaluated and reported. Also needed is expanded use of classic pharmacologic tools, including use of a variety of blocking agents and antagonists, to define receptors, both individually and as they interact with vasoactive agents. The studies reported here are in vivo preparations with the complicating factors in such systems of anesthesia, unknown basal neural tone, and unknown humoral substances being produced in tissue and carried in the blood. These may only serve to complicate the interpretation of arteriolar responses. Recently, Gore et al. (41) described an isolated arteriolar preparation from the hamster cheek pouch. The isolated arteriole is attached from both sides to a leak-proof perfusion system so that solutions on intimal and adventitial surfaces can be altered individually. In this system, responses to pharmacologic agents are measured as changes in vessel diameter. The value of an in vitro arteriolar preparation, in which drugs can be selectively applied to either surface, has become even more apparent with the observation of the important role played by the endothelium in a number of vasodilator responses (42,43). The isolated arteriolar preparation, in combination with the in vivo studies of small arterioles, will provide some of the answers required to appreciate and understand pharmacology at this level of the arterial network where the major resistance changes, responsible for the control of blood flow through the individual organ, occur.