Modulation of alpha 1-adrenergic contractility in isolated vascular tissues by heptanol: a functional demonstration of the potential importance of intercellular communication to vascular response generation.

After years of intensive investigation, the mechanism(s) underlying syncytial vascular smooth muscle responses both in vitro and in vivo is still poorly understood. Neither perivascular innervation nor regenerative electrical events appear sufficient to coordinate responses among vascular smooth muscle cells in many blood vessels. The implication of these observations is that another mechanism is required for organizing syncytial vascular responses. Although gap junctions are ubiquitously distributed among vascular wall cells throughout the vascular tree, their contribution to the modulation of vasomotor tone is still considered controversial. Resolution of the long standing debate awaits a clear demonstration that gap junctions modulate contraction or relaxation responses to vascular smooth muscle. Despite the absence of specific gap junctional uncoupling agents, it has still been possible to identify reasonable experimental conditions under which the contribution of gap junctions to contractile responses in isolated vascular tissues could be evaluated. Studies in isolated preparations known to contain gap junctions have indicated that alpha 1-adrenergic receptor-mediated contractile responses of diverse isolated vascular tissues, are significantly modulated by selective disruption of intercellular communication with the well studied lipophilic uncoupling agent heptanol. Interpretation of these pharmacological studies is explicitly dependent on the selectivity of the uncoupling actions of heptanol. Considerable experimental evidence suggests that, at the concentrations used, in the preparations thus far examined, heptanol does indeed have selective uncoupling actions. In fact, recent experiments provide empirical support for an operational definition of the selectivity of heptanol, and a functional role for gap junctions in modulating contractile responses in isolated vascular tissues. The operational definition states only that there exists a narrow, albeit identifiable, concentration range over which it is reasonable to assume that the effects of heptanol are primarily related to its uncoupling actions on gap junctions. The functional role for gap junctions is defined by their requisite contribution to tension development during contraction of isolated tissues. Experimentally, this can be visualized as a significant diminution in the contractile responses of isolated vascular tissues in the presence of selective uncoupling heptanol concentrations. Thus, a cogent interpretation of available data is that they provide compelling indirect evidence for a principle role of gap junctions in modulating the alpha 1-adrenergic contractility of isolated vascular tissues.