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.

[1]  Cliff Wj The aortic tunica media in growing rats studied with the electron microscope. , 1967 .

[2]  P. Brink Gap Junction Channels and Cell‐to‐Cell Messengers in Myocardium , 1991 .

[3]  J. Rhodin,et al.  The ultrastructure of mammalian arterioles and precapillary sphincters. , 1967, Journal of ultrastructure research.

[4]  D. Deamer,et al.  Sensitivity to Anesthesia by Pregnanolone Appears Late in Evolution a , 1991, Annals of the New York Academy of Sciences.

[5]  B. Hille Ionic channels of excitable membranes , 2001 .

[6]  S. Segal,et al.  Cell-to-cell communication coordinates blood flow control. , 1994, Hypertension.

[7]  B. Ljung,et al.  Spread of excitation in the smooth muscle of the rat portal vein. , 1967, Acta physiologica Scandinavica.

[8]  J. Bevan,et al.  Movement of Norepinephrine through the Media of Rabbit Aorta , 1970, Circulation research.

[9]  M. McGrath,et al.  Hyperosmolarity: effects on nerves and smooth muscle of cutaneous veins. , 1976, The American journal of physiology.

[10]  S S Segal,et al.  Flow control among microvessels coordinated by intercellular conduction. , 1986, Science.

[11]  E. Hertzberg,et al.  Gap junctions: New tools, new answers, new questions , 1991, Neuron.

[12]  C. Haudenschild,et al.  Gap junction messenger RNA expression by vascular wall cells. , 1990, Circulation research.

[13]  A. Hodgkin The conduction of the nervous impulse , 1964 .

[14]  G. Christ,et al.  Intercellular communication through gap junctions: a potential role in pharmacomechanical coupling and syncytial tissue contraction in vascular smooth muscle isolated from the human corpus cavernosum. , 1991, Life sciences.

[15]  T. Kenakin On the importance of agonist concentration‐gradients within isolated tissues. Increased maximal responses of rat vasa deferentia to (–)‐noradrenaline after blockade of neuronal uptake , 1980, The Journal of pharmacy and pharmacology.

[16]  G. Christ,et al.  Dynamic gap junctional communication: a delimiting model for tissue responses. , 1994, Biophysical journal.

[17]  S. Maayani,et al.  Kinetic characterization of the rabbit aorta contractile response to an alpha adrenergic agonist. , 1984, The Journal of pharmacology and experimental therapeutics.

[18]  E. Hertzberg,et al.  Gap junctions formed of connexin43 are found between smooth muscle cells of human corpus cavernosum. , 1993, The Journal of urology.

[19]  N. Sperelakis,et al.  Ion channels of vascular smooth muscle cells and endothelial cells , 1991 .

[20]  S. Finkbeiner,et al.  Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. , 1990, Science.

[21]  L. Barr,et al.  Electrical Transmission at the Nexus between Smooth Muscle Cells , 1968, The Journal of general physiology.

[22]  D. Haydon,et al.  Actions of n‐Alcohols on Nicotinic Acetylcholine Receptor Ion Channels in Cultured Rat Muscle Cells , 1991, Annals of the New York Academy of Sciences.

[23]  T. Kobayasi,et al.  Electron microscopy of the normal rabbit aorta. , 2009, Acta pathologica et microbiologica Scandinavica.

[24]  L. Barr,et al.  Intercellular Connection between Smooth Muscle Cells: the Nexus , 1962, Science.

[25]  G. Christ,et al.  Gap junctions modulate tissue contractility and alpha 1 adrenergic agonist efficacy in isolated rat aorta. , 1993, The Journal of pharmacology and experimental therapeutics.

[26]  J. A. Wilson,et al.  Some properties of the smooth muscle of rabbit portal vein , 1968, The Journal of physiology.