Endothelin-1-induced alterations in phenylephrine-induced contractile responses are largely additive in physiologically diverse rabbit vasculature.

Endothelin-1 (ET-1) is an important modulator of vasomotor tone that is thought to participate in the etiology of cardiovascular disease by virtue of its ability to amplify the contractile responses of vascular smooth muscle cells to the effects of other vasoactive agents. Despite this fact, few studies have quantitated the expected contribution of ET-1 to the enhanced contractile responses elicited in the presence of another spasmogen. As a first step in this direction, ET-1 and phenylephrine (PE) were used to evaluate the effects of co-activation of the ETA/B or alpha-1 adrenergic receptors, respectively, on contractile responses in isolated rings of rabbit aorta, mesenteric and femoral artery, or strips of corporal tissue. Cumulative steady-state concentration-response curves (CRCs) were constructed to PE alone before the construction of a CRC to ET-1 alone, or a mixture of PE and ET-1 using a previously described drug concentration paradigm. Computer fits of the logistic equation to CRC data revealed that in all vascular tissues examined, the partial substitution of PE with ET-1 was associated with a significant vessel-dependent approximately 3- to 30-fold leftward shift in the CRC (P < .01, Student's t test for paired samples), as judged by a significant increase in the pEC50 (negative logarithm of the concentration of drug that elicits one-half of the calculated maximal effect), in the absence of any detectable effect on the calculated maximal contractile response (Emax) or the slope factor (rho). A theoretical CRC constructed using the Pöch and Holzmann method for equiactive substitution demonstrated that the responses to mixtures of PE and ET-1 were often the result of simple additivity of agonist effects in these preparations, and thus, were "expected" based on detailed knowledge of the individual effects of these two agonists. Regardless of the precision of the Poch and Holzmann CRC in predicting the effects of this drug mixture in these vascular tissues, comparison of the "expected" contractile response with the "observed" response represents an important first step toward establishing a more uniform nomenclature for describing the physiological/pathophysiological effects of mixtures of drugs on diverse vasculature.

Accelerated nerve regeneration mediated by Schwann cells expressing a mutant form of the POU protein SCIP.

After injury, the peripheral nervous system (PNS) is capable of full regeneration and recovery of function. Many molecular events that are the hallmarks of the regenerating PNS are recapitulations of developmental processes. The expression of one such molecule, the POU transcription factor suppressed cAMP-inducible POU protein (SCIP), is required for the establishment of normal nerves and is reexpressed during regeneration. Here we describe markedly accelerated regeneration and hypertrophy of both myelin and axons in transgenic mice that express an amino-terminal deletion of the SCIP molecule. This mutant SCIP molecule retains the POU-specific and POU homeodomain moieties, which allow for both DNA binding and some protein-protein interaction. We demonstrate that the transgene indirectly effects dramatic axonal changes. This is the first demonstration of a genetically controlled acceleration of neural regeneration.

Augmentation in the kinetic characteristics of phenylephrine- and 5-hydroxytryptamine-induced contractions in the isolated rat aorta following eight weeks of STZ-diabetes.

Kinetic studies were conducted on the contractile response elicited by phenylephrine (PE) and 5-hydroxytryptamine (5-HT) activation of the alpha 1-adrenergic- and 5-HT2 receptor subtypes, respectively, in aortic rings isolated from streptozotocin (STZ)-diabetic and age-matched control rats. The maximal PE- and 5-HT-induced contractile responses were separated into distinct phasic and tonic components, and the tonic portion of the response was assessed by evaluation of the calculated maximal rate constant for onset of contraction (kobsmax; min-1). Statistical analysis revealed that the mean kobsmax values for PE alone (10 microM), 5-HT alone (10 microM) and mixtures of PE and 5-HT (10 microM each) were significantly greater in diabetic animals than in age-matched control animals. These increases in kobsmax resulted in significant diabetes-related increases in the rate and relative magnitude of response generation during the initial minutes of contraction. Such observations emphasize the importance of kinetic studies, and given the central role played by the aorta in cardiovascular homeostasis, suggest that altered aortic contractility may play a role in some aspects of diabetic vascular disease. Moreover, if these kinetic alterations reflect a more generalized feature of diabetic vasculature (e.g., resistance vessels), then it is conceivable that such changes may further exacerbate diabetic vasculopathy.

Kinetic characteristics of alpha 1-adrenergic contractions in human corpus cavernosum smooth muscle.

Kinetic studies were conducted on the contractile response elicited by phenylephrine (PE) activation of the alpha 1-adrenergic receptor subtype in vascular smooth muscle isolated from the corpus cavernosum of impotent men. PE-induced contractions were separated into distinct phasic and tonic components, and the tonic portion was analyzed using a first-order rate equation to determine the maximal rate constant for onset of contraction (kobs max) and the maximum amplitude of the steady-state contractile response (Req max). The kobs max value in tissues from insulin-dependent diabetic patients was significantly greater than that in tissues from either noninsulin-dependent diabetics or nondiabetics. Additionally, the mean kobs max value in older patients (60-70 yr) was significantly greater than the mean kobs max value in younger patients (32-59 yr). Significant diabetes-related, but not age-related, alterations were also found in Req max. The observed changes in contractility resulted in dramatic age- and pathology-dependent alterations in the initial rate and/or magnitude of PE-induced response generation. These kinetic studies extend our previous observations at steady state and provide further evidence for heightened corporal tissue tone in the etiology of erectile dysfunction.