Mediation of contraction in rat cauda epididymidis by alpha-adrenoceptors

Subtypes of alpha-adrenoceptors responsible for contractions of the rat cauda epididymidis were studied in vivo by micropuncture using a servo-nulling pressure transducer system. Administration of both non-selective and selective alpha-adrenoceptor agonists in doses of 1-40 microg noradrenaline kg(-1) body weight (BW), 1-100 microg clonidine kg(-1) BW, or 100-800 mg methoxamine kg(-1) BW enhanced contractions of the proximal cauda epididymidis in a dose-response manner. The potency of the agonists were noradrenaline > or = clonidine>methoxamine. Pre-treatments with selective alpha(1)-adrenoceptor antagonist (prazosin) and alpha(2)-adrenoceptor antagonist (yohimbine) at the doses of 400 and 800 microg kg(-1) BW, respectively, had very little effect on spontaneous contractions, but effectively blocked the responses to the maximal doses of methoxamine and clonidine. The responses could not be explained by the systemic effects of agonists and antagonists. The results suggest that contraction of the proximal cauda epididymidis of rats is mediated by both alpha(1)- and alpha(2)-adrenoceptors. The latter appears to be more abundant.

A novel effect of norepinephrine on cardiac cells is mediated by alpha 1-adrenoceptors

In the heart, alpha-adrenergic agonists have long been known to produce a positive inotropic effect that is rate dependent and associated with action potential prolongation but is not accompanied by adenosine 3',5'-cyclic monophosphate (cAMP) elevation. The ionic mechanism of these effects is unknown. We report that a transient outward K+ current, a major determinant of plateau duration in rabbit and human atria, is strongly inhibited by norepinephrine and the alpha-adrenoceptor agonists methoxamine and phenylephrine. These effects of alpha-stimulation can be blocked by prazosin. The reduction in the transient outward current substantially slows action potential repolarization. These results can explain the regional and species-dependent positive inotropic effects of alpha-adrenergic stimulation in the heart and give important new insight into the autonomic regulation of cardiac function. In addition, reduction in this repolarizing current during the enhanced alpha-adrenergic responsiveness of myocardial ischemia may be a factor in the genesis of arrhythmias produced by catecholamines.

Pathogenesis of Arterial Lesions Induced by Dopaminergic Compounds in the Rat

Fenoldopam mesylate (FM), a selective post-junctional dopaminergic (DA1) vasodilator, causes lesions of large caliber splanchnic arteries (100–800 μm) in the rat characterized by necrosis of medial smooth muscle cells and hemorrhage. FM does not induce lesions in other vascular beds of the rat, or in dogs or monkeys. Dopamine, like FM, causes hemorrhagic lesions of large caliber splanchnic arteries in the rat, as well as fibrinoid necrosis of small caliber arteries (<100 μm) of the splanchnic, cerebral, coronary and renal vascular beds. Dopamine is an alpha- and beta-adrenoceptor and a dopaminergic receptor agonist. Because these arterial lesions are thought to result from the pharmacologic activity of these 2 compounds, we sought to ascertain the presence of DA1 receptors in mesenteric arteries of the rat and to determine the role of these or other vascular receptor subtypes in lesion induction. We also studied the process of repair after arterial injury caused by FM or dopamine. The presence of DA1 receptors was confirmed in isolated perfused mesenteric arteries by standard pharmacologic techniques; stimulation by FM resulted in vasodilation which was inhibited by the DA1 receptor antagonist SK&F 83566-C. Likewise, SK&F 83566-C prevented the induction of hemorrhagic lesions of large caliber arteries in rats upon infusion of FM or dopamine. In rats co-exposed to the alpha-adrenoreceptor antagonist phenoxybenzamine (PBZ) and either FM or dopamine, the incidence and severity of hemorrhagic lesions of large caliber arteries were increased, but PBZ prevented the formation of dopamine-induced fibrinoid lesions in arteries of small caliber. Rats exposed concurrently to dopamine, phenoxybenzamine, and SK&F 83566-C were free of all arterial lesions. Thus, the induction of splanchnic arterial lesions in the rat by dopamine and FM is caused by stimulation of, and interaction between, alpha-adrenoceptors and dopaminergic DA1 receptors. Fibrinoid lesions of small arteries (alpha-adrenoceptor-mediated) were repaired, as observed morphologically by 14 d after exposure to dopamine. Hemorrhagic lesions of large caliber arteries (DA1 receptor-mediated) had undergone significant repair by 28 d after exposure to FM but these arteries possessed a thicker media surrounded by adventitial fibrosis. Thus, morphologically distinct receptor-mediated splanchnic arterial lesions induced by dopaminergic and alpha-adrenoceptor agonists follow a markedly different course of repair. Arterial lesions induced by FM or dopamine by activation of post-junctional dopaminergic DA1 receptors may represent a model of polyarteritis nodosa.