Biomedical subjects

Petter Hedlund

Publications and source records attributed to Petter Hedlund.

8 recordsLinked to original sources

PubMed2003

Genes and erectile function.

PURPOSE OF REVIEW: Few human studies have been performed with specific genetic endpoints coupled with erectile function or dysfunction. Most knowledge of gene expression and the function thereof on penile erection has been acquired in experimental models. The purpose of the present review is to give an overview of the available information obtained in studies of genes or genetic products versus erectile function or dysfunction. RECENT FINDINGS: The association of, for example, systemic vascular disease with diminished erectile function has brought attention to investigations of the distribution, in men with erectile dysfunction, of some genotype variants proposed to be involved in cardiovascular disease. Altered expression or activities of some smooth muscle regulatory components of the ischaemic, diabetic, or ageing penis have been reported. SUMMARY: Although penile erection can be considered a polygenic trait, some key effectors for normal erectile function within, for example, the nitric oxide/cyclic guanosine monophosphate pathway may be identified. Findings in future population-based studies may disclose the presence of a particular mutation of a gene or gene variants that may predispose to the development of erectile dysfunction. The exact molecular pathogenesis of erectile dysfunction is not known, and may vary between different forms of erectile dysfunction. With integrated approaches in genetic, molecular, and functional investigations, we can learn more of the impact of a particular genotype on erectile function, and also identify targets for preventive, pharmacological, or molecular measures.

Erectile Dysfunction↗

PubMed2003

Morphology, phenotype and ultrastructure of fibroblastic cells from normal and neuropathic human detrusor: absence of myofibroblast characteristics.

PURPOSE: Fibroblasts are functionally diverse and fibroblastic cells with smooth muscle-like characteristics (myofibroblasts) regulate smooth muscle activity in certain tissues. The presence of myofibroblasts has been reported in the bladder with important implications for normal function and detrusor overactivity. We assessed fibroblastic cell characteristics to discern features suggesting a myofibroblast phenotype in normal or neuropathic human detrusor. MATERIALS AND METHODS: A total of 25 control samples were obtained from cadaveric organ donors or patients with a mean age of 42.3 years investigated for hematuria and compared with samples from 18 patients with a mean age of 37.4 years with neurogenic detrusor overactivity. Morphology, phenotypic expression of various markers and the ultrastructure of each fibroblastic cell visible in multiple sections from each specimen was evaluated by 2 independent assessors. RESULTS: Fibroblastic cells were observed throughout the smooth muscle and connective tissue. They were located peripherally on muscle fascicles and had a polar stellate appearance with processes ramifying in interfascicular planes and muscle. They possessed vimentin-like immunoreactivity and weak c-kit-like immunoreactivity but not desmin or alpha-smooth muscle actin-like immunoreactivity. Ultrastructurally they showed dilated rough endoplasmic reticulum with a moderately electron dense amorphous content and prominent golgi complexes. Nuclei had clumped peripheral heterochromatin. There were extensive flattened processes that lacked basal laminae. There was no specific contact with nerve fibers or smooth muscle. Neuropathic bladder samples did not differ overtly from those of controls. CONCLUSIONS: The detrusor possesses an extensive network of fibroblastic cells and processes. No evidence of myofibroblast differentiation was discerned in normal or neuropathic detrusor, although a minority subpopulation or regional variability in cellular phenotype could not be excluded.

Adult↗

PubMed2003

Partial outlet obstruction enhances modular autonomous activity in the isolated rat bladder.

PURPOSE: Autonomous bladder activity can take the form of localized micromotions (MMs), suggesting that the detrusor may be arranged into component modules, of which each is capable of contracting autonomously. We examined MMs in isolated whole rat bladder and the effects of partial bladder outlet obstruction as a model of detrusor overactivity (DO) to ascertain whether altered modular activity could be an etiological factor in DO. MATERIALS AND METHODS: A total of 12 adult female Sprague-Dawley rats underwent obstruction or sham operation for 1 or 4 weeks. Bladders were microsurgically removed and mounted in whole organ tissue baths. Recordings of intravesical pressure and simultaneous registration of intramural contractions were performed under standardized conditions. RESULTS: Prior to filling MMs took the form of localized contractions near the vesicoureteral junction in sham operated animals and multifocal microcontractions in obstructed animals. Intravesical volume increases were associated with a change in localized MMs to propagated contraction waves. In sham operated animals stretch resulted in increased MM frequency but decreased amplitude. After obstruction stretch elicited highly coordinated MMs and enhanced intravesical pressure transmission. The time since surgery did not alter observations in the sham or obstructed group. CONCLUSIONS: Detrusor muscle in isolated bladders under conditions modeling urine storage may have a functional modular arrangement with the basolateral region most active prior to filling. Peripheral factors determining intravesical pressure include the number of modules active, coordination and intramural tension at other sites. After bladder outlet obstruction more modules are active at baseline and their coordination is enhanced by stretch, leading to increased pressure fluctuations. Such changes may contribute to the development of DO.

Animals↗

PubMed2003

Estrogen receptor subtypes and afferent signaling in the bladder.

PURPOSE: The influence of estrogen on bladder function has been the subject of several experimental and clinical studies. In addition to the well-known estrogen receptor (ER)alpha, recently the ER subtype ERbeta was discovered. We investigated potential changes in bladder function in mice lacking either 1 or both receptor subtypes compared with WT mice. MATERIALS AND METHODS: Female mice lacking genes for ERalpha (ERKO), ERbeta (BERKO) or both and their WT littermates were used for the study. Continuous cystometry in awake animals was performed before and after intravesical administration of capsaicin. In addition, in vitro responses to electrical field stimulation before and after incubation with scopolamine and alpha,beta-methylene adenosine triphosphate, and to carbachol were investigated. RESULTS: Control cystometry revealed no significant difference in urodynamic parameters among all strains. After capsaicin instillation the micturition interval and volume decreased, and micturition pressure increased in WT, ERbeta and 2 gene mice, while no changes were seen in ERKO mice. In vitro contractility was similar in all groups. Incubation with scopolamine and alpha,beta-methylene adenosine triphosphate led to significant decreases in the response to electrical field stimulation. There was no difference in the response to carbachol among the groups. CONCLUSIONS: The lack of ERalpha and/or ERbeta had little effect on in vitro contractility or on continuous cystometry in awake animals. The lack of response to capsaicin instillation in ERKO suggests that ER subtypes are important for vanilloid receptor function and mechano-afferent signaling.

Animals↗

PubMed2002

alpha-Melanocyte stimulating hormone and oxytocin induced penile erections, and intracavernous pressure increases in the rat.

PURPOSE: alpha-Melanocyte stimulating hormone (alpha-MSH; Fluka Chemie AG, Geneva, Switzerland) and oxytocin induce erection in rats after intracerebroventricular administration. We studied possible interactions of alpha-melanocyte stimulating hormone with mechanisms pertaining to oxytocin or nitric oxide. MATERIALS AND METHODS: We used 78 anesthetized male Sprague-Dawley rats. Catheters were implanted in the lateral cerebral ventricle or into the subarachnoid space at L6 to S1. Intracavernous pressure was documented and arterial blood pressure was directly measured. RESULTS: Intracerebroventricular alpha-MSH (3 microg.) produced a mean of 2.6 +/- 0.6 erectile responses (p <0.05) with a mean duration of 3.4 +/- 1.1 minutes (p <0.05). Mean peak intracavernous pressure was 114 +/- 8 cm. water. An intracerebroventricular dose of 100 microg. N-nitro-L-arginine-methyl ester HCl (Sigma Chemical Co., St. Louis, Missouri) given in intracerebroventricular fashion abolished alpha-MSH induced erectile responses, whereas intracerebroventricular administration of 500 ng. of the oxytocin receptor antagonist l-deamino, 2-D-Tyr(Oet), 4-Thr, 8-Orn-OT (Ferring AB, Malmö, Sweden) had no effect. Intracerebroventricular oxytocin (30 ng.) induced a mean of 3.2 +/- 0.9 erectile responses (p <0.05) with a mean peak intracavernous pressure of 81 +/- 8 cm. water and a mean duration of 3.3 +/- 1.1 minutes. Intrathecal alpha-MSH (3 microg.) did not produce any erectile responses, whereas a mean of 5.7 +/- 0.9 responses (p <0.001) with a mean peak intracavernous pressure of 142 +/- 8 cm. water and mean duration of 5.0 +/- 1.3 minutes was obtained with 30 ng. oxytocin intrathecally. Responses induced by intrathecal oxytocin were abolished by 100 microg. N-nitro-L-arginine-methyl ester HCl intrathecally. CONCLUSIONS: We confirmed by monitoring intracavernous pressure and blood pressure that supraspinal erectile responses induced by alpha-melanocyte stimulating hormone involve effects mediated by nitric oxide but are independent of oxytocinergic mechanisms. At the spinal level oxytocin produces erectile responses involving nitric oxide. alpha-Melanocyte stimulating hormone does not seem to have a spinal site of action.

Animals↗

PubMed2002

Pharmacologic perspective on the physiology of the lower urinary tract.

Myogenic activity, distention of the detrusor, and signals from the urothelium may initiate voiding. In the bladder, afferent nerves have been identified not only in the detrusor, but also suburothelially, where they form a plexus that lies immediately beneath the epithelial lining. Extracellular adenosine triphosphate (ATP) has been found to mediate excitation of small-diameter sensory neurons via P2X3 receptors, and it has been shown that bladder distention causes release of ATP from the urothelium. In turn, ATP can activate P2X3 receptors on suburothelial afferent nerve terminals to evoke a neural discharge. However, most probably, not only ATP but also a cascade of inhibitory and stimulatory transmitters and mediators are involved in the transduction mechanisms underlying the activation of afferent fibers during bladder filling. These mechanisms may be targets for future drugs. The central nervous control of micturition involves many transmitter systems, which may be suitable targets for pharmacologic intervention. gamma-Aminobutyric acid, dopamine, enkephalin, serotonin, and noradrenaline receptors and mechanisms are known to influence micturition, and potentially, drugs that affect these systems could be developed for clinical use. However, a selective action on the lower urinary tract may be difficult to obtain. Most drugs currently used for treatment of detrusor overactivity have a peripheral site of action, mainly the efferent (cholinergic) neurotransmission and/or the detrusor muscle itself. In the normal bladder, muscarinic receptor stimulation produces the main part of detrusor contraction, but evidence is accumulating that in disease states, such as neurogenic bladders, outflow obstruction, idiopathic detrusor instability, and interstitial cystitis, as well as in the aging bladder, a noncholinergic activation via purinergic receptors may occur. If this component of activation is responsible not only for part of the bladder contractions, but also for the symptoms of the overactive bladder, it should be considered an important target for therapeutic interventions.

Animals↗

PubMed2002

Enhancement of apomorphine-induced penile erection in the rat by a selective alpha(1D)-adrenoceptor antagonist.

1. Effects of A-322312 (alpha(1B)-adrenoceptor (AR) antagonist), A-119637 (alpha(1D)-AR antagonist), prazosin (non-selective alpha(1)-AR antagonist), and yohimbine (alpha(2)-AR antagonist) were studied in rat corpus cavernosum (CC) and cavernous artery (Acc) preparations. Effects of intracavernous (i.c.) or intraperitoneal (i.p.) administration of alpha(1)-AR antagonists on apomorphine-induced erections were investigated. 2. A-119637 attenuated electrically induced contractions in isolated CC (-logIC(50); 8.12+/-0.15), and relaxed noradrenaline (NA)-contracted preparations by more than 90% at 10(-7) M. At the same concentration, the -logEC(50) value for NA in Acc was altered from 6.79+/-0.07 to 4.86+/-0.13. In the CC and Acc, prazosin similarly inhibited contractile responses. 3. Inhibitory effects of A-322312 (10(-7) M) in electrically activated CC were 32.3+/-5.1%, whereas no effect on concentration-response curves for NA was observed in the Acc. Yohimbine (10(-8) M and 10(-7) M), enhanced electrically-induced contractions in isolated CC by 20 to 50%. At 10(-6) M, inhibitory effects of yohimbine were obtained. 4. A-119637 (0.3 micromol kg(-1), i.p.) tripled the number of erections, and produced a 6 fold increase in the duration of apomorphine-induced erectile responses. A-322312, prazosin, or yohimbine did not enhance erections induced by apomorphine. None of the alpha(1)-AR antagonists significantly increased ICP upon i.c. administration. Decreases in blood pressure were seen with A-119637 and prazosin. 5. The present findings show that there is a functional predominance of the alpha(1D)-AR subtype in the rat erectile tissue, and that blockade of this receptor facilitates rat penile erection induced by a suboptimal dose of apomorphine.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2002

Carbon monoxide relaxes the female pig urethra as effectively as nitric oxide in the presence of YC-1.

PURPOSE: Nitric oxide (NO) and carbon monoxide (CO) have been suggested to relax smooth muscle by activating soluble guanylate cyclase (sGC), binding to the same site of the enzyme. 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) (Cayman Co., Malmö, Sweden) increases the catalytic rate of sGC by binding to an allosteric site. We investigated whether YC-1 can modulate the relaxant responses of isolated urethral smooth muscle to exogenous CO, (NO) and electrical field stimulation. MATERIALS AND METHODS: In spontaneously active and noradrenaline (Sigma-Aldrich Chemie GmbH, Steinheim, Germany) pre-contracted preparations of circular urethral smooth muscle from female pigs relaxant responses were evoked by electrical field stimulation before and after incubation with 10(-5) M. YC-1. The concentration-response curves for CO and NO were investigated in noradrenaline pre-contracted strips before and after incubation with YC-1. The tissue contents of cyclic 3',5'-guanosine monophosphate (cGMP) and cyclic adenosine monophosphate after electrical field stimulation, and the administration of CO or NO was investigated in the absence and presence of YC-1. RESULTS: YC-1 significantly increased the amplitude of the relaxations evoked by electrical field stimulation, CO and NO, and simultaneously caused significant increases in the cGMP content in all preparations. The effect on CO induced relaxant responses was conspicuous. In the presence of YC-1 the potency and maximal relaxant effect of CO were similar to those of NO in the absence of YC-1. CONCLUSIONS: YC-1 enhances cGMP dependent relaxant responses of the female pig urethra in vitro. The finding that the response to CO was greatly increased after sensitizing sGC suggests a potential for CO as a relaxant mediator in urethral smooth muscle.

Animals↗