F. Holmquist

Characterization of inhibitory neurotransmission in the isolated corpus cavernosum from rabbit and man.

1. NG‐nitro‐L‐arginine (L‐NOARG, 10(‐4) M), an inhibitor of nitric oxide (NO) synthesis, had no contractile effect on isolated preparations of rabbit and human corpus cavernosum at baseline tension, but increased tension in preparations contracted by noradrenaline (rabbit 10(‐5) M, man 3 x 10(‐7)‐3 x 10(‐6) M) or K+ (rabbit 60 mM). 2. Electrical field stimulation (supramaximal voltage, 0.8 ms pulses, 5 s train duration, 0.5‐35 Hz) of rabbit and human corpus cavernosum preparations contracted by noradrenaline (rabbit 10(‐5) M, man 3 x 10(‐6) M) or endothelin‐1 (rabbit 10(‐8) M) produced relaxations that were sensitive to tetrodotoxin (10(‐6) M), and dependent on the frequency and number of pulses delivered. L‐NOARG (10(‐6)‐10(‐4) M), but not NG‐nitro‐D‐arginine (D‐NOARG, 10(‐6)‐10(‐4) M), inhibited electrically induced relaxations in a concentration‐dependent manner, and at 10(‐4) M the relaxations were virtually abolished. L‐Arginine (10(‐3) M), but not D‐arginine (10(‐3) M), partly reversed the inhibitory effect of L‐NOARG (10(‐4) M). In rabbit corpus cavernosum preparations, as with Methylene Blue (3 x 10(‐5) M), an inhibitor of the soluble guanylate cyclase, and haemoglobin (10(‐5) M), sequestering NO in the extracellular space, significantly reduced electrically evoked relaxations. Scopolamine (10(‐6) M) had little or no effect on relaxations induced by electrical field stimulation. 3. Preparations of rabbit and human corpus cavernosum contracted by noradrenaline (rabbit 10(‐5) M, man 3 x 10(‐6) M) were relaxed by carbachol (10(‐9)‐10(‐4) M) in a concentration‐dependent manner. Scopolamine (10(‐6) M) and L‐NOARG (10(‐4) M) abolished, and Methylene Blue (3 x 10(‐5) M) and haemoglobin (10(‐5) M) greatly reduced, the carbachol‐induced relaxation, while D‐NOARG (10(‐4) M) had no significant effect. 4. In rabbit corpus cavernosum preparations contracted by noradrenaline (10(‐5) M), L‐NOARG (10(‐4) M) had no significant effect on relaxations induced by vasoactive intestinal polypeptide (10(‐6) M). 5. SIN‐1 (3‐morpholino‐sydnonimin hydrochloride, 10(‐8)‐3 x 10(‐4) M), which spontaneously liberates NO, relaxed preparations of rabbit and human corpus cavernosum contracted by noradrenaline (rabbit 10(‐5) M, man 3 x 10(‐6) M) or endothelin‐1 (rabbit 10(‐8) M, man 3 x 10(‐9) M) in a concentration‐dependent way.(ABSTRACT TRUNCATED AT 400 WORDS)

Preliminary Results with the Nitric Oxide Donor Linsidomine Chlorhydrate in the Treatment of Human Erectile Dysfunction

Recent experimental studies showed an important role of endothelium derived relaxing factor for cavernous smooth muscle relaxation. Since nitric oxide seems to account for the biological actions of endothelium derived relaxing factor, a study was done to examine a possible role of the nitric oxide donor linsidomine chlorhydrate (SIN-1) in the treatment of erectile dysfunction. To determine a therapeutically useful dose 0.1, 0.2, 0.5 and 1 mg. SIN-1 were injected intracavernously in patients with erectile dysfunction. Each dose was given to 2 patients. Then, 63 patients received 1 mg. SIN-1, including 7 who had prolonged erections to minimal doses of papaverine plus phentolamine and 4 who did not respond with a full erection to other pharmacological agents. Intracavernous injection of SIN-1 induced a dose-dependent erectile response by increasing the arterial inflow and relaxing cavernous smooth muscles. Of the patients 29 had a full, 21 an almost full and 13 a moderate erection to 1 mg. SIN-1. There were no systemic or local side effects. In the patients with prolonged erections to papaverine plus phentolamine the mean duration of a full erectile response to SIN-1 was 57 minutes. Compared to the responses to a papaverine (15 mg./ml.) and phentolamine (0.5 mg./ml.) mixture, the erection induced by SIN-1 was superior in 10, comparable in 47 and inferior in 6 patients. Our data suggest a possible role for SIN-1 in the treatment of erectile dysfunction. Possible advantages may be that erection is induced by a mechanism similar to that occurring physiologically, a decreased risk of inducing prolonged erections and low therapy costs.

Eighty-peak kilovoltage 16-channel multidetector computed tomography and reduced contrast-medium doses tailored to body weight to diagnose pulmonary embolism in azotaemic patients

The aim of this study was to assess the feasibility of minimising contrast-medium (CM) doses using 80-peak kilovoltage (kVp) 16-channel multidetector computed tomography (MDCT) with CM dose tailored to body weight, when diagnosing pulmonary embolism (PE) in azotaemic patients. Twenty-nine patients (68–93 years; 38–79xa0kg) with an estimated glomerular filtration rate of 12–49xa0ml/min underwent 80xa0kVp MDCT at a median dose of 200xa0mg iodine (I)/kg and 15xa0s injection time. Pulmonary artery (PA) enhancement where compared with our own reference material using 320xa0mg I/kg at 120xa0kVp and with reported figures in the literature at 120–140xa0kVp and a 42xa0g iodine CM dose. Median (1st and 3rd quartiles) values regarding CM dose were 12.2 (9.9–12.8)xa0g iodine; density of left main and lower lobe segmental PA 339 (275–395)xa0Hounsfield units (HU) and 354 (321–442)xa0HU, respectively. Those enhancement values were similar to those obtained from the reference population at 120xa0kVp and those reported in the literature at 120–140xa0kVp. One patient had a transient increase in plasma creatinine. Three months’ follow-up revealed deep venous thrombosis among 1/18 patients with negative results from computed tomography (CT). We conclude that 80 kVp 16-channel MDCT to diagnose PE in azotaemic patients may be performed with markedly reduced CM doses, implying a lesser risk for CM-induced nephropathy.

Muscarinic Receptor Stimulation of Phosphoinositide Hydrolysis in the Human Isolated Urinary Bladder

The stimulatory action of carbachol and acetylcholine (ACh) on phosphoinositide turnover, as well as their contractile effects, were investigated in human isolated detrusor muscle. Carbachol, and ACh in combination with 10(-7) M physostigmine, induced increases in phosphoinositide turnover. However, at all the concentrations tested, carbachol was more effective than ACh (plus physostigmine), and at the highest concentration used (10(-4) M), the difference was significant (p less than 0.05). Also in a Ca(2+)-free medium containing the chelator EGTA (10(-4) M), both agonists (10(-4) M) induced small but distinct increases in phosphoinositide breakdown. Carbachol and ACh contracted the detrusor preparations concentration-dependently, and the responses were almost identical when ACh was combined with 10(-7) M physostigmine. In Ca(2+)-free medium the agonists elicited a moderate but concentration-dependent contractile response at high concentrations. The results show that muscarinic receptor agonists stimulate phosphoinositide turnover in the human bladder. Possibly, this effect is coupled to multiple muscarinic receptor subtypes. More studies are required to elucidate to what extent phosphoinositide breakdown participates in the contractile activation of this tissue.

Minimizing Contrast Medium Doses to Diagnose Pulmonary Embolism with 80-kVp Multidetector Computed Tomography in Azotemic Patients.

Background: In diagnosing acute pulmonary embolism (PE) in azotemic patients, scintigraphy and magnetic resonance imaging are frequently inconclusive or not available in many hospitals. Computed tomography is readily available, but relatively high doses (30–50 g I) of potentially nephrotoxic iodine contrast media (CM) are used. Purpose: To report on the diagnostic quality and possible contrast-induced nephropathy (CIN) after substantially reduced CM doses to diagnose PE in azotemic patients using 80-peak kilovoltage (kVp) 16-row multidetector computed tomography (MDCT) combined with CM doses tailored to body weight, fixed injection duration adapted to scan time, automatic bolus tracking, and saline chaser. Material and Methods: Patients with estimated glomerular filtration rate (eGFR) <50 ml/min were scheduled to undergo 80-kVp MDCT using 200 mg I/kg, and those with eGFR ≥50 ml/min, 120-kVp MDCT with 320 mg I/kg. Both protocols used an 80-kg maximum dose weight and a fixed 15-s injection time. Pulmonary artery density and contrast-to-noise ratio were measured assuming 70 Hounsfield units (HU) for a fresh clot. CIN was defined as a plasma creatinine rise >44.2 µmol/l from baseline. Results: 89/148 patients (63/68 females) underwent 80-/120-kVp protocols, respectively, with 95% of the examinations being subjectively excellent or adequate. Mean values in the 80-/120-kVp cohorts regarding age were 82/65 years, body weight 66/78 kg, effective mAs 277/117, CM dose 13/23 g I, pulmonary artery density 359/345 HU, image noise (1 standard deviation) 24/21 HU, contrast-to-noise ratio 13/13, and dose-length product 173/258 mGy·cm. Only 1/65 and 2/119 patients in the 80- and 120-kVp cohorts, respectively, with negative CT and no anticoagulation suffered non-fatal thromboembolism during 3-month follow-up. No patient developed CIN. Conclusion: 80-kVp 16-row MDCT with optimization of injection parameters may be performed with preserved diagnostic quality, using markedly reduced CM doses compared with common routine practice, which should be to the benefit of patients at risk of CIN.

K(+)-channel openers for relaxation of isolated penile erectile tissue from rabbit.

The effects of the K(+)-channel openers (KCOs) cromakalim (BRL 34915) and pinacidil were investigated and compared with those of papaverine on isolated corpus cavernosum from rabbit. Preparations were mounted in organ baths and isometric tension was recorded. Spontaneous contractile activity was effectively abolished by the KCOs tested, cromakalim being the most potent of them. The KCOs concentration-dependently and effectively depressed electrically induced contractions and also contractions induced by exogenously applied noradrenaline and by low (less than or equal to 20 mM) concentrations of K+. Cromakalim was three to four times more potent than pinacidil. Pinacidil and cromakalim were shown to cause increases in the efflux of 86Rb from preloaded cavernous tissue. Papaverine also effectively depressed spontaneous contractile activity, and contractions evoked by electrical stimulation and noradrenaline. It had a potency 19 to 36 times lower than that of cromakalim. However, papaverine did not increase 86Rb efflux from preloaded tissue. The results show that cromakalim and pinacidil effectively relax penile erectile tissue, probably by the opening of K(+)-channels and subsequent hyperpolarization. Further investigations on human material seems motivated in order to elucidate if the principle of K(+)-channel opening offers any therapeutic advantages to other drugs in the diagnosis and treatment of penile erectile dysfunction.

Ultralow contrast medium doses at CT to diagnose pulmonary embolism in patients with moderate to severe renal impairment: a feasibility study

ObjectivesTo analyse 80-kVp 16-MDCT in patients with clinically suspected pulmonary embolism (PE) and diminished renal function after a reduction in dose of contrast medium (CM) from 200 to 150xa0mgxa0I/kg.MethodsFifty patients with suspected PE and glomerular filtration rate (GFR) less than 50xa0mL/min underwent 80-kVp 16-MDCT with 150xa0mgxa0I/kg. Mean density/image noise (1 standard deviation) was measured in a region of interest in the left pulmonary artery (LPA) and a lower lobe segmental artery (LLSA), and the contrast-to-noise ratio (CNR) was calculated. The values of LPA and LLSA were averaged.ResultsMedian values/2.5–97.5 percentiles were: age 84/67–96xa0years, weight 65/43–84xa0kg, GFR 36/21–45xa0mL/min, CM dose 9.6/6.4–12xa0g of iodine, PA density 353/164–495xa0HU and CNR 11/4.4–20. PE incidence was 16%, and 8% and 12% of the examinations were regarded suboptimal by observer 1 and 2, respectively. Density/CNR values were within ranges reported for common 120-kVp MDCT protocols. None of 32 patients with plasma-creatinine follow-up within 1xa0week experienced a rise of more than 44.2xa0μmol/L and none of 50 patients had oliguria/anuria or dialysis. None of 40 patients with a negative CT/no anticoagulation had thromboembolism during follow-up.Conclusion80-kVp MDCT combined with individualised ultralow CM doses may provide satisfactory diagnostic quality, which should be to the benefit of patients at risk of contrast medium-induced nephropathy.

Effects of nicorandil on human isolated corpus cavernosum and cavernous artery

Nitric oxide (NO) released from nonadrenergic-noncholinergic (NANC) nerves seems to be a principal mediator of the relaxation of penile erectile tissue necessary for erection, and drugs acting by release of NO have been shown to produce erection when injected intracorporeally into impotent patients. By producing hyperpolarization, K+ channel openers are effective in relaxing isolated penile erectile tissue from rabbit and man, and can produce tumescence and erection when injected intracorporeally into animals. Nicorandil is classified as a K+ channel opener, but it also acts as a donor of NO. In the present study, the effects of nicorandil on isolated preparations from human corpus cavernosum (CC) and deep cavernous artery (Acc) were compared with those of cromakalim (K+ channel opener) and SIN-1 (NO donor). Nicorandil produced a concentration-dependent relaxation of CC and Acc preparations. The relaxations obtained at the highest nicorandil concentration used (10(-4) M.) were 75 +/- 3% and 66 +/- 4% in CC preparations contracted by noradrenaline and endothelin-1, respectively. The corresponding effects in Acc preparations were 70 +/- 14% and 73 +/- 5%. Glibenclamide (blocking ATP-dependent K+ channels) significantly reduced the nicorandil-induced relaxation in CC, but not in Acc. Methylene blue (believed to block soluble guanylate cyclase) reduced nicorandils relaxant effect in CC, although statistical significance was not obtained. NG-nitro-L-arginine 10(-4) M. (NO synthase inhibitor) did not significantly influence the effect of nicorandil on precontracted preparations in either tissue. In CC preparations contracted by electrical field stimulation, nicorandil and cromakalim concentration dependently inhibited the responses. This effect was significantly counteracted by glibenclamide. It is concluded that nicorandil is effective in relaxing human CC chiefly by its K+ channel opening action, and to some extent by its ability to release NO. For nicorandils relaxing effect on Acc, ATP dependent K+ channels seem to be of limited importance. If effective in impotent patients, the drug may represent a new, interesting approach to the treatment of erectile dysfunction.

Preliminary report on the effect of the nitric oxide donor SIN-1 on human cavernous tissue in vivo

SummaryRecent experimental studies showed an important role of endothelium-derived relaxing factor in penile erection. Therefore, an in vivo study was done to examine the effect of the nitric oxide donor SIN-1 on human erection. Eight patients with erectile dysfunction received doses of 0.1 to 1 mg SIN-1 intracavernously. In all patients, SIN-1 induced a dose-dependent erectile response. Although applied in 2 patients with prolonged erections to minimal doses of a papaverine-phentolamine combination, the duration of the full erection achieved in response to 1 mg SIN-1 was limited to about 60 min. The erectile response was due to an increase in arterial inflow and to cavernous smooth muscle relaxation. There were no systemic or local side-effects. Our preliminary study suggests SIN-1 to be an attractive alternative for autoinjection therapy in the treatment of erectile dysfunction.

Some pre- and postjunctional effects of castration in rabbit isolated corpus cavernosum and urethra

Pre- and postjunctional effects of castration were investigated in isolated corpus cavernosum (CC) and prostatic and preprostatic urethral preparations obtained from rabbits that had been castrated surgically 14 days before investigation. Preparations obtained from untreated animals were used as controls. Castration did not change the relaxing effects of SIN-1 (NO donor) or papaverine in CC preparations contracted by noradrenaline (NA). Electrical field stimulation of CC preparations contracted by NA or endothelin-1 produced frequency-dependent and tetrodotoxin-sensitive relaxations. As compared with controls, the electrically induced relaxations were increased in preparations from castrated animals. Pretreatment with prazosin increased the electrically induced relaxations in CC from untreated rabbits, but had no effect on preparations from castrated animals. In CC preparations incubated with 3H-NA, castration significantly reduced the electrically evoked release of 3H. L-NOARG, an inhibitor of NO synthase, had no effect on 3H-efflux. In prostatic, but not preprostatic, urethral preparations contracted by NA, the relaxant effects of SIN-1 and vasoactive intestinal polypeptide were significantly smaller following castration. Furthermore, castration significantly reduced electrically evoked relaxations in prostatic urethral preparations contracted by NA, while in preprostatic urethra, no such effect was seen. Castration or L-NOARG had no effect on the electrically induced release of 3H-NA in either of the urethral tissues. The results suggest that the hormonal changes caused by castration may modulate the functional effects in vitro of some parts of the urogenital tract. In penile erectile tissue, the relaxations induced by electrical field stimulation are increased, probably for the most part through a decrease in the neuronal release of NA. In prostatic urethra, on the other hand, electrically evoked relaxations are decreased, possibly as a result of an impaired ability of the smooth muscle itself to respond to relaxant agents. In preprostatic urethra, castration has no obvious functional effects. The physiological consequences of these findings in the in vivo situation remain to be established.