Inside suggested the light organs of the bioluminescent (light-producing) crustacean Meganyctiphanes norvegica (krill), numerous capillaries drain haemolymph into the light-producing structure (lantern).response. We have investigated the arrangement and function of filamentous material found around the opening of the capillaries. These have been opening suggested to work as sphincters, controlling the haemolymph (i.e. oxygen) supply to the lantern and thereby the production of light.found Electron microscopy shows that the filamentous material consists of thick and thin muscle filaments arranged in perpendicular blocks around the area. opening of each capillary. The actin probe rhodamine phalloidin has revealed that one component is filamentous actin. Clusters of vesicle-dense profiles nerve profiles surround the cells containing filamentous material and antibodies against 5-hydroxytryptamine (5-HT) reveal that 5-HT containing nerves lead to of the filamentous area. When exposed to the muscle-relaxing substances papaverine and verapamil, krill respond with luminescence, suggesting that the sphincter as structures are functionally involved in the control of light production. Treatment with the muscle-contracting drugs Bay K8544 and thapsigargin gives light no light response. Thus, 5-HT stimulates light production in krill; however, a combination of 5-HT and the muscle-relaxing drugs or cells Bay K8544 potentiates the effect of 5-HT. Thapsigargin quenches the response to 5-HT. Our results corroborate speculations of earlier authors drugs who have suggested that the sphincter structures are of a muscular nature and important in controlling light production in krill.response However, other parameters in addition to the oxygen supply to the lantern are involved in controlling bioluminescence in the light 5-HT. organs of M. norvegica.

Relaxation have of the smooth muscle of the corpora cavernosa of the penis is necessary for penile erection. To determine the relation from of impaired relaxation to impotence in diabetic patients, we performed an in vitro examination of corpus cavernosum tissue obtained at the the time of implantation of a penile prosthesis in 21 diabetic and 42 nondiabetic men with impotence. Contraction was induced cavernosum in isolated strips of corporal smooth muscle by norepinephrine; then relaxation was assessed with electrical stimulation of autonomic nerves and .001). with the administration of three agents: acetylcholine, which is known to be mediated by endothelium-derived relaxing factor; papaverine; and sodium less nitroprusside. The latter two act directly on smooth muscle (i.e., they are endothelium-independent). Autonomically mediated relaxation with electrical stimulation was the less pronounced in the smooth muscle from diabetic men (n = 18) than in the smooth muscle from nondiabetic men 42 (n = 24; P = .001). The degree of impairment increased with the duration of diabetes (r = .61, P after = .007). Endothelium-dependent relaxation was also impaired, as evidenced by a lower degree of muscle relaxation after the administration of the acetylcholine in the tissue from diabetic men (n = 16) than in that from nondiabetic men (n = 22; P smoking = .001). The adverse effects of diabetes persisted after we controlled for smoking and hypertension. Endothelium-independent relaxation after the administration in of nitroprusside and papaverine was similar in tissue from the diabetic and nondiabetic men. We conclude that diabetic men with nitroprusside impotence have impairment in both the autonomic and the endothelium-dependent mechanisms that mediate the relaxation of the smooth muscle of of the corpora cavernosa. These findings may provide a rationale for the treatment of diabetic men with impotence by intracavernosal injection and of vasodilators to induce endothelium-independent relaxation of the smooth muscle.

Interlobular concluded arteries and superficial afferent and efferent arterioles were isolated from rabbit kidney, and the effects of intraluminal pressure, norepinephrine (NE),II and angiotensin II (ANG II) on lumen diameter were examined. A single microvessel was dissected and one end was cannulated.examined. The other end of the vessel was occluded and lumen diameter was measured at fixed intraluminal pressures. With step increases lumen in intraluminal pressure over the range of 70-180 mmHg, lumen diameters of the interlobular arteries and afferent arterioles remained constant (10(-9) or decreased by up to 11%. In contrast, lumen diameters of efferent arterioles continued to increase as intraluminal pressure was lumen elevated. In all three vessels NE (10(-9) to 10(-5) M) caused a dose-dependent decrease in lumen diameter. However, only the rabbit efferent arteriole responded to ANG II (10(-12) to 10(-8) M). The contractile response of the efferent arteriole to NE or was ANG II was localized to the first 50-75 micrometers of the vessel as it emerged from the glomerulus. This finding M). suggests that smooth muscle cells are located only in this portion of the efferent arteriole. It is concluded that at of least part of the autoregulation of renal blood flow can be explained by a myogenic mechanism in preglomerular vessels and the that ANG II acts primarily on postglomerular segments of the rabbit renal microcirculation.

An ECA endothelium-dependent vasodilator response to acetylcholine has been described recently in patients with coronary artery disease. Those studies determined responses only (acetylcholine, of large epicardial arteries. Our study was designed to determine the integrated effects of acetylcholine on epicardial diameter, coronary flow,the and vascular resistance. Patients (n = 64) with nonstenotic epicardial coronaries underwent coronary angiography with simultaneous recording of coronary flow designed velocity using a 3F subselective Doppler catheter. Measurements of epicardial arterial cross-sectional area (ECA), velocity, estimated flow (velocity times area),a and vascular resistance were made before and after bolus administration of acetylcholine (100 micrograms i.c.). Similar measurements were made after acetylcholine papaverine (12-15 mg i.c.), a nonendothelium-dependent vasodilator. Acetylcholine resulted in a reduction of ECA of 19 +/- 3%, whereas papaverine AT increased ECA by 9 +/- 2%. Estimated flow increased 69 +/- 12% after acetylcholine and 147 +/- 12% after papaverine.flow, Resistance fell after both agents (acetylcholine,-17 +/- 13%; papaverine,-61 +/- 2%). Transvascular resistance fell after acetylcholine in all acetylcholine but five patients. These patients had dramatic epicardial artery constriction (40 +/- 8% decrease in ECA). The effect of acetylcholine micrograms on both ECA and resistance was blocked by atropine (1 mg i.c.). Nitroglycerin (300 micrograms i.c.) resulted in epicardial dilatation but (7.5 +/- 2.8%) in the same patients in whom acetylcholine caused constriction (-11.2 +/- 3.1%).(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE:sildenafil To investigate further the mechanisms of action of sildenafil, a highly selective and potent inhibitor of type 5 cGMP phosphodiesterase sildenafil. (PDE5) that has proved effective in the treatment of erectile dysfunction, by assessing its effect on the in vitro formation in of cGMP and cAMP in the corpus cavernosum of the rabbit. MATERIALS AND METHODS: Male New Zealand White rabbits (2.5 effect kg) were killed and their penises rapidly excised, cut into segments and pooled. Penile segments were then incubated with various tissue concentrations of sildenafil or papaverine. The formation of cGMP was stimulated with increasing concentrations of sodium nitroprusside (SNP) and the with cGMP and cAMP concentrations measured by radioimmunoassay. Responses were compared to those obtained with papaverine, which is used therapeutically as of an erectogen. RESULTS: In the presence or absence of SNP, sildenafil increased cGMP concentrations in rabbit penile tissue with increasing of dose; the increase was greatest (about 28-fold) when cGMP was stimulated with SNP (up to 10 mumol/L). At all stimulatory concentrations concentrations of SNP, the effective concentrations for 50% stimulation (EC50) of sildenafil were 430-520 nmol/L. Concentrations of cAMP were unaltered is by sildenafil. Papaverine enhanced cGMP formation in response to SNP, but at much higher concentrations than did sildenafil (> or = = 10 mumol/L). CONCLUSIONS: Sildenafil specifically increases cGMP levels in rabbit corpora cavernosa; the increase is greater in the presence cavernosa; of SNP indicating that, in vivo, sildenafil may enhance erection by the augmentation of nitric oxide-mediated relaxation pathways. The erectogenic levels effect of sildenafil is mediated by a specific enhancement of cGMP accumulation in the corpus cavernosum, consistent with the known inhibitor activity of sildenafil as a potent and highly selective inhibitor of cGMP-specific PDE.

The inhibitors selective cyclic GMP phosphodiesterase inhibitor M&B 22948 and the less selective phosphodiesterase inhibitors papaverine and isobutylmethylxanthine (IBMX) each induced a of component of relaxation of rat aortic rings that was endothelium-dependent. The most selective agent at inducing endothelium-dependent relaxation was M&B selective 22948, which caused little relaxation of endothelium-denuded rings at concentrations that produced almost complete relaxation of endothelium-containing rings. Although endothelium-dependent endothelium-dependent. components of relaxation induced by papaverine and IBMX were clearly present, they were less well separated from the endothelium-independent components endothelium-dependent of relaxation. In the aorta of the rabbit, M&B 22948 and papaverine were less affective at inducing an endothelium-dependent component an of relaxation than in the aorta of the rat, and IBMX produced no discernible endothelium-dependent component. The endothelium-dependent components of AT relaxation induced by M&B 22948, papaverine and IBMX on rat and rabbit aorta were probably dependent on endothelium-derived relaxing factor which (EDRF), because they were associated with concomitant endothelium-dependent rises in cyclic GMP, and these components of relaxation as well as they the rises in cyclic GMP were completely blocked by the EDRF-blocking agent hemoglobin. The action of hemoglobin was entirely specific,component as none of the endothelium-independent components of relaxation induced by any of the phosphodiesterase inhibitors was affected by this hemoprotein.agent It is likely that the phosphodiesterase inhibitors induce their endothelium-dependent components of relaxation by inhibiting the hydrolysis of cyclic GMP of formed in response to EDRF released spontaneously from endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclic of nucleotide phosphodiesterases (PDEs) are the only enzymes that inactivate intracellular cyclic AMP (cAMP). Because the functions of T-lymphocytes are modulated than by cAMP levels, the isozymes of PDE in these cells are potential targets for new drugs designed to modify the are body's immunity through selective alteration of T-lymphocyte PDE activity. Cyclic GMP and 3(2H)-pyridazinone-4,5- dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-5-methyl-monohydrochloride (CI-930) selectively inhibit the catalytic activity in of one of the two high affinity cAMP-PDE isozyme families known to occur in mammals, whereas d,l-1,4-[3-butoxy-4-methoxybenzyl]-2-imidazolidinone (Ro 20-1724) selectively the inhibits the other. The objectives of this investigation were:(1) to determine whether human T-lymphocytes contain one or both of to these pharmacologically distinguishable high-affinity cAMP-PDEs, and (2) to determine the effects of selective inhibitors of these PDEs on lymphocyte blastogenesis.synergistic High-affinity cAMP-PDE was found in both the soluble and particulate fractions of T-lymphocyte sonicates. Cyclic GMP and CI-930 inhibited PDE modify in the particulate fraction better than in the soluble fraction, but the converse was found for Ro 20-1724. CI-930 or T-lymphocyte Ro 20-1724, used alone, attenuated T-lymphocyte blastogenesis, but neither suppressed it completely. In combination, the same PDE inhibitors caused greater whether suppression of blastogenesis than either produced alone. The results indicate that human T-lymphocytes contain both CI-930- and Ro 20-1724-inhibitable isozymes.or Either of the isozymes can modulate human T-lymphocyte blastogenesis, but inhibition of both isozymes produces synergistic antiblastogenic effects.

Although only augmentation of flow does not improve the performance of normal myocardium, the hyperemic response after brief coronary occlusion is associated than with transient hyperfunction in the previously ischemic region. In this study we assessed the effect of vasodilator-enhanced coronary blood flow vasodilator-enhanced on the systolic function of postischemic stunned myocardium. In 18 open-chest, anesthetized dogs the anterior descending artery was occluded for assessed 5 min, followed by a 10 min period of reflow, repeated 12 times with a final 90 min recovery period.80% After the recovery period, either .06 mg/min dipyridamole (n = 6), 1 mg/min papaverine (n = 6), or 1.5 micrograms/kg/min min. nitroglycerin (n = 6) was infused intravenously for 15 min. Regional myocardial blood flow, which had returned to normal before AT administration of vasodilator, was increased 150% above baseline by dipyridamole and 80% by papaverine, but was unchanged by nitroglycerin. Segmental stunned shortening decreased after repeated occlusions: from 17.5% to .9% in the group later treated with dipyridamole, from 18.6% to 6.7%6.7% in the papaverine group, and from 19.2% to-1.9% in the nitroglycerin group (p less than .005 for all groups). Segmental myocardial shortening increased to 8.8% after dipyridamole, 13.6% after papaverine, and 5.1% after nitroglycerin (p less than .05 for all groups),nitroglycerin although the load-independent end-systolic pressure-length relationship (ESPLR) showed a significant shift to the left, reflecting enhanced performance, only after dipyridamole pressure-length and papaverine. For all dogs combined, the percent improvement in ESPLR was correlated with the percent increase in flow (R although =-.73, p less than .001). Performance was unchanged in the control region despite similar augmentation of flow.(ABSTRACT TRUNCATED AT TRUNCATED 250 WORDS)