Imaging low-mass planets within the habitable zone of α Centauri.

Giant exoplanets on wide orbits have been directly imaged around young stars. If the thermal background in the mid-infrared can be mitigated, then exoplanets with lower masses can also be imaged. Here we present a ground-based mid-infrared observing approach that enables imaging low-mass temperate exoplanets around nearby stars, and in particular within the closest stellar system, α Centauri. Based on 75-80% of the best quality images from 100 h of cumulative observations, we demonstrate sensitivity to warm sub-Neptune-sized planets throughout much of the habitable zone of α Centauri A. This is an order of magnitude more sensitive than state-of-the-art exoplanet imaging mass detection limits. We also discuss a possible exoplanet or exozodiacal disk detection around α Centauri A. However, an instrumental artifact of unknown origin cannot be ruled out. These results demonstrate the feasibility of imaging rocky habitable-zone exoplanets with current and upcoming telescopes.

Diuretic activity of N'-disubstituted morpholinoguanidine analogs of U-37883A in rats and dogs.

U-37883A is a K+ sparing diuretic which selectively blocks openers of vascular ATP-sensitive K channels. Many N'-disubstituted morpholinoguanidine (N'-DMG) analogs of U-37883A were synthesized and tested for diuretic activity. In conscious rats, 10-100 mg/kg orally of the most active N'-DMGs increased urine volume (V) and Na+ excretion by up to 4-fold with little kaliuresis. The N'-DMGs U-37997A and U-38658A were less potent than standard diuretics, but did not induce the K+ loss seen with hydrochlorothiazide and furosemide or the K+ retention of amiloride and triamterene. In conscious dogs, 10 mg/kg i.v. of the N'-DMGs U-40389A and U-52090 increased V and Na+ excretion by over 7-fold with little kaliuresis. Despite their attractive diuresis, all of the N'-DMGs had narrow margins of safety. Reflecting their direct myocardial depressant action, in isolated rat hearts, bolus intracoronary U-37883A, U-18177A, and U-38658A (0.25-10 mumol) severely reduced the rate (-10 to -100%) and force (-9 to -100%) of contraction. These studies characterize the eukalemic diuretic activity of N'-DMG analogs of U-37883A, and demonstrate the marked cardiac depression characteristic of the morpholinoguanidine diuretic series.

Synthesis and diuretic activity of alkyl- and arylguanidine analogs of N,N'-dicyclohexyl-4-morpholinecarboxamidine in rats and dogs.

Random screening identified N,N'-dicyclohexyl-4-morpholinecarboxamidine (U-18177, 1) as an orally effective nonkaliuretic diuretic in rats. The diuretic profile of 1 and its 1-adamantyl analog (U-37883A, 4) was confirmed orally in dogs, when they were less potent than standard diuretics but showed furosemide-like natriuresis at > or = 100 mumol/kg. However, acute 1 at 61 and 90 mumol/kg iv resulted in lethal cardiac toxicity in dogs. Many analogs of 1 exhibited qualitatively similar diuretic profiles, but none was sufficiently safe to warrant development. Compound 1 also reversed minoxidil's vasodilation in dogs, which led to vascular interaction studies suggesting that analog 4 may block ATP-sensitive K channels. This K channel-blocking mechanism may contribute to the diuretic activity of the series. This is the first report broadly characterizing the diuretic activity of 1 and representative guanidine analogs in rats and dogs and its toxicity and minoxidil-blocking effects in dogs.

Executives share management tips.

Members of the American College of Physician Executives were asked earlier this year to share their experiences in solving particularly nettlesome management problems. The goal was to construct a problem-solving tool for the widest possible array of problems in the full range of health care environments. This article is a distillation of the responses that were received, including contacts for further information on the problems and their solutions.

Pathogenesis of cardiovascular alterations in dogs treated with minoxidil.

Minoxidil and other potent vasodilators cause coronary arterial injury, right atrial hemorrhagic lesions, and subendocardial necrosis in dogs. This paper discusses the pathogenesis of coronary arterial and right atrial lesions associated with minoxidil in the dog. Acute coronary vascular injury characterized by segmental medial hemorrhage and necrosis and perivascular inflammation occurred only during the first few days of treatment, after which tolerance to further acute injury developed. At 30 d or more of treatment, coronary vascular injury was characterized by perivascular fibrosis rarely attended by medial distortion or hyperplasia and subintimal thickening, changes consistent with responses to previous injury. Right atrial hemorrhagic lesions, unlike coronary vascular injury, often became progressively more extensive with continued treatment. At 3 d, atrial hemorrhage and inflammation were confined to the subepicardium of the right atrium, evidently around affected subepicardial branches of the right coronary artery. At 30 d, fibrovascular proliferative right atrial lesions (granulation tissue with evidence of continual hemorrhage) extended from the epicardium to the myocardium, with eventual replacement of the atrial wall by mature connective tissue at 1 yr of treatment. Minoxidil-induced cardiovascular lesions were not prevented by treatment with a beta-blocker (propranolol), or an alpha-blocker (dibenzylene), or by sympathetic neural activity suppression (surgical sympathectomy or constant carotid sinus nerve stimulation), suggesting that the sympathetic response to the pharmacologic activity of minoxidil was not responsible for the induction of the cardiovascular lesions. Minoxidil-related vascular lesions were confined to the most pharmacologically responsive segment of the arterial system, the coronary arteries, suggesting that medial injury may have been associated with tensile changes in the arterial wall.

The effects of indomethacin on the systemic and regional vasodilator responses to minoxidil in the conscious dog.

To define the role of endogenous prostaglandin (PG) synthesis in the vasodilator response to minoxidil (MNX), whole body and regional hemodynamics were measured in conscious, MNX-pretreated dogs before and after the administration of the cyclooxygenase inhibitor indomethacin (INDO). Twenty minutes after an i.v. dose of 2.0 mg/kg, INDO did not affect the reductions in mean arterial pressure and total peripheral resistance achieved with 1.0 mg/kg of MNX i.v. INDO appeared to selectively reverse MNX's vasodilation in the skin and stomach, as vascular resistance in these two tissues increased to pre-MNX levels. Since INDO also exerts a selective vasoconstriction in the skin and stomach of conscious, nonpretreated dogs (Humphrey and Zins, 1983), the fact that skin and stomach resistances were near baseline with this drug combination implies that MNX continues to exert a net vasodilation in these vascular beds. In contrast to INDO's negligible hemodynamic interactions, MNX's vasodilation was nearly completely reversed by continuous i.v. infusions of the direct vasoconstrictor arginine vasopressin (ADH) administered at a mean dose of 35 mU/kg/min. MNX's reversal by ADH was not matched by maximally effective i.v. infusions of the alpha-adrenergic agonist norepinephrine at a mean dose of 0.4 micrograms/kg/min. These results indicate that the sustained peripheral vasodilation seen with MNX in the conscious dog is not dependent upon the synthesis of endogenous, PG-like dilator substances, as defined by concomitant INDO administration.

Whole body and regional hemodynamic effects of minoxidil in the conscious dog.

Microsphere estimates of whole body hemodynamics and tissue blood flow were made in conscious and pentobarbital-anesthetized dogs treated orally with the peripheral vasodilator minoxidil. Under both circumstances, 1.0-30 mg/kg minoxidil significantly reduced mean arterial pressure 21-41% and total peripheral resistance 52-75% 4 h after administration. Dose-dependent increases in heart rate and cardiac output were evident under conscious conditions, with both parameters approximately doubling at 1.0 mg/kg. The near maximal vasodilation achieved with this dose of minoxidil was due to diminished vascular resistance in all major tissue beds. The enhanced cardiac output was associated with significant 50-87% increases in blood flow to the skin, skeletal muscle, bone, stomach, large intestine, and pancreas. Far more dramatic six- to 10-fold increases in regional myocardial blood flow were seen at this dose, which appeared to be only partially dependent on increased cardiac work. Comparable blood flow patterns were seen with acute minoxidil at doses greater than 1.0 mg/kg, and with chronic minoxidil at 1.0 and 30 mg/kg/day. These experiments establish minoxidil's relative vasodilation in the major tissue beds of the dog which contributes to its hypotensive activity.

The effects of indomethacin on systemic hemodynamics and blood flow in the conscious dog.

Systemic hemodynamics and blood flow were measured in conscious beagle dogs treated with the nonsteroidal antiinflammatory agent indomethacin. Twenty minutes after 2 mg/kg of indomethacin i.v., mean arterial blood pressure increased 5%, but cardiac output fell 24%, due to a decline in heart rate (-10%) and stroke volume (-18%). Small nonsignificant reductions in total bone, coronary, spleen, renal, and brain blood flow paralleled this fall in cardiac output. Larger, statistically significant reductions in arterial perfusion were seen in the skin (-30%), stomach (-47%), and small intestine (-27%). The corresponding 83, 101, and 38% increases in vascular resistance in these tissue beds largely accounted for the 41% increase in total peripheral resistance with indomethacin. Vascular resistance increased slightly in the vehicle control group due to reduced skeletal muscle blood flow seen in both treatment groups. Ovarian and thyroid blood flow also decreased with indomethacin. Indomethacin thus exerts a relatively specific vasoconstriction in the skin and upper gastrointestinal tract of the conscious dog.

Renal prostaglandins.

Relative renal ischemia, produced by a variety of interventions, is modulated or buffered by prostaglandins synthesized within the kidney. These prostaglandins, however, do not account for renal autoregulation in its classic sense. They can facilitate salt and water excretion, largely through effects on physical forces in proximal peritubular capillaries, as evidenced by augmented renal blood flow. Renal prostaglandins may play a role in chronic water balance, but they probably are not important in chronic electrolyte homeostasis. There are several potential mechanisms by which renal prostaglandins could exert antihypertensive efects. Establishment of the importance of these agents, however, as antihypertensive hormones remains a challenge for future investigation.