Biomedical subjects

H E Garner

Publications and source records attributed to H E Garner.

At least 19 recordsLinked to original sources

PubMed1996

Equine coronary hemodynamics during brief coronary occlusions at three levels of collateral function.

Adult-grade ponies were surgically instrumented with a Doppler flow probe and pneumatic cuff occluder on the left anterior descending coronary artery (LAD), sonomicrometry crystals and intraventricular micromanometer in the left ventricle, and catheters in the left atrium, anterior interventricular vein, and, in some animals, the LAD. Conscious-animal studies were begun 2 wk after surgery. Measured variables included regional left ventricular systolic function, end-diastolic wall thickness, oxygen extraction, lactate extraction, and hydrogen ion release. Changes in collateral perfusion were deduced from changes in these variables. Serial data were obtained during a 3-min LAD occlusion before stimulation of collateral function by the intermittent coronary occlusion method and during a 10-min LAD occlusion after 14 +/- 2 and 27 +/- 2 days of stimulation. Hemodynamic interpretation of data was based on a model of the equine coronary circulation consisting of collateral and arteriolar resistances in series. It was concluded that 1) chronic stimulation of collateral function leads to the emergence of a time-dependent reduction in total collateral resistance during acute coronary occlusion; 2) with enhancement of collateral function, the major resistance controlling collateral blood flow shifts from the collateral circulation to the recipient vessel arterioles; and 3) at a certain level of enhanced collateral function, coronary occlusion results in a triphasic blood flow response in collateral-dependent myocardium consisting of early hypoperfusion, transient hyperperfusion, and late autoregulated perfusion. This study demonstrates that chronic stimulation of collateral function is accompanied by specific alterations in coronary hemodynamics during acute coronary occlusion that hasten the recovery of ischemic myocardium.

Animals↗

PubMed1993

Serum tumor necrosis factor alpha concentrations and clinical abnormalities in colostrum-fed and colostrum-deprived neonatal foals given endotoxin.

We examined the effect of infusion of lipopolysaccharide (LPS) on serum tumor necrosis factor alpha (TNF alpha) concentration and clinical attitude in 2- 3-day-old colostrum-fed (CF) and colostrum-deprived (CD) foals. Eleven CF and 8 CD neonatal foals were given a bolus i.v. infusion of Escherichia coli O55:B5 lipopolysaccharide (0.5 microgram/kg of body weight) in sterile saline (0.9% NaCl) solution. Four CF and 2 CD foals were given saline solution alone. Serum IgG concentration and serum anti-LPS IgG(T) antibody titer were determined for each foal prior to infusion. A depression index was used to score clinical abnormalities. Serum TNF alpha concentration was estimated by use of an in vitro cytotoxicity bioassay that used WEHI 164 clone 13 cells as targets. The cytotoxic serum factor was identified as TNF alpha by immunoprecipitation with caprine antisera raised against the 15 NH2-terminal amino acids of human TNF alpha. Tumor necrosis factor alpha was not detected in any preinfusion serum samples nor in any samples from foals given saline solution alone. Serum TNF alpha concentration increased in all LPS-infused foals and peaked between 60 and 90 minutes after infusion. Serum TNF alpha concentrations, expressed as mean percentage of peak serum TNF alpha concentration, persisted longer in CD foals given LPS than in CF foals given LPS. All LPS-infused foals displayed clinical signs of endotoxemia, but mean depression index scores of the CF and CD foals given LPS were not significantly different at any time. Serum TNF alpha concentrations were correlated with depression index scores in both LPS-infused groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Serum interleukin-6 concentrations in endotoxin-infused neonatal foals.

Serum interleukin-6 (IL-6) concentration was measured in 11 colostrum-fed (CF) and 8 colostrum-deprived (CD) 2- to 3-day-old foals after foals were infused with lipopolysaccharide (LPS; Escherichia coli O55:B5 endotoxin, 0.5 microgram/kg of body weight in sterile saline [0.9% NaCl] solution). Four CF and 2 CD foals were given saline solution alone. Serum IL-6 concentration was estimated by use of an in vitro proliferative bioassay, using the IL-6 dependent B.13.29 clone 9 cells. Interleukin-6 concentration increased in all LPS-infused foals, and geometric mean serum IL-6 concentration was significantly higher in CF than CD foals 30 and 90 minutes after infusion. Both LPS-infused groups had multiple spikes of mean IL-6 concentration that peaked at 120 minutes in CF foals and 150 minutes in CD foals. Results indicated that IL-6 is produced in neonatal foals in response to LPS infusion. Furthermore, colostrum deprivation resulted in longer times to peak mean serum IL-6 concentration and tended to reduce serum IL-6 concentration in neonatal foals.

Animals↗

PubMed1992

Disuse inhibition of newly functional coronary collateral circulation in ponies.

We evaluated the loss of coronary collateral function in the absence of stimulation (disuse inhibition) by doubling the interval between successive left anterior descending coronary artery (LAD) occlusions in ponies in which collateral function initially had been enhanced by 2-min occlusions at 30-min intervals. Before collateralization, occlusion caused segment systolic shortening, velocity of shortening, and stroke work index in the LAD-dependent left ventricular apex to decrease, whereas heart rate and left ventricular end-diastolic pressure increased. After 476 +/- 102 occlusions, segment function recovered to preocclusion levels and hemodynamics were unchanged during occlusion. Occlusion did not elicit sustained functional deterioration until the occlusion interval was greater than or equal to 32 h. During the occlusion after the 128-h interval, segment systolic shortening, velocity of shortening, and stroke work index were reduced 69 +/- 8, 38 +/- 9, and 46 +/- 13%, respectively. Percent recovery of systolic shortening during successive occlusions declined exponentially (T1/e = 102.0 +/- 17.3 h). Thus, in ponies collateral function progressively declines when the occlusion interval is greater than or equal to 32 h, but complete inhibition does not occur even after 128 h without occlusion. This indicates that collateral function in ponies can be maintained by occlusions that are far less frequent than those needed for initial collateral development. The long time constant of collateral disuse inhibition suggests that equine collaterals are quite resistant to the effects of occlusion cessation and differ from canine collaterals in that respect.

Animals↗

PubMed1992

Distribution of coronary collateral blood flow at different levels of collateral growth in conscious ponies.

Coronary collateral growth was stimulated in chronically instrumented conscious ponies by a previously validated intermittent coronary occlusion method. Changes in regional myocardial function (sonomicrometry) and reactive hyperemia (Doppler method) were used to monitor collateral growth and to program measurements of regional myocardial blood flow (microsphere method). A serial analysis of the transmural and lateral distributions of collateral blood flow was performed at the native and three superimposed levels of collateral growth. Results in nine animals undergoing an average of 553 +/- 188 brief coronary occlusions over 68 +/- 18 days demonstrated that as collateral conductance increased, the perfusion field within the ischemic region increased from the epicardium to the endocardium but not from the lateral edges to the center of the ischemic region. The findings are consistent with an analog model consisting of interarterial collaterals whose collective resistance is in series with arteriolar resistance of the recipient artery. No special protection of deeper myocardial layers by a subendocardial plexus or intramural collaterals was noted. Instead, the findings suggest that coronary extravascular compressive forces play a more important role than the transmural location of collaterals in determining the volume and spatial distribution of collateral blood flow during collateral growth in the pony.

Animals↗

PubMed1992

Cardiac cycle length variability in ponies at rest and during exercise.

We evaluated cardiac cycle length variability in ponies at rest and during strenuous exercise with and without premedication with atropine. In the absence of premedication, cardiac cycle length at rest was 1,112 +/- 53 ms, the individual cardiac cycle length standard deviation (SDCL) was 75 +/- 23 ms, and the individual cycle length coefficient of variation (CVCL) was 6.32 +/- 1.62. Exercise significantly decreased (P < 0.05) all three indexes (290 +/- 9 ms, 5 +/- 1 ms, and 1.65 +/- 0.20, respectively). Atropine premedication significantly reduced resting cardiac cycle length (685 +/- 46 ms), SDCL (10 +/- 2 ms), and CVCL (1.45 +/- 0.19) compared with nonpremedicated values. Cardiac cycle length was significantly decreased by exercise after atropine premedication, but no statistically significant changes occurred in SDCL or CVCL. Thus, although considerable cardiac cycle length variability exists in nonpremedicated ponies at rest, it is nearly completely abolished by strenuous exercise. The absence of significant differences between the indexes of variability during exercise without premedication, at rest after atropine, and during exercise after atropine indicates that cardiac cycle length variability in the pony is mediated primarily through activity of the parasympathetic system.

Animals↗

PubMed1992

Mathematical modelling of post-exercise heart rate recovery in ponies.

Using a recently developed nonlinear algorithm which identifies reference points on left ventricular pressure waveforms and other waveforms, we analyzed heart rate recovery in ponies after strenuous treadmill exercise. Each pony performed exercise tests with and without premedication with atropine methyl nitrate. Resting and exercise heart rates were 54 +/- 3 and 209 +/- 6 beats/min, respectively, without premedication and 85 +/- 8 and 212 +/- 5 beats/min, respectively, following atropine premedication. Post-exercise heart rate recovery without premedication was best described by a biexponential curve with a rapid initial period (duration = 55 +/- 6 sec, Tl/e = 15 +/- 2 sec) and a slower secondary period (duration = 267 +/- 5 sec, Tl/e = 455 +/- 78 sec). After atropine premedication, heart rate recovery followed a monoexponential curve (Tl/e = 174 +/- 46 sec) in 4 ponies, but remained biexponential (Part 1 duration = 74 sec, Tl/e = 20 sec; Part 2 duration = 243 sec, Tl/e = 342 sec) in the other ponies. The calculated time required for heart rate to return to resting levels after atropine premedication was 11.3 +/- 2.2 min, compared to 26.3 +/- 3.9 min without premedication. However, without premedication, only 6.6 +/- 1.6 min were required to reach the post-atropine resting heart rate, indicating that the time difference was due to the higher resting heart rate after atropine premedication. Thus, heart rate recovery in the non-premedicated pony follows a biexponential curve similar to that observed in other species.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithms↗

PubMed1991

Myocardial blood flow, metabolism, and function with repeated brief coronary occlusions in conscious ponies.

Studies were performed in the conscious pony instrumented with a Doppler flow probe and hydraulic occluder on the left anterior descending coronary artery (LAD), sonomicrometry crystals and intraventricular micromanometer in the left ventricle, and catheters in the left atrium and anterior interventricular vein. Two-minute LAD occlusions were performed every 30 min continuously or during working hours. Data on release of catabolites (potassium, hydrogen ions, and lactate) and norepinephrine from the initially dysfunctional region were obtained periodically during a regimen of 445 +/- 56 occlusions in six animals. Regional myocardial blood flow was measured (microsphere method) before and after an occlusion regimen in four animals. Marked release of catabolites and norepinephrine from the initially dysfunctional region was noted in association with early occlusions when myocardial segment function was severely reduced. With further occlusions, release of these substances decreased while segment function improved. Blood flow was markedly decreased in the initially dysfunctional region during an early occlusion but was at the control level during a later occlusion. Although the metabolic findings are consistent with protection due to "ischemic preconditioning" and no increase in collateral perfusion, the inverse relationship noted between catabolite release and segment function is best explained by flow-dependent mechanisms. These results, together with the myocardial blood flow data, serve to validate a previous assumption that protection against regional myocardial dysfunction under these conditions is due to increased collateral perfusion.

Animals↗

PubMed1991

Effects of coronary occlusion duration on reactive hyperemia in conscious dogs and ponies.

Coronary reactive hyperemia duration (RHD) and coronary blood flow debt repayment (BFDR) were compared in conscious dogs and ponies instrumented with coronary artery Doppler flow probes and pneumatic occluders. Additional ponies were instrumented with pacing electrodes. With the use of a Latin square design, eight animals of each species were subjected to a randomized series of nine coronary occlusions ranging from 5 s to 2 min in duration. In both species, postocclusion blood flow velocity rose rapidly and plateaued at similar peak levels relative to control, but in ponies this plateau lasted significantly longer. The interspecies difference in plateau duration increased as a function of coronary occlusion duration (COD). RHD ranged from 19.5 +/- 5.9 to 139.7 +/- 5.9 s in dogs and from 26.6 +/- 9.0 to 395.0 +/- 9.0 s in ponies. The slope of the RHD vs. COD curve was steeper in ponies. BFDR was similar in dogs and ponies at the shortest COD (418.1 +/- 26 vs. 451.4 +/- 58%) but declined in dogs as a function of COD to 232.3 +/- 26%. In ponies, BFDR increased as a function of COD to a maximum of 945.4 +/- 58% with a 60-s occlusion and then declined to 614.3 +/- 58%. RHD was not significantly altered in ponies when heart rate was changed to match that in dogs. Although the underlying basis for these interspecies differences in RHD and BFDR was not determined, the differences were considered to be too large to be explained by animal model differences in coronary conductance, collateral blood flow, or myocardial oxygen consumption.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Reduced blood flow to peripheral and core body tissues in sheep and cattle induced by endophyte-infected tall fescue.

Four wethers and 14 steers (environmentally heat stressed, 32 degrees C, 60% relative humidity) were evaluated for changes in blood flow induced by endophyte-infected tall fescue. Concentration of the ergopeptide ergovaline was used as an indicator of diet toxicity due to the endophytic fungus Acremonium coenophialum. Blood flow to specific tissues was measured using radiolabeled microspheres. Wethers received one of two dietary treatments for 30 d before determination of tissue blood flow: 1) a low-endophyte diet (less than .05 ppm ergovaline) or 2) a high-endophyte (1.18 ppm ergovaline) diet. Blood flows to the adrenal glands and skin covering the inner hind leg were less (P less than .10) in wethers consuming the high-endophyte diet than in those consuming the low-endophyte diet. Tissue blood flows in steers were determined on two occasions: 1) after steers had received a low- (less than .01 ppm ergovaline) or high-endophyte (.52 ppm ergovaline) fescue diet for 14 d and 2) 8 d after steers had been switched to a common, fescue-free diet. Blood flows to skin covering the ribs, cerebellum of the brain, duodenum, and colon were less (P less than .10) in steers consuming the high-endophyte diet. However, 8 d after consuming fescue-free diets, steers that had previously consumed the high-endophyte diet had greater (P = .08) blood flow to the coronary bands of the front hooves than steers that had consumed the low-endophyte diet. Blood flows to all other tissues were similar between treatments. We inferred from these experiments that the toxin(s) associated with endophyte-infected tall fescue caused decreased blood flow to peripheral and core body tissues and that this effect was abated within 8 d of removing the toxin(s).

Adrenal Glands↗

PubMed1989

Cardiovascular effects of detomidine, a new alpha 2-adrenoceptor agonist, in the conscious pony.

The cardiovascular effects of detomidine and xylazine were compared in six chronically instrumented, conscious ponies. Ponies were instrumented with a micromanometer in the left ventricular chamber, a Doppler flow probe on a coronary artery and sonomicrometer crystals in the left ventricular free wall. Heart rate, ventricular systolic pressure, stroke work, dP/dtmax, minute work and coronary blood flow were measured for 4 h following intravenous injection of detomidine at several doses or xylazine at 1.1 mg/kg. Both drugs caused a profound hypertensive response at 15 s post-injection. The magnitude of the pressure change did not increase with detomidine doses greater than 20 micrograms/kg. There was a dose-dependent effect on the duration of the hypertension. Bradycardia and A-V blockade of similar magnitude followed the hypertension at all drug doses. Both drugs caused a negative inotropic effect on the heart at all doses. Minute work, a mechanical index of myocardial O2 demand, and coronary flow decreased to a similar extent following all drug treatments. With the exception of a greater hypertensive response, detomidine at the dosages studied, produced cardiovascular effects that were very similar to those of the recommended dosage of xylazine.

Adrenergic alpha-Agonists↗

PubMed1989

Left ventricular function and haemodynamics in ponies during exercise and recovery.

Myocardial and haemodynamic responses to strenuous treadmill exercise were monitored with chronically implanted instrumentation in seven physically untrained ponies. In two other ponies, haemodynamics were monitored using a conventional catheter technique. During exercise (mean +/- sem heart rate = 203 +/- 3 beats/min), left ventricular peak systolic ahd end-diastolic blood pressure significantly increased from 125 +/- 2 to 208 +/- 6 mmHg and from 29 +/- 1 to 58 +/- 3 mmHg, respectively (P less than 0.05). Peak positive first derivative of left ventricular pressure (dP/dt) was also increased significantly, (1397 +/- 144 to 6016 +/- 325 mmHg/sec), as were myocardial segment velocity of shortening during systole (dL/dtsys) and stroke work (193 and 109 per cent, respectively). Paradoxically, segment systolic shortening was reduced significantly (P less than 0.05) with respect to resting control values for 10 mins after cessation of exercise, with the maximal reduction of 22 per cent occurring at 2 mins post exercise. In addition, left ventricular segment stroke work decreased significantly to 67 per cent of resting control value at 2 mins post exercise. This study demonstrates that analysis of regional myocardial performance in conjunction with haemodynamic data permits a detailed description of cardiac events during and immediately following exercise, facilitating definition of changes which are not readily reflected by haemodynamics. Based on these findings, the authors conclude that untrained ponies may readily complete short bouts of near-maximal exercise, yet experience significantly diminished left ventricular function in the immediate post exercise period.

Animals↗

PubMed1989

Effects of polymyxin B on selected features of equine carbohydrate overload.

Gram negative endotoxins play a contributory role in the syndrome which results from over consumption of carbohydrates by horses and ponies. Since the antibiotic polymyxin B exerts a direct anti-endotoxin effect by chemically modifying the active lipid A moiety of endotoxin, it might be expected to protect horses after carbohydrate overload and provide a new therapeutic and experimental tool for this condition. The present study was undertaken to evaluate the effect of polymyxin B on hemostatic, hemodynamic, acid-base, and clinical aspects of the syndrome resulting from carbohydrate overload. Experimentally-induced carbohydrate overload resulted in lactic acidosis, hypercoagulability, hypovolemic shock and lameness. Although there was a slight delay in the onset of clinical signs resulting from experimental carbohydrate overload in treated animals, polymyxin B administered iv at 2.5 mg/kg every 6 hr failed to significantly ameliorate the coagulopathy, acidosis, lameness and shock induced by alimentary carbohydrate overload.

Acid-Base Imbalance↗

PubMed1988

Effect of feeding on renin-angiotensin-aldosterone system of the horse.

The effect of feeding frequency and associated meal size on the renin-angiotensin-aldosterone system (RAAS) in seven horses was examined. A daily maintenance ration of hay-grain pellets was provided either as a multiple feeding regimen (MF), in which the ration was divided into six equal portions fed at 4-h intervals, or as a single large feeding (SF) given from 9 A.M. until 11 A.M. Plasma renin activity (PRA), aldosterone (PAC), cortisol (PCC), protein concentration (TP), packed cell volume (PCV), and serum sodium and potassium were measured serially. To prevent significant RAAS stimulation due to strenuous exercise or by assuming orthostatism after a period of recumbency, the horses were trained to stand in 1 X 4-m tie stalls during the experiments. Changes in Na intake were prevented by disallowing nonration salt sources. A 12:12 light-dark interval was maintained. During the MF experiment, only serum Na changed diurnally, with concentrations lowest in early morning and highest before midday. In contrast, during the SF experiment, PRA was increased at 0.5, 1.0, and 3.0 h and PAC was increased at 3.0, 5.0, and 7.0 h after onset of feeding (P less than 0.005). Increased TP and PCV suggested transient hypovolemia was responsible for renin release. Significant increases in Na and decreases in K occurred while eating; however, K increased postprandially to be coincident with aldosterone. Except for a transient increase during feeding in SF, PCC demonstrated a similar circadian rhythm in both experiments. It was concluded that 1) episodic feeding (SF) causes significant diurnal variation of the RAAS in the horse, and 2) spontaneous circadian activity of the RAAS cannot be demonstrated in this species during a steady-state feeding regimen (MF).

Aldosterone↗

PubMed1987

Ischaemia induced development of functional coronary collateral circulation in ponies.

The response of coronary collaterals in nine ponies subjected to repeated reversible occlusions (2 min duration, 30 min interval) of the left anterior descending coronary artery was studied at rest. Each pony was instrumented with a Doppler flowmeter and hydraulic cuff occluder around the left anterior descending coronary artery, left ventricular subendocardial sonomicrometers, and a left ventricular micromanometer. Initial occlusions increased end diastolic myocardial segment length by 3% and decreased segment systolic shortening, stroke work, and velocity of shortening by 103%, 95%, and 79% respectively in the left ventricular apex. Left ventricular systolic and end diastolic pressure, peak positive dP/dt, and heart rate were not significantly changed by occlusion. After 421(70) (mean(SEM)) occlusions no sustained alterations in myocardial segment function occurred in response to occlusion. Thus the presence of a subendocardial plexus did not protect against a severe loss of myocardial segment function when the ponies were initially subjected to occlusions of the left anterior descending coronary artery. However, repeated reversible occlusions enhanced coronary collateral blood flow such that it was adequate to maintain left ventricular function in the absence of left anterior descending coronary artery flow. It is concluded that the pony is highly suitable for use in studies of coronary collateral circulation because of its coronary anatomical similarity to man and its capacity to develop functional collateralisation.

Animals↗

PubMed1987

Plasma endotoxin levels in horses subjected to carbohydrate induced laminitis.

Thirteen (65 per cent) of 20 horses subjected to carbohydrate overload developed Obel Grade 3 lameness within 56 h. Increases in plasma endotoxin from control levels of less than 0.1 ng/litre to values ranging from 2.4 to 81.53 ng/litre were measured in 11 (85 per cent) of 13 horses during the onset of Obel Grade 3 lameness. Obel Grade 3 lameness was associated with rises in plasma Gram-negative endotoxin levels in 11 (92 per cent) of 12 horses. Two peak increases separated by 16 h were verified in five (45 per cent) of 11 horses that exhibited both endotoxaemia and Obel Grade 3 lameness. The first peak occurred, on average, at 32 h and the second peak at 48 h post overload when only one peak was measured, this occurred in four horses at the average time of 24 h whereas in another three horses only a 48 h or 56 h peak was detected after carbohydrate overload.

Animals↗

PubMed1987

Left ventricular hypertrophy in chronically hypertensive ponies.

Systemic arterial hypertension is associated with equine laminitis, a disease precipitated by gross over-ingestion of carbohydrates. We examined the hearts from nine chronically hypertensive (161 +/- 11/99 +/- 6 mmHg) laminitic ponies and nine normotensive (128 +/- 2/76 +/- 3 mmHg) ponies postmortem for signs of left ventricular hypertrophy. The hypertensive ponies had hearts which were significantly larger (7.77 +/- 0.26 g/kg bodyweight (BW) vs. 5.67 +/- 0.22 g/kg BW), as well as increased combined left ventricle and septum weight (4.99 +/- 0.21 g/kg BW vs. 3.67 +/- 0.20 g/kg BW) and left ventricular free wall weight (3.71 +/- 0.23 g/kg BW vs. 2.62 +/- 0.19 g/kg BW) (p less than 0.05). The right ventricular free wall weights were not significantly different. Mean left ventricular free wall thickness was increased significantly in the hypertensive ponies compared to the normotensive group (26.1 +/- 0.4 mm and 22.5 +/- 1 mm, respectively), but neither septal nor right ventricular free wall thickness was different. These findings demonstrate that left ventricular hypertrophy accompanies equine laminitis-induced hypertension.

Animals↗

PubMed1987

Distribution and implications of beta-endorphin and ACTH-immunoreactive cells in the intermediate lobe of the hypophysis in healthy equids.

The distribution of cells that stain positive for beta-endorphin and ACTH immunoreactivity was studied in the pars intermedia (PI) of the hypophysis in 3 healthy horses and 2 healthy ponies. Serial sections treated with commercial antibodies generated against beta-endorphin or ACTH were processed for immunocytochemical studies, using the avidin biotin immunoperoxidase-complex method. Distribution patterns of cells reacting with antibodies were similar in cells from all equids. Cells immunostained for ACTH were numerous and widely distributed in the PI. Cells immunopositive for ACTH probably contain corticotrophin-like intermediate lobe peptide that cross-reacts with antisera to ACTH. Cells immunopositive for beta-endorphin were fewer in number and had a more limited distribution in the PI. Most beta-endorphin-positive cells were located along the border of the PI adjacent to the lobus nervosus and had abundant eosinophilic cytoplasm when stained with hematoxylin and eosin. Cells with prominent eosinophilic cytoplasm were not common in other areas of the PI. When serial sections were examined, cells that stained positive for beta-endorphin immunoreactivity also appeared positive for ACTH.

Adrenocorticotropic Hormone↗