Biomedical subjects

R J Boucek

Publications and source records attributed to R J Boucek.

At least 37 records · Page 2Linked to original sources

PubMed1991

Dietary lipids modify receptor- and non-receptor-dependent components of alpha 1-adrenoceptor-mediated contraction.

Dietary lipid modulation of alpha-adrenoceptor (adrenergic receptor)- and non-adrenoceptor-mediated contractile properties of isolated rat abdominal aortic segments were assessed during the early developmental period. Rats were raised from conception to 90 days of age on semisynthetic diets containing various types and amounts of lipids. Aortic segments from three groups of rats fed high-fat diets (15% wt/wt) consisting of olive oil, corn oil, or lard as the sole lipid sources were compared with those from rats fed a low-fat control diet containing corn oil (5% wt/wt). alpha-Adrenoceptor activities were assessed by measuring the norepinephrine dose response of the tissue rings with and without partial inactivation of alpha-receptors by benextramine. alpha-Adrenoceptor sensitivity to norepinephrine increased, whereas receptor affinity decreased significantly in rats raised on high-fat diets. Qualitative features of dietary lipids influenced non-adrenoceptor-dependent aspects of vascular contractility. Diets rich in polyunsaturated fatty acids (high- and low-fat corn oil) raised the maximum response to norepinephrine and the contractile response to 60 mM potassium compared with more-saturated diets (olive oil and lard). These results demonstrate an effect of chronic feeding of high dietary fat on alpha-adrenoceptor-mediated contractility of abdominal aortic rings from young Sprague-Dawley rats. Qualitative features of dietary lipids also appear to modify receptor-independent parameters of the contractile response of the arterial tissue rings in these animals.

Animals↗

PubMed1991

Haloperidol administration to rats during pregnancy induces permanent alterations in serum lipoprotein patterns of progeny.

The rat is notoriously resistant to vascular disease, but administration of haloperidol prenatally to the pregnant dam results in hyperlipidemic changes in F1 and F2 progeny. Total serum cholesterol concentrations in the F1 males reach levels three or more times greater than controls by one year of age. The phenomenon indicates a link between dopaminergic elements of the autonomic nervous system and cholesterol metabolism, a phenomenon heretofore unrecognized. Transfer of the hypercholesterolemia into the second generation further suggests that haloperidol induces a permanent change in the genetic control of lipoprotein metabolism. Although the observations are preliminary, they warrant consideration when administering the drug to pregnant women.

Animals↗

PubMed1989

Absence of left ventricular volume loading in infants with coarctation of the aorta and a large ventricular septal defect.

Clinical characteristics and angiographic ventricular volume data were obtained in 25 infants aged 1 to 66 days who presented with coarctation of the aorta, ventricular septal defect and congestive heart failure to determine if left ventricular volume loading was present and if there were hemodynamic or volumetric variables that were predictive of operative mortality in this group. Pulmonary to systemic flow ratio averaged 2.8 +/- 0.8 and right ventricular/left ventricular peak pressure ratio was 0.96 +/- 0.12. Left ventricular end-diastolic volume averaged 116 +/- 49% of normal and was less than the investigators' lower limit of normal in 5 (20%) of 25 patients. In contrast, right ventricular end-diastolic volume, measured in eight patients, averaged 173 +/- 47% of normal and was greater than the investigators' upper limit of normal in seven (88%) of eight. Left ventricular ejection fraction averaged 0.47 +/- 0.17 and was below normal (less than 0.55) in 14 (58%) of 24 patients. Preoperative volume and ejection fraction data did not differ in infants with coarctation plus ventricular septal defect and a similar group of 19 infants with isolated coarctation. Abnormal left ventricular operative volume distensibility was inferred by normal or decreased left ventricular end-diastolic volume and increased left ventricular end-diastolic pressure (greater than 12 mm Hg) in 12 (55%) of 24 patients. Early plus late mortality was related to left ventricular size: 3 of 5 patients with a small left ventricular end-diastolic volume died, compared with only 4 of 20 with a normal or increased volume (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Multiple↗

PubMed1989

Effects of methoxamine and phenylephrine on left ventricular contractility in rabbits.

The end-systolic pressure-volume relation is employed to evaluate left ventricular contractility. In clinical studies, pharmacologic vasoconstriction is used to increase left ventricular systolic pressure to assess pressure-volume relations. However, the effect of vasoconstrictors on the ventricular contractile state is not well characterized. The effects of methoxamine and phenylephrine on systemic arterial pressure and left ventricular contractility in rabbits were studied with three protocols. In protocol 1, anesthetized rabbits (n = 10) were injected with incremental doses of methoxamine and phenylephrine intravenously. Methoxamine (4 mg) increased the mean arterial pressure by 50 +/- 12% (mean +/- SE) (n = 5, p = 0.001). Phenylephrine (0.2 mg) increased mean arterial pressure by 82 +/- 14% (n = 5, p = 0.004). In protocol 2, isolated blood-perfused hearts were injected with incremental doses of these drugs in the ascending aorta in amounts approximately equal to the concentrations injected in the intact rabbits. Methoxamine (2 mg) reduced isovolumic peak systolic left ventricular pressure by 43 +/- 9% (n = 7, p = 0.003), whereas phenylephrine (0.1 mg) increased the isovolumic pressure by 24 +/- 9% (n = 7, p less than 0.05). These responses indicated an enhanced contractile state with phenylephrine and a reduced contractile state with methoxamine. Pretreatment with propranolol blunted the effect of phenylephrine on isovolumic pressure (n = 6, p less than 0.02). In protocol 3, cross-circulation experiments allowed study of the effect of these drugs on isovolumic left ventricular pressure in the isolated heart and simultaneously on the systemic arterial pressure in the intact anesthetized rabbit (support rabbit).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Comparison of the calcium release channel of cardiac and skeletal muscle sarcoplasmic reticulum by target inactivation analysis.

The calcium release channel of sarcoplasmic reticulum which triggers muscle contraction in excitation-contraction coupling has recently been isolated. The channel has been found to be morphologically identical with the feet structures of the junctional face membrane of terminal cisternae and consists of an oligomer of a unique high molecular weight polypeptide. In this study, we compare the target size of the calcium release channel from heart and skeletal muscle using target inactivation analysis. The target molecular weights of the calcium release channel estimated by measuring ryanodine binding after irradiation are similar for heart (139,000) and skeletal muscle (143,000) and are smaller than the monomeric unit (estimated to be about 360,000). The target size, estimated by measuring polypeptide remaining after irradiation, was essentially the same for heart and skeletal muscle, 1,061,000 and 1,070,000, respectively, indicating an oligomeric association of protomers. Thus, the calcium release channel of both cardiac and skeletal muscle reacts uniquely with regard to target inactivation analysis in that (1) the size by ryanodine binding is smaller than the monomeric unit and (2) a single hit leads to destruction of more than one polypeptide, by measuring polypeptide remaining. Our target inactivation analysis studies indicate that heart and skeletal muscle receptors are structurally very similar.

Alkaloids↗

PubMed1989

Uniqueness of dietary olive oil in stimulating aortic prostacyclin production in post-weanling rats.

Groups of weanling Sprague-Dawley rats developed from conception through gestation, and weanling periods on a formulated diet fed to the dams were continued on the same diet until sacrificed at 30 days of age. The diet groups consisted of control (5% corn oil, w/w) and experimental (15%, w/w) olive, safflower (hi-oleic and hi-linoleic), soy oil, and lard. The object of the study was to identify the effect of high and low fat content and differing proportions of polyunsaturated:saturated (P:S) and mono:polyunsaturated (M:P) fatty acids on arachidonate stimulated aortic prostacyclin (PGI2) production (measured as 6-keto-PGF1 alpha). Neither the amounts of dietary fat or wide ranging P:S or M:P fatty acid ratio levels (P:S or M:P) affected PGI2 production. PGI2 production was, however, markedly enhanced (2x) in aortic segments from rats raised on diets containing olive oil. The unique stimulation of aortic PGI2 production by the olive oil diet suggests an effect of the extraordinarily high M:P fatty acid ratio or, alternatively, of a still-to-be identified substance(s) in this ancient food.

6-Ketoprostaglandin F1 alpha↗

PubMed1988

Decreased early diastolic function after indomethacin administration in premature infants.

The effect of indomethacin on systolic and diastolic cardiac function was assessed in 15 premature infants. Seven infants (group 1) received indomethacin to treat a clinically significant patent ductus arteriosus (PDA), and eight infants (group 2) received indomethacin prophylactically at 24 hours of age because of their high risk for PDA. Diastolic cardiac function was assessed using instantaneous rates of change of left ventricular (LV) cavity dimension, derived from M-mode echocardiography. The maximum velocity of lengthening of the LV cavity dimension, an index of early diastolic function, fell from 63 +/- 19 mm/sec before indomethacin to 48 +/- 16 mm/sec 1 hour after indomethacin in group 1 (P less than 0.01), with the ductus still patent and the LV chamber still dilated, and also decreased in group 2, from 52 +/- 7 mm/sec to 38 +/- 6 mm/sec (P less than 0.01). This index, when normalized for loading conditions, was decreased 1 hour after indomethacin at 12 +/- 2 sec-1 and 12 +/- 1 sec-1 for groups 1 and 2, respectively, compared with values before indomethacin of 15 +/- 3 sec-1 and 15 +/- 2 sec-1. There was no effect of indomethacin on the indices of systolic function. We conclude that indomethacin decreases early diastolic function in premature infants.

Diastole↗

PubMed1988

Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol.

Doxorubicin (former generic name, adriamycin), a highly effective anticancer drug, produces cardiotoxicity, which limits its therapeutic potential. The mechanism of this cardiotoxicity has remained elusive. Our data suggest that this toxicity could involve doxorubicinol, the primary circulating metabolite of doxorubicin. Doxorubicinol was markedly more potent than doxorubicin at compromising both systolic and diastolic cardiac function. Similarly, doxorubicinol was much more potent than doxorubicin at inhibiting the calcium pump of sarcoplasmic reticulum [ATP phosphohydrolase (Ca2+-transporting), EC 3.6.1.38], the Na+/K+ pump of sarcolemma [ATP phosphohydrolase (Na+/K+-transporting), EC 3.6.1.37], and the F0F1 proton pump of mitochondria [ATP phosphohydrolase (H+-transporting, EC 3.6.1.34]. Our finding that this highly toxic metabolite was produced by cardiac tissue exposed to doxorubicin suggests that doxorubicinol could accumulate in the heart and contribute significantly to the chronic cumulative cardiotoxicity of doxorubicin therapy. Our observation that doxorubicin was more potent than doxorubicinol in inhibiting tumor cell growth in vitro suggests that the cardiotoxicity of doxorubicin is dissociable from its anticancer activity.

Animals↗

PubMed1987

The major metabolite of doxorubicin is a potent inhibitor of membrane-associated ion pumps. A correlative study of cardiac muscle with isolated membrane fractions.

Doxorubicin (adriamycin) is a highly effective cancer chemotherapeutic drug but its clinical utility is limited by its cardiotoxicity. Doxorubicinol, the major metabolite of doxorubicin, is up to 10 times more potent than doxorubicin at inhibiting isometric contraction of the papillary muscle isolated from the right ventricle of rabbit heart. Doxorubicinol also increases resting tension of isolated cardiac muscle indicative of incomplete relaxation between contractions, a characteristic of doxorubicinol but not of doxorubicin. This study assesses the effect(s) of doxorubicinol on a variety of ion pumps which may explain, in part, the action of the metabolite in the intact muscle. We find the doxorubicinol is a potent inhibitor (IC50 less than 5 micrograms/ml) of calcium-stimulated ATPase activity of sarcoplasmic reticulum from canine heart and rabbit skeletal muscle. At comparable levels, doxorubicinol is also a potent inhibitor of (Na + K)-ATPase of cardiac sarcolemma and the Mg-dependent ATPase activity referable to the F0F1 proton pump of mitochondria. For each of these ion pumps, doxorubicinol is at least 80 times more potent an inhibitor than doxorubicin. Doxorubicinol, between 10 and 50 micrograms/ml, increases resting tension up to 4-fold in isolated papillary muscles cyclically contracting at 30 times/min. Resting stress is relatively insensitive to doxorubicin. Thus, doxorubicinol is a potent inhibitor of several key cationic pumps that directly or indirectly regulate cell calcium and inhibits relaxation in the isolated fiber preparation. These observations add a new dimension to understanding the cardiotoxicity of doxorubicin.

5'-Nucleotidase↗

PubMed1987

Target size of the ryanodine receptor from junctional terminal cisternae of sarcoplasmic reticulum.

Target inactivation analysis was carried out on the ryanodine receptor. This receptor recently has been implicated as the channel involved in the calcium release process in excitation-contraction coupling and was localized to the junctional terminal cisternae of sarcoplasmic reticulum from skeletal muscle [Fleischer, S., Ogunbunmi, E. M., Dixon, M. C., & Fleer, E.A.M. (1985) Proc. Natl. Acad. Sci. U.S.A. 82, 7256-7259]. Irradiation of the junctional terminal cisternae resulted in an exponential decrease in ryanodine binding with radiation dose, thereby consistent with target theory. The target molecular weight was found to be 138,000 +/- 21,000, i.e., smaller than the polypeptide that binds ryanodine. The calcium pump protein in the same membrane preparation served as an internal control to validate the methodology.

Animals↗

PubMed1987

Altered early left ventricular diastolic cardiac function in the premature infant.

Developmental changes in diastolic ventricular function were assessed in 31 premature infants and in 10 normal-term infants. They were studied during the first 72 hours of life using instantaneous rates of change of left ventricular (LV) cavity dimension, derived from M-mode echocardiography. Maximal velocity of lengthening of the LV cavity was significantly lower in premature infants (38 +/- 7 mm/s) than in term infants (88 +/- 15 mm/s). This variable increased with increasing maturity over the 4 gestational age groups evaluated (r = 0.87). This index normalized for instantaneous LV dimension was lower in the most immature infants (4.5 +/- 1 s-1) than in term infants (6.8 +/- 2 s-1). Eight of the premature infants were studied serially at 1, 3 and 7 days of age. Maximal velocity of lengthening divided by stroke dimension improved from 12.9 +/- 2 s-1 at 1 day of age to 16.5 +/- 3 s-1 at 7 days. These results suggest depressed early diastolic function in premature infants.

Diastole↗

PubMed1987

Hemodynamic effects of hydralazine in infants with idiopathic dilated cardiomyopathy and congestive heart failure.

We evaluated the acute hemodynamic responses to hydralazine during cardiac catheterization in 13 infants with idiopathic dilated cardiomyopathy. Ages ranged from 2 to 13 months (6.7 +/- 4.0 months, mean +/- SD). Each infant had congestive heart failure and angiographic evidence of markedly depressed left ventricular ejection fraction (0.24 +/- 0.11; normal = 0.58-0.78) with left ventricular dilation (left ventricular end-diastolic volume = 349 +/- 125% of normal). Hydralazine (0.5 to 1.0 mg/kg administered intravenously) acutely decreased systemic arteriolar resistance from 21.1 +/- 3.3 to 12.0 +/- 2.7 U/m2 (p less than 0.001). This 41 +/- 14% decrease in systemic resistance was accompanied by a 45 +/- 16% increase in cardiac index (3.24 +/- 0.53 to 4.71 +/- 0.99 L/min/m2; p less than 0.001). Mean arterial blood pressure declined from 70 +/- 8 to 60 +/- 11 mm Hg (p less than 0.001). Hydralazine also increased heart rate (122 +/- 19 to 138 +/- 18 bpm; p less than 0.001), but this increase did not account entirely for the change in cardiac index as evidenced by a rise in stroke volume index (26.9 +/- 4.9 to 34.5 +/- 7.5 ml/beat/m2; p less than 0.001). Pulmonary arteriolar resistance and pulmonary capillary wedge pressure fell slightly in response to hydralazine. Subsequently, oral hydralazine was included in the treatment regimen of 10 infants followed for 3 to 38 months (mean = 15 months). Of these, eight demonstrated sustained clinical improvement. We conclude that hydralazine may be a beneficial adjunct to the management of congestive heart failure in young infants with a dilated cardiomyopathy.

Angiography↗

PubMed1987

Myocardial adenosine triphosphate content as a measure of metabolic and functional myocardial protection in children undergoing cardiac operation.

In an effort to quantitate the metabolic and functional response to global myocardial ischemia as a prelude to specific interventions to improve myocardial protection in children, the following data were collected. Twenty children (age, 1.16 +/- 0.3 years) underwent repair of congenital intracardiac malformations using aortic cross-clamping and cold potassium cardioplegia (ischemic time, 56.1 +/- 4.5 minutes). Metabolic protection was assessed by measuring the myocardial adenosine triphosphate (ATP) content by microbioluminescence. Before and after ischemia 10-mg myocardial samples were obtained from the left ventricular apex using a Tru-cut biopsy needle. In 15 patients, postoperative ventricular function was measured by radionuclide ventriculography at 72 to 96 hours following operation. Five of 6 patients with a postischemic ATP level less than 40% of control (26.3 +/- 2.8) had a left ventricular ejection fraction (EF) lower than 55% (50.3 +/- 2.3). Seven of 9 patients with an ATP level greater than 40% of the preischemic level (98.0 +/- 14.4) had a normal EF (61.8 +/- 2.9; p less than 0.04). Two other patients with postischemic ATP levels lower than 40% of control died of low cardiac output and had no postoperative ventricular function studies. Thus, of 7 patients with postischemic ATP levels lower than 40% of preischemic levels, 2 died and 5 had depressed left ventricular function. These data support the concept that low postischemic ATP levels correlate with death or poor postoperative ventricular function, and indicate that this variable will be useful to assess future improvements in myocardial protection during pediatric cardiac operations.

Adenosine Triphosphate↗

PubMed1987

Effects of postnatal maturation on postrest potentiation in isolated rabbit atria.

Ultrastructural changes in cardiac sarcoplasmic reticulum (SR) have been reported during postnatal development of the mammalian heart, but the functional significance of these observations has not been well characterized. Calcium release from SR in intact myocardial preparations was determined by the contractile characteristics of postrest contractions. Isometric tension and the maximum rate of tension development of the first contraction following intervals of electromechanical quiescence (rest) were related to steady-state tension and maximum rate of tension development during contraction at constant frequency (1.0 Hz) in isolated left atrial strips from newborn (1-7 days), immature (14-21 days), and adult (more than 6 months) rabbits. The first postrest contraction was increased as a function of the rest interval rate of tension development, defined as postrest potentiation, in all three age groups and reached a maximum value at rest intervals of more than 20 s. Tension developed by the first contraction following a 60-s rest interval was potentiated less in newborn and immature atria than in adult atria at an extracellular calcium concentration ([Ca]e) of 2.5 mM, an age-related difference most marked in the immature. Ryanodine (5.0 X 10(-9) M), a putative blocker of calcium release from cardiac SR, abolished postrest potentiation providing evidence that calcium release from SR is the predominant determinant of the postrest contraction. Postrest tension in atria from the immature rabbit heart was significantly increased both in absolute terms and relative to steady-state tension following stabilization under conditions which increase intracellular [Ca] [( Ca]i), i.e. increasing [Ca]e, increasing tonicity, or decreasing extracellular sodium concentration ([Na]e).(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1986

Dietary fat and cholesterol modification of rat abdominal aorta prostacyclin and leukotriene production (in vitro).

Groups of weanling male Sprague-Dawley rats fed formulated diets containing 15% by weight of corn oil (CO), linseed oil (LNO), or corn oil plus 1% cholesterol and 0.25% cholic acid (CH-CH) were sacrificed after 8 weeks and the aortas removed. Three mm length cross-sectional rings were cut from the distal abdominal aorta segment and incubated in either Tris buffer (pH 7.4, 37 degrees, 10 min.) for measurements of prostacyclin as 6-Keto-prostaglandin in F1 alpha (6-Keto-PGF1 alpha) or Tris buffer plus 10 microM ionophore A23187 for measurement of leukotriene C4 (LTC4) production using radioimmunoassay (RIA) procedures. 6-Keto-PGF1 alpha production was greater (p less than 0.01) in the CO than in the LNO and CH-CH fed rats by 54% and 40% respectively. LNO diets significantly lowered LTC4 production when compared to tissues from CO-fed rats (p less than 0.05). LTC4 production by tissues from the CH-CH-fed animals was lower than tissues from CO-fed animals, however, the difference failed to reach levels of significance because of data spread and the number of tissues. Tissues from the CH-CH-fed and LNO-fed rats were significantly different than those of the CO since LTC4 formation was high relative to 6-Keto-PGF1 alpha production (LTC4/6-Keto-PGF1 alpha). These results suggest distinctive effects of dietary fat and cholesterol on the syntheses of vasoactive eicosanoids that may be relevant to arterial tissue physiology and pathology.

6-Ketoprostaglandin F1 alpha↗

PubMed1986

Surgical management of patients with pulmonary valve dysplasia.

Pulmonary valve dysplasia is a distinct pathological entity consisting of markedly thickened, deformed, and largely immobile pulmonary valve leaflets. The clinical features and surgical management of 21 consecutive patients operated upon between 1975 and 1985 were reviewed. Mean age at operation was 26.7 months (range: 1 month to 9.5 years). Initial surgical intervention in 3 patients consisted of closed valvotomy or systemic pulmonary artery shunt. One of these patients subsequently had a partial pulmonary valvectomy; the other 2 had total valvectomy and pulmonary annuloplasty. Two patients had partial valvectomy as a primary procedure, and 1 has subsequently required total valvectomy and annuloplasty. Sixteen patients initially had total pulmonary valvectomy, 4 with a simultaneous transannular outflow tract patch. One patient subsequently required a transannular outflow tract patch. Therefore, definitive repair consisted of partial valvectomy in 2 patients, total valvectomy in 19, and a transannular outflow tract patch in 9 patients with a hypoplastic pulmonary annulus. There were no operative deaths, and all patients are asymptomatic at a mean follow-up of 37.9 months. Five patients who underwent total valvectomy were catheterized postoperatively. The mean residual gradient was 25 mm Hg. Pulmonary valvectomy appears to provide both effective relief of stenosis and long-term asymptomatic status in patients with pulmonary valve dysplasia. Total excision of all valve leaflets is recommended. Careful consideration should be given to a simultaneous transannular outflow tract patch if the annulus is hypoplastic.

Child↗

PubMed1986

Antiguanosine antibodies: a new marker for procainamide-induced systemic lupus erythematosus.

Antinuclear antibodies are present in most patients receiving procainamide. To ascertain whether IgG antiguanosine antibodies are associated with the development of the symptoms of systemic lupus erythematosus, we compared the levels of these antibodies in the sera of 65 patients receiving procainamide: 18 with procainamide-induced symptoms and 47 asymptomatic patients. Antinuclear antibodies measured by immunofluorescence were present in the 18 patients with drug-induced symptoms but also in 24 asymptomatic patients. Similarly, elevated serum levels of antibodies to single-stranded DNA were found in 15 patients with symptoms and in 20 asymptomatic patients. In contrast, levels of IgG antiguanosine antibodies were elevated in 15 patients with drug-induced symptoms, but in only 3 asymptomatic patients. Antiguanosine antibodies binding to single-stranded DNA were found primarily in patients with arthritis, pleuritis, and pericarditis. These results suggest a strong association between IgG antiguanosine antibodies and major manifestations of procainamide-induced systemic lupus erythematosus.

Adult↗

PubMed1986

Effects of endotoxin on coronary vascular resistance in the isolated blood-perfused rabbit heart.

Rabbit hearts were excised and perfused with blood pumped through a cannula placed in the aortic root. A fluid-filled balloon-tipped catheter was positioned in the left ventricle for the measurement of left ventricular pressure and dP/dt. Total coronary vascular resistance (CVR) was calculated by dividing the coronary perfusion pressure by the rate of coronary blood flow. Following stabilization, coronary blood flow was held at a constant rate. Compared to control hearts, endotoxin (E. coli) added directly to the blood perfusate (6 mg/80 ml of circulating blood) had no effect on CVR or left ventricular dP/dt. In contrast, changing the perfusate to blood obtained from rabbits previously given endotoxin (LD100; 6 mg/kg IV) resulted in significantly higher CVR, without depression of left ventricular dP/dt. This increase in CVR was observed not only when the endotoxemic donor rabbits were hypotensive at the time the blood was obtained (4-6 hours following endotoxin administration), but also when the endotoxemic donors remained normotensive (blood withdrawn 30 minutes following endotoxin administration). A pathologic increase in CVR might contribute to the myocardial ischemia and contractile dysfunction observed in endotoxin shock.

Animals↗