ACE inhibitors in HF restore canine pulmonary endothelial function and ANG II vasoconstriction.

Chronic mitral regurgitation (MR) in dogs results in pulmonary congestion and increased cardiac angiotensin-converting enzyme (ACE) activity and angiotensin (ANG) II levels. ACE could contribute to altered pulmonary vasomotion in heart failure, and ACE inhibitor (ACEI) therapy may normalize pulmonary vasomotion. We evaluated pulmonary artery (PA) responses to ANG II and bradykinin (BK) in control dogs, in dogs with 4 mo of MR, in MR dogs treated with the ACEI ramipril (MR + R), and in control dogs treated with ramipril (C + R). Mean PA systolic pressure increased in MR dogs (21 +/- 4 mmHg) but was normal in MR + R dogs (13 +/- 1 mmHg). Constriction of PA rings to ANG II was depressed in MR dogs. ACEI treatment (MR + R) restored ANG II responsiveness, but peak ANG II response (3.6 +/- 0.2 g) in MR + R dogs remained lower than in C + R dogs (4.7 +/- 0.2 g). Endothelium-dependent relaxation to BK was decreased (-87 +/- 4% C, -65 +/- 4% MR; P < 0.05). Ramipril (MR + R) restored relaxation to BK. This demonstrates that pulmonary congestion results in impaired pulmonary vasomotion to ANG II and BK, which ACEIs could normalize, supporting the use of ACEIs in clinical management of chronic congestive heart failure.

Volume-overload cardiac hypertrophy is unaffected by ACE inhibitor treatment in dogs.

We tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitor therapy prevents volume-overload hypertrophy in dogs with chronic mitral regurgitation (MR). Seven adult mongrel dogs receiving ramipril (R; 10 mg orally, twice/day) for 4 mo were compared with 11 dogs receiving no R (N) for 4 mo after induction of MR. Cine-magnetic resonance imaging demonstrated that left ventricular (LV) mass increased in the R-MR dogs [80 +/- 4 (SE) to 108 +/- 7 g, P < 0.01] and in the N-MR dogs (92 +/- 7 to 112 +/- 8 g, P < 0.001). LV myocyte cell length was greater in the R-MR and N-MR dogs (203 +/- 6 and 177 +/- 10 microns, respectively) than in normal (144 +/- 4 microns, P < 0.05) dogs. There was significant loss of the collagen weave pattern by scanning electron microscopy in both R-MR and N-MR dogs. LV ACE and chymase activities were significantly elevated in R-MR and N-MR compared with normal dogs. LV angiotensin II (ANG II) levels in the R-MR dogs (28 +/- 12 pg/g) were reduced to levels seen in normal dogs (28 +/- 4 pg/g) compared with N-MR dogs (72 +/- 11 pg/g, P < 0.05). Steady-state AT1-receptor mRNA levels decreased 66% in N-MR compared with normal dogs (P < 0.001) and increased 1.5-fold in R-MR compared with normal dogs (P < 0.01). Thus upregulation of the AT1 receptor in the R-MR hearts may provide a mechanism by which normal intracardiac ANG II levels could continue to mediate LV hypertrophy. However, the mechanism of dissolution collagen weave in both N-MR and R-MR hearts may be related to the stretch of volume overload.

Effects of acepromazine maleate and phenoxybenzamine on urethral pressure profiles of anesthetized, healthy, sexually intact male cats.

OBJECTIVES: To evaluate the effects of 2 compounds with alpha adrenergic antagonist properties on the urethral pressures of anesthetized, healthy, sexually intact male cats, and to evaluate one of the compounds for effect on striated muscle. ANIMALS: 20 healthy, sexually intact male cats. PROCEDURE: Cats were anesthetized with halothane, and urethral pressure profilometry was performed before and after treatment. 125I-labeled alpha-bungarotoxin bound to nicotinic receptors of murine skeletal muscle was used in a competitive binding study with acepromazine maleate. RESULTS: Acepromazine maleate significantly decreased intraurethral pressures in the preprostatic (19%) and prostatic (21%) regions of the urethra. There was no effect on the postprostatic/penile segment. Acepromazine did not inhibit 125I-labeled alpha-bungarotoxin binding to nicotinic receptors in murine skeletal muscle. Phenoxybenzamine significantly decreased intraurethral pressures (14%) in the preprostatic region of the urethra only. CONCLUSIONS: Acepromazine maleate and phenoxybenzamine have effects on the smooth muscle of the urethra of healthy, male cats. Acepromazine has no effect on striated muscle. CLINICAL RELEVANCE: alpha-Adrenergic compounds may be used in the pharmacologic management of feline urinary tract disease.

1H NMR spectroscopic imaging of myocardial triglycerides in excised dog hearts subjected to 24 hours of coronary occlusion.

BACKGROUND: Myocardial ischemic insult causes depression of fatty-acid beta-oxidation and increased fatty-acid esterification with triglyceride (TG) accumulation. This accumulation has been demonstrated to occur in the territory with diminished blood flow surrounding an infarct, ie, the region at risk. To evaluate whether the extent of TG accumulation in the canine heart after 24 hours of ischemia could be detected, we applied myocardial 1H nuclear magnetic resonance (NMR) spectroscopic imaging (SI). METHODS AND RESULTS: Seven adult mongrel dogs underwent 24 hours of left anterior descending coronary artery occlusion. Postmortem, the hearts were excised and the size and location of the infarct were determined. With a Philips 1.5-T clinical NMR imaging/spectroscopic system, two-dimensional (2D) 1H NMR SI was performed. TG 1H NMR chemical shift images were reconstructed from the frequency domain spectra by numerical integration. A statistically significant (P < .05) increase in TG signal intensity was demonstrated in the region at risk compared with the nonischemic control region. There was an intermediate quantity of TG in the infarct region. Biochemical determination of tissue TG content (milligrams per gram wet weight) in the control, at-risk, and infarct regions confirmed the 1H NMR measurements. Histological evaluation with oil red O staining also demonstrated graded TG accumulation in myocytes. The highest TG levels were found in the at-risk region and the lowest levels in the control region. CONCLUSIONS: By use of 2D 1H NMR SI, the present study confirms and extends previous work that demonstrates preferential accumulation of TG in the reversibly injured myocardium after 24 hours of coronary occlusion. This study provides an important step toward the clinical application of TG imaging. When TG imaging is ultimately possible, resultant data would have diagnostic, prognostic, and therapeutic implications.

Increased ACE and chymase-like activity in cardiac tissue of dogs with chronic mitral regurgitation.

The current study was designed to test the hypothesis that intracardiac angiotensin-converting enzyme (ACE) activity, chymase-like activity, and angiotensin (ANG) peptide levels are increased and are positively related to wall stress estimates in response to the chronic low pressure volume overload of mitral regurgitation produced by percutaneous chordal rupture in the dog. Chronic mitral regurgitation (MR) resulted in an increase in left ventricular (LV) end-diastolic volume [59 +/- 11 (SD) to 103 +/- 32 ml, P < 0.001], LV mass (96 +/- 17 to 114 +/- 23 g, P < 0.001), and a decrease in the LV mass-to-end-diastolic volume ratio (1.64 +/- 0.22 to 1.16 +/- 0.23 g/ml, P < 0.001) measured by magnetic resonance imaging. In vitro studies of heart tissue extracts demonstrated that the majority of ANG II-forming activity was from chymase-like activity rather than from ACE activity in five normal (83.5 +/- 7.5 vs. 6.04 +/- 5.2%) and seven MR hearts (86 +/- 3.9 vs. 2.6 +/- 1.7%). ACE activity (1.22 +/- 0.22 vs. 3.55 +/- 0.62 mU/g, P < 0.05) and chymase-like activity (9.42 +/- 4.64 vs. 20.60 +/- 8.41 nmol.g-1.min-1, P < 0.05) were increased in MR compared with normal hearts. ACE activity correlated with the LV mass-to-volume ratio (r = -0.93, P < 0.001) and LV diastolic wall stress ( r = 0.71, P < 0.05); however, chymase-like activity did not correlate with any hemodynamic parameter. ANG II levels were significantly higher in the midwall of the left ventricle in MR hearts than in normal controls (85 +/- 39 vs. 27 +/- 16 pg/g, P < 0.01). Our results demonstrate a positive correlation between LV diastolic wall stress and increased ACE activity with increased ANG II stores, suggesting that mechanical wall stress activated intracardiac ACE. Although chymase accounted for most ANG II formation in vitro in extracts of both normal and MR dog hearts, the significance of this enzyme in vivo remains unclear.

Urethral pressure response to smooth and skeletal muscle relaxants in anesthetized, adult male cats with naturally acquired urethral obstruction.

The effects of the skeletal muscle-relaxing drug dantrolene sodium alone, and in combination with the alpha 1-adrenergic antagonist prazosin, on the urethral pressure profile were investigated in male cats with obstructive lower urinary tract disease. Decreases in mean segmental intraurethral pressure induced by dantrolene (n = 3) or dantrolene in combination with prazosin (n = 3) were evaluated statistically, using a paired design. Statistical analysis was applied to absolute (mm of Hg) pressure values. Intravenous administration of dantrolene alone (1 mg/kg of body weight, n = 3) significantly decreased pressure in the postprostatic/penile urethral segment, but did not decrease prostatic urethral pressures. Dantrolene in combination with prazosin (0.03 mg/kg IV) caused a 20% pressure decrease in the prostatic segment (P = 0.060). Preprostatic urethral pressure was not significantly affected by either treatment regimen in the small pool of cats studied. There was no difference in baseline pressures (mm of Hg) in the 3 intraurethral segments of these 6 recently obstructed male cats, compared with historic baseline pressures (mm of Hg) in the 3 intraurethral segments of 28 healthy male cats. These results indicate that dantrolene and prazosin may be effective in relaxing intraurethral skeletal and smooth musculature in male cats clinically afflicted with obstructive lower urinary tract disease. However, it is not certain that administration of muscle relaxants would facilitate urethral catheterization and removal of the obstruction in male cats with blockage of the lower urinary tract. Strikingly, results of this study suggest that urethral muscle spasm had a minor role in these cats.

Effect of succinylcholine, diazepam, and dantrolene on the urethral pressure profile of anesthetized, healthy, sexually intact male cats.

Effects of the neuromuscular blocking agent succinylcholine (n = 9), the centrally acting skeletal muscle relaxant diazepam (n = 11), and the directacting skeletal muscle relaxant dantrolene sodium (n = 8) on the urethral pressure profile were evaluated in anesthetized, healthy, sexually intact, adult male cats. Intravenous administration of succinylcholine (0.075 mg/kg of body weight) significantly decreased mean absolute pressure in the prostatic and post-prostatic/penile intraurethral segments by -9.5 and -6.5 mm of Hg, respectively (P = 0.0002 and P = 0.0006, respectively). Dantrolene (1.0 mg/kg, IV) significantly decreased mean prostatic and postprostatic/penile intraurethral segmental pressures by -3.5 and -2.8 mm of Hg, respectively (P = 0.005 and P = 0.0181, respectively). Diazepam (0.8 mg/kg, IV) did not significantly alter mean intraurethral segmental pressures. None of the drugs caused a change in segmental lengths of the urethra. These results indicate that skeletal muscle makes a substantial contribution to intraurethral tone in anesthetized, healthy, sexually intact male cats and that skeletal muscle relaxation may be successful in reducing prostatic and post-prostatic/penile urethral segmental tone in male cats. These results also suggest that dantrolene sodium may be valuable for the pharmacologic management of urethral disorders in male cats.