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2.
J Card Fail ; 7(2): 158-64, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11420768

ABSTRACT

BACKGROUND: Past studies have suggested that amlodipine, a dihydropyridine L-type Ca(2+) channel antagonist, may exert useful effects in congestive heart failure (CHF). The present study examined the effects of amlodipine or nifedipine treatment in a model of developing CHF on left ventricular (LV) pump function and myocyte contractility. METHODS AND RESULTS: Pigs (25 kg) were randomly assigned to 1 of 4 groups: 1) pacing-induced CHF (rapid atrial pacing at 240 bpm) for 3 weeks (n = 9), 2) concomitant Ca(2+) channel blockade with amlodipine (1.5 mg/kg/day) and rapid pacing (n = 7), 3) concomitant Ca(2+) channel blockade with nifedipine (0.7 mg/kg twice daily) and rapid pacing (n = 7), and 4) sham controls (n = 7). LV fractional shortening fell with pacing CHF from baseline values (17% +/- 1% v 42% +/- 1%, P <.05). With rapid pacing and concomitant amlodipine treatment, LV fractional shortening increased from pacing CHF values (24% +/- 1%, P <.05) but was unchanged with concomitant nifedipine treatment (20% +/- 2%, P =.2). LV myocyte velocity of shortening, as measured by high speed videomicroscopy, was reduced with pacing CHF compared with controls (42 +/- 2 microm/s v 87 +/- 9 microm/s, P <.05), and increased from pacing CHF values with amlodipine or nifedipine treatment (62 +/- 8 microm/s, 64 +/- 4 microm/s, respectively; P <.05). Inotropic response to extracellular Ca(2+) (8 mmol/L) was reduced with pacing CHF (94 +/- 5 microm/s v 160 +/- 15 microm/s, P <.05) and increased from CHF values with amlodipine or nifedipine treatment (132 +/- 14 microm/s and 133 +/- 7 microm/s, respectively, P <.05) CONCLUSIONS: These results suggest that the primary mechanism for the effects of amlodipine on myocyte contractility in developing CHF is because of direct Ca(2+) channel blockade.


Subject(s)
Amlodipine/pharmacology , Amlodipine/therapeutic use , Calcium Channel Blockers/pharmacology , Calcium Channel Blockers/therapeutic use , Heart Failure/drug therapy , Myocardial Contraction/drug effects , Nifedipine/pharmacology , Nifedipine/therapeutic use , Animals , Disease Models, Animal , Heart Failure/diagnostic imaging , Male , Microscopy, Video , Pacemaker, Artificial , Swine , Ultrasonography , Ventricular Function, Left/drug effects
3.
Circulation ; 103(2): 308-13, 2001 Jan 16.
Article in English | MEDLINE | ID: mdl-11208694

ABSTRACT

BACKGROUND: Exogenous administration of growth hormone (GH) and subsequently increased production of insulin-like growth factor-1 can influence left ventricular (LV) myocardial growth and geometry in the setting of congestive heart failure (CHF). This study determined the effects of an orally active GH secretagogue (GHS) treatment that causes a release of endogenous GH on LV function and myocyte contractility in a model of developing CHF. METHODS AND RESULTS: Pigs were randomly assigned to the following treatment groups: (1) chronic rapid pacing at 240 bpm for 3 weeks (n=11); (2) chronic rapid pacing and GHS (CP-424,391 at 10 mg x kg(-1) x d(-1), n=9); and (3) sham controls (n=8). In the untreated pacing CHF group, LV fractional shortening was reduced (21+/-2% versus 47+/-2%) and peak wall stress increased (364+/-21 versus 141+/-5 g/cm(2)) from normal control values (P:<0.05). In the GHS group, LV fractional shortening was higher (29+/-2%) and LV peak wall stress lower (187+/-126 g/cm(2)) than untreated CHF values (P:<0.05). With GHS treatment, the ratio of LV mass to body weight increased by 44% from untreated values. Steady-state myocyte velocity of shortening was reduced with pacing CHF compared with controls (38+/-1 versus 78+/-1 microm/s, P:<0.05) and was increased from pacing CHF values with GHS treatment (55+/-7 microm/s, P:<0.05). CONCLUSIONS: The improved LV pump function that occurred with GHS treatment in this model of CHF was most likely a result of favorable effects on LV myocardial remodeling and contractile processes. On the basis of these results, further studies are warranted to determine the potential role of GH secretagogues in the treatment of CHF.


Subject(s)
Growth Hormone/metabolism , Heart Failure/physiopathology , Myocytes, Cardiac/drug effects , Piperidines/pharmacology , Pyrazoles/pharmacology , Ventricular Function/drug effects , Animals , Cardiac Pacing, Artificial , Echocardiography , Heart Failure/diagnostic imaging , Male , Myocardial Contraction/drug effects , Swine
4.
Circulation ; 102(12): 1447-53, 2000 Sep 19.
Article in English | MEDLINE | ID: mdl-10993866

ABSTRACT

BACKGROUND: The goal of this study was to determine the comparative effects of angiotensin II type 1 (AT(1)) receptor inhibition alone, endothelin-1 (ET) receptor blockade alone, and combined receptor blockade on left ventricular (LV) function, contractility, and neurohormonal system activity in a model of congestive heart failure (CHF). METHODS AND RESULTS: Pigs were randomly assigned to each of 5 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) concomitant AT(1) receptor blockade (valsartan, 3 mg/kg per day) and rapid pacing (n=8), (3) concomitant ET receptor blockade (bosentan, 50 mg/kg BID) and rapid pacing (n=8), (4) concomitant combined AT(1) and ET receptor inhibition and rapid pacing (n=8), and (5) sham-operated control (n=9). LV stroke volume was reduced from the control value after rapid pacing, was unchanged with either AT(1) or ET receptor blockade alone, but was improved with combination treatment. LV peak wall stress was reduced in both groups with ET receptor blockade compared with the rapid pacing group. Plasma norepinephrine levels were increased by >3-fold after rapid pacing, remained increased in the monotherapy groups, but were reduced after combination treatment. LV myocyte velocity of shortening was reduced after rapid pacing-induced CHF, remained reduced after AT(1) receptor blockade, increased after ET receptor blockade (compared with rapid pacing-induced CHF values), and returned to within control values after combined blockade. CONCLUSIONS: Combined AT(1) and the ET receptor blockade in this model of CHF improved LV pump function, and contributory factors included the effects of LV loading conditions, neurohormonal system activity, and myocardial contractile performance. Thus, combined receptor blockade may provide a useful combinatorial therapeutic approach in CHF.


Subject(s)
Angiotensin II , Angiotensin Receptor Antagonists , Endothelin Receptor Antagonists , Heart Failure/therapy , Myocardial Contraction , Valine/analogs & derivatives , Ventricular Dysfunction, Left/therapy , Angiotensin II/blood , Animals , Antihypertensive Agents/therapeutic use , Bosentan , Cardiac Pacing, Artificial , Combined Modality Therapy , Endothelin-1/blood , Heart Failure/blood , Heart Failure/physiopathology , Norepinephrine/blood , Receptor, Endothelin A , Renin/blood , Sulfonamides/therapeutic use , Swine , Tetrazoles/therapeutic use , Valine/therapeutic use , Valsartan , Ventricular Dysfunction, Left/blood , Ventricular Dysfunction, Left/physiopathology
5.
J Pharmacol Exp Ther ; 293(3): 852-60, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10869385

ABSTRACT

With developing congestive heart failure (CHF), activation of the vasopressin V(1a) and angiotensin II type 1 (AT(1)) receptors can occur. In the present study, we examined the direct effects of V(1a) receptor blockade (V(1a) block), selective AT(1) receptor blockade (AT(1) block), and dual V(1a)/AT(1) receptor blockade (dual block) with respect to left ventricular (LV) function and contractility during the progression of CHF. LV and myocyte functions were examined in pigs with pacing CHF (rapid pacing, 240 beats/min, 3 weeks, n = 10), pacing CHF with concomitant V(1a) block (SR49059, 60 mg/kg, n = 8), pacing CHF with concomitant AT(1) block (irbesartan, 30 mg/kg, n = 7), or pacing CHF with dual block (n = 7). LV end-diastolic dimension and peak wall stress were reduced in all receptor blockade groups compared with CHF values. However, LV fractional shortening was increased only in the dual block group compared with CHF values (29 +/- 3 versus 21 +/- 2, P <.05). Basal LV myocyte percent shortening increased in the dual block group compared with CHF values (3.44 +/- 0.23 versus 2.88 +/- 0.11, P <. 05). Although V(1a) or AT(1) block reduced LV loading conditions, only dual block resulted in improved LV and myocyte shortening.


Subject(s)
Angiotensin Receptor Antagonists , Antidiuretic Hormone Receptor Antagonists , Heart Failure/drug therapy , Angiotensin II/blood , Angiotensin II/pharmacology , Animals , Atrial Natriuretic Factor/blood , Blood Pressure/drug effects , Heart Failure/physiopathology , Hemodynamics/drug effects , Male , Myocardial Contraction/drug effects , Receptor, Angiotensin, Type 1 , Receptor, Angiotensin, Type 2 , Sodium/blood , Swine , Vasopressins/blood , Vasopressins/pharmacology , Ventricular Function, Left/drug effects
6.
Anesth Analg ; 90(5): 1080-5, 2000 May.
Article in English | MEDLINE | ID: mdl-10781456

ABSTRACT

Transient left ventricular (LV) dysfunction can occur after cardioplegic arrest. The contributory mechanisms for this phenomenon are not completely understood. We tested the hypothesis that exposure of LV myocytes to endothelin (ET) during simulated cardioplegic arrest would have direct effects on contractile processes with subsequent reperfusion. LV porcine myocytes were randomly assigned to three groups: 1) CONTROL: normothermic (37 degrees C) cell media (n = 204); 2) Cardioplegia: simulated cardioplegic arrest (K(+) 24 mEq/L, 4 degrees C x 2 h) followed by reperfusion and rewarming with cell media (n = 164); and 3) Cardioplegia/ ET: simulated cardioplegic arrest in the presence of ET (200 pM) followed by reperfusion with cell media containing ET (n = 171). Myocyte contractility was measured by computer-assisted video microscopy. In a subset of experiments, myocyte intracellular calcium was determined after Fluo-3 (Molecular Probes, Eugene, OR) loading by digital fluorescence image analysis. Myocyte shortening velocity was reduced after cardioplegic arrest compared with controls (52 +/- 2 vs 84 +/- 3 microm/s, respectively; P < 0.05) and was further reduced with cardioplegic arrest and ET exposure (43 +/- 2 microm/s, P < 0.05). Intracellular calcium was significantly increased in myocytes exposed to cardioplegia compared with normothermic control myocytes and was further augmented by cardioplegia with ET supplementation (P < 0.05). Exposure of the LV myocyte to ET during cardioplegic arrest directly contributed to contractile dysfunction after reperfusion. Moreover, alterations in intracellular calcium may play a role in potentiating the myocyte contractile dysfunction associated with ET exposure during cardioplegic arrest.


Subject(s)
Endothelin-1/pharmacology , Heart Arrest, Induced , Myocardial Contraction , Myocardial Reperfusion , Myocardium/cytology , Adrenergic beta-Agonists/pharmacology , Animals , Calcium/analysis , Heart Ventricles/cytology , In Vitro Techniques , Isoproterenol/pharmacology , Microscopy, Video , Myocardial Contraction/drug effects , Myocardium/chemistry , Swine
7.
J Pharmacol Exp Ther ; 291(2): 799-811, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10525103

ABSTRACT

The progression of congestive heart failure (CHF) is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) contribute to tissue remodeling and therefore MMP inhibition may serve as a useful therapeutic target in CHF. Angiotensin converting enzyme (ACE) inhibition favorably affects LV myocardial remodeling in CHF. This study examined the effects of specific MMP inhibition, ACE inhibition, and combined treatment on LV systolic and diastolic function in a model of CHF. Pigs were randomly assigned to five groups: 1) rapid atrial pacing (240 beats/min) for 3 weeks (n = 8); 2) ACE inhibition (fosinopril, 2.5 mg/kg b.i.d. orally) and rapid pacing (n = 8); 3) MMP inhibition (PD166793 2 mg/kg/day p.o.) and rapid pacing (n = 8); 4) combined ACE and MMP inhibition (2.5 mg/kg b.i.d. and 2 mg/kg/day, respectively) and rapid pacing (n = 8); and 5) controls (n = 9). LV peak wall stress increased by 2-fold with rapid pacing and was reduced in all treatment groups. LV fractional shortening fell by nearly 2-fold with rapid pacing and increased in all treatment groups. The circumferential fiber shortening-systolic stress relation was reduced with rapid pacing and increased in the ACE inhibition and combination groups. LV myocardial stiffness constant was unchanged in the rapid pacing group, increased nearly 2-fold in the MMP inhibition group, and was normalized in the ACE inhibition and combination treatment groups. Increased MMP activation contributes to the LV dilation and increased wall stress with pacing CHF and a contributory downstream mechanism of ACE inhibition is an effect on MMP activity.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Heart Ventricles/drug effects , Hemodynamics/drug effects , Hydroxamic Acids/pharmacology , Matrix Metalloproteinase Inhibitors , Oligopeptides/pharmacology , Peptidyl-Dipeptidase A/metabolism , Animals , Blood Chemical Analysis , Disease Models, Animal , Heart Ventricles/anatomy & histology , Heart Ventricles/enzymology , Microscopy, Electron, Scanning , Polypharmacy , Random Allocation , Swine , Time Factors
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