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Cardiac and vascular responses in deoxycorticosterone acetate-salt hypertensive rats
1Department of Physiology and Pharmacology, University of Queensland, Brisbane, Australia. brown@plpk.uq.edu.au
Insights
Deoxycorticosterone acetate (DOCA)-salt hypertension in rats causes ventricular hypertrophy but minimally affects cardiac function. This contrasts with human heart failure, indicating unique adaptations in this rat model.
Area of Science:
- Cardiovascular Physiology
- Renal and Hypertension Research
- Molecular Pharmacology
Background:
- Hypertension is a major cause of ventricular hypertrophy, a precursor to heart failure.
- The deoxycorticosterone acetate (DOCA)-salt model in rats mimics aspects of human hypertension and cardiac remodeling.
- Understanding the functional consequences of this hypertrophy is crucial for differentiating it from heart failure.
Purpose of the Study:
- To investigate the functional effects of DOCA-salt induced hypertension and left ventricular hypertrophy in rats.
- To assess the inotropic, chronotropic, and vascular responses to various stimuli in this hypertensive model.
- To compare the cardiac and vascular adaptations in DOCA-salt hypertensive rats with those in failing human hearts.
Main Methods:
- Rats were administered DOCA and high salt (NaCl) to induce hypertension and left ventricular hypertrophy.
- Cardiac function was assessed by measuring inotropic responses in papillary muscles and chronotropic responses in right atria.
- Vascular reactivity was evaluated using thoracic aortic rings, examining responses to noradrenaline (NA), forskolin, and theophylline.
Main Results:
- DOCA-salt treatment significantly increased left ventricular weight, indicating hypertrophy.
- Cardiac inotropic and chronotropic responses to noradrenaline, forskolin, and theophylline were largely preserved.
- Vascular responses to noradrenaline varied, with reduced vasoconstriction in DOCA-KCI rats and increased vasoconstriction in DOCA-CaCl2 rats.
Conclusions:
- Cardiac function remains minimally affected during the development of hypertrophy in DOCA-salt hypertensive rats.
- The observed hypertrophy does not lead to functional deficits comparable to those seen in the failing human heart.
- This suggests distinct pathophysiological mechanisms underlying cardiac remodeling in this rat model versus human heart failure.
Abstract:
1. Hypertension leads to ventricular hypertrophy and, eventually, to heart failure. The present study has investigated the functional consequences of deoxycorticosterone acetate (DOCA)-salt hypertension in rats by defining the inotropic, chronotropic and vascular responses to noradrenaline (NA; beta1-adrenoceptor agonist), forskolin (adenylate cyclase activator) and theophylline (phosphodiesterase inhibitor). 2. Administration of DOCA (25 mg, s.c., every 4th day) and excess salt (1% NaCl in drinking water) to uninephrectomized rats increased left ventricular wet weight by 35 and 71% after 4 and 8 weeks, respectively. Addition of KCl (0.4%) or CaCl2 (1%) in the drinking water for 4 weeks attenuated blood pressure increases, but not ventricular weight increases (46 and 28%, respectively). 3. Positive inotropic responses in papillary muscles from uninephrectomized rats to NA (-log EC50 6.73+/-0.38; n = 7), forskolin (-log EC50 6.15+/-0.31; n = 7) and CaCl2 (-log EC50 2.40+/-0.02; n = 14) were unchanged in hypertrophied left ventricles of DOCA and DOCA-CaCl2 rats, although maximal responses to NA were decreased in DOCA-KCI rats (1.2+/-0.6 mN, n = 8; DOCA-salt 2.9+/-0.5 mN, n = 6); theophylline was less potent in DOCA-salt rats. Positive chronotropic responses to NA, forskolin and theophylline in right atria and negative inotropic responses to carbachol in papillary muscles were unchanged. 4. Maximal vasoconstrictor responses to NA in thoracic aortic rings were reduced in DOCA-KCI rats to 2.4+/-0.9 mN (n = 5), but were increased in DOCA-CaCl2 rats to 26.6+/-2.2 mN (n = 7; DOCA-salt 7.8+/-2.2 mN, n = 9). Vasorelaxant responses to forskolin and theophylline were unchanged. 5. These results show that cardiac responses are only minimally affected during the development of DOCA-salt hypertension-induced hypertrophy, despite the reported decreases in adenylate cyclase activity, in these rats. This is in contrast with the decreased responses reported in other rat models of cardiac hypertrophy and in the failing human heart. Thus, hypertrophy in hearts of DOCA-salt hypertensive rats does not produce similar changes to the failing human heart.