Coronary blood flow responses are impaired independent of NO and endothelial function in conscious dogs with dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is characterized by nitric oxide (NO) deficiency and endothelial dysfunction. Whether endothelium-independent vasodilation is preserved, particularly in the coronary circulation, remains controversial. METHODS AND RESULTS: We studied systemic and coronary flow responses to the endothelium-dependent agonist, acetylcholine, the cGMP-dependent NO-donor, nitroglycerin, the predominantly endothelium-independent agonist, adenosine, the beta-adrenergic cAMP-dependent agonist, isoproterenol, and the calcium channel antagonist, nicardipine, in conscious dogs with pacing-induced DCM. Systemic blood flow response was impaired to acetylcholine but preserved to other vasodilators in DCM. In contrast, coronary blood flow response was significantly ( P < .05) depressed to all agonists. (Peak coronary blood flow response, control versus DCM: acetylcholine: 221 +/- 14% versus 156 +/- 11%; nitroglycerin: 220 +/- 17% versus 138 +/- 9%; adenosine: 635 +/- 65% versus 376 +/- 56%; nicardipine: 338 +/- 59% versus 115 +/- 23%; isoproterenol: 219 +/- 18% versus 86 +/- 20%). The attenuation was independent of systemic hemodynamic differences. CONCLUSION: In contrast to systemic responses, coronary blood flow responses in DCM are impaired dependent or independent of NO or second messenger mechanisms, implying either distal signaling defects or structural abnormalities in the coronary vasculature.

Quantitative reverse transcription-polymerase chain reaction of GABA(A) alpha1, beta1 and gamma2S subunits in epileptic rats following photothrombotic infarction of neocortex.

Photothrombotic brain infarction can result in altered expression of cortical GABA(A) receptors and in epileptic seizures. We sought to determine whether infarct size and/or epileptic seizures resulted in a differential expression of cortical GABA(A) receptor subunit mRNA in adult rats. A reverse transcription-polymerase chain reaction (RT-PCR) was used with internal standards for GABA(A) receptor subunits to quantify alpha(1), beta(1), and gamma(2S) subunit mRNA expression in cortex ipsilateral and contralateral to left cerebral infarcts in small or large infarct/nonepileptic cohorts, a large infarct/epileptic cohort, and a young adult control cohort. Unilateral hemispheric subunit mRNA was pooled for each cohort, quantified, and expressed as mean values+/-S.E.M. In general, the magnitude of mRNA expression (pg/1 microg total RNA) was different for the individual subunits: gamma(2S) (10(4)), alpha(1) (10(2)), and beta(1) (10(1)). Hemispheric subunit mRNA expression for the different cohorts was compared by ANOVA testing, which noted significant differences for the alpha(1) (P<0.001) and beta(1) (P<0.001) subunits in ipsilateral cortex. Bonferroni post-testing for alpha(1) cohorts indicated that mRNA expression for the large infarct/epilepsy cohort (624.2+/-6.8 pg) was greater than all other cohorts (P<0.001); control (162.7+/-32.2 pg). For beta(1) cohorts, there was decreased mRNA expression in the large infarct/nonepileptic cohort (9.2+/-0.8 pg; P<0.01) and the large infarct/epileptic cohort (10.5+/-2.2 pg; P<0.05) compared to control (23.2+/-2.6 pg). Additionally, paired t-tests compared subunit mRNA expression within individual animal cohorts (ipsilateral vs. contralateral) and indicated decreased mRNA expression ipsilaterally for the beta(1) subunit in the small infarct cohort (14.2+/-2.6 vs. 22.9+/-3.0 pg; P=0.0102) and the large infarct/epilepsy cohort (10.5+/-2.3 vs. 18.0+/-3.6 pg; P=0.0462). These findings suggest that large photothrombotic infarcts of the neocortex can result in a long-lasting differential expression of GABA(A) receptor subunit mRNAs in ipsilateral cortex variably associated with the epileptic state.