No abstract

Inotropic response to four different types of pharmacological stimuli were compared in isolated right ventricular papillary muscles from newborn (24-48 h of age), immature (14-16 days), and adult (6-7 mo) rabbits. Forskolin, a direct activator of adenylate cyclase, produced a 12.5-fold increase in the maximal rate of tension development in the newborn group. The maximum response to isoproterenol was only 45% of the maximum forskolin response, suggesting incomplete physiological coupling of myocardial beta-adrenergic receptors to adenylate cyclase at birth. In contrast to the substantial inotropic response to agents that stimulate adenosine 3',5'-cyclic monophosphate (cAMP) generation (forskolin and isoproterenol), a selective inhibitor of cAMP hydrolysis (milrinone) was relatively ineffective in the newborn group. Sulmazole, a drug that enhances calcium sensitivity of the contractile proteins, produced its greatest inotropic effect in immature myocardium. Cytosolic high-affinity cAMP phosphodiesterase activity was partially purified from ventricular homogenates by anion-exchange chromatography. The kinetics of cAMP hydrolysis (Km and Vmax) and inhibitory potency of milrinone were comparable in each age group. Thus the age-related differences in inotropic responsiveness may not be attributable to postnatal changes in myocardial cytosolic high-affinity cAMP phosphodiesterase activity.

Objectives-The efficacy of spironolactone (SPIRO) and hydrochlorothiazide (HCTZ) as monotherapy in older hypertensive patients in blood pressure control and measures of vascular stiffness is unknown.Design/Setting/Participants/Intervention-45 hypertensive subjects (24 men, 21 women, mean age 69 yrs) were randomized (double blind) and completed 6 months HCTZ (n=21) or SPIRO (n=24) therapy titrated to a target SBP < 140 mmHg.Measurements-Baseline (following 4 week antihypertensive drug wash out) and 6-month 24-hr ambulatory BP data were obtained. Pulse pressure was calculated as the difference between the 24-hour average SBP and DBP. Pulse wave velocity (PWV) was determined by non-invasive recordings of the carotid and femoral artery pulse waves.Results-Six months of HCTZ and SPIRO treatment was associated with significant decreases in 24-hr and nocturnal SBP and DBP (ANOVA P < 0.001). At the 6-month time period, average 24-hr and nocturnal SBP were both lower in the SPIRO compared to the HCTZ group (P < 0.001). Pulse pressure and PWV also decreased significantly with both HCTZ and SPIRO treatments (ANOVA P < 0.001).Conclusions-Six months of therapy with either HCTZ or SPIRO resulted in comparable reductions in 24-hr average and nocturnal SBP and DBP, pulse pressure and PWV in older hypertensive subjects.

Guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP) are mediators of smooth muscle relaxation. In this study, selective inhibitors of phosphodiesterase (PDE) isozymes were used to assess the role of cyclic nucleotide hydrolysis in angiotensin II (ANG II) and hypoxic pulmonary vasoconstriction. In isolated rat lungs, the hypoxic pressor response (HPR) was induced with a 95% N2-5% CO2 gas mixture. When administered during the plateau of the HPR, trequinsin (nonselective PDE inhibitor) and indolidan (cGMP-inhibitable cAMP PDE inhibitor) significantly (P = 0.01) decreased the pulmonary arterial pressure (Ppa) by 60 +/- 7 and 53 +/- 3%, respectively, compared with zaprinast (cGMP PDE inhibitor), rolipram (cGMP-insensitive cAMP PDE inhibitor), and the 0.1% dimethyl sulfoxide (DMSO) vehicle control, which decreased the Ppa by 6 +/- 3, 4 +/- 3, and 0%, respectively. In the trequinsin and indolidan groups, the subsequent ANG II pressor responses and HPRs were significantly (P = 0.01) decreased when compared with the zaprinast, rolipram, and DMSO groups. During normoxia, none of the PDE inhibitor (0.3-30 microM) had an effect on the baseline Ppa. These results suggest that cAMP hydrolysis by the cGMP-inhibitable cAMP PDE play a significant role in pulmonary vascular tone regulation.