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Four chronic experiments were performed to assess changes in the activity and gene expression of type I nitric oxide synthase (NOS) at the macula densa (MD) and of renin expression and immunoreactivity (IR) at the juxtaglomerular apparatus (JGA) of rat kidney, as follows: 1) two-kidney, one-clip Goldblatt hypertension (2K1C, for 3 and 40 days; sham operation for controls), 2) furosemide treatment (150 mg/kg-1.day-1 ip for 5 days), 3) chronic low-salt diet (0.02%) vs. high-salt diet (3%; both for 11 days), and 4) chronic blockade of NOS by nitro-L-arginine methyl ester (L-NAME, 40 mg.kg-1.day-1 for 2 mo). NOS and renin gene expression, NOS enzyme activity and renin IR were semiquantitatively evaluated with histochemical methods (NADPH diaphorase, in situ hybridization, immunohistochemistry). In 2K1C, marked increases were induced in NOS and renin in the ischemic vs. contralateral kidneys both after 3 and 40 days, respectively (P < 0.05). Related to controls, significant increases in the ischemic kidney were encountered after 3 and 40 days, whereas contralateral suppression of NOS and renin was found only after 40 days. Furosemide treatment resulted in a marked increase of both NOS and renin levels compared with controls (P < 0.05). Salt restriction induced a significant elevation of NOS levels compared with salt loading (P < 0.05), whereas only minor changes were evident in renin levels. L-NAME treatment resulted in a moderate reduction of NOS activity (not significant), whereas renin levels were markedly reduced (P < 0.05). These results show that NOS activity and gene expression are inversely related to chronic changes in renal perfusion, salt balance, and salt transport at the distal tubule in parallel with the known response of renin to these changes. Inhibition of NOS decreases renin levels at the JGA. The histochemical findings support previous concepts that MD-derived NO is involved in the control of renin synthesis.

The effects of long-term (6 months) antihypertensive treatment with three different types of beta-blockers (propranolol, nonselective without ISA; pindolol, nonselective with ISA; metoprolol, beta 1-selective without ISA) on submaximal exercise capacity and metabolic variables during submaximal endurance exercise were studied in seven subjects with essential hypertension. Exercise tests were performed on a bicycle ergometer at 70% of estimated VO2 max. Similar reductions of resting and exercise blood pressure and exercise heart rate were obtained with the three beta-blockers. Exercise time was significantly reduced by all three beta-blockers during chronic antihypertensive therapy. The reduction tended to be more pronounced after 5-6 months of treatment than after 1 week (P = 0.06). During exercise, the plasma glycerol and nonesterified fatty acid concentrations were reduced. Plasma glucose concentration was reduced at the end of the exercise test during propranolol treatment only. Plasma lactate concentrations tended to be increased, but the difference was significant during pindolol treatment only. Oxygen uptake tended to decrease and respiratory exchange ratio to increase. Plasma potassium concentrations during exercise were significantly increased with all three beta-blockers. The effects on the metabolic variables during exercise were similar after 1 week and during long-term (20/24 weeks) beta-blocker treatment. The study shows that submaximal endurance exercise capacity is impaired in patients with essential hypertension on beta-blocker therapy and that the impairment is maintained during long-term antihypertensive beta-blocker treatment.

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The pharmacokinetics of propranolol after oral and intravenous administration was studied at rest and on an exercise day in 8 healthy subjects. On the exercise day the subjects performed physical exercise for 7 h, consisting of bicycle ergometer exercise at 50% of maximal work capacity and outdoor walking. Propranolol (80 mg p.o., or 0.2 mg/kg body weight i.v.) was administered 30 min before the start of the exercise. After oral administration the terminal phase halflife, (t1/2 beta) and area under the curve (AUC) were both significantly reduced on the exercise day compared to the rest day. The bioavailability of propranolol was reduced by prolonged physical exercise and plasma levels of propranolol were about 30% lower at the end of the exercise day than at the end of the rest day. After intravenous administration, t1/2 beta was also reduced on the exercise day as compared to the rest day. AUC, clearance and volume of distribution did not differ on the two days. On the other hand, indocyanine green (ICG) clearance was significantly reduced during the bicycle ergometry periods on the exercise day. The combination of reduced ICG clearance, suggesting a reduction in hepatic blood flow, and a decreased t1/2 beta and unchanged clearance of propranolol on the exercise day was unexpected.