1 When administered to young spontaneously hypertensive rats (SHRs), dihydralazine (25 mg kg-', daily) and captopril (100mg kg-, daily) prevent with the same efficacy genetic hypertension development (GHD). 2 Dihydralazine treatment increased vascular mesenteric compliance, as shown by a significant decrease in the stiffness of the vessels (-27%), and induced slight reductions in contractility (-12%) and in wall to lumen (W/L) ratio (-15%). After treatment withdrawal, all these parameters returned to control values within 7 weeks, as did blood pressure. 3 Captopril treatment also strongly increased the mesenteric vessels compliance, vessel stiffness being decreased by 16%, and reduced their contractility (-15%) and their W/L ratio (-30%). These effects as well as those exerted on blood pressure persisted up to 7 weeks after treatment ceased although there was a slight trend to a progressive reduction in the intensity of both phenomena. 4 These experiments show that captopril but not dihydralazine has a long-lasting effect in opposing the functional and morphological vascular alterations occurring during GHD in SHRs and this phenomenon probably contributes to a large extent to the sustained preventive effects of the drug against GHD.

Captopril (100mg/kg) administered daily by gavage to young spontaneously hypertensive rats (SHRs) from their 6th to 20th weeks of age almost completely inhibited genetic hypertension development (GHD). This effect was correlated with an early and long-lasting limitation of the progressive increase in peripheral resistance which normally develops in SHRs during their growth. Heart rate, cardiac and systolic indexes remained unchanged, plasma renin concentration was significantly increased and heart weight/body weight ratio was significantly decreased. At last, captopril's GHD preventive effect persisted up to 12 weeks after treatment discontinuation.

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1 The kinetics of captopril plasma levels and of the drug-induced plasma converting enzyme activity (PCEA), plasma renin activity (PRA) and diastolic blood pressure (DBP) modifications were studied over 24 h after oral administration of captopril, 1 mg/kg, to ten hypertensive patients. 3 The onset of PCEA inhibition and of DBP decrease closely followed the rise of captopril's plasma levels, while that of PRA increase was delayed. In contrast, while captopril rapidly disappeared from plasma, its biological and antihypertensive effects were long-lasting. 4 The lack of correlation between the relative bioavailability of captopril and the induced reduction in DBP (evaluated by the corresponding AUCs) suggests that free unchanged captopril plasma monitoring is not an adequate indicator of hypertensive patients' potential responsiveness to captopril's blood pressure lowering effects.

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We previously reported that chronic inhibition of NO synthase (NOS) in dogs leads to an upregulation of the cyclooxygenase (COX) pathway in the endothelium of the coronary artery after stimulation by bradykinin (BK) in vitro. The present experiments were designed to identify the nature of the COX isoform involved in this phenomenon. Rings of circumflex (LCX) and left anterior descending (LAD) coronary arteries were isolated from six control dogs and six dogs treated with the NOS-inhibitor, N omega-nitro-L-arginine (L-NNA, 30 mg/kg/d, i.v., during 7 days). Concentration-response curves to BK in U46619-contracted rings from LCX coronary arteries were constructed in the presence and absence of another NOS inhibitor (NG-monomethyl-L-arginine, L-NMMA), of selective inhibitors of the inducible isoform of COX (NS-398 and L-745,337) and of a non selective inhibitor of the inducible and constitutive isoforms of COX (indomethacin). Finally, measurements of 6-keto-prostaglandin F1 alpha, the stable metabolite of prostacyclin, were performed in the incubation medium by enzymo-immuno-assay on rings of isolated LAD coronary arteries in the presence and absence of the same inhibitors of COX, before and after stimulation by BK. In rings taken from control dogs, BK evoked a concentration-dependent relaxation (Emax: 115 +/- 10%; EC50: 8 +/- 4 nM). In the presence of L-NMMA, the concentration-relaxation curve to BK was significantly shifted to the right (Emax: 77 +/- 8%; EC50: 43 +/- 22 nM, P < 0.05). Addition of NS-398, L-745,337 and indomethacin to L-NMMA did not further modify the concentration-relaxation curve to BK. After chronic inhibition of NOS, the concentration-relaxation curve to BK was similar to that observed in rings taken from control dogs in the presence of L-NMMA (Emax: 75 +/- 5%; EC50: 69 +/- 36 nM). Addition of L-NMMA, alone or in combination with NS-398 or L-745,337 did not significantly modify this concentration-relaxation curve to BK. In contrast, the L-NMMA-indomethacin combination blunted the BK-induced relaxation of the coronary artery (Emax: 28 +/- 10%, P < 0.01). Basal release of prostacyclin was not different in rings taken from control and L-NNA treated dogs (56 +/- 16 vs 58 +/- 15 pg.mm-2). BK significantly increased this release but the increment was twofold greater in rings taken from L-NNA treated dogs than in rings taken from control dogs (P < 0.05). In rings taken from control and L-NNA treated dogs, the BK-stimulated production of prostacyclin observed in the presence of the solvent was not significantly modified by L-NMMA or the L-NMMA-L-745,337 combination. In contrast, the L-NMMA-indomethacin combination as well as endothelium removal completely suppressed the BK-stimulated production of prostacyclin. These findings demonstrate that in dogs submitted to chronic inhibition of NO synthesis (1) the residual relaxation to BK of canine isolated coronary arteries is mainly due to production of prostacyclin of endothelial origin, and (2) the enhancement of prostacyclin production by these vessels is ...

The effects of enalapril, 20 mg orally, on the responses to baroreflex activation and deactivation by respectively phenylephrine and nitroglycerin were investigated in normotensive subjects on a normal sodium diet, with simultaneous measurement of plasma renin activity (PRA), converting enzyme activity (PCEA), aldosterone and catecholamines. Enalapril, 4 h after administration, lowered artificial blood pressure without modifying heart rate and plasma catecholamines. PCEA was abolished, PRA increased and plasma aldosterone decreased. Enalapril (a) displaced to the left the baroreflex set‐point, (b) did not affect baroreflex sensitivity since the slopes of the RR‐ interval/systolic blood pressure regression lines remained unchanged during both activation and deactivation and (c) did not modify baroreflex efficacy since the maximal RR‐interval responses as well as the overall RR‐interval‐time products to identical blood pressure variations were not modified. Thus, enalapril induced a resetting of the baroreflex, which probably accounts for the lack of reflex tachycardia observed during the drug‐induced fall in blood pressure.

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