Involvement of nitric oxide, but not prostaglandins, in the vascular sympathoinhibitory effects of losartan in the pithed spontaneously hypertensive rat.
1. The aim of this study was to investigate whether nitric oxide (NO) and/or vasodilator prostaglandins (PGs) are involved in the sympathoinhibitory effects exerted by losartan versus the vascular responses elicited by spinal cord electrical stimulation (SCS) in pithed spontaneously hypertensive rats (SHRs). 2. SHRs were given orally and for 8 days either losartan (10 mg kg-1 daily) or distilled water (controls). After pithing, blood pressure, heart rate, cardiac output, renal and muscular blood flows (pulsed Doppler technique) and the corresponding vascular resistance values were measured or calculated at baseline. Then, animals from both groups were given i.v. either saline, or NG-nitro-L-arginine methyl ester (L-NAME, 1 mg kg-1), or diclofenac (4 mg kg-1). Thereafter, haemodynamic parameters were determined in the six subgroups of animals in response (a) to SCS at increasing frequencies, and (b) to a noradrenaline bolus injection. 3. Losartan significantly decreased mean arterial pressure as well as renal and total peripheral resistances. In addition, losartan exhibited strong vascular sympathoinhibitory effects, significantly decreasing the systemic pressor and regional vasoconstrictor responses to SCS, but did not affect those to exogenous noradrenaline. In contrast, SCS-induced tachycardia was not modified by losartan. 4. L-NAME significantly increased total peripheral and regional vascular resistances but did not affect blood pressure and heart rate basal values. L-NAME potentiated the haemodynamic responses to SCS in control and, to a larger extent, in losartan-treated SHRs so that, with the exception of the renal vascular bed, the sympathoinhibitory effects of losartan were attenuated in all vascular beds studied. L-Arginine (300 mg kg-1) caused reversal of L-NAME effects in both control and losartan-treated SHRs. 5. Diclofenac did not affect the basal values of haemodynamic parameters in control and losartan-treated SHRs. Diclofenac potentiated the pressor and vasoconstrictor responses to SCS and to a similar extent, in both control and losartan-treated SHRs, so that the sympathoinhibitory effects of losartan were fully maintained. 6. These results demonstrate that in pithed SHRs: (a) NO but not PGs contribute to the basal vasomotor tone, (b) both NO and PGs attenuate the pressor and vasoconstrictor responses to SCS, (c) NO plays a major role in the vascular sympathoinhibitory effects of losartan, except at the renal level, and (d) endogenous PGs are not involved in these sympathoinhibitory effects.
Richer
C
C
Département de Pharmacologie, Faculté de Médecine Paris-Sud, Kremlin-Bicêtre, France.
Domergue
V
V
Vincent
M P
MP
Giudicelli
J F
JF
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003655:Decerebrate State / Q000503:physiopathology; D004008:Diclofenac / Q000494:pharmacology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011453:Prostaglandins / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D012039:Regional Blood Flow / Q000187:drug effects; D013116:Spinal Cord / Q000502:physiology; D013565:Sympatholytics / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology*
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011453:Prostaglandins; D013565:Sympatholytics; D013777:Tetrazoles; D004008:Diclofenac; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019808:Losartan; D019331:NG-Nitroarginine Methyl Ester