Exaggerated Hypotensive Responses to Calcium Antagonists in Spontaneously Hypertensive Rats

Abstract

The hypotensive effects of intravenous injection and infusion of diltiazem, l- and d-verapamil were investigated in conscious and anaesthetized rats with spontaneous hypertension (SHR) and normal blood pressure (NT-WKY). The inhibitory actions of these calcium-influx blockers on the pressor responses to angiotensin II (AII) and noradrenaline (NA) were also examined in anaesthetized SHR and NT-WKY. The intravenous injections of these three drugs (0.03, 0.1, 0.3, 1.0 mg/kg) lowered mean arterial pressure (MAP) in a dose related manner in conscious NT-WKY and SHR. The small dose of the blockers administered by intravenous infusion (0.02 mg/kg per min) also decreased MAP in both groups. The potency of the antihypertensive action was in the order l-verapamil greater than d-verapamil = diltiazem. The fall in blood pressure expressed as percentage of the initial MAP produced by the compounds was significantly enhanced in SHR compared to NT-WKY. The pressor responses to AII (0.03, 0.1, 0.3, 1.0 micrograms/kg i.v.) were suppressed by the intravenous infusion of 20 micrograms/kg per min with l-verapamil but not with d-verapamil, diltiazem and vehicle in NT-WKY, while no calcium blocker significantly diminished the vasopressor action of AII in SHR. The pressor effects of NA (0.3, 1.0, 3.0, 10.0 micrograms/kg i.v.) were inhibited by the same doses of l-verapamil and diltiazem but not with d-verapamil and vehicle in NT-WKY. Diltiazem reduced the response to NA in SHR but the other compounds (l- and d-verapamil) did not alter the pressor response to NA in SHR. The pressor responses to arginine vasopressin (3, 10, 30 and 100 mU/kg i.v.) were not altered by diltiazem infusion in either SHR or NT-WKY. It is concluded that these compounds are different in the potency of their hypotensive action and also the inhibition of the pressor responses to AII and NA. Calcium entry blockers are more effective antihypertensive agents in SHR than in NT-WKY. It appears that their inhibitory effects on the responses to AII and NA do not explain the exaggerated hypotensive responses in SHR.

Upregulation of L-Type Ca 2+ Channels in Mesenteric and Skeletal Arteries of SHR

“…This concept concurs with reports that CCBs lower blood pressure in SHR but do not significantly affect pressure in WKY rats. [1][2][3] Similarly, nifedipine significantly reduces blood pressure in some humans with essential hypertension but has relatively little effect on blood pressure levels in normotensive individuals. 27 Thus, the upregulation of the ␣ 1C subunit in some forms of hypertension may predispose an individual to the vasodilator effect of CCBs, and similarly, drug sensitivity differences to CCBs between hypertensive individuals may relate to the further modulation of the ␣ 1C gene by other regulatory factors that alter channel expression.…”

“…To determine if these Ca 2ϩ channel abnormalities extended to the SHR skeletal muscle bed, we repeated a similar series of studies in WKY and SHR hind limb arteries. Skeletal muscle arteries from SHR also expressed higher levels of [1][2][3] Similarly, the arterioles of the mesenteric and skeletal muscle beds of SHR develop an abnormal Ca 2ϩ -dependent vascular tone and show increased myogenic responsiveness. 4 -6 Isolated mesenteric and femoral arteries of SHR also develop abnormal Ca 2ϩ -dependent tone, whereas similar arteries from WKY rats are quiescent.…”

“…For example, organic Ca 2ϩ channel blockers profoundly reduce blood pressure in spontaneously hypertensive rats (SHR) but have little hypotensive effect in normotensive Wistar Kyoto (WKY) rats, attesting to the obligatory role that voltage-gated Ca 2ϩ influx plays in elevating peripheral vascular resistance in SHR. [1][2][3] Similarly, the arterioles of the mesenteric and skeletal muscle beds of SHR develop an abnormal Ca 2ϩ -dependent vascular tone and show increased myogenic responsiveness. 4 -6 Isolated mesenteric and femoral arteries of SHR also develop abnormal Ca 2ϩ -dependent tone, whereas similar arteries from WKY rats are quiescent.…”

Vascular calcium channels and high blood pressure: Pathophysiology and therapeutic implications

“…Fortuitously, the increased abundance of the vascular α 1C subunits during hypertension may provide more binding sites for CCBs, thereby amplifying their vasodilator action proportional to blood pressure elevation. This may help to explain why CCBs effectively lower blood pressure in hypertensive animals and humans, but only mildly reduce blood pressure levels in normotensive individuals (Godfraind et al, 1991;Miyamori et al, 1987;Narita et al, 1983;Takata and Hutchinson, 1983).…”

Regional haemodynamic effects of prolonged infusions of human α‐calcitonin gene‐related peptide in conscious, Long Evans rats

“…It is feasible that the results obtained by Marshall et al (1987) were due to the use of hypertensive animals, since it is well known that such animals are more sensitive to acute hypotensive stimuli (Takata & Hutchinson, 1983), possibly due to impaired baroreflexes (Thoren et al, 1979;Verberne et al, 1988; but see also Unger et al, 1987). In addition, impaired baroreflexes might have contributed to a chronic failure of hypertensive rats to counteract the hypotensive effects of human a-CGRP.…”